Quantifying the association between Campylobacter infection and Guillain-Barré syndrome: a systematic review.
Guillain-Barré Syndrome (GBS) is a neurologic disease that causes ascending paralysis and is triggered by a preceding bacterial or viral infection. Several studies have shown that patients with GBS have a recent history of infection due to Campylobacter jejuni. A literature review of published studies that reported rates of Campylobacter infection before or in conjunction with GBS was done. These reported data were used for calculating the proportion of GBS cases who tested positive for Campylobacter compared to the control population and the incidence of GBS among patients infected with Campylobacter. Results of the analysis suggest that 31% of 2,502 GBS cases included in these papers are attributable to Campylobacter infection.


ACE2 Deficiency Worsens Epicardial Adipose Tissue Inflammation and Cardiac Dysfunction in Response to Diet-Induced Obesity.
Obesity is increasing in prevalence and is strongly associated with metabolic and cardiovascular disorders. The renin-angiotensin system (RAS) has emerged as a key pathogenic mechanism for these disorders; angiotensin (Ang)-converting enzyme 2 (ACE2) negatively regulates RAS by metabolizing Ang II into Ang 1-7. We studied the role of ACE2 in obesity-mediated cardiac dysfunction. ACE2 null (ACE2KO) and wild-type (WT) mice were fed a high-fat diet (HFD) or a control diet and studied at 6 months of age. Loss of ACE2 resulted in decreased weight gain but increased glucose intolerance, epicardial adipose tissue (EAT) inflammation, and polarization of macrophages into a proinflammatory phenotype in response to HFD. Similarly, human EAT in patients with obesity and heart failure displayed a proinflammatory macrophage phenotype. Exacerbated EAT inflammation in ACE2KO-HFD mice was associated with decreased myocardial adiponectin, decreased phosphorylation of AMPK, increased cardiac steatosis and lipotoxicity, and myocardial insulin resistance, which worsened heart function. Ang 1-7 (24 µg/kg/h) administered to ACE2KO-HFD mice resulted in ameliorated EAT inflammation and reduced cardiac steatosis and lipotoxicity, resulting in normalization of heart failure. In conclusion, ACE2 plays a novel role in heart disease associated with obesity wherein ACE2 negatively regulates obesity-induced EAT inflammation and cardiac insulin resistance.


Generation of antitumor immunity by cytotoxic T lymphocyte epitope peptide vaccination, CpG-oligodeoxynucleotide adjuvant, and CTLA-4 blockade.
Although peptide immunization often leads to the induction of strong T-cell responses, it is seldom effective against established tumors. One possibility is that these T-cell responses are not strong enough or do not last sufficiently long to have an effect in tumor eradication. Here, we examined the role of synthetic oligodeoxynucleotide (ODN) adjuvants containing unmethylated cytosine-guanine motifs (CpG-ODN) and CTLA-4 blockade in enhancing the antitumor effectiveness of peptide vaccines intended to elicit CTL responses. The results show that combination immunotherapy consisting of vaccination with a synthetic peptide corresponding to an immunodominant CTL epitope derived from tyrosinase-related protein-2 administered with CpG-ODN adjuvant and followed by systemic injection of anti-CTLA-4 antibodies increased the survival of mice against the poorly immunogenic B16 melanoma. Interestingly, whereas this combination therapy was effective when administered to tumor-bearing mice (therapeutic protocol), it had no significant effect when applied in the prophylactic mode (i.e., before the tumor challenge). Moreover, the antitumor effect of the combination immunotherapy required the participation of CD4+ and CD8+ T lymphocytes and was accompanied by the induction of antitumor CD4+ T-cell responses. The overall results suggest that peptide vaccination of tumor-bearing mice, applied in combination with a strong adjuvant and CTLA-4 blockade, is capable of eliciting durable antitumor T cell responses that provide survival benefit. These findings bear clinical significance for the design of peptide-based therapeutic vaccines for human cancer patients.


Ethnic Differences in Magnesium Intake in U.S. Older Adults: Findings from NHANES 2005⁻2016.
Magnesium plays a crucial role in hundreds of bodily processes relevant to aging, but consumption of dietary magnesium intake has been shown to be inadequate in a large proportion of older adults. Identifying groups at risk of low magnesium intake is important for informing targeted advice. Using data from the National Health and Nutrition Examination Survey (NHANES) 2005⁻2016, we examined the association between ethnicity (Caucasian/African American/Hispanic/other) and magnesium intake in a large representative sample of U.S. older adults (≥65 y, n = 5682, mean (SD) 72.9 (0.10) y). Analyses adjusted for total energy intake and a range of relevant covariates. Overall, 83.3% of participants were not meeting the recommended level of dietary magnesium intake, ranging from 78.1% of other ethnic groups to 90.6% of African Americans. In the fully adjusted model, magnesium intake was lower among African American older adults (-13.0 mg/d, 95% CI: -18.8 to -7.2), and higher among Hispanics (14.0 mg/d, 95% CI: 7.5 to 20.5) and those from other ethnic groups (17.2, 95% CI: 3.8 to 30.5) compared with Caucasian older adults. These results highlight the need for targeted interventions to increase magnesium intake in U.S. older adults, with a focus on African Americans, in order to reduce the burden of morbidity and ethnic inequalities in health in later life.


Sphenopalatine ganglion neuromodulation in migraine: what is the rationale?
The objective of this article is to review the prospect of treating migraine with sphenopalatine ganglion (SPG) neurostimulation. Fuelled by preliminary studies showing a beneficial effect in cluster headache patients, the potential of treating migraine with neurostimulation has gained increasing interest within recent years, as current treatment strategies often fail to provide adequate relief from this debilitating headache. Common migraine symptoms include lacrimation, nasal congestion, and conjunctival injection, all parasympathetic manifestations. In addition, studies have suggested that parasympathetic activity may also contribute to the pain of migraineurs. The SPG is the largest extracranial parasympathetic ganglion of the head, innervating the meninges, lacrimal gland, nasal mucosa, and conjunctiva, all structures involved in migraine with cephalic autonomic symptoms. We propose two possible mechanisms of action: 1) interrupting the post-ganglionic parasympathetic outflow to inhibit the pain and cephalic autonomic symptoms, and 2) modulating the sensory processing in the trigeminal nucleus caudalis. To further explore SPG stimulation in migraineurs as regards therapeutic potential and mode of action, randomized clinical trials are warranted.


Shifts in composition of microbial communities of subtidal sandy sediments maximise retention of nutrients.
The density and composition of microbial communities of subtidal sandy sediments determines their role in the cycling of nutrients in coastal waters. It has previously been found that sediments disturbed by waves and currents have reduced biomass, greater productivity to respiration (P/R) ratios and a tendency to take up nutrients. Conversely, with shelter and greater biomass, P/R ratios were smaller and nutrients released. This study, in warm temperate waters, examined the consequences of high and low levels of hydrodynamic energy on the microbial community structure and biogeochemistry at two locations at different times of year. Measurements included biomarkers, sediment properties and exchanges of gases and nutrients. Microbial communities were dominated by diatoms and bacteria. Exposed sites, relative to paired sheltered sites, had smaller ratios of bacteria to benthic microalgae (BMA), larger C/N ratios, smaller indices of diagenetic activity, but smaller P/R ratios. The bacteria in exposed sediments exhibited biomass-normalised rates of respiration almost double those in sheltered sediments. This increased activity was most likely fuelled by elevated concentrations of photosynthates, secreted by BMA attached to sand grains. Changes in community composition owing to different levels of disturbance led to shifts in functioning that resulted in consistently small exchanges of nutrients.


SOCS2 can enhance interleukin-2 (IL-2) and IL-3 signaling by accelerating SOCS3 degradation.
Cytokine responses can be regulated by a family of proteins termed suppressors of cytokine signaling (SOCS) which can inhibit the JAK/STAT pathway in a classical negative-feedback manner. While the SOCS are thought to target signaling intermediates for degradation, relatively little is known about how their turnover is regulated. Unlike other SOCS family members, we find that SOCS2 can enhance interleukin-2 (IL-2)- and IL-3-induced STAT phosphorylation following and potentiate proliferation in response to cytokine stimulation. As a clear mechanism for these effects, we demonstrate that expression of SOCS2 results in marked proteasome-dependent reduction of SOCS3 and SOCS1 protein expression. Furthermore, we provide evidence that this degradation is dependent on the presence of an intact SOCS box and that the loss of SOCS3 is enhanced by coexpression of elongin B/C. This suggests that SOCS2 can bind to SOCS3 and elongin B/C to form an E3 ligase complex resulting in the degradation of SOCS3. Therefore, SOCS2 can enhance cytokine responses by accelerating proteasome-dependent turnover of SOCS3, suggesting a mechanism for the gigantism observed in SOCS2 transgenic mice.


Neutrophil elastase in respiratory epithelial lining fluid of individuals with cystic fibrosis induces interleukin-8 gene expression in a human bronchial epithelial cell line.
The respiratory manifestations of cystic fibrosis (CF) are characterized by neutrophil-dominated airway inflammation. Since a variety of inflammatory stimuli are capable of inducing bronchial epithelial cells to express the gene for IL-8, a cytokine that attracts and activates neutrophils, mediators in respiratory epithelial lining fluid (ELF) of CF individuals might induce IL-8 production by epithelial cells, thus recruiting neutrophils to the airways. BET-1A human bronchial epithelial cells at rest or incubated with normal ELF showed little IL-8 gene expression, but after incubation with CF ELF, a marked increase in IL-8 transcript levels was observed. CF ELF contained high levels of neutrophil elastase (NE) and various serine protease inhibitors prevented CF ELF from inducing IL-8 gene expression in BET-1A cells, suggesting that NE was the dominant inducer for IL-8 production in CF ELF. The addition of purified NE caused BET-1A cells to increase IL-8 gene transcription with accumulation of mRNA transcripts and to release IL-8-like neutrophil chemotactic activity. These observations suggest a self-perpetuating inflammatory process on the CF bronchial surface where NE released by neutrophils induced the bronchial epithelium to secrete IL-8, which in turn recruits additional neutrophils to the bronchial surface.


Bone marrow derived cells are involved in the pathogenesis of cardiac hypertrophy in response to pressure overload.
Bone marrow (BM) cells possess broad differentiation potential and can form various cell lineages in response to pathophysiological cues. The present study investigated whether BM-derived cells contribute to the pathogenesis of cardiac hypertrophy, as well as the possible cellular mechanisms involved in such a role. Lethally irradiated wild-type mice were transplanted with BM cells from enhanced green fluorescent protein-transgenic mice. The chimeric mice were subjected to either prolonged hypoxia or transverse aortic constriction. BM-derived enhanced green fluorescent protein-expressing cardiomyocytes increased in number over time, emerging predominantly in the pressure-overloaded ventricular myocardium, although they constituted <0.01% of recipient cardiomyocytes. To determine whether BM-derived cardiomyocytes were derived from cell fusion or transdifferentiation at the single-cell level, lethally irradiated Cre mice were transplanted with BM cells from the double-conditional Cre reporter mouse line Z/EG. BM-derived cardiomyocytes were shown to arise from both cell fusion and transdifferentiation. Interestingly, BM-derived myofibroblasts expressing both vimentin and alpha-smooth muscle actin were concentrated in the perivascular fibrotic area. These cells initially expressed MAC-1/CD14 but lost expression of these markers during the chronic phase, which suggests that they were derived from monocytes. A similar phenomenon occurred in cultured human monocytes, most of which ultimately expressed vimentin and alpha-smooth muscle actin. We found that BM-derived cells were involved in the pathogenesis of cardiac hypertrophy via the dual mechanisms of cell fusion and transdifferentiation. Moreover, the present results suggest that BM-derived monocytes accumulating in the perivascular space might play an important role in the formation of perivascular fibrosis via direct differentiation into myofibroblasts.


Development of a self-report measure of capability wellbeing for adults: the ICECAP-A.
The benefits of health and social care are not confined to patient health alone and therefore broader measures of wellbeing may be useful for economic evaluation. This paper reports the development of a simple measure of capability wellbeing for adults (ICECAP-A). In-depth, informant-led, interviews to identify the attributes of capability wellbeing were conducted with 36 adults in the UK. Eighteen semi-structured, repeat interviews were carried out to develop a capability-based descriptive system for the measure. Informants were purposively selected to ensure variation in socio-economic status, age, sex, ethnicity and health. Data analysis was carried out inductively and iteratively alongside interviews, and findings were used to shape the questions in later interviews. Five over-arching attributes of capability wellbeing were identified for the measure: "stability", "attachment", "achievement", "autonomy" and "enjoyment". One item, with four response categories, was developed for each attribute for the ICECAP-A descriptive system. The ICECAP-A capability measure represents a departure from traditional health economics outcome measures, by treating health status as an influence over broader attributes of capability wellbeing. Further work is required to value and validate the attributes and test the sensitivity of the ICECAP-A to healthcare interventions.


Ecological ethics in captivity: balancing values and responsibilities in zoo and aquarium research under rapid global change.
Ethical obligations to animals in conservation research and management are manifold and often conflicting. Animal welfare concerns often clash with the ethical imperative to understand and conserve a population or ecosystem through research and management intervention. The accelerating pace and impact of global environmental change, especially climate change, complicates our understanding of these obligations. One example is the blurring of the distinction between ex situ (zoo- and aquarium-based) conservation and in situ (field-based) approaches as zoos and aquariums become more active in field conservation work and as researchers and managers consider more intensive interventions in wild populations and ecosystems to meet key conservation goals. These shifts, in turn, have consequences for our traditional understanding of the ethics of wildlife research and management, including our relative weighting of animal welfare and conservation commitments across rapidly evolving ex situ and in situ contexts. Although this changing landscape in many ways supports the increased use of captive wildlife in conservation-relevant research, it raises significant ethical concerns about human intervention in populations and ecosystems, including the proper role of zoos and aquariums as centers for animal research and conservation in the coming decades. Working through these concerns requires a pragmatic approach to ethical analysis, one that is able to make trade-offs among the many goods at stake (e.g., animal welfare, species viability, and ecological integrity) as we strive to protect species from further decline and extinction in this century.


Significance and potential of marine microbial natural bioactive compounds against biofilms/biofouling: necessity for green chemistry.
Natural products from the unique environments of sea water and oceans represent a largely unfamiliar source for isolation of new microbes, which are potent producers of secondary bioactive metabolites. These unique life-forms from the marine ecosphere have served as an important source of drugs since ancient times and still offer a valuable resource for novel findings by providing remedial treatments. Therefore, it can be expected that many naturally bioactive marine microbial compounds with novel structures and bioactivities against those from terrestrial environments may be found among marine metabolites. Biofilms in aquatic environment possess serious problems to naval forces and oceanic industries around the globe. Current anti-biofilm or anti-biofouling technology is based on the use of toxic substances that can be harmful to their surrounding natural locales. Comprehensive research has been done to examine the bioactive potential of marine microbes. Results are remarkably varied and dynamic, but there is an urgent need for bioactive compounds with environmentally friendly or "green" chemical activities. Marine microbes have the potential as upcoming and promising source of non-toxic compounds with sustainable anti-biofouling/anti-biofilm properties as they can produce substances that can inhibit not only the chemical components required for biofilm production but also the attachment, microorganism growth, and/or cell-cell communication.


Blockade of cardiac sodium channels by amitriptyline and diphenylhydantoin. Evidence for two use-dependent binding sites.
Cardiac toxicity is a frequent manifestation in amitriptyline overdose and is felt to be due, in part, to sodium channel blockade by the drug. Another agent with sodium channel blocking properties, diphenylhydantoin, has been used clinically to reverse cardiac conduction abnormalities induced by amitriptyline. This reversal of toxicity is believed to occur secondary to competition for the sodium channel binding site. We evaluated individually and in combination the effects of amitriptyline (0.4 microM) and diphenylhydantoin (10-80 microM) on the sodium current in isolated rabbit atrial and ventricular myocytes at 17 degrees C. Using the whole-cell variant of the patch-clamp technique, we found that both amitriptyline and diphenylhydantoin reduced the sodium current in a use-dependent fashion. The time constant of recovery (tau r) from block by amitriptyline at -130 mV was very slow (13.6 +/- 3.2 seconds), whereas tau r during diphenylhydantoin exposure was fast (0.71 +/- 0.21 seconds, p less than 0.0001 compared with amitriptyline). During exposure of cells to a mixture of the two drugs, tau r was found to be 6.6 +/- 1.8 seconds, but no evidence of direct competition between amitriptyline and diphenylhydantoin was seen. Attempts to fit the recovery data of the mixture to two exponentials resulted in no significant improvement in the fit when compared with that using a single exponential. Use of the sodium channel blocking agent lidocaine (similar kinetics to diphenylhydantoin) in competition with amitriptyline resulted in findings consistent with direct competition of these two drugs for a single binding site. These observations prompted us to evaluate the possibility that diphenylhydantoin was not acting at (and therefore not competing for) the same channel binding site as amitriptyline. Experiments altering pHi and pHo revealed dramatic differences between amitriptyline and diphenylhydantoin. When pHo was increased from 7.4 to 8.0, tau r was reduced approximately threefold (from 13.6 +/- 3.2 to 4.2 +/- 0.1 seconds, p less than 0.0001) during exposure to amitriptyline, but no effect was seen on tau r after exposure to diphenylhydantoin. Conversely, when pHi was increased from 7.3 to 8.0, tau r after amitriptyline was unaffected, but tau r after diphenylhydantoin markedly increased (from 0.71 +/- 0.21 to 2.60 +/- 1.30 seconds, p less than 0.001). Additionally, diphenylhydantoin block demonstrated profound voltage dependence across the range of -130 to -90 mV, whereas amitriptyline block appeared less voltage sensitive. Single-channel studies using patch-clamp techniques in isolated ventricular myocytes supported these data.(ABSTRACT TRUNCATED AT 400 WORDS)


Diverse patterns of perilymphatic space enhancement in the rat inner ear after intratympanic injection of two different types of gadolinium: a 9.4-tesla magnetic resonance study.
To compare the quality of perilymphatic enhancement in the rat inner ear after intratympanic injection of two types of gadolinium with a 9.4-tesla micro-MRI. Gadolinium was injected into the middle ear in 6 Sprague-Dawley rats via the transtympanic route. The left ear was injected with Gd-DO3A-butrol first, and then the right ear was injected with Gd-DOTA. MR images of the inner ear were acquired 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, and 4 h after intratympanic (IT) injection using an Agilent MRI system 9.4T/160/AS. The normalized signal intensity was quantitatively analyzed at the scala vestibuli (SV), scala media, and scala tympani (ST) using a Marosis M-view system. Then the normalized signal intensities (SIs) were compared between the two contrast agents. For Gd-DO3A-butrol, the SI was as low as 1.0-1.5 throughout 1-4 h at the SV and ST of the basal turn. The maximum SI was 1.5 ± 0.5 at the SV (2 h) and 1.3 ± 0.5 at the ST (2 h). For Gd-DOTA, the 1-hour postinjection SI at the basal turn was 2.5 ± 0.5 at the SV, 1.6 ± 0.3 at the ST, and 1.2 ± 0.3 at the scala media. In the apical turn, the maximum SI was reached after 2.5 h. The maximum SI in the apical turn was 1.8 ± 0.4 at the SV (3.5 h), 1.8 ± 0.4 at the ST (4 h), and 1.4 ± 0.3 at the scala media (4 h). We were able to clearly visualize and separate the ST and SV using IT Gd and 9.4-tesla micro-MRI. We recommend using Gd-DO3A-butrol over Gd-DOTA and to perform the MRI 2.5 h after using IT Gd in the rat inner ear.


CT guided percutaneous adrenal biopsy for lesions with equivocal findings in chemical shift MR imaging.
The aim of this study was to evaluate the usefulness of CT guided adrenal biopsy in patients with equivocal MR chemical shift imaging findings. Fifty seven patients, 32 with history of malignancy and 25 without history of malignancy, 30 men and 27 women (33-82 years, mean age:58.8 years), with equivocal findings in chemical shift MR imaging, were subjected to CT guided percutaneous adrenal biopsy. From the 57 lesions that were sent for histopathological evaluation, 31 proved to be metastases (54.4%), 20 adenomas (35.1%), 3 cortical carcinomas (5.3%), 1 benign pheochromocytoma (1.8%) and 2 samples were non diagnostic(3.5%). In oncology patients metastases were found in 28/32 of the patients (87.5%) and adenomas in 3/32 (9.4%), while in patients without history of malignancy, metastases were found in 3/25 of the patients (12%) and adenomas in 17/25 (68%). CT guided percutaneous adrenal biopsy is a safe and accurate method for a definite diagnosis of adrenal lesions. Since most adrenal lesions are benign, dedicated adrenal imaging is necessary for choosing which of them have to be further evaluated by biopsy. Chemical shift adrenal imaging alone seems to be a reliable method and can be used alternatively to CT enhancement washout technique for selecting which lesions are suspicious of malignancy and have to be investigated with biopsy, especially in cases where iodine contrast media is contraindicated.


Mental distress and personality in women undergoing GnRH agonist versus GnRH antagonist protocols for assisted reproductive technology.
Do mental distress and mood fluctuations in women undergoing GnRH agonist and GnRH antagonist protocols for assisted reproductive technology (ART) differ depending on protocol and the personality trait, neuroticism? ART treatment did not induce elevated levels of mental distress in either GnRH antagonist or agonist protocols but neuroticism was positively associated with increased mental distress, independent of protocols. ART treatment may increase mental distress by mechanisms linked to sex hormone fluctuations. General psychological characteristics, such as personality traits indexing negative emotionality, e.g. neuroticism, are likely to affect mental distress during ART treatment. A total of 83 women undergoing their first ART cycle were consecutively randomized 1:1 to GnRH antagonist (n = 42) or GnRH agonist (n = 41) protocol. The study population was a subgroup of a larger ongoing Danish clinical randomized trial and was established as an add-on in the period 2010-2012. Women in the GnRH antagonist protocol received daily injections with recombinant follicle-stimulating hormone, Puregon(®) and subcutaneous injections with GnRH antagonist, Orgalutran(®). Women in the GnRH agonist protocol received nasal administration of the GnRH agonist, Synarela(®) and subcutaneous injections with FSH, Puregon(®). The study design did not allow for a blinding procedure. All women self-reported the Profile of Mood States, the Perceived Stress Scale, the Symptom Checklist-92-Revised, and the Major Depression Inventory questionnaires, at baseline, at ART cycle day 35, on the day of oocyte pick-up, and on the day of hCG testing. Also, a series of Profile of Mood States were reported daily during pharmacological treatment to monitor mood fluctuations. The personality trait Neuroticism was assessed at baseline by the self-reported NEO-PI-R questionnaire. ART did not induce within- or between-protocol changes in any of the applied measures of mental distress. However, the GnRH antagonist protocol was associated with more pronounced median mood fluctuations during the stimulation phase (antagonist, 11.0 SD, [IQR = 21.1-6.1]; agonist, 8.9 SD, [IQR = 11.3-5.7], P = 0.025). This association became non-significant after applying a Bonferroni-Holm correction. Neuroticism was highly positively associated with increased levels of mental distress throughout treatment independent of protocols (all P-values <0.006), and cross-sectional analysis revealed that women with high or low Neuroticism scores at baseline showed a significant trend towards lower chances of a positive pregnancy test (P-value =0.028). Information on prognostic factors such as preceding length of infertility, number of retrieved oocytes and number of prior insemination treatments was not accounted for in the analyses. The stratification of protocols by age in the subgroups of women included in this study was suboptimal. Women with prior or current use of antidepressant medication were excluded from our study. Our results imply that mental distress emerging during ART treatment is not causally linked to hypogonadism per se or to the choice of protocol. Rather, our data highlight the potential importance of (i) rapid increases in ovarian steroids and (ii) addressing personality traits indexing negative emotionality, i.e. Neuroticism, in women undergoing ART treatment, to optimize both emotional adjustment and, possibly, the chances of obtaining pregnancy. The Danish Research Council for Independent Research and MSD, Denmark kindly supported the study. The authors declare no competing financial interests. EudraCT - 2008-005452-24.


Event-related potentials reflect individual differences in age-invariant auditory skills.
Previous work has found that auditory event-related potentials show maturational changes, with latency and amplitude of late components (N1 and P2) decreasing and increasing with age respectively. Our goal was to test the hypothesis that these changes reflect increased speed of neural processing in the auditory system. Thirty-three listeners, aged 10-50 years, were tested on a frequency discrimination task and an auditory backward recognition masking task. P1 and N1b event-related potential components were measured to tones. The N1b became larger and earlier with age, and the latency of P1 decreased with age. However, thresholds on the behavioural tasks did not change with age. Nevertheless, individual differences in the peak amplitude of N1b were independently related to frequency discrimination and degree of masking. Thus, the relationship that does exist between individual differences in psychoacoustic performance and the auditory N1b reflect a stable characteristic of the individual rather than a maturational change.


Inhibition of KSHV-infected primary effusion lymphomas in NOD/SCID mice by gamma-secretase inhibitor.
Primary effusion lymphoma (PEL) is a common cancer in AIDS patients closely associated with Kaposi's sarcoma-associated herpesvirus (KSHV). Previously, we showed that KSHV latency associated nuclear antigen (LANA) stabilizes intracellular activated Notch1 (ICN) involved in maintenance of the malignant phenotype of KSHV infected PEL cells in vitro. The gamma-secretase inhibitor (GSI) which specifically blocks the production of ICN slows down the proliferation of the KSHV infected PEL cell lines BCBL1, BC3 as well as JSC1 in vitro. In this study, we extended these studies to explore the possibility that manipulation of the Notch signaling by GSI would prevent the growth of the PEL tumors in vivo. We observed that the onset of tumorigenesis of KSHV infected PELs was significantly delayed in GSI treated SCID mice harboring the PEL cell lines. We also found that GSI treatment resulted in necrosis as well as apoptosis in tumors generated by the xenotransplanted KSHV positive PEL cell lines. In contrast, GSI had no effect on mice harboring BJAB cells, a KSHV negative Burkitt's lymphoma cell line where ICN levels were negligible. Our study provides further evidence to suggest that targeted downregulation of abnormal Notch signaling has therapeutic potential for KSHV related primary effusion lymphomas.


Nonattendance in mammographic screening: a study of intraurban differences in Malmö, Sweden, 1990-1994.
Mammographic screening may reduce breast cancer mortality. Not all women, however, come for examination. The objective in this study from Malmö has been to assess extent to which the rate of nonattendance varies between residential areas with different sociodemographic profiles. The study is based on 32,605 women, 45 to 68 years old and living in 17 areas, who between 1990 and 1994 were invited to screening. Between age groups, the age-specific nonattendance rate ranged from 31% to 35 % (P < .01). The nonattendance rate was highest for women 65 years or older. Between residential areas, age-adjusted nonattendance rates ranged from 23% to 43% (P < .01). A socioeconomic score was developed to express the socioeconomic circumstances in the residential areas and ranged from -7.18 in the most deprived area to 5.01 in the least. Nonattendance covaried in an inverse fashion with the socioeconomic score (r = -0.78; P < .01). One of three women in this urban population did not accept the invitation to mammographic screening. Our conclusion is that women in areas with less favorable circumstances seem to be less willing to participate.


Effects of dietary supplementation with arachidonic acid on platelet and renal function in patients with cirrhosis.
Advanced cirrhosis is associated with reduced platelet function and altered renal function and sodium handling. Arachidonic acid (AA) metabolites contribute to platelet aggregation and to maintain the response to diuretics in advanced cirrhosis. In the present study, we tested the effects of a dietary supplementation for 8 weeks with a triacylglycerol (triglyceride) enriched in AA (ARASCO; 4 g/day) or oleic acid (OA) on plasma and membrane fatty acid composition, platelet aggregation and renal prostaglandin (PG) metabolism. At baseline, all patients had reduced platelet aggregation. Patients treated with AA showed a significant increase in the percentage of AA in plasma lipids and membrane phospholipids. These changes were associated with an increased platelet aggregation in response to collagen (from 55.83 +/- 20.63 to 67.67 +/- 14.44%; P<0.05). At baseline, all urinary AA metabolites, including PGE2, 6-keto-PGF1alpha, 8-epi-PGF2alpha and 11-dehydro-thromboxane B2, were elevated in cirrhotic patients when compared with a group of normal subjects. After furosemide treatment, urinary excretion of 11-dehydro-thromboxane B2 increased significantly. Supplementation with AA did not result in any significant change in urinary PG excretion either before or after diuretic administration. The results of the present study show that dietary supplementation with AA effectively increases the levels of this fatty acid in plasma and membrane phospholipids and improves platelet aggregation. These data suggest a possible novel approach to the treatment of the haemostatic defect observed in these patients.


Congenital heart disease reminiscent of partial trisomy 2p syndrome in mice transgenic for the transcription factor Lbh.
Partial trisomy 2p syndrome includes a spectrum of congenital heart disease (CHD) that is characterized by complex malformations of the outflow and inflow tracts, defects in cardiac septation, heart position, as well as abnormal ventricular development. Lbh (limb-bud and heart) is a novel, highly conserved putative transcriptional regulatory protein, which displays a unique spatiotemporal gene expression pattern during early mouse heart development. Here we show that human LBH maps to chromosome 2p23, a genomic region related to CHD in partial trisomy 2p syndrome. Remarkably, transgenic overexpression of Lbh in mice throughout the embryonic myocardium from a cardiomyocyte-specific promoter of the cardiac ankyrin repeat protein gene (Carp/Ankrd1) models CHD reported in humans with partial trisomy 2p syndrome. The malformations in Carp-Lbh transgenic mice reflect impaired pulmonary outflow tract valvulogenesis, cardiac septation, inflow tract morphogenesis, as well as abnormalities in ventricular cardiomyocyte growth. Furthermore, we demonstrate that overexpression of Lbh in cultured mammalian cells represses the synergistic activity of key cardiac transcription factors, Nkx2.5 and Tbx5, leading to reduced activation of the common target gene, Anf (Nppa). Strikingly, reduced levels of Anf expression were also observed in embryonic day 9.5 Carp-Lbh transgenic mice. Thus, repression of Nkx2.5 and Tbx5-mediated gene expression by deregulated Lbh may account in part for the cardiac anomalies observed in these mice. Our findings implicate LBH as a candidate gene for CHD associated with partial trisomy 2p syndrome and suggest an important role of Lbh in transcriptional control during normal cardiogenesis.


Childhood overweight and obesity and the risk of depression across the lifespan.
Obesity has been longitudinally associated with depression but only few studies take a life course approach. This longitudinal study investigates whether being overweight or obese at age 8 and 13 years is associated with depressive symptoms more than 60 years later and whether this association is independent of late-life body mass index (BMI). We also investigated the association of being overweight/obese at age 8 or 13 years with ever having major depressive disorder (lifetime MDD). This analysis is based on a sub-sample of 889 AGES-Reykjavik participants with measured BMI data from early life. Late-life depressive symptoms were measured with the Geriatric Depression Scale (GDS) and lifetime MDD was assessed at late-life using the Mini International Neuropsychiatric Interview. Logistic regression analysis was used to estimate the relationships between BMI (continuous and categorical) at age 8 or 13 years, and late-life depressive symptoms (measured as GDS ≥ 5) or lifetime MDD, adjusted for sex, education, physical activity, smoking status and alcohol use. In a separate model, additional adjustments were made for late-life BMI. One hundred and one subjects (11%) had depressive symptoms at late-life (GDS ≥ 5), and 39 subjects (4.4%) had lifetime MDD. Being overweight or obese at age 8 or 13 years was not associated with higher depressive symptoms during late-life, irrespective of late-life BMI. Being overweight or obese at age 8 years, but not age 13 years was associated with an increased risk of lifetime MDD (Odds Ratio (OR) (95% confidence interval [CI]) for age 8 = 4.03[1.16-13.96]P = 0.03 and age 13 = 2.65[0.69-10.26] P = 0.16, respectively). Being overweight in childhood was associated with increased odds of lifetime MDD, although the magnitude of the risk is uncertain given the small numbers of participants with lifetime MDD. No clear association was observed between childhood and adolescent overweight/obesity and late-life depressive symptoms irrespective of late life BMI.


A qualitative exploration of the "critical window": factors affecting Australian children's after-school physical activity.
The after-school period is potentially a "critical window" for promoting physical activity in children. The purpose of this study was to qualitatively explore children's perceptions of the factors influencing their engagement in physical activity during the after-school period as the first phase in the development of a questionnaire. Fifty-four South Australian children age 10-13 years participated in same gender focus groups. Transcripts, field notes, and activity documents were analyzed using content analysis. Through an inductive thematic approach, data were coded and categorized into perceived barriers and facilitators according to a social ecological model. Children identified a number of factors, including safety in the neighborhood and home settings, distance to and from places, weather, availability of time, perceived competence, enjoyment of physical activity, peer influence, and parent influence. New insights into bullying and teasing by peers and fear of dangerous animals and objects were revealed by the children. In this study, hearing children's voices allowed the emergence of factors which may not be exposed using existing surveys. These findings are grounded in children's perceptions and therefore serve as a valuable contribution to the existing literature, potentially leading to improved intervention and questionnaire design.


The diving behavior of blue and fin whales: is dive duration shorter than expected based on oxygen stores?
Many diving seabirds and marine mammals have been found to regularly exceed their theoretical aerobic dive limit (TADL). No animals have been found to dive for durations that are consistently shorter than their TADL. We attached time-depth recorders to 7 blue whales and 15 fin whales (family Balaenopteridae). The diving behavior of both species was similar, and we distinguished between foraging and traveling dives. Foraging dives in both species were deeper, longer in duration and distinguished by a series of vertical excursions where lunge feeding presumably occurred. Foraging blue whales lunged 2.4 (+/-1.13) times per dive, with a maximum of six times and average vertical excursion of 30.2 (+/-10.04) m. Foraging fin whales lunged 1.7 (+/-0.88) times per dive, with a maximum of eight times and average vertical excursion of 21.2 (+/-4.35) m. The maximum rate of ascent of lunges was higher than the maximum rate of descent in both species, indicating that feeding lunges occurred on ascent. Foraging dives were deeper and longer than non-feeding dives in both species. On average, blue whales dived to 140.0 (+/-46.01) m and 7.8 (+/-1.89) min when foraging, and 67.6 (+/-51.46) m and 4.9 (+/-2.53) min when not foraging. Fin whales dived to 97.9 (+/-32.59) m and 6.3 (+/-1.53) min when foraging and to 59.3 (+/-29.67) m and 4.2 (+/-1.67) min when not foraging. The longest dives recorded for both species, 14.7 min for blue whales and 16.9 min for fin whales, were considerably shorter than the TADL of 31.2 and 28.6 min, respectively. An allometric comparison of seven families diving to an average depth of 80-150 m showed a significant relationship between body mass and dive duration once Balaenopteridae whales, with a mean dive duration of 6.8 min, were excluded from the analysis. Thus, the short dive durations of blue whales and fin whales cannot be explained by the shallow distribution of their prey. We propose instead that short duration diving in large whales results from either: (1) dispersal behavior of prey; or (2) a high energetic cost of foraging.


Comparison of indicators assessing the quality of drug prescribing for asthma.
To compare different indicators for assessing the quality of drug prescribing and establish their agreement in identifying doctors who may not adhere to treatment guidelines. Data from 181 general practitioners (GPs) from The Netherlands. The case of asthma is used as an example because, in this area, different quality indicators exist whose validity is questioned. The study is part of the European Drug Education Project. Spearman rank correlations were assessed among the GPs' scores on self-report instruments, aggregated prescribing indicators, and individualized prescribing indicators. Kappa values were calculated as agreement measures for identifying low adherence to the guidelines. Prescribing data from GPs were collected through pharmacies, public health insurance companies, or computerized GP databases. Two self-report instruments were mailed to the GPs. The GPs first received a questionnaire assessing their competence regarding the treatment of asthma patients. Three months later they received a series of 16 written asthma cases asking for their intended treatment for each case. Correlations between scores based on self-report instruments and indicators based on actual prescribing data were mostly nonsignificant and varied between 0 and 0.21. GPs identified as not adhering to the guidelines by the prescribing indicators often had high scores on the self-report instruments. Correlations between 0.20 and 0.55 were observed among indicators based on aggregated prescribing data and those based on individualized data. The agreement for identifying low adherence was small, with kappa values ranging from 0.19 to 0.30. Indicators based on self-report instruments seem to overestimate guideline adherence. Indicators assessing prescribing quality at an aggregated level give clearly different results, as compared to indicators evaluating prescribing data on an individual patient level. Caution is needed when using such prescribing indicators to identify low adherence to guidelines. Further validation studies using a gold standard comparison are needed to define the best possible indicator.


Translating basic behavioral and social science research to clinical application: the EVOLVE mixed methods approach.
To describe a mixed-methods approach to develop and test a basic behavioral science-informed intervention to motivate behavior change in 3 high-risk clinical populations. Our theoretically derived intervention comprised a combination of positive affect and self-affirmation (PA/SA), which we applied to 3 clinical chronic disease populations. We employed a sequential mixed methods model (EVOLVE) to design and test the PA/SA intervention in order to increase physical activity in people with coronary artery disease (post-percutaneous coronary intervention [PCI]) or asthma (ASM) and to improve medication adherence in African Americans with hypertension (HTN). In an initial qualitative phase, we explored participant values and beliefs. We next pilot tested and refined the intervention and then conducted 3 randomized controlled trials with parallel study design. Participants were randomized to combined PA/SA versus an informational control and were followed bimonthly for 12 months, assessing for health behaviors and interval medical events. Over 4.5 years, we enrolled 1,056 participants. Changes were sequentially made to the intervention during the qualitative and pilot phases. The 3 randomized controlled trials enrolled 242 participants who had undergone PCI, 258 with ASM, and 256 with HTN (n = 756). Overall, 45.1% of PA/SA participants versus 33.6% of informational control participants achieved successful behavior change (p = .001). In multivariate analysis, PA/SA intervention remained a significant predictor of achieving behavior change (p < .002, odds ratio = 1.66), 95% CI [1.22, 2.27], controlling for baseline negative affect, comorbidity, gender, race/ethnicity, medical events, smoking, and age. The EVOLVE method is a means by which basic behavioral science research can be translated into efficacious interventions for chronic disease populations.


Cross-sectional relationships between dietary fat intake and serum cholesterol fatty acids in a Swedish cohort of 60-year-old men and women.
The present study aimed to describe the relationship between self-reported dietary intake and serum cholesterol fatty acids (FAs) in a Swedish population of 60-year-old men and women. Cross-sectional data collected in 1997-1998 from 4232 individuals residing in Stockholm County were used. Five diet scores were created to reflect the intake of saturated fats in general, as well as fats from dairy, fish, processed meat and vegetable oils and margarines. Gas chromatography was used to assess 13 FAs in serum cholesterol esters. The association between each diet score and specific FAs was assessed by percentile differences (PD) with 95% confidence intervals (CI) at the 10th, 25th, 50th, 75th and 90th percentile of each FA across levels of diet scores using quantile regression. Fish intake was associated with high proportions of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). For each point increase in fish score, the 50th PD in EPA and DHA was 32.78% (95% CI = 29.22% to 36.35%) and 10.63% (95% CI = 9.52% to 11.74%), respectively. Vegetable fat intake was associated with a high proportion of linoleic acid and total polyunsaturated fatty acids (PUFA) and a low proportion of total saturated fatty acids (SFA). The intake of saturated fats in general and dairy fat was slightly associated with specific SFA, although the intake of fat from meat was not. In the present study population, using a rather simple dietary assessment method, the intake of fish and vegetable fats was clearly associated with serum PUFA, whereas foods rich in saturated fats in general showed a weak relationship with serum SFA. Our results may contribute to increased knowledge about underlying biology in diet-cardiovascular disease associations.


Identification of quantitative trait loci associated with calmness and gentleness in honey bees using whole-genome sequences.
The identification of quantitative trait loci (QTL) through genome-wide association studies (GWAS) is a powerful method for unravelling the genetic background of selected traits and improving early-stage predictions. In honey bees (Apis mellifera), past genetic analyses have particularly focused on individual queens and workers. In this study, we used pooled whole-genome sequences to ascertain the genetic variation of the entire colony. In total, we sampled 216 Apis mellifera mellifera and 28 Apis mellifera carnica colonies. Different experts subjectively assessed the gentleness and calmness of the colonies using a standardised protocol. Conducting a GWAS for calmness on 211 purebred A. m. mellifera colonies, we identified three QTL, on chromosomes 8, 6, and 12. The two first QTL correspond to LOC409692 gene, coding for a disintegrin and metalloproteinase domain-containing protein 10, and to Abscam gene, coding for a Dscam family member Abscam protein, respectively. The last gene has been reported to be involved in the domestication of A. mellifera. The third QTL is located 13 kb upstream of LOC102655631, coding for a trehalose transporter. For gentleness, two QTL were identified on chromosomes 4 and 3. They are located within gene LOC413669, coding for a lap4 protein, and gene LOC413416, coding for a bicaudal C homolog 1-B protein, respectively. The identified positional candidate genes of both traits mainly affect the olfaction and nervous system of honey bees. Further research is needed to confirm the results and to better understand the genetic and phenotypic basis of calmness and gentleness.


Deep subsurface mine stalactites trap endemic fissure fluid Archaea, Bacteria, and Nematoda possibly originating from ancient seas.
Stalactites (CaCO3 and salt) from water seeps are frequently encountered in ceilings of mine tunnels whenever they intersect water-bearing faults or fractures. To determine whether stalactites could be mineralized traps for indigenous fracture water microorganisms, we analyzed stalactites collected from three different mines ranging in depth from 1.3 to 3.1 km. During sampling in Beatrix gold mine (1.4 km beneath the surface), central South Africa, CaCO3 stalactites growing on the mine tunnel ceiling were collected and observed, in two cases, to contain a living obligate brackish water/marine nematode species, Monhystrella parvella. After sterilization of the outer surface, mineral layers were physically removed from the outside to the interior, and DNA extracted. Based upon 16S and 18S rRNA gene sequencing, Archaea, Bacteria, and Eukarya in different combinations were detected for each layer. Using CT scan and electron microscopy the inner structure of CaCO3 and salt stalactites were analyzed. CaCO3 stalactites show a complex pattern of lamellae carrying bacterially precipitated mineral structures. Nematoda were clearly identified between these layers confirming that bacteria and nematodes live inside the stalactites and not only in the central straw. Salt stalactites exhibit a more uniform internal structure. Surprisingly, several Bacteria showing highest sequence identities to marine species were identified. This, together with the observation that the nematode M. parvella recovered from Beatrix gold mine stalactite can only survive in a salty environment makes the origin of the deep subsurface colonization enigmatic. The possibility of a Permian origin of fracture fluids is discussed. Our results indicate stalactites are suitable for biodiversity recovery and act as natural traps for microorganisms in the fissure water long after the water that formed the stalactite stopped flowing.


Intramuscular extended-release naltrexone: current evidence.
Extended-release naltrexone (XR-NTX; Vivitrol), developed to address poor adherence in addictive disorders, is approved for use in alcohol and opioid-dependence disorders. In alcohol-dependent adults with ≥ 4-day initial abstinence, XR-NTX increased initial and 6-month abstinence. An fMRI study found that XR-NTX attenuated the salience of alcohol visual and olfactory cues in the absence of alcohol, and post hoc analyses demonstrated efficacy even during high cue-exposure holiday periods. Safety and tolerability have generally been good, without adverse hepatic impact or intractable acute pain management. XR-NTX use appears feasible in primary care and public systems, and retrospective claims analyses have found cost savings and decreased intensive service utilization relative to oral agents. In opioid dependence, following detoxification, XR-NTX shows efficacy for maintaining abstinence, improving retention, decreasing craving, and preventing relapse. Trials are also exploring its use for the treatment of stimulant dependence. XR-NTX appears compatible with counseling and self-help attendance. While more research is needed, current findings suggest that a formulation of naltrexone that was sought beginning over three decades ago is fulfilling its promise as an extended-release pharmacotherapeutic.


Working-memory capacity protects model-based learning from stress.
Accounts of decision-making have long posited the operation of separate, competing valuation systems in the control of choice behavior. Recent theoretical and experimental advances suggest that this classic distinction between habitual and goal-directed (or more generally, automatic and controlled) choice may arise from two computational strategies for reinforcement learning, called model-free and model-based learning. Popular neurocomputational accounts of reward processing emphasize the involvement of the dopaminergic system in model-free learning and prefrontal, central executive-dependent control systems in model-based choice. Here we hypothesized that the hypothalamic-pituitary-adrenal (HPA) axis stress response--believed to have detrimental effects on prefrontal cortex function--should selectively attenuate model-based contributions to behavior. To test this, we paired an acute stressor with a sequential decision-making task that affords distinguishing the relative contributions of the two learning strategies. We assessed baseline working-memory (WM) capacity and used salivary cortisol levels to measure HPA axis stress response. We found that stress response attenuates the contribution of model-based, but not model-free, contributions to behavior. Moreover, stress-induced behavioral changes were modulated by individual WM capacity, such that low-WM-capacity individuals were more susceptible to detrimental stress effects than high-WM-capacity individuals. These results enrich existing accounts of the interplay between acute stress, working memory, and prefrontal function and suggest that executive function may be protective against the deleterious effects of acute stress.


Prevalence of left-ventricular systolic dysfunction and heart failure in the Echocardiographic Heart of England Screening study: a population based study.
Accurate data for prevalence rates for heart failure due to various causes, and for left-ventricular systolic dysfunction in all adults are unavailable. Our aim was to assess prevalence of left-ventricular systolic dysfunction and heart failure in a large representative adult population in England. Of 6286 randomly selected patients aged 45 years and older, 3960 (63%) participated in the study. They came from 16 randomly selected general practices. We assessed patients by history and examination, electrocardiography, and echocardiography. Prevalence of left-ventricular systolic dysfunction (defined as ejection fraction <40%) and heart failure was calculated for the overall population on the basis of strict criteria and, when necessary, adjudication by a panel. Left-ventricular systolic dysfunction was diagnosed in 72 (1.8% [95% CI 1.4-2.3]) participants, half of whom had no symptoms. Borderline left-ventricular function (ejection fraction 40-50%) was seen in 139 patients (3.5% [3.0-4.1]). Definite heart failure was seen in 92 (2.3%, [1.9-2.8]) and was associated with an ejection fraction of less than 40% in 38 (41%) patients, atrial fibrillation in 30 (33%), and valve disease in 24 (26%). Probable heart failure was seen in a further 32 (0.8% [0.6-1.1]) patients. In total, 124 (3.1% [2.6-3.7]) patients aged 45 years or older had definite or probable heart failure. Heart failure is often misdiagnosed or underdiagnosed in primary care. Our results suggest that assessment of left-ventricular function in patients with suspected heart failure could lead to more effective diagnosis and treatment of this disorder.


International epidemiology databases to evaluate AIDS (IeDEA) in sub-Saharan Africa, 2012-2019.
The objectives of the International epidemiology databases to evaluate AIDS (IeDEA) are to (i) evaluate the delivery of combination antiretroviral therapy (ART) in children, adolescents and adults in sub-Saharan Africa, (ii) to describe ART regimen effectiveness, durability and tolerability, (iii) to examine HIV-related comorbidities and coinfections and (iv) to examine the pregnancy-related and HIV-related outcomes of women on ART and their infants exposed to HIV or ART in utero or via breast milk. IeDEA is organised in four regions (Central, East, Southern and West Africa), with 240 treatment and care sites, six data centres at African, European and US universities, and almost 1.4 million children, adolescents and adult people living with HIV (PLWHIV) enrolled. The data include socio-demographic characteristics, clinical outcomes, opportunistic events, treatment regimens, clinic visits and laboratory measurements. They have been used to analyse outcomes in PLWHIV-1 or PLWHIV-2 who initiate ART, including determinants of mortality, of switching to second-line and third-line ART, drug resistance, loss to follow-up and the immunological and virological response to different ART regimens. Programme-level estimates of mortality have been corrected for loss to follow-up. We examined the impact of coinfection with hepatitis B and C, and the epidemiology of different cancers and of (multidrug resistant) tuberculosis, renal disease and of mental illness. The adoption of 'Treat All', making ART available to all PLWHIV regardless of CD4+ cell count or clinical stage was another important research topic. IeDEA has formulated several research priorities for the 'Treat All' era in sub-Saharan Africa. It recently obtained funding to set up sentinel sites where additional data are prospectively collected on cardiometabolic risks factors as well as mental health and liver diseases, and is planning to create a drug resistance database.


Do cardiotoxins possess a functional site? Structural and chemical modification studies reveal the functional site of the cardiotoxin from Naja nigricollis.
Examination of the literature has revealed that regarding the amino acid sequences, cardiotoxins constitute a family of homogeneous compounds. In contrast, cardiotoxins appear heterogeneous as far as their biological and spectroscopic properties are concerned. As a result, comparison between these molecules with a view to establishing structure-activity correlations is complicated. We have therefore reviewed recent works aiming at identifying the functional site of a defined cardiotoxin, ie toxin gamma from the venom of the spitting cobra Naja nigricollis. The biological and structural properties of toxin gamma are first described. In particular, a model depicting the 3-dimensional structure of the toxin studied by NMR spectroscopy is proposed. The toxin polypeptide chain is folded into 3 adjacent loops rich in beta-sheet structure connected to a small globular core containing the 4 disulfide bonds. A number of derivatives chemically modified at a single aromatic or amino group have been prepared. The structure of each derivative was probed by emission fluorescence, circular dichroism and NMR spectroscopy. Also tested was the ability of the derivatives to kill mice, depolarize excitable cell membranes and lyse epithelial cells. Modification of some residues in the first loop, in particular Lys-12 and at the base of the second loop substantially affected biological properties, with no sign of concomitant structural modifications other than local changes. Modifications in other regions much less affected the biological properties of the toxin. A plausible functional site for toxin gamma involving loop I and the base of loop II is presented. It is stressed that the functional site of other cardiotoxins may be different.


Treatment results for patients with localized, completely resected (Group I) alveolar rhabdomyosarcoma on Intergroup Rhabdomyosarcoma Study Group (IRSG) protocols III and IV, 1984-1997: a report from the Children's Oncology Group.
To assess local control, event-free survival (EFS), and overall survival (OS) rates in 71 patients with localized, completely resected (Group I) alveolar rhabdomyosarcoma (ALV RMS) and their relation to radiation therapy (RT) on IRSG Protocols III and IV, 1984-1997. Chart review and standard statistical procedures. PATIENTS AND TUMORS: Patients were 1-18 years at diagnosis (median, 6 years). Primary tumor sites were extremity/trunk (N = 54), head/neck (N = 9), genitourinary tract (N = 7), and perineum (N = 1). Thirty patients received VA +/- C with RT; 41 received VA +/- C alone. RT was assigned, not randomized. Fifty-four patients had Stage 1 (favorable site, any size) or Stage 2 (unfavorable site, < or = 5 cm) tumors. Eight-year EFS was 90%, with 100% local control for 17 patients given RT. Eight-year EFS was 88%, with 92% local control for 37 patients without RT; P = 0.52 for EFS comparisons, 0.3 for local control comparisons. In 17 Stage 3 patients (unfavorable site, tumors >5 cm, N0), 8-year EFS was 84% with 100% local control in 13 patients given RT; 8-year EFS was only 25% and local control 50% in 4 patients without RT. Local recurrence was the most common site of first failure in non-irradiated patients. Patients with Stage 1-2 ALV RMS had slightly but statistically insignificantly improved local control, EFS, and OS rates when local RT was given. The need for local RT in Stage 1-2 patients deserves evaluation in a randomized study. Local control, EFS, and OS rates were significantly improved in Stage 3 patients receiving local RT.


The renal epithelial sodium channel: genetic heterogeneity and implications for the treatment of high blood pressure.
The renal epithelial sodium channel (ENaC) is of fundamental importance in the control of sodium reabsorption through the distal nephron. ENaC is an important component in the overall control of sodium balance, blood volume and thereby of blood pressure. This is clearly demonstrated by rare genetic disorders of sodium channel activity (Liddle's Syndrome and Pseudohypoaldosteronism type 1 associated with contrasting effects on blood pressure). Subtle dysregulation of ENaC however may also be important in essential hypertension - a common condition and a major cause of cardiovascular morbidity and mortality. The epithelial sodium channel is formed from three partly homologous subunits. In this review we deals firstly with current views of structural and functional features of the renal epithelial sodium channel with particular emphasis on mechanisms and processes involved in the control of sodium channel activity at the biochemical and cellular levels. We then focus on genetic aspects with reference to the significance of genetic variation in the sodium channel genes in relation to blood pressure. In particular, we review recent investigations on the potential clinical significance of mutations within the genes encoding ENaC subunits in individuals with high blood pressure. Lastly, we also examine the potential value of pharmacological targeting of the renal epithelial sodium channel with the sodium channel inhibitor amiloride for the treatment of hypertension.


Trends in Otolaryngology Consultation Patterns at an Academic Quaternary Care Center.
The consultation patterns of an otolaryngology-head and neck surgery service have not previously been reported. The time, resources, and attention required to operate such a consultation service are unknown. To assess trends in otolaryngology-head and neck surgery consultations conducted in emergency departments (EDs) and inpatient services. A retrospective analysis was conducted of the medical records of patients at a quaternary care center receiving inpatient otolaryngology consultations from January 1 to December 31, 2014. Clinical evaluation and bedside and operative procedures performed by the otolaryngology-head and neck surgery service. Demographics, reason for consultation, diagnosis, bedside procedures, operative interventions, and admission variables. A total of 1491 consultations were completed for adult (1091 [73.2%]; 854 men and 637 women; mean [SD] age 50.3 [19.3] years) and pediatric (400 [26.8%]; 232 boys and 168 girls; mean [SD] age, 4.0 [5.2] years) patients. Of the 1491 consultations, 766 (51.4%) originated from inpatient teams vs 725 (48.6%) from the ED. A total of 995 of all consultations (66.7%) resulted in a bedside procedure, and 243 (16.3%) required operative intervention. Consultations regarding airway evaluation (362 [47.3%] vs 143 [19.7%]), management of epistaxis (78 [10.2%] vs 33 [4.6%]), and rhinologic evaluation (79 [10.3%] vs 18 [2.5%]) were more frequent from inpatient teams than from the ED. Consultations regarding management of head and neck infections (162 [22.3%] vs 32 [4.2%]), facial trauma (235 [32.4%] vs 16 [2.1%]), and postoperative complications (73 [10.1%] vs 2 [0.3%]) were more frequent in the ED. Of the 725 consultations performed in the ED, 212 patients (29.2%) required hospitalization. The consultation volume of an otolaryngology-head and neck surgery service requires significant time and resources. Consultations are most often for rhinologic or laryngologic issues and are reflective of the clinical setting in which the patient is evaluated. Cost savings may be realized by increasing health care access points for nonurgent concerns that can be evaluated in an outpatient setting.


Comparing outcomes of sheet grafting with 1:1 mesh grafting in patients with thermal burns: a randomized trial.
In many units, the standard mesh ratio is 1.5:1, but in our unit we have a 1:1 mesher, which does not expand the skin but provides regular fenestrations. There is some evidence that the unexpanded 1.5:1 meshed graft compares favourably with sheet grafts from a cosmetic perspective whilst reducing the risk of graft failure secondary to a subgraft haematoma, but none comparing the 1:1 meshed graft with the sheet graft. We conducted a randomized trial to compare surgical outcomes in unfenestrated sheet grafts with 1:1 meshed grafts. All patients aged ≥16 years undergoing skin grafts with either a sheet or a 1:1 mesh for burn reconstruction were included. Patients on steroids, those with conditions that impair healing, and burns >20% were excluded. Patients were randomized into the sheet grafting or mesh graft using a computer-generated allocation system. The mean percentage of graft loss was assessed by a Visitrak overlay system. At 3-4 months, 7-8 months and at 1 year, photos were taken for scar assessment using the Vancouver Scar Score (VSS). Out of 72 patients, 48 patients (24 sheet vs. 24 mesh) completed the trial at 12 months. The mean age was 58 years (range 21-90). There was no total loss of graft in either group. The mean percentage of graft loss due to haematoma formation was higher in the sheet graft group (10%) compared to the 1:1 mesh group (6%) (P<0.062). The VSS score was 5 in both groups at 12 months. There was no significant difference in scar quality between the treatment groups. These results show that the 1:1 mesh graft is superior to the sheet graft with regard to graft loss, although this result is not statistically significant. There are comparable findings in terms of cosmetic perspective at 12 months post-operatively in both arms of the trial.


Polybrominated diphenyl ether (PBDE) levels in livers of U.S. human fetuses and newborns.
Polybrominated diphenyl ether (PBDE) brominated flame retardants have recently been found to contaminate humans in the United States and other countries. U.S. human breast milk and blood levels of PBDEs are presently the highest in the world. U.S. cord blood samples tested positive for PBDEs, but until now there have been no peer-reviewed published data concerning levels of PBDEs in human tissue prior to and immediately after birth. Liver tissues were obtained from 4 stillborn fetuses and 7 liveborn infants, ranging from 20.5 to 39 wk gestational age; only 2 of the liveborn infants lived longer than 4 h and none were formula-fed or nursed, so tissue levels reflect intrauterine PBDE intake only. All samples were contaminated with PBDEs. Levels varied from 4 to 98 ppb, lipid. The mean level was 23.1 and the median 15.2 ppb, lipid. PBDE levels did not increase with gestational age. These data document the transfer of PBDEs from maternal to fetal tissue. PBDE concentrations are somewhat lower than those reported in adult blood or breast milk. The health consequences of prenatal contamination are not clear at present.


Directed nickel-catalyzed 1,2-dialkylation of alkenyl carbonyl compounds.
A nickel-catalyzed conjunctive cross-coupling of non-conjugated alkenes, alkyl halides, and alkylzinc reagents is reported. Regioselectivity is controlled by chelation of a removable bidentate 8-aminoquinoline directing group. Under optimized conditions, a wide range of 1,2-dialkylated products can be accessed in moderate to excellent yields. To the best of our knowledge, this report represents the first example of three-component 1,2-dialkylation of non-conjugated alkenes to introduce differentiated alkyl fragments.


Chromosome length and perinuclear attachment constrain resolution of DNA intertwines.
To allow chromosome segregation, topoisomerase II (topo II) must resolve sister chromatid intertwines (SCI) formed during deoxynucleic acid (DNA) replication. How this process extends to the full genome is not well understood. In budding yeast, the unique structure of the ribosomal DNA (rDNA) array is thought to cause late SCI resolution of this genomic region during anaphase. In this paper, we show that chromosome length, and not the presence of rDNA repeats, is the critical feature determining the time of topo II-dependent segregation. Segregation of chromosomes lacking rDNA also requires the function of topo II in anaphase, and increasing chromosome length aggravates missegregation in topo II mutant cells. Furthermore, anaphase Stu2-dependent microtubule dynamics are critical for separation of long chromosomes. Finally, defects caused by topo II or Stu2 impairment depend on attachment of telomeres to the nuclear envelope. We propose that topological constraints imposed by chromosome length and perinuclear attachment determine the amount of SCI that topo II and dynamic microtubules resolve during anaphase.


Testosterone-induced DNA synthesis in cultured rat ventral prostate. I. Effects of cyproterone acetate.
Testosterone-induced DNA synthesis in cultured rat ventral prostate was evaluated as an in vitro model for screening the direct effects of anticancer agents on prostatic growth. Optimal conditions for this bioassay, particularly the concentration of testosterone, were established using the inhibitory effects of cyproterone acetate on testosterone-induced 125iododeoxyuridine (I-UdR) uptake as an index of DNA synthesis inhibition. Using 4 X 10(-7) M testosterone, only the highest concentration (X 10(-5) M) of cyproterone acetate inhibited I-UdR uptake and histological observations indicated that this was due to a non-specific cytotoxic effect. In contrast, cyproterone acetate had a dose-dependent inhibitory effect on the proliferative response to 4 X 10(-9) M testosterone. Cyproterone acetate (4 X 10(-7) M) combined with 4 X 10(-9) M testosterone exerted an inhibitory effect on I-UdR uptake and caused epithelial atrophy indicative of androgen deprivation. The results are consistent with similar in vivo studies and confirm the hypothesis that cyproterone acetate acts by directly antagonising testosterone action at the target tissue level. Thus, this in vitro method provides a useful model for screening the direct effects of antiprostatic drugs.


High-order interactions among genetic variants in DNA base excision repair pathway genes and smoking in bladder cancer susceptibility.
Cancer is a common multifactor human disease resulting from complex interactions between many genetic and environmental factors. In this study, we used a multifaceted analytic approach to explore the relationship between eight single nucleotide polymorphisms in base excision repair (BER) pathway genes, smoking, and bladder cancer susceptibility in a hospital-based case-control study. Overall, we did not find an association between any single BER gene single nucleotide polymorphism and bladder cancer risk. However, in stratified analysis, the OGG1 S326C variant genotypes in ever smokers (odds ratio, 0.74; 95% confidence interval, 0.56-0.99) and ADP-ribosyltransferase (ADPRT) V762A variant genotypes in never smokers (odds ratio, 0.58; 95% confidence interval, 0.37-0.91) conferred a significantly reduced risk. Using logistic regression, we observed that there was a two-way interaction between ADPRT V762A and smoking status. We next used classification and regression tree analysis to explore high-order gene-gene and gene-environment interactions. We found that smoking is the most important influential factor for bladder cancer risk. Consistent with the above findings, we found that the ADPRT V762A was only significantly involved in bladder cancer risk in never smokers and the OGG1 S326C was only significantly involved in ever smokers. We also observed gene-gene interactions among OGG1 S326C, XRCC1 R194W, and MUTYH H335Q in ever smokers. Using multifactor dimensionality reduction approach, the four-factor model, including smoking status, OGG1 S326C (rs1052133), APEX1 D148E (rs3136820), and ADPRT762 (rs1136410), had the best ability to predict bladder cancer risk with the highest cross-validation consistency (100%) and the lowest prediction error (37.02%; P < 0.001). These results support the hypothesis that genetic variants in BER genes contribute to bladder cancer risk through gene-gene and gene-environmental interactions.


Qualitatively different T cell phenotypic responses to IL-2 versus IL-15 are unified by identical dependences on receptor signal strength and duration.
IL-2 and IL-15 are common γ-chain family cytokines involved in regulation of T cell differentiation and homeostasis. Despite signaling through the same receptors, IL-2 and IL-15 have non-redundant roles in T cell biology, both physiologically and at the cellular level. The mechanisms by which IL-2 and IL-15 trigger distinct phenotypes in T cells remain elusive. To elucidate these mechanisms, we performed a quantitative comparison of the phosphotyrosine signaling network and resulting phenotypes triggered by IL-2 and IL-15. This study revealed that the signaling networks activated by IL-2 or IL-15 are highly similar and that T cell proliferation and metabolism are controlled in a quantitatively distinct manner through IL-2/15R signal strength independent of the cytokine identity. Distinct phenotypes associated with IL-2 or IL-15 stimulation therefore arise through differential regulation of IL-2/15R signal strength and duration because of differences in cytokine-receptor binding affinity, receptor expression levels, physiological cytokine levels, and cytokine-receptor intracellular trafficking kinetics. These results provide important insights into the function of other shared cytokine and growth factor receptors, quantitative regulation of cell proliferation and metabolism through signal transduction, and improved design of cytokine based clinical immunomodulatory therapies for cancer and infectious diseases.


Anxiolytic effects of cytotoxic hippocampal lesions in rats.
Rats with cytotoxic lesions of the hippocampus were given 3 anxiety tests: social interaction with a novel rat, the elevated zero-maze (a modification of the plus-maze), and hyponeophagia (eating familiar and novel foods in a novel place). Marked anxiolytic effects were seen in the social interaction and hyponeophagia tests, but not on the zero-maze. These results confirm and extend previous experiments that used traditional lesion techniques. The zero-maze result was consistent with other experiments using the plus-maze, in which intrahippocampal administrations of pharmacological agents were not anxiolytic, although variability in ethological tests may also be a factor. As the hyponeophagia test used an elevated apparatus, as in the zero- and plus-mazes, the lack of a lesion effect in the zero-maze was unlikely to have been due to an inability to relieve height-induced anxiety.


Lipids versus proteins as major targets of pro-oxidant, direct-acting hemolytic agents.
Lipid peroxidation and the accompanying translocation of phosphatidylserine (PS) from the inner to the outer leaflet of the lipid bilayer have recently been identified as key components of a signaling pathway for phagocytosis of apoptotic cells by macrophages. Drug-induced hemolytic anemia has long been known to be caused by an accelerated uptake of damaged (but intact) erythrocytes by macrophages in the spleen, and this process has been associated with enhanced formation of reactive oxygen species (ROS). However, the role of lipid peroxidation in hemolytic injury has remained unclear, and the effect of hemolytic agents on the distribution of PS in the erythrocyte membrane is unknown. The present studies were undertaken to determine whether lipid peroxidation and PS translocation could be detected in rat and human erythrocytes by three types of direct-acting hemolytic agents--dapsone hydroxylamine, divicine hydroquinone, and phenylhydrazine. 2',7'-Dichlorodihydrofluorescein diacetate was employed as a probe for intracellular ROS formation; lipid peroxidation was assessed by GC/MS analysis of F2-isoprostanes; and PS externalization was measured by annexin V labeling and the prothrombinase assay. The data confirmed that all three hemolytic agents generate ROS within erythrocytes under hemolytic conditions; however, no evidence for lipid peroxidation or PS translocation was detected. Instead, ROS production by these hemolytic agents was associated with extensive binding of oxidized and denatured hemoglobin to the membrane cytoskeleton. The data suggest that the transmembrane signal for macrophage recognition of hemolytic injury may be derived from oxidative alterations to erythrocyte proteins rather than to membrane lipids.


Synergistic effects of combined Wnt/KRAS inhibition in colorectal cancer cells.
Activation of Wnt signalling due to inability to degrade β-catenin is found in >85% of colorectal cancers. Approximately half of colon cancers express a constitutively active KRAS protein. A significant fraction of patients show both abnormalities. We previously reported that simultaneous down-regulation of both β-catenin and KRAS was necessary to induce significant cell death and tumor growth inhibition of colorectal cancer cells. Although attractive, an RNAi-based therapeutic approach is still far from being employed in the clinical setting. Therefore, we sought to recapitulate our previous findings by the use of small-molecule inhibitors of β-catenin and KRAS. We show here that the β-catenin inhibitors PKF115-584 and pyrvinium pamoate block β-catenin-dependent transcriptional activity and synergize with the KRAS inhibitor S-trans, trans-farnesylthiosalicylic acid (FTS, salirasib) in colon cancer cells driven by Wnt and KRAS oncogenic signals, but not in cells carrying BRAF mutations. The combined use of these compounds was superior to the use of any drug alone in inducing cell growth arrest, cell death, MYC and survivin down-modulation, and inhibition of anchorage-independent growth. Expression analysis of selected cancer-relevant genes revealed down-regulation of CD44 as a common response to the combined treatments. These data provide a proof of principle for a combination therapeutic strategy in colorectal cancer.


Isolation and characterization of a baculovirus associated with the insect parasitoid wasp, Cotesia marginiventris, or its host, Trichoplusia ni.
A multiple nucleopolyhedrovirus (MNPV) was isolated from Trichoplusia ni (Hübner) (Lepidoptera: Noctuidae) larvae that had been stung by the parasitoid Cotesia marginiventris (Cresson) (Hymenoptera: Braconidae). The wild type virus was plaque purified by infecting a Heliothis subflexa (BCIRL- HsAM1) cell line and isolating several clones. The mean estimated genomic size of this virus based on PstI, BstEII, StyI, HindIII restriction profiles was estimated to be 106 +/- 2.5 kbp (mean+/-SE). A clone designated as TnMNPV/CmBCL9 was used in bioassays against several lepidopteran pests and in comparative studies with the baculoviruses AcMNPV, AgMNPV, AfMNPV, PxMNPV and HzSNPV of Autographa califomica, Anticarsia gemmatalis, Anagrapha falcifera, Plutella xylostella, and Helicoverpa zea, respectively. Infectivity studies showed that TnMNPV/CmBCL9 was highly infectious for Heliothis subflexa and T. ni, with an LC(50) value 0.07 occlusion bodies/mm(2) in both species and also infectious for H. zea and Heliothis virescens with LC(50) values of 0.22 and 0.27 occlusion bodies/mm(2), respectively. Restriction endonuclease analysis of the isolate and selected baculoviruses revealed profiles that were very similar to AfMNPV but different from the restriction endonuclease profiles of the other baculoviruses. Hybridization studies suggest that the TnMNPV/CmBCL9 was closely related to AfMNPV and AcMNPV-HPP. Further support for this comes from a phylogenetic analysis employing a split-graphs network, comparing the polh, egt, and p10 genes from TnMNPV/CmBCL9 with those from other baculoviruses and suggests that this virus is closely related to the AcMNPV variants, AfMNPV and RoMNPV of Rachiplusia ou.


Optical coherence tomography detection of shear wave propagation in inhomogeneous tissue equivalent phantoms and ex-vivo carotid artery samples.
In this work, we explored the potential of measuring shear wave propagation using optical coherence elastography (OCE) in an inhomogeneous phantom and carotid artery samples based on a swept-source optical coherence tomography (OCT) system. Shear waves were generated using a piezoelectric transducer transmitting sine-wave bursts of 400 μs duration, applying acoustic radiation force (ARF) to inhomogeneous phantoms and carotid artery samples, synchronized with a swept-source OCT (SS-OCT) imaging system. The phantoms were composed of gelatin and titanium dioxide whereas the carotid artery samples were embedded in gel. Differential OCT phase maps, measured with and without the ARF, detected the microscopic displacement generated by shear wave propagation in these phantoms and samples of different stiffness. We present the technique for calculating tissue mechanical properties by propagating shear waves in inhomogeneous tissue equivalent phantoms and carotid artery samples using the ARF of an ultrasound transducer, and measuring the shear wave speed and its associated properties in the different layers with OCT phase maps. This method lays the foundation for future in-vitro and in-vivo studies of mechanical property measurements of biological tissues such as vascular tissues, where normal and pathological structures may exhibit significant contrast in the shear modulus.


Molecular and functional characterisation of E2F-5, a new member of the E2F family.
The transcription factor DRTF1/E2F is implicated in the control of cellular proliferation due to its interaction with key regulators of cell cycle progression, such as the retinoblastoma tumour suppressor gene product and related pocket proteins, cyclins and cyclin-dependent kinases. DRTF1/E2F DNA binding activity arises when a member of two distinct families of proteins, DP and E2F, interact as DP/E2F heterodimers. Here, we report the isolation and characterisation of a new member of the E2F family of proteins, called E2F-5. E2F-5 was isolated through a yeast two hybrid assay in which a 14.5 d.p.c. mouse embryo library was screened for molecules capable of binding to murine DP-1, but also interacts with all known members of the DP family of proteins. E2F-5 exists as a physiological heterodimer with DP-1 in the generic DRTF1/E2F DNA binding activity present in mammalian cell extracts, an interaction which results in co-operative DNA binding activity and transcriptional activation through the E2F site. A potent transcriptional activation domain, which functions in both yeast and mammalian cells and resides in the C-terminal region of E2F-5, is specifically inactivated upon pocket protein binding. Comparison of the sequence with other members of the family indicates that E2F-5 shows a greater level of similarity with E2F-4 than to E2F-1, -2 and -3. The structural and functional similarity of E2F-5 and E2F-4 defines a subfamily of E2F proteins.


Improving communication to tackle obesity in the UK.
Obesity is a serious health issue. In the UK the prevalence of obesity has trebled in the last 20 years and today one in five adults is clinically obese. Research shows that obesity is a predictable response to an environment that favours the consumption of energy-dense foods and allows minimal physical activity. This finding implies that the efficacy of public health messages to individuals to inform their lifestyle choices will be enhanced by environmental changes that support and facilitate healthy options. The present paper focuses on the importance of communicating scientific knowledge to the stakeholders with a responsibility for tackling obesity and addresses some of the barriers that are encountered.


Size of the anterior fontanelle: three-dimensional measurement of a key trait in human evolution.
The anterior fontanelle (AF) is an integral element of the developing human infant craniofacial system. Consideration of the AF is crucial for assessing craniofacial growth, as altered development of this feature may indicate abnormal growth. Moreover, prolonged patency of the AF may represent a derived hominin feature. The AF is regarded as essential for fetal head molding during birth in humans, with deformation of the head during birth often necessary for successful delivery. However, the function of a patent AF among fossil hominins is unclear. Because the AF represents an important structure in both a clinical and evolutionary context, techniques for estimating the size of the AF must be accurate and reproducible. Therefore, we have developed a novel method for assessing surface area of the AF with the goal of creating a more accurate measure of this feature. In this study, we test the accuracy and repeatability of a novel three-dimensional (3D) method for assessing the size of the AF in human infants and compare the results obtained for surface area of the AF using the conventional and 3D methods.


Rapid sequence induction and intubation: current controversy.
The changing opinion regarding some of the traditional components of rapid sequence induction and intubation (RSII) creates wide practice variations that impede attempts to establish a standard RSII protocol. There is controversy regarding the choice of induction drug, the dose, and the method of administration. Whereas some prefer the traditional rapid injection of a predetermined dose, others use the titration to loss of consciousness technique. The timing of neuromuscular blocking drug (NMBD) administration is different in both techniques. Whereas the NMBD should immediately follow the induction drug in the traditional technique, it is only given after establishing loss of consciousness in the titration technique. The optimal dose of succinylcholine is controversial with advocates and opponents for both higher and lower doses than the currently recommended 1.0 to 1.5 mg/kg dose. Defasciculation before succinylcholine was traditionally recommended in RSII but is currently controversial. Although the priming technique was advocated to accelerate onset of nondepolarizing NMBDs, its use has decreased because of potential complications and the introduction of rocuronium. Avoidance of manual ventilation before tracheal intubation was traditionally recommended to avoid gastric insufflation, but its use is currently acceptable and even recommended by some to avoid hypoxemia and to "test" the ability to mask ventilate. Cricoid pressure remains the most heated controversy; some believe in its effectiveness in preventing pulmonary aspiration, whereas others believe it should be abandoned because of the lack of scientific evidence of benefit and possible complications. There is still controversy regarding the best position and whether the head-up, head-down, or supine position is the safest during induction of anesthesia in full-stomach patients. These controversial components need to be discussed, studied, and resolved before establishing a standard RSII protocol.


Dietary energy density and adiposity: employing bias adjustments in a meta-analysis of prospective studies.
Dietary studies differ in design and quality making it difficult to compare results. This study quantifies the prospective association between dietary energy density (DED) and adiposity in children using a meta-analysis method that adjusts for differences in design and quality through eliciting and incorporating expert opinion on the biases and their uncertainty. Six prospective studies identified by a previous systematic literature search were included. Differences in study quality and design were considered respectively as internal and external biases and captured in bias checklists. Study results were converted to correlation coefficients; biases were considered either additive or proportional on this scale. The extent and uncertainty of the internal and external biases in each study were elicited in a formal process by five quantitatively-trained assessors and five subject-matter specialists. Biases for each study were combined across assessors using median pooling and results combined across studies by random-effects meta-analysis. The unadjusted combined correlation between DED and adiposity change was 0.06 (95%CI 0.01, 0.11; p = 0.013), but with considerable heterogeneity (I² = 52%). After bias-adjustment the pooled correlation was 0.17 (95%CI - 0.11, 0.45; p = 0.24), and the studies were apparently compatible (I² = 0%). This method allowed quantitative synthesis of the prospective association between DED and adiposity change in children, which is important for the development of evidence-informed policy. Bias adjustment increased the magnitude of the positive association but the widening confidence interval reflects the uncertainty of the assessed biases and implies that higher quality studies are required.


Current information about vaccination practice in pediatric rheumatic diseases and recommendations for future applications.
Açarı C, Ünsal E. Current information about vaccination practice in pediatric rheumatic diseases and recommendations for future applications. Turk J Pediatr 2017; 59: 357-368. Pediatric patients with autoinflammatory or rheumatic diseases are at increased risk of infections; therefore, safe and effective immunizations are crucial in the management of these group of patients. Current aggressive treatments involving the early use of immunosuppressive drugs and biological agents have further increased the susceptibility to infections in this group of patients. Therefore, effective and safe vaccination with adequate serological responses is important. In patients with rheumatic diseases, immunogenicity of a vaccine can differ from the healthy population, because of the disease itself or the immunosuppressive treatment received. Moreover, possible effects of vaccination on the underlying disease should be considered. In general, live attenuated vaccines should not be administered when high-dose immunosuppressive drugs are used for immunosuppressed patients. Inactivated vaccine agents have proven to be generally safe in patients with RD. The immune-modulating of biologic agents effects can last for weeks to months after discontinuation, depending on their half lifes. Also, live virus vaccines are contraindicated during therapy and for weeks to months following discontinuation of the biologics. The aim of this review is to cover the current information about vaccination practice in pediatric rheumatologic diseases and to give recommendations for future applications.


Patient Characteristics and Outcomes of Outpatient Parenteral Antimicrobial Therapy: A Retrospective Study.
Outpatient parenteral antimicrobial therapy (OPAT) is a safe and effective alternative to hospitalization for many patients with infectious diseases. The objective of this study was to describe the OPAT experience at a Canadian tertiary academic centre in the absence of a formal OPAT program. This was achieved through a retrospective chart review of OPAT patients discharged from Sunnybrook Health Sciences Centre within a one-year period. Between June 2012 and May 2013, 104 patients (median age 63 years) were discharged home with parenteral antimicrobials. The most commonly treated syndromes included surgical site infections (33%), osteoarticular infections (28%), and bacteremia (21%). The most frequently prescribed antimicrobials were ceftriaxone (21%) and cefazolin (20%). Only 56% of the patients received follow-up care from an infectious diseases specialist. In the 60 days following discharge, 43% of the patients returned to the emergency department, while 26% required readmission. Forty-eight percent of the return visits were due to infection relapse or treatment failure, and 23% could be attributed to OPAT-related complications. These results suggest that many OPAT patients have unplanned health care encounters because of issues related to their infection or treatment, and the creation of a formal OPAT clinic may help improve outcomes.


Indications for use of damage control surgery and damage control interventions in civilian trauma patients: A scoping review.
Variation in the use of damage control (DC) surgery across trauma centers may partially be driven by uncertainty as to when the procedure is indicated. We sought to scope the literature on DC surgery and DC interventions, identify their reported indications, and examine the content and evidence upon which they are based. We searched MEDLINE, EMBASE, PubMed, Scopus, Web of Science, and the Cochrane Library (1950-February 14, 2014) and the grey literature for original and nonoriginal citations reporting indications for DC surgery or DC interventions in civilian trauma patients. Among 27,732 citations identified, we included 270 peer-reviewed articles in the scoping review. Of these, 156 (57.8%) represented original research, primarily (75.0%) cohort studies. The articles reported 1,099 indications for DC surgery and 418 indications for 15 different DC interventions. The majority of indications for DC interventions were for abdominal (56.5%) procedures, including therapeutic perihepatic packing (56.5%), temporary abdominal closure/open abdominal management (40.7%), and staged pancreaticoduodenectomy (2.8%). Most DC surgery indications were based on intraoperative findings (71.7%) and represented characteristics of the injured patient (94.5%), including their physiology (57.6%), injuries (38.9%), and/or the amount or type of resuscitation provided (14.3%). Others were dependent on characteristics of the treating surgeon (12.1%), the patient's physiologic response to trauma care (9.6%), and/or the trauma care environment (1.5%). Approximately half (49.5%) included a decision threshold (e.g., pH < X) and, while most (74.7%) were based on a single clinical finding/injury, 25.3% required the presence of multiple findings concurrently. Only 87 indications were evaluated in original research studies and only 9 by more than one study. The vast number, varying underlying content, and lack of original research relating to indications for DC suggests that substantial uncertainty exists around when the procedure is indicated and highlights the need to establish evidence-informed consensus indications.


Current and Retrospective Childhood Ratings of Emotional Fluctuations in Adults With ADHD.
Introduction: Emotional fluctuations and mood swings are common among adults with Attention Deficit/Hyperactivity Disorder (ADHD). Here we investigated if these problems could be retrospectively traced back to childhood behavior. Methods: Adults with an ADHD diagnosis (n = 502, 48% female) and a population-based control sample (n = 818, 59% female) completed the Adult ADHD Self-report Scale (ASRS), the Wender Utah Rating Scale (WURS) and the Mood Disorder Questionnaire (MDQ). All participants also provided self-reported information about co-existent psychiatric and somatic diseases, and demographic data. Reports on the MDQ were used to define subgroups with [MDQ(+)] and without [MDQ(-)] life-time periods of emotional fluctuations and the WURS scale was used to retrospectively assess childhood ADHD related behaviors and symptoms. Results: 50.2% of the ADHD group and 5% of the controls were defined with emotional fluctuations [MDQ(+)]. Childhood behavior ratings of "impulsivity," "loosing of control," and "trouble with authorities" independently predicted emotional fluctuations reported in adulthood via logistic regression analyses. Inclusion of these three items in a classification analysis gave an accuracy score around 70% in identifying each of the two MDQ categories in the ADHD group. Discussion: The strong association between self-reported features of emotional problems in childhood and in adulthood suggests a trajectory that should be detected and remediated at an early age. Future longitudinal studies should prioritize the examination of developmental mechanisms explaining the persistence of emotional problems from childhood into adulthood.


Long-term neurodevelopmental follow-up of children with congenital muscular torticollis.
Congenital muscular torticollis is a common condition, but long-term neurodevelopmental follow-up is lacking. This study reports on neurodevelopmental outcome of 68 children, aged 7 to 9 years, with a history of congenital muscular torticollis, excluding children with torticollis due to other conditions. Thirty-eight children were examined for presence of neurodevelopmental disorders. Telephone interview data were available for an additional 30 children. Of those examined, 22/38 (57.9%) had or were at risk for a developmental disorder (attention-deficit hyperactivity disorder (ADHD), developmental coordination disorder, language impairment, autistic spectrum disorder) on at least 1 of the assessments administered, 23/38 (60.5%) had received developmental treatment during childhood. One child, based on a telephone interview, had a history of developmental treatment. Therefore, 30/68 (44.1%) children of the total sample demonstrated a developmental delay/disorder, currently (22/68) or previously (8/68). Our findings suggest congenital muscular torticollis to be a significant risk factor for later neurodevelopmental conditions with disorders presenting at different stages of development.