The tick saliva immunosuppressor, Salp15, contributes to Th17-induced pathology during Experimental Autoimmune Encephalomyelitis.
Salp15 is a tick saliva protein that inhibits CD4(+) T cell differentiation through its interaction with CD4. The protein inhibits early signaling events during T cell activation and IL-2 production. Because murine Experimental Autoimmune Encephalomyelitis development is mediated by central nervous system-infiltrating CD4(+) T cells that are specific for myelin-associated proteins, we sought to determine whether the treatment of mice with Salp15 during EAE induction would prevent the generation of proinflammatory T cell responses and the development of the disease. Surprisingly, Salp15-treated mice developed more severe EAE than control animals. The treatment of EAE-induced mice with the tick saliva protein did not result in increased infiltration of T cells to the central nervous system, indicating that Salp15 had not affected the permeability of the blood-brain barrier. Salp15 treatment did not affect the development of antibody responses against the eliciting peptide or the presence of IFNγ in the sera. The treatment with Salp15 resulted, however, in the increased differentiation of Th17 cells in vivo, as evidenced by higher IL-17 production from PLP(139-151)-specific CD4(+) T cells isolated from the central nervous system and the periphery. In vitro, Salp15 was able to induce the differentiation of Th17 cells in the presence of IL-6 and the absence of TGFβ These results suggest that a conductive milieu for the differentiation of Th17 cells can be achieved by restriction of the production of IL-2 during T cell differentiation, a role that may be performed by TGFβ and other immunosuppressive agents.


Standardizing the Assessment of Macular Pigment Using a Dual-Wavelength Autofluorescence Technique.
It is essential to have an appropriate measure to assess macular pigment (MP) that can provide an accurate, valid, and reliable representation of the MP within the macula. The aim of this study was to describe and introduce MP optical volume (MPOV) as an optimal value for reporting MP. Three hundred ninety-three subjects were analyzed using the Heidelberg Spectralis with the investigational MP optical density (MPOD) module to measure MPOV and MPOD at four foveal eccentricities (0.23°, 0.51°, 0.98°, 1.76° [7° as reference point]). Lutein (L) and zeaxanthin (Z) dietary intake and serum concentrations were evaluated. MPOV mean was 5094 (95%CI, 4877-5310); range: 527 to 10,652. MPOV was inversely correlated with body mass index and positively correlated with education (r = -0.156, P = 0.002 and r = 0.124, P = 0.014, respectively). Serum concentrations of L and Z were positively correlated with MPOV (r = 0.422, P < 0.001 and r = 0.285, P < 0.001, respectively). MPOV was positively correlated to MPOD at all measured eccentricities, with the strongest agreement at 1.76° (r = 0.906, P < 0.001). Serum concentrations of L and Z, BMI, education, and age (P < 0.001) were found to be significant predictors of MPOV. The Spectralis MPOV measurement provided a comprehensive and detailed evaluation of the MP profile. The Spectralis MPOV should be considered a preferred metric for the assessment of MP. Applying a standardized method for the assessment and report of MP will allow to fully derive meaning from observational studies and to successfully implement this MP measurement technique in research and clinical settings.


The persistence of cognitive deficits in remitted and unremitted ADHD: a case for the state-independence of response inhibition.
Response inhibition, working memory, and response variability are possible endophenotypes of ADHD based on their association with the disorder and evidence of heritability. One of the critical although rarely studied criteria for a valid endophenotype is that it persists despite waxing and waning of the overt manifestations of the disorder, a criterion known as state-independence. This study examined whether these aspects of cognition exhibit state-independence in ADHD. One hundred and seventy-nine children diagnosed with ADHD in a rigorous baseline assessment were contacted for follow-up assessment in adolescence. Of this sample, 130 (73%) were reascertained. At follow-up, children previously diagnosed with ADHD were identified as remittent (n = 24), persistent (n = 64), or in partial remission (n = 42) based on symptoms and impairment of the disorder. Response inhibition, working memory, and response variability were assessed both in childhood (baseline) and adolescence (follow-up) and were compared with age-matched controls (40 children and 28 adolescents) seen at either time point. Relative to controls, ADHD children showed baseline deficits in response inhibition, working memory, and response variability. Only the group difference in response inhibition remained significant in adolescence. In general, cognitive performance among ADHD participants improved with age and did so regardless of changes in ADHD symptoms and impairment. Within the ADHD group, however, cognitive performance in childhood and in adolescence did not differ amongst those with persistent, remittent, and partially remittent forms of the disorder. Results demonstrate that response inhibition not only distinguishes ADHD children from their unaffected peers but is also state-independent, such that deficits remain present irrespective of changes in the disease phenotype. In other words, inhibitory deficits measured in childhood persist into adolescence even when the ADHD phenotype remits. These findings provide further evidence that the ability to stop prepotent actions is an endophenotype of ADHD.


Routine development of objectively derived search strategies.
Over the past few years, information retrieval has become more and more professionalized, and information specialists are considered full members of a research team conducting systematic reviews. Research groups preparing systematic reviews and clinical practice guidelines have been the driving force in the development of search strategies, but open questions remain regarding the transparency of the development process and the available resources. An empirically guided approach to the development of a search strategy provides a way to increase transparency and efficiency. Our aim in this paper is to describe the empirically guided development process for search strategies as applied by the German Institute for Quality and Efficiency in Health Care (Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen, or "IQWiG"). This strategy consists of the following steps: generation of a test set, as well as the development, validation and standardized documentation of the search strategy. We illustrate our approach by means of an example, that is, a search for literature on brachytherapy in patients with prostate cancer. For this purpose, a test set was generated, including a total of 38 references from 3 systematic reviews. The development set for the generation of the strategy included 25 references. After application of textual analytic procedures, a strategy was developed that included all references in the development set. To test the search strategy on an independent set of references, the remaining 13 references in the test set (the validation set) were used. The validation set was also completely identified. Our conclusion is that an objectively derived approach similar to that used in search filter development is a feasible way to develop and validate reliable search strategies. Besides creating high-quality strategies, the widespread application of this approach will result in a substantial increase in the transparency of the development process of search strategies.


CTLA4Ig prevents lymphoproliferation and fatal multiorgan tissue destruction in CTLA-4-deficient mice.
Mice lacking CTLA-4 develop a fatal spontaneous lymphoproliferative disease with massive lymphocytic infiltrates and tissue destruction in many organs. CTLA-4-deficient (-/-) splenocytes and lymph node cells proliferate without added stimuli in vitro. We report here that CTLA4Ig treatment of CTLA-4 -/- mice prevents lymphoproliferation and fatal multiorgan tissue damage in vivo and proliferation of CTLA-4 -/- splenocytes and lymph node cells in vitro. Therefore, stimulation via CD28-B7 interactions appears necessary for CTLA-4 -/- T cell proliferation and the production of lymphoproliferative disease in vivo. When CTLA4Ig treatment is terminated, CTLA-4 -/- T cells become activated and lymphoproliferative disease develops. The lack of long term protective effects of CTLA4Ig treatment suggests that CTLA-4 is needed for the induction and or maintenance of tolerance.


Pacifier habit: history and multidisciplinary view.
To review the history of pacifiers and to compile a multidisciplinary literature review, searching for pros and cons with the purpose of providing health professionals with arguments when parents request guidance. History and art books, as well as non-medical literature and museums were used in the historical survey. Multidisciplinary data were collected from MEDLINE, LILACS, SciELO, and The Cochrane Library. Search criteria were: the keyword "pacifiers" present in articles published in the last 5 years that included abstract and were written in Portuguese, English, or Spanish. There is evidence that their precursors have been used since the Neolithic Period to calm down children. Small balls made of fabric containing food were portrayed in paintings. Other balls made of non-perishable material persisted throughout time. Pacifiers have been used to stimulate sucking or to coordinate this reflex, promoting an earlier beginning of the oral feeding of newborns. Some authors suggest that pacifiers reduce the incidence of the sudden death syndrome, but the topic is controversial. Pacifiers prevent the establishment of breastfeeding and lead to weaning. Their use may cause suffocation, poisoning, or allergies and increases the risk of caries, infections, and intestinal parasitic diseases. Harmful effects are related to frequency, duration, and intensity of the habit. It should be discontinued by the age of 3 or 4 in order not to affect speech and dentition. There are more harmful effects than benefits. It is advisable that health professionals inform parents of the pros and cons of pacifiers so that they can make a conscious decision regarding its use.


Fine mapping, gene content, comparative sequencing, and expression analyses support Ctla4 and Nramp1 as candidates for Idd5.1 and Idd5.2 in the nonobese diabetic mouse.
At least two loci that determine susceptibility to type 1 diabetes in the NOD mouse have been mapped to chromosome 1, Idd5.1 (insulin-dependent diabetes 5.1) and Idd5.2. In this study, using a series of novel NOD.B10 congenic strains, Idd5.1 has been defined to a 2.1-Mb region containing only four genes, Ctla4, Icos, Als2cr19, and Nrp2 (neuropilin-2), thereby excluding a major candidate gene, Cd28. Genomic sequence comparison of the two functional candidate genes, Ctla4 and Icos, from the B6 (resistant at Idd5.1) and the NOD (susceptible at Idd5.1) strains revealed 62 single nucleotide polymorphisms (SNPs), only two of which were in coding regions. One of these coding SNPs, base 77 of Ctla4 exon 2, is a synonymous SNP and has been correlated previously with type 1 diabetes susceptibility and differential expression of a CTLA-4 isoform. Additional expression studies in this work support the hypothesis that this SNP in exon 2 is the genetic variation causing the biological effects of Idd5.1. Analysis of additional congenic strains has also localized Idd5.2 to a small region (1.52 Mb) of chromosome 1, but in contrast to the Idd5.1 interval, Idd5.2 contains at least 45 genes. Notably, the Idd5.2 region still includes the functionally polymorphic Nramp1 gene. Future experiments to test the identity of Idd5.1 and Idd5.2 as Ctla4 and Nramp1, respectively, can now be justified using approaches to specifically alter or mimic the candidate causative SNPs.


Risk factors for Kaposi's sarcoma among HHV-8 seropositive homosexual men with AIDS.
Kaposi's sarcoma (KS) is a frequent complication of the acquired immunodeficiency syndrome (AIDS) in homosexual men. Risk factors for developing this malignancy are uncertain, other than immunosuppression and coinfection with human herpesvirus 8 (HHV-8). We therefore examined factors associated with KS in a cross-sectional analysis of 99 cases among 503 HHV-8 seropositive homosexual men with AIDS. Data were collected by computer-assisted personal interviews and medical chart reviews. HHV-8 seroreactivity was determined by enzyme-linked immunosorbent assay for antibodies against HHV-8 K8.1 glycoprotein. KS was significantly less common in blacks compared to whites [risk ratio (RR) = 0.4; 95% CI = 0.2 =0.8] and more common in subjects who had completed college (RR = 1.7; 95% CI = 1.1-2.7) or had annual income greater than dollar 30,000 (RR = 1.5; 95% CI = 1.1-2.2). KS was less common in cigarette smokers (RR = 0.6; 95% CI = 0.5-0.9) and users of crack cocaine (RR = 0.4; 95% CI = 0.1-0.8). KS was less common in bisexual men compared to men who were exclusively homosexual (estimated RR = 0.6; 95% CI = 0.4-0.9) and inversely associated with number of female partners. KS was also less common in men who had received pay for sex (RR = 0.6; 95% CI = 0.4-1.0). These cross-sectional associations could be biased by potential differences in relative timing of HHV-8 and HIV infection, a postulated determinant of KS risk. Alternatively, our findings may reflect factors protective against KS in individuals infected with HHV-8. Future research should focus on identifying practical measures for countering KS that do not increase the risk of other diseases.


A unique spacer domain of synaptotagmin IV is essential for Golgi localization.
Synaptotagmin (Syt) family members consist of six separate domains: a short amino terminus, a single transmembrane domain, a spacer domain, a C2A domain, a C2B domain and a short carboxyl (C) terminus. Despite sharing the same domain structures, several synaptotagmin isoforms show distinct subcellular localization. Syt IV is mainly localized at the Golgi, while Syt I, a possible Ca(2+)-sensor for secretory vesicles, is localized at dense-core vesicles and synaptic-like microvesicles in PC12 cells. In this study, we sought to identify the region responsible for the Golgi localization of Syt IV by immunocytochemical and biochemical analyses as a means of defining the distinct subcellular localization of the synaptotagmin family. We found that the unique C-terminus of the spacer domain (amino acid residues 73-144) between the transmembrane domain and the C2A domain is essential for the Golgi localization of Syt IV. In addition, the short C-terminus is probably involved in proper folding of the protein, especially the C2B domain. Without the C-terminus, Syt IVdeltaC proteins are not targeted to the Golgi and seem to colocalize with an endoplasmic reticulum (ER) marker (i.e. induce crystalloid ER-like structures). On the basis of these results, we propose that the divergent spacer domain among synaptotagmin isoforms may contain certain signals that determine the final destination of each isoform.


Is this finding relevant? Generalisation and epidemiology.
The decision about whether the findings from analytical epidemiological studies can be extrapolated to another setting is an important one. We discuss some of the issues involved in the process of generalisation. A critical systematic qualitative approach should be used. This involves an assessment of the internal validity of the study and of the nature of the study base. The study subject matter and choice of epidemiologic measure should be considered. A study base similar to the target population is essential if the study is descriptive or if there is concern about effect modifiers whose effects cannot be predicted. In addition, data from quantitative tests of study findings in different populations should be considered.


Differences in adolescent smoker and nonsmoker perceptions of strategies that would help an adolescent quit smoking.
This study assessed adolescent smoker and nonsmoker perceptions of strategies that would help an adolescent smoker in his or her attempt to stop smoking. Surveys were distributed primarily in the schools at 4 geographic and ethnically diverse study sites. Respondents were 965 adolescents (49% female; 46% minority). Current smokers (n = 232) were asked to rate the extent to which they agreed or disagreed that supportive behaviors of friends and family, quitting strategies, or learning about quitting strategies would be helpful if they decided to quit. Nonsmokers (n = 733) were asked to indicate the degree to which they agreed or disagreed that these behaviors and strategies would be helpful if a friend decided to quit. Responses to each of the 33 attitude items were rated on a 5-point scale ranging from strongly disagree to strongly agree. Marked differences were observed between smokers and nonsmokers in the level of agreement on each item. In general, smokers reported far less enthusiasm for cessation strategies than nonsmokers. After adjusting for gender, age, and other covariates, smoking status was the strongest independent predictor of the number of items endorsed as agree or strongly agree. The results have implications for the design of peer-based and other interventions for adolescent smokers.


Resolution and functional characterization of two mitochondrial iron-sulphur centres of the 'high-potential iron-sulphur protein' type.
Two distinct iron-sulphur centres of the 'HiPIP' (high-potential iron-protein) type are distinguished in both pigeon heart and ox heart mitochondria. These two species, although both are paramagnetic in the oxidized state, exhibit signals which differ in their detailed line shape, field position, and temperature- and power-dependence. They also exhibit different thermodynamic and kinetic behaviour and are located on opposite sides of the mitochondrial coupling membrane. One of these centres corresponds to Centre S-3. The other 'HiPIP'-type centre is removed readily from the mitochondrial membrane and its physiological function is not known.


[Posttherapeutic feed-back evaluation in oral rehabilitation].
The goal of this study was to assess the subjective post-therapeutic feedback for a group of patients in order to evaluate the possibility of including the psycho-behavioral parameters into the analysis structure of an expert system. 135 patients diagnosed with class I and II Kennedy edentation, aged between 40 and 89 years old, where clinically examined. All patients filled in structured questionnaires focused on psycho-behavioral parameters. Prosthetic treatment in oral rehabilitation improves subjective perception of facial aesthetic (66.86% total and moderate accord), psychological status (71.14% total and moderate accord) and of the social relations (77.47% total, moderate and low accord) but it is not subjective associated with the improving of general health (55.49% disagreement). We can establish statistical support correlation between psycho-behavioral parameters and therapeutic solutions applied in oral rehabilitation, correlation that can be later quantified and used in the development of an expert system.


Evidence that atriopeptin is not a physiological regulator of sodium excretion.
Although much experimental evidence is consistent with the concept that atrial natriuretic factor (atriopeptin) is an important physiological regulator of renal sodium excretion, this hypothesis remains unproven. Indeed, a rapidly expanding collection of experimental data appears to be more compatible with the opposite conclusion, namely that circulating atriopeptin exerts only a trivial effect on renal sodium excretion during normal day-to-day living conditions. In this review, the substantial evidence demonstrating that elevations of plasma atriopeptin from threefold to 13-fold produce only a slowly developing and relatively modest natriuresis is reassessed in light of recently published data indicating that the acute intake of food (the pathway by which essentially all sodium enters the body under normal living conditions) does not increase circulating atriopeptin. These considerations imply that atriopeptin does not contribute to the process that elicits a postprandial natriuresis, a process that presumably is of primary importance in the physiological regulation of sodium balance. In addition, consideration is given to a number of common physiological, experimental, and pathophysiological conditions in which circulating atriopeptin does not correlate with renal sodium excretion. This lack of correlation implies that atriopeptin is not an important regulator of sodium excretion in these situations.


External validation of the Cardiff model of information sharing to reduce community violence: natural experiment.
Community violence is a substantial problem for the NHS. Information sharing of emergency department data with community safety partnerships (CSP) has been associated with substantial reductions in assault attendances in emergency departments supported by academic institutions. We sought to validate these findings in a setting not supported by a public health or academic structure. We instituted anonymous data sharing with the police to reduce community violence, and increased involvement with the local CSP. We measured the effectiveness of this approach with routinely collected data at the emergency department and the police. We used police data from 2009, and emergency department data from 2000. Initially, the number of assault patients requiring emergency department treatment rose after we initiated data sharing. After improving the data flows, the number of assault patients fell back to the predata-sharing level. There was no change in the number of hospital admissions during the study period. There were decreases in the numbers of violent crimes against the person, with and without injury, recorded by the police. We have successfully implemented data sharing in our institution without the support of an academic institution. This has been associated with reductions in violent crime, but it is not clear whether this association is causal.


Self-organization of feed-forward structure and entrainment in excitatory neural networks with spike-timing-dependent plasticity.
Spike-timing dependent plasticity (STDP) is an organizing principle of biological neural networks. While synchronous firing of neurons is considered to be an important functional block in the brain, how STDP shapes neural networks possibly toward synchrony is not entirely clear. We examine relations between STDP and synchronous firing in spontaneously firing neural populations. Using coupled heterogeneous phase oscillators placed on initial networks, we show numerically that STDP prunes some synapses and promotes formation of a feedforward network. Eventually a pacemaker, which is the neuron with the fastest inherent frequency in our numerical simulations, emerges at the root of the feedforward network. In each oscillatory cycle, a packet of neural activity is propagated from the pacemaker to downstream neurons along layers of the feedforward network. This event occurs above a clear-cut threshold value of the initial synaptic weight. Below the threshold, neurons are self-organized into separate clusters each of which is a feedforward network.


Hepatitis B virus infection, diabetes mellitus, and their synergism for cholangiocarcinoma development: a case-control study in Korea.
To identify possible risk factors and their synergism for cholangiocarcinoma development. A hospital-based, case-control study in which we included 276 cholangiocarcinoma patients [193 extrahepatic cholangiocarcinoma (ECC) and 83 intrahepatic cholangiocarcinoma (ICC)], diagnosed at a training hospital in Korea between 2007 and 2013, and 552 healthy controls matched 2:1 for age, sex, and date of diagnosis. Risk factors for cholangiocarcinoma and possible synergism between those factors were evaluated using conditional logistic regression and synergism index, respectively. There was an association between cholangiocarcinoma and hepatitis B virus (HBV) infection, diabetes mellitus (DM), cholecystolithiasis, choledocholithiasis, and hepatolithiasis, with the adjusted odds ratios (AORs) of 4.1, 2.6, 1.7, 12.4, and 39.9, respectively. Synergistic interaction on the additive model was investigated between HBV infection and DM (AOR = 12.2; 95%CI: 1.9-80.1). In the subgroup analyses, cholecystolithiasis, choledocholithiasis, hepatolithiasis, and DM were significant risk factors for ECC (AOR = 2.0, 18.1, 14.9, and 2.0, respectively), whereas choledocholithiasis, hepatolithiasis, HBV infection, and DM were risk factors for ICC (AOR = 8.6, 157.4, 5.3 and 4.9, respectively). Synergistic interaction was also observed between HBV infection and DM (OR = 22.7; 95%CI: 2.4-214.1). However, there was no synergistic interaction between other significant risk factors for cholangiocarcinoma. In this Korean study, HBV infection and DM were found to exert independent and synergistic effects on the risk for cholangiocarcinoma, including ICC. Exploring the underlying mechanisms for such synergy may lead to the development of cholangiocarcinoma prevention strategies in high-risk individuals.


[Mammography screening in Tromsö. Realization and results of the first mammography screening in Norway].
The screening was carried out as a part of a health survey. Women aged 40 or more, (N = 4,290), were eligible. The acceptance rate were 84.4%. Altogether 5.3% was selected fro detailed mammographic examination, 1.7% were referred to a surgeon and 1.1% underwent surgery. In ten (25%) of them breast cancer was proven histologically. The mammograms were read independently by two radiologists. The predictive value was highest if only women on which both radiologists agreed were referred to detailed mammography. Of the women attending the health survey, 98% in the urban and, 79% in the rural part of the municipality were screened for breast cancer. The latter group had to make an appointment and travel to the city center to have their mammograms taken. The interpretation of the breast cancer screening was centrally administered. The follow-up was organized locally.


High-efficiency GaN-based light-emitting diodes fabricated with identical Ag contact formed on both n- and p-layers.
The authors report high-efficiency GaN-based light-emitting diodes (LEDs) fabricated with identical Ag contact formed on both n- and p-layers. Ag contacts thermally annealed at optimized conditions yielded low specific contact resistances of 4.5 × 10(-4) and 9.4 × 10(-4) Ωcm(2), and high optical reflectivity (at 450 nm) of 88.1 and 85.3% for n- and p-contact, respectively. LEDs fabricated with identical Ag contacts formed on both layers showed 31% brighter light output power and nearly the same forward voltages as compared to reference LEDs. This indicates that Ag contact can be used as a reflective electrode for both n- and p-layers, leading to enhanced extraction efficiency and fewer process steps.


Ongoing Research Protocols for the Pharmacological Treatment of Neuropsychiatric Symptoms in Dementia.
The implementation of effective interventions for neuropsychiatric symptoms (NPS) is perceived as one of the most pressing research priorities in the field of dementia and one of the main unmet needs from the perspective of affected individuals and their caregivers and relatives. Nevertheless, to date, only a relatively marginal part of dementia research has focused on NPS. This study aimed to describe and discuss the state of the art concerning the identification and development of new pharmacological treatments for NPS in dementia. A review of 320 ongoing phase 1, 2, 3, and 4 protocols registered in the clinicaltrials.gov database was performed. All the trials enrolling patients with dementia were selected. Only studies adopting clinical measures of NPS frequency and/or severity as primary outcome were retained and analyzed. Overall, only a minority of ongoing phase 1, 2, 3 and 4 protocols on dementia (i.e., 9.0%) is primarily targeting NPS. Most of these studies are adopting a placebo-controlled parallel assignment design, testing oral compounds, and targeting specific NPS (mostly agitation and/or aggression). A total of 3,445 subjects with dementia will tentatively be recruited in these trials. The methodologies adopted in these studies, the characteristics of the tested interventions, the eligibility criteria, and the operational definitions of NPS are presented and discussed. The relevance of NPS is not yet matched by an adequate research effort. The current tendency at privileging disease-modifying approaches and other symptoms of dementia and the methodological complexity of studying NPS are still substantially contributing to the gap between research activities and clinical needs.


An Acute Care for Elders Quality Improvement Program for Complex, High-Cost Patients Yields Savings for the System.
Acute Care for Elders (ACE) programs improve outcomes for older adults; however, little is known about whether impact varies with comorbidity severity. To describe differences in hospital-level outcomes between ACE and routine care across various levels of comorbidity burden. Cross-sectional quality improvement study. A 716-bed teaching hospital. Medical inpatients aged ≥70 years hospitalized between September 2014 and August 2017. ACE care, including interprofessional rounds, geriatric syndromes screening, and care protocols, in an environment prepared for elders MEASUREMENTS: Total cost, length of stay (LOS), and 30-day readmissions. We calculated median differences for cost and LOS between ACE and usual care and explored variations across the distribution of outcomes at the 25th, 50th, 75th and 90th percentiles. Results were also stratified across quartiles of the combined comorbidity score. A total of 1,429 ACE and 10,159 non-ACE patients were included in this study. The mean age was 81 years, 57% were female, and 81% were white. ACE patients had lower costs associated with care ranging from $171 at the 25th percentile to $3,687 at the 90th percentile, as well as lower LOS ranging from 0 days at the 25th percentile to 1.9 days at the 90th percentile. After stratifying by comorbidity score, the greatest differences in outcomes were among those with higher scores. There was no difference in 30-day readmission between the groups. The greatest reductions in cost and LOS were in patients with greater comorbidity scores. Risk stratification may help hospitals prioritize admissions to ACE units to maximize the impact of the more intensive intervention.


Systematic review of the risks of carotid endarterectomy in relation to the clinical indication for and timing of surgery.
Reliable data on the risk of carotid endarterectomy (CEA) in relation to clinical indication and timing of surgery are necessary to target CEA more effectively, to inform patients, to adjust risks for case mix, and to understand the mechanisms of operative stroke. We performed a systematic review of all studies published from 1980 to 2000 inclusive that reported the risk of stroke and death resulting from CEA. Pooled estimates of risk by type of presenting ischemic event and time since the last event were obtained by Mantel-Haenszel meta-analysis. Of 383 published studies, only 103 stratified risk by indication. Although the operative risk for symptomatic stenosis overall was higher than for asymptomatic stenosis (odds ratio [OR], 1.62; 95% confidence interval [CI], 1.45 to 1.81; P<0.00001; 59 studies), risk in patients with ocular events only tended to be lower than for asymptomatic stenosis (OR, 0.75, 95% CI, 0.50 to 1.14; 15 studies). Operative risk was the same for stroke and cerebral transient ischemic attack (OR, 1.16; 95% CI, 0.99 to 1.35; P=0.08; 23 studies) but higher for cerebral transient ischemic attack than for ocular events only (OR, 2.31; 95% CI, 1.72 to 3.12; P<0.00001; 19 studies) and for CEA for restenosis than primary surgery (OR, 1.95; 95% CI, 1.21 to 3.16; P=0.018; 6 studies). Urgent CEA for evolving symptoms had a much higher risk (19.2%, 95% CI, 10.7 to 27.8) than CEA for stable symptoms (OR, 3.9; 95% CI, 2.7 to 5.7; P<0.001; 13 studies), but there was no difference between early (<3 to 6 weeks) and late (>3 to 6 weeks) CEA for stroke in stable patients (OR, 1.13; 95% CI, 0.79 to 1.62; P=0.62; 11 studies). All observations were highly consistent across studies. Risk of stroke and death resulting from CEA is highly dependent on the clinical indication. Audits of risk should be stratified accordingly, and patients should be informed of the risk that relates to their presenting event.


Xenopus phospho-CDK7/cyclin H expressed in baculoviral-infected insect cells.
The cyclin-dependent kinase-activating kinase (CAK) catalyzes the phosphorylation of the cyclin-dependent protein kinases (CDKs) on a threonine residue (Thr160 in human CDK2). The reaction is an obligatory step in the activation of the CDKs. In higher eukaryotes, the CAK complex has been characterized in two forms. The first consists of three subunits, namely CDK7, cyclin H, and an assembly factor called MAT1, while the second consists of phospho-CDK7 and cyclin H. Phosphorylation of CDK7 is essential for cyclin association and kinase activity in the absence of the assembly factor MAT1. The Xenopus laevis CDK7 phosphorylation sites are located on the activation segment of the kinase at residues Ser170 and at Thr176 (the latter residue corresponding to Thr160 in human CDK2). We report the expression and purification of X. laevis CDK7/cyclin H binary complex in insect cells through coinfection with the recombinant viruses, AcCDK7 and Accyclin H. Quantities suitable for crystallization trials have been obtained. The purified CDK7/cyclin H binary complex phosphorylated CDK2 and CDK2/cyclin A but did not phosphorylate histone H1 or peptide substrates based on the activation segments of CDK7 and CDK2. Analysis by mass spectrometry showed that coexpression of CDK7 with cyclin H in baculoviral-infected insect cells results in phosphorylation of residues Ser170 and Thr176 in CDK7. It is assumed that phosphorylation is promoted by kinase(s) in the insect cells that results in the correct, physiologically significant posttranslational modification. We discuss the occurrence of in vivo phosphorylation of proteins expressed in baculoviral-infected insect cells.


Primary Cell Cultures from the Mouse Retinal Pigment Epithelium.
The retinal pigment epithelium (RPE) is a highly polarized multi-functional epithelium that is located between the neural retina and the choroid of the eye. It is a single sheet of pigmented cells that are hexagonally packed and connected by tight junctions. The main functions of the RPE include absorption of light, phagocytosis of the shed photoreceptor outer segments, spatial buffering of ions, transport of nutrients, ions and water as well as active involvement in the visual cycle. With such important and diverse functions, it is critically important to study the biology of RPE cells. A number of RPE cell lines have been established; however, passaged and immortalized cells are known to quickly lose some of the morphological and physiological characteristics of natural RPE cells. Thus, primary cells are more suitable for studying different aspects of RPE cell biology and function. Mouse primary RPE cell culture is very useful to researchers since mouse models are widely used in biological studies, however collecting RPE cells from mouse is also very challenging due to their small size. Here, we present a protocol for establishing primary mouse RPE cell cultures which includes enucleation and dissection of the eyes and isolation of the RPE sheets to yield the cells for culturing. This method enables efficient cell recovery. The RPE cells obtained from two mice can reach confluency on one 12 mm polyester membrane insert pre-loaded in culture plate after one week of culture and display some of the original properties of bona fide RPE cells such as hexagonal shape and pigmentation after two weeks of culture.


Comparative genomic analysis of European and Middle Eastern community-associated methicillin-resistant Staphylococcus aureus (CC80:ST80-IV) isolates by high-density microarray.
Infections as a result of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) are an issue of increasing global healthcare concern. In Europe, this principally involves strains of multi-locus sequence type clonal complex 80 sequence type 80 with methicillin resistance in a staphylococcal chromosomal cassette (SCCmec) type IV arrangement (CC80:ST80-IV). As with other CA-MRSA strains, CC80:ST80-IV isolates tend to appear uniform when analysed by common molecular typing methods (e.g. pulsed field gel electrophoresis, multi-locus sequence type, SCCmec). To explore whether DNA sequence-based differences exist, we compared the genetic composition of six CC80:ST80-IV isolates of diverse chronological and geographic origin (i.e. Denmark and the Middle East) using an Affymetrix high-density microarray that was previously used to analyse CA-MRSA USA300 isolates. The results revealed a high degree of homology despite the diversity in isolation date and origin, with isolate differences primarily in conserved hypothetical open reading frames and intergenic sequences, but also including regions of known function. This included the confirmed loss of SCCmec recombinase genes in two Danish isolates representing potentially new SCCmec types. Microarray analysis grouped the six isolates into three relatedness pairs, also identified by pulsed field gel electrophoresis, which were consistent with both the clinical and molecular data.


Pico and nanoplankton abundance and carbon stocks along the Brazilian Bight.
Pico and nanoplankton communities from the Southwest Atlantic Ocean along the Brazilian Bight are poorly described. The hydrography in this region is dominated by a complex system of layered water masses, which includes the warm and oligotrophic Tropical Water (TW), the cold and nutrient rich South Atlantic Central Water (SACW) and the Coastal Water (CW), which have highly variable properties. In order to assess how pico- and nanoplankton communities are distributed in these different water masses, we determined by flow cytometry the abundance of heterotrophic bacteria, Prochlorococcus, Synechococcus and autotrophic pico and nanoeukaryotes along three transects, extending from 23°S to 31°S and 39°W to 49°W. Heterotrophic bacteria (including archaea, maximum of 1.5 × 106 cells mL-1) were most abundant in Coastal and Tropical Water whereas Prochlorococcus was most abundant in open-ocean oligotrophic waters (maximum of 300 × 103 cells mL-1). Synechococcus(up to 81 × 103 cells mL-1), as well as autotrophic pico and nanoeukaryotes seemed to benefit from the influx of nutrient-rich waters near the continental slope. Autotrophic pico and nanoeukaryotes were also abundant in deep chlorophyll maximum (DCM) layers from offshore waters, and their highest abundances were 20 × 103 cells mL-1 and 5 × 103 cells mL-1, respectively. These data are consistent with previous observations in other marine areas where Synechococcus and autotrophic eukaryotes dominate mesotrophic waters, whereas Prochlorococcus dominate in more oligotrophic areas. Regardless of the microbial community structure near the surface, the carbon stock dominance by autotrophic picoeukaryotes near the DCM is possibly linked to vertical mixing of oligotrophic surface waters with the nutrient-rich SACW and their tolerance to lower light levels.


Pilot randomised controlled trial of the ENGAGER collaborative care intervention for prisoners with common mental health problems, near to and after release.
Rates of common mental health problems are much higher in prison populations, but access to primary care mental health support falls short of community equivalence. Discontinuity of care on release is the norm and is further complicated by substance use and a range of social problems, e.g. homelessness. To address these problems, we worked with criminal justice, third sector social inclusion services, health services and people with lived experiences (peer researchers), to develop a complex collaborative care intervention aimed at supporting men with common mental health problems near to and following release from prison. This paper describes an external pilot trial to test the feasibility of a full randomised controlled trial. Eligible individuals with 4 to 16 weeks left to serve were screened to assess for common mental health problems. Participants were then randomised at a ratio of 2:1 allocation to ENGAGER plus standard care (intervention) or standard care alone (treatment as usual). Participants were followed up at 1 and 3 months' post release. Success criteria for this pilot trial were to meet the recruitment target sample size of 60 participants, to follow up at least 50% of participants at 3 months' post release from prison, and to deliver the ENGAGER intervention. Estimates of recruitment and retention rates and 95% confidence intervals (CIs) are reported. Descriptive analyses included summaries (percentages or means) for participant demographics, and baseline characteristics are reported. Recruitment target was met with 60 participants randomised in 9 months. The average retention rates were 73% at 1 month [95% CI 61 to 83] and 47% at 3 months follow-up [95% CI 35 to 59]. Ninety percent of participants allocated to the intervention successfully engaged with a practitioner before release and 70% engaged following release. This pilot confirms the feasibility of conducting a randomised trial for prison leavers with common mental health problems. Based on this pilot study and some minor changes to the trial design and intervention, a full two-centre randomised trial assessing the clinical and cost-effectiveness of the ENGAGER intervention is currently underway.


Posterior Eye Shape Measurement With Retinal OCT Compared to MRI.
Posterior eye shape assessment by magnetic resonance imaging (MRI) is used to study myopia. We tested the hypothesis that optical coherence tomography (OCT), as an alternative, could measure posterior eye shape similarly to MRI. Macular spectral-domain OCT and brain MRI images previously acquired as part of the Singapore Epidemiology of Eye Diseases study were analyzed. The right eye in the MRI and OCT images was automatically segmented. Optical coherence tomography segmentations were corrected for optical and display distortions requiring biometry data. The segmentations were fitted to spheres and ellipsoids to obtain the posterior eye radius of curvature (Rc) and asphericity (Qxz). The differences in Rc and Qxz measured by MRI and OCT were tested using paired t-tests. Categorical assignments of prolateness or oblateness using Qxz were compared. Fifty-two subjects (67.8 ± 5.6 years old) with spherical equivalent refraction from +0.50 to -5.38 were included. The mean paired difference between MRI and original OCT posterior eye Rc was 24.03 ± 46.49 mm (P = 0.0005). For corrected OCT images, the difference in Rc decreased to -0.23 ± 2.47 mm (P = 0.51). The difference between MRI and OCT asphericity, Qxz, was -0.052 ± 0.343 (P = 0.28). However, categorical agreement was only moderate (κ = 0.50). Distortion-corrected OCT measurements of Rc and Qxz were not statistically significantly different from MRI, although the moderate categorical agreement suggests that individual differences remained. This study provides evidence that with distortion correction, noninvasive office-based OCT could potentially be used instead of MRI for the study of posterior eye shape.


The impact of a streamlined funding application process on application time: two cross-sectional surveys of Australian researchers.
To examine if streamlining a medical research funding application process saved time for applicants. Cross-sectional surveys before and after the streamlining. The National Health and Medical Research Council (NHMRC) of Australia. Researchers who submitted one or more NHMRC Project Grant applications in 2012 or 2014. Average researcher time spent preparing an application and the total time for all applications in working days. The average time per application increased from 34 working days before streamlining (95% CI 33 to 35) to 38 working days after streamlining (95% CI 37 to 39; mean difference 4 days, bootstrap p value <0.001). The estimated total time spent by all researchers on applications after streamlining was 614 working years, a 67-year increase from before streamlining. Streamlined applications were shorter but took longer to prepare on average. Researchers may be allocating a fixed amount of time to preparing funding applications based on their expected return, or may be increasing their time in response to increased competition. Many potentially productive years of researcher time are still being lost to preparing failed applications.


Yogurt containing probiotic Lactobacillus rhamnosus GR-1 and L. reuteri RC-14 helps resolve moderate diarrhea and increases CD4 count in HIV/AIDS patients.
HIV/AIDS is changing the human landscape in sub-Saharan Africa. Relatively few patients receive antiretroviral therapy, and many suffer from debilitating diarrhea that affects their quality of life. Given the track record of probiotics to alleviate diarrhea, conventional yogurt fermented with Lactobacillus delbruekii var bulgaricus and Streptococcus thermophilus was supplemented with probiotic Lactobacillus rhamnosus GR-1 and L. reuteri RC-14. Twenty-four HIV/AIDS adult female patients (18 to 44 y) with clinical signs of moderate diarrhea, CD4 counts over 200, and not receiving antiretrovirals or dietary supplements, consumed either 100 mL supplemented or unsupplemented yogurt per day for 15 days. Hematologic profiles, CD4 cell counts, and quality of life was evaluated at baseline, 15 and 30 days postprobiotic-yogurt feeding. There was no significant alteration in the hematologic parameters of both groups before and after the probiotic-yogurt feeding. The probiotic yogurt group at baseline, 15 and 30 days had a mean WBC count of 5.8+/-0.76 x 10(9)/L, 6.0+/-1.02 x 10(9)/L, and 5.4+/-0.14 x 10(9)/L, respectively. However, the mean CD4 cell count remained the same or increased at 15 and 30 days in 11/12 probiotic-treated subjects compared to 3/12 in the control. Diarrhea, flatulence, and nausea resolved in 12/12 probiotic-treated subjects within 2 days, compared to 2/12 receiving yogurt for 15 days. This is the first study to show the benefits of probiotic yogurt on quality of life of women in Nigeria with HIV/AIDS, and suggests that perhaps a simple fermented food can provide some relief in the management of the AIDS epidemic in Africa.


Effects of tensioning errors in split transfers of tibialis anterior and posterior tendons.
Split transfers of the tibialis anterior and posterior tendons are commonly performed to address hindfoot varus deformities in patients with cerebral palsy, stroke, or brain injury. Poor outcomes from these procedures are often attributed to a failure to tension the transferred tendon properly, but the mechanical effects of this aspect of the procedure have not been quantified, to our knowledge. The purpose of the present study was to use a cadaver model to examine changes in the actions of these muscles that occur when the tensions in the halves of the split tendon are intentionally balanced or unbalanced to varying degrees. Tendon excursion was measured in seven cadaveric specimens before and after split tendon transfer with experimentally controlled tensions in the halves of the split tendon. The muscle moment arm, a quantitative indicator of the action of a muscle about a joint axis, was calculated as the derivative of tendon excursion with respect to the subtalar joint angle. The tibialis anterior had an eversion moment arm with the subtalar joint in a neutral position following surgery, but the tibialis posterior had virtually no action in the neutral position. Following the split transfers with ideally balanced tension, subtalar joint rotations of >5 degrees strongly influenced the moment arm of the tibialis posterior (p < 0.0002), indicating that its action depends on the position of the hindfoot. The moment arm of the tibialis anterior, however, was influenced only by rotations of >/=20 degrees (p > 0.1741 for each angle pair comparison of <20 degrees ). Moment arms were generally insensitive to imbalances in tension between the medial and lateral tendon halves; significant differences in the moment arm (p < 0.05), compared with that in the balanced condition, were seen only when one half was slack or nearly so. These results suggest that it is possible for a split tendon transfer to be successful over a large range of tensionings. Split transfer of the tibialis posterior tendon produced the desired mechanical outcome in that the tibialis posterior had an eversion moment arm when the foot was inverted and an inversion moment arm when the foot was everted. Split transfer of the tibialis anterior to the cuboid, however, produced a muscle that consistently functioned as an everter regardless of the position of the hindfoot.


RNABC: forward kinematics to reduce all-atom steric clashes in RNA backbone.
Although accurate details in RNA structure are of great importance for understanding RNA function, the backbone conformation is difficult to determine, and most existing RNA structures show serious steric clashes (>or= 0.4 A overlap) when hydrogen atoms are taken into account. We have developed a program called RNABC (RNA Backbone Correction) that performs local perturbations to search for alternative conformations that avoid those steric clashes or other local geometry problems. Its input is an all-atom coordinate file for an RNA crystal structure (usually from the MolProbity web service), with problem areas specified. RNABC rebuilds a suite (the unit from sugar to sugar) by anchoring the phosphorus and base positions, which are clearest in crystallographic electron density, and reconstructing the other atoms using forward kinematics. Geometric parameters are constrained within user-specified tolerance of canonical or original values, and torsion angles are constrained to ranges defined through empirical database analyses. Several optimizations reduce the time required to search the many possible conformations. The output results are clustered and presented to the user, who can choose whether to accept one of the alternative conformations. Two test evaluations show the effectiveness of RNABC, first on the S-motifs from 42 RNA structures, and second on the worst problem suites (clusters of bad clashes, or serious sugar pucker outliers) in 25 unrelated RNA structures. Among the 101 S-motifs, 88 had diagnosed problems, and RNABC produced clash-free conformations with acceptable geometry for 71 of those (about 80%). For the 154 worst problem suites, RNABC proposed alternative conformations for 72. All but 8 of those were judged acceptable after examining electron density (where available) and local conformation. Thus, even for these worst cases, nearly half the time RNABC suggested corrections suitable to initiate further crystallographic refinement. The program is available from http://kinemage.biochem.duke.edu .


Impact of methoxyacetic acid on mouse Leydig cell gene expression.
Methoxyacetic acid (MAA) is the active metabolite of the widely used industrial chemical ethylene glycol monomethyl ether, which is associated with various developmental and reproductive toxicities, including neural toxicity, blood and immune disorders, limb degeneration and testicular toxicity. Testicular toxicity is caused by degeneration of germ cells in association with changes in gene expression in both germ cells and Sertoli cells of the testis. This study investigates the impact of MAA on gene expression in testicular Leydig cells, which play a critical role in germ cell survival and male reproductive function. Cultured mouse TM3 Leydig cells were treated with MAA for 3, 8, and 24 h and changes in gene expression were monitored by genome-wide transcriptional profiling. A total of 3,912 MAA-responsive genes were identified. Ingenuity Pathway analysis identified reproductive system disease, inflammatory disease and connective tissue disorder as the top biological functions affected by MAA. The MAA-responsive genes were classified into 1,366 early responders, 1,387 mid-responders, and 1,138 late responders, based on the time required for MAA to elicit a response. Analysis of enriched functional clusters for each subgroup identified 106 MAA early response genes involved in transcription regulation, including 32 genes associated with developmental processes. 60 DNA-binding proteins responded to MAA rapidly but transiently, and may contribute to the downstream effects of MAA seen for many mid and late response genes. Genes within the phosphatidylinositol/phospholipase C/calcium signaling pathway, whose activity is required for potentiation of nuclear receptor signaling by MAA, were also enriched in the set of early MAA response genes. In contrast, many of the genes responding to MAA at later time points encode membrane proteins that contribute to cell adhesion and membrane signaling. These findings on the progressive changes in gene expression induced by MAA in a cultured Leydig cell model may help elucidate signaling pathways that lead to the testicular pathophysiological responses induced by MAA exposure and may identify useful biomarkers of MAA toxicity.


Identification of the product of growth arrest-specific gene 6 as a common ligand for Axl, Sky, and Mer receptor tyrosine kinases.
Axl, Sky, and Mer, members of an Axl/Sky receptor tyrosine kinase subfamily, are typified by the cell adhesion molecule-related extracellular domain. The product of growth arrest-specific gene 6 (Gas6), structurally homologous to the anticoagulant protein S, was recently identified as the ligand for Axl and Sky, but the ligand for Mer remained unknown. We have now obtained evidence that Gas6 can also function as a ligand for Mer. Co-precipitation analysis, using soluble receptors of Axl, Sky, and Mer (Axl-Fc, Sky-Fc, and Mer-Fc) composed of the extracellular domain of receptors fused to the Fc domain of immunoglobulin G1, clearly showed that Gas6, but not protein S, specifically bound to Axl-Fc, Sky-Fc, and Mer-Fc fusion proteins. Quantitative kinetic analyses using a BIAcore biosensor instrument revealed dissociation constants (Kd) of the binding of rat Gas6 to Axl-Fc, Sky-Fc, and Mer-Fc are 0.4, 2.7, and 29 nM, respectively. We also found that Gas6 stimulated tyrosine phosphorylation of Axl, Sky, and Mer receptors ectopically expressed in Chinese hamster ovary cells. Taken together, these findings suggest that Gas6 is a common ligand for Axl, Sky, and Mer, all known members of an Axl/Sky receptor subfamily.


Application of a behavioral approach to measuring dietary change: the fat- and fiber-related diet behavior questionnaire.
This study reports the validity, reliability, and responsiveness of a 33-item fat- and fiber-related behavior questionnaire (FFB) and describes how this instrument provides insight into the process of adopting healthy diets. Data are from the Eating Patterns Study, a randomized clinical trial of a physician-delivered, self-help intervention to reduce fat and increase fiber intake. Intervention (n = 850) and control participants (n = 945) completed both a food frequency questionnaire and the FFB at baseline and at 3 and 12 months postintervention. Validity, as assessed by correlation of the FFB with the food frequency questionnaire at baseline, was 0.53 for fat (fat scale with percentage energy from fat) and 0.50 for fiber (fiber scale with fiber g/1000 kcal; both P < 0.001). Reliability, as assessed by the intraclass correlation in controls across all three time points, was 0.77 for the fat scale and 0.74 for the fiber scale (both P < 0.001). The largest changes in fat-related behavior were in avoiding fat as a flavoring and in using specially manufactured low-fat foods, and the largest changes in fiber-related behavior were in substituting high-fiber versions of common foods. Overall, the FFB was a reasonably valid and reliable measure of dietary intake, which provided insight into the behavioral effects of the dietary intervention.


Excited-state symmetry breaking in cofacial and linear dimers of a green perylenediimide chlorophyll analogue leading to ultrafast charge separation.
Photoexcitation of chromophoric dimers constrained to a symmetric pi-stacked geometry by their molecular structure usually produces excimers independent of solvent polarity, while dimers with edge-to-edge perpendicular pi systems undergo excited-state symmetry breaking in highly polar solvents leading to intradimer charge separation. We present direct evidence for symmetry breaking in the lowest excited singlet state of a symmetric cofacial dimer of 1,7-bis(pyrrolidin-1'-yl)-perylene-3,4:9,10-bis(dicarboximide) (5PDI) in the low polarity solvent toluene to produce a radical ion pair quantitatively. This dimer, cof-5PDI2, was synthesized by attaching two 5PDI chromophores via imide groups to a xanthene spacer. For comparison, a linear symmetric dimer, lin-5PDI2, was prepared in which the 5PDI chromophores are linked end-to-end via a N-N single bond between their imides. The edge-to-edge pi systems of the 5PDI chromophores within lin-5PDI2 are perpendicular to one another. Ground-state absorption spectra of both 5PDI dimers show exciton coupling, which is consistent with the orientation of the 5PDI chromophores relative to one another. Ultrafast transient absorption spectroscopy following excitation of the dimers with 700 nm, 100 fs laser pulses shows that quantitative intradimer electron transfer occurs in cof-5PDI2 in toluene with tau = 0.17 ps followed by charge recombination to the ground state with tau = 222 ps. Similar measurements on lin-5PDI2 reveal that photoinduced electron transfer does not occur in toluene, but occurs in more polar solvents such as 2-methyltetrahydrofuran, wherein tau = 55 ps for charge separation and tau = 99 ps for charge recombination. Excited-state symmetry breaking in 5PDI dimers provides new routes to biomimetic charge separation and storage assemblies that can be more easily prepared and modified than those based on multiple tetrapyrrole macrocycles.


Bethanidine sulfate: efficacy in prevention of ventricular tachyarrhythmias during programmed stimulation. Report of a multicenter study of 56 patients.
Twelve cardiac electrophysiology centers conducted an open label prospective trial of bethanidine sulfate, an oral bretylium analog, for the prevention of ventricular tachyarrhythmias during programmed electrical stimulation. The study group included 56 patients (44 men, 12 women; mean age 60 years; 55 with structural heart disease). Sixteen patients had both ventricular tachycardia and fibrillation, 30 had ventricular tachycardia alone and 10 had ventricular fibrillation alone. Programmed stimulation on no antiarrhythmic drugs induced sustained ventricular tachycardia in 46 patients, nonsustained ventricular tachycardia in 4 patients and ventricular fibrillation in 6 patients. During programmed ventricular stimulation after 59 trials of 20 to 30 mg/kg body weight of oral bethanidine (acute dosing in 40 patients, and divided dosing over 24 hours in 19 patients), no ventricular tachyarrhythmias were inducible in 6 patients (11%), sustained ventricular tachycardia was converted to nonsustained ventricular tachycardia in 3 patients (5%), ventricular tachyarrhythmias remained inducible in 39 patients (70%) and spontaneous ventricular tachyarrhythmias occurred more frequently in 4 patients (7%). Side effects prevented repeat testing in four patients. The 10 patients presenting with only ventricular fibrillation appeared to have a higher response rate: no ventricular tachyarrhythmias were inducible in 2 patients and sustained ventricular tachycardia was converted to nonsustained ventricular tachycardia in 2 patients. Despite protriptyline administration in 54 of 59 bethanidine trials, symptomatic hypotension occurred in 30 trials (51%). In conclusion, the efficacy of bethanidine for preventing ventricular tachyarrhythmias as assessed by programmed stimulation is low. Patients presenting with only ventricular fibrillation may have a more favorable response to bethanidine sulfate. Symptomatic hypotension occurs frequently despite concomitant use of protriptyline.


Polarization recording and reconstruction in Disperse Red 1 -doped cellulose acetate.
Cellulose acetate films doped with the azo dye Disperse Red 1 were prepared by dip coating. This matrix provides holograms of comparable efficiency for gratings recorded by intensity and polarization modulations. We used this matrix to store and successfully reconstruct the polarization state of an elliptically polarized object beam. A single plane-polarized reference beam was used for both recording and reconstruction.


Interaction between the vitamin D receptor gene and collagen type Ialpha1 gene in susceptibility for fracture.
Osteoporosis is a common disease with a strong genetic component. Polymorphisms in the vitamin D receptor (VDR) gene have been implicated in osteoporosis but explain only a small part of the genetic effect on bone mineral density (BMD) while their effect on fractures is still uncertain. Recently, a G to T polymorphism in an Sp1 site in the collagen type Ialpha1 (COLIA1) gene was found to be associated with reduced BMD and with increased fracture risk. To analyze the combined influence of polymorphisms in the VDR gene and the COLIA1 gene in determining the susceptibility to osteoporotic fracture, we studied 1004 postmenopausal women. The "baT" VDR haplotype, constructed from three adjacent restriction fragment length polymorphisms, was found to be overrepresented among fracture cases (p = 0.009). This corresponded to an odds ratio (OR) of 1.8 (95% CI, 1.0-3.3) for heterozygous carriers and 2.6 (95% CI, 1.4-5.0) for homozygous carriers of the risk haplotype. The effect was similar for vertebral and nonvertebral fractures and, most importantly, independent of BMD. We observed significant interaction (p = 0.03) between VDR and COLIA1 genotype effects. Fracture risk was not VDR genotype-dependent in the COLIA1 "reference" group (genotype GG) while in the COLIA1 "risk" group (genotypes GT and TT) the risk of fracture was 2.1 (95% CI, 1.0-4.4) for heterozygous and 4.4 (95% CI, 2.0-9.4) for homozygous carriers of the VDR risk haplotype. We conclude that both the VDR and the COLIA1 polymorphisms are genetic markers for osteoporotic fracture in women, independent of BMD. Our data indicate that interlocus interaction is likely to be an important component of osteoporotic fracture risk.


Porous polymer catalysts with hierarchical structures.
The emergence of porous organic polymers (POPs) has provided great opportunities for new applications in heterogeneous catalysis owing to their unprecedented intrinsic structural features such as high surface areas, extraordinary framework stabilities and chemically adjustable compositions. In this tutorial review, representative recent developments in the POPs-based catalysts with hierarchically porous structures are presented. Various strategies for the syntheses of hierarchically porous polymers including hard-templating, soft-templating and template-free approaches and the design of catalytically active porous polymers including post-modification, co-polymerization and self-polymerization have been discussed. In addition, their catalytic properties are compared. Finally, we emphasize the importance of the synthesis of hierarchically porous polymer based heterogeneous catalysts using sustainable routes under template-free and metal-free conditions.


STK38 is a critical upstream regulator of MYC's oncogenic activity in human B-cell lymphoma.
The MYC protooncogene is associated with the pathogenesis of most human neoplasia. Conversely, its experimental inactivation elicits oncogene addiction. Besides constituting a formidable therapeutic target, MYC also has an essential function in normal physiology, thus creating the need for context-specific targeting strategies. The analysis of post-translational MYC activity modulation yields novel targets for MYC inactivation. Specifically, following regulatory network analysis in human B-cells, we identify a novel role of the STK38 kinase as a regulator of MYC activity and a candidate target for abrogating tumorigenesis in MYC-addicted lymphoma. We found that STK38 regulates MYC protein stability and turnover in a kinase activity-dependent manner. STK38 kinase inactivation abrogates apoptosis following B-cell receptor activation, whereas its silencing significantly decreases MYC levels and increases apoptosis. Moreover, STK38 knockdown suppresses growth of MYC-addicted tumors in vivo, thus providing a novel viable target for treating these malignancies.


In vitro Hypolipidemic and Antioxidant Effects of Leaf and Root Extracts of Taraxacum Officinale.
Adipose tissue dysfunction constitutes a primary defect in obesity and might link this disease to severe chronic health problems. We aimed to evaluate the antioxidant activity of three extracts from Taraxacum officinale (dandelion) as well as their effects on mature 3T3-L1 adipocytes concerning intracellular lipid accumulation and cytotoxicity, this would give indications regarding therapeutic interest of dandelion as potential anti-obesity candidate. Antioxidant activities of extracts from dandelion roots and leaves were evaluated in vitro using 1,1-diphenyl-2-picrylhyorazyl (DPPH) and Ferric Reducing Antioxidant Power (FRAP) methods at the concentration range used in cellular assays (300-600 µg/mL). The influence of the extracts on mature 3T3-L1 adipocyte viability was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Lipid content was determined by Oil-red-O staining. The extracts showed effective antioxidant activity correlating with total flavonoid and polyphenol contents. However, the functionality level was weakly associated with the antioxidant activity. Further, our data demonstrated that mature 3T3-L1 adipocytes reduced in size and number when incubated with the extracts, which suggests a significant increase in lipolysis activity. Particularly, leaf extract and crude powdered root of dandelion reduced triglyceride accumulation in mature 3T3-L1 adipocytes to a greater extent that the extract from the root. Our study shows anti-lipogenic effects of dandelion extracts on adipocytes as well as radical scavenging and reducing activity. Importantly, along with previous results indicating that cell populations cultivated in the presence of the dandelion extracts decrease in 3T3-L1 adipogenesis capacity, these results suggests that these extracts might represent a treatment option for obesity-related diseases by affecting different processes during the adipocyte life cycle.


Interleukin-12 is produced by macrophages in response to live or killed Bordetella pertussis and enhances the efficacy of an acellular pertussis vaccine by promoting induction of Th1 cells.
Using a murine respiratory infection model, we have demonstrated previously that infection with Bordetella pertussis or immunization with a whole-cell pertussis vaccine induced antigen-specific Th1 cells, which conferred a high level of protection against aerosol challenge. In contrast, immunization with an acellular vaccine, consisting of the B. pertussis components detoxified pertussis toxin, filamentous hemagglutinin, and pertactin adsorbed to alum, generated Th2 cells and was associated with delayed bacterial clearance following challenge. In this study, we demonstrated that addition of interleukin-12 (IL-12) either in vitro or in vivo enhanced type 1 T-cell cytokine responses induced with an acellular vaccine. Furthermore, the rate of bacterial clearance in mice coinjected with IL-12 and the acellular vaccine was similar to that observed following immunization with a potent whole-cell vaccine. Analysis of IL-12 secretion by murine macrophages suggested that this cytokine is produced in vivo following B. pertussis infection or immunization with the whole-cell vaccine. IL-12 was detected in the supernatants of lung, splenic, and peritoneal macrophages infected with live B. pertussis or stimulated with heat-killed whole B. pertussis or B. pertussis lipopolysaccharide. In contrast, IL-12 could not be detected following stimulation of macrophages with the bacterial antigens filamentous hemagglutinin, detoxified pertussis toxin, and pertactin, the components of acellular vaccines. Our findings suggest that induction of endogenous IL-12 may contribute to the high efficacy of pertussis whole-cell vaccines and also demonstrate that it is possible to attain these high levels of protection with a less reactogenic acellular vaccine incorporating IL-12 as an adjuvant.


Agroforestry leads to shifts within the gammaproteobacterial microbiome of banana plants cultivated in Central America.
Bananas (Musa spp.) belong to the most important global food commodities, and their cultivation represents the world's largest monoculture. Although the plant-associated microbiome has substantial influence on plant growth and health, there is a lack of knowledge of the banana microbiome and its influencing factors. We studied the impact of (i) biogeography, and (ii) agroforestry on the banana-associated gammaproteobacterial microbiome analyzing plants grown in smallholder farms in Nicaragua and Costa Rica. Profiles of 16S rRNA genes revealed high abundances of Pseudomonadales, Enterobacteriales, Xanthomonadales, and Legionellales. An extraordinary high diversity of the gammaproteobacterial microbiota was observed within the endophytic microenvironments (endorhiza and pseudostem), which was similar in both countries. Enterobacteria were identified as dominant group of above-ground plant parts (pseudostem and leaves). Neither biogeography nor agroforestry showed a statistically significant impact on the gammaproteobacterial banana microbiome in general. However, indicator species for each microenvironment and country, as well as for plants grown in Coffea intercropping systems with and without agri-silvicultural production of different Fabaceae trees (Inga spp. in Nicaragua and Erythrina poeppigiana in Costa Rica) could be identified. For example, banana plants grown in agroforestry systems were characterized by an increase of potential plant-beneficial bacteria, like Pseudomonas and Stenotrophomonas, and on the other side by a decrease of Erwinia. Hence, this study could show that as a result of legume-based agroforestry the indigenous banana-associated gammaproteobacterial community noticeably shifted.


Stoic survival: the journey of parenting a premature infant in the bush.
The birth of a premature infant is a stressful and emotionally challenging time for parents. Families living in rural areas often have reduced access to the specialist services premature infants require, and different concerns from their metropolitan counterparts. Rural families may have to spend extended periods of time at a metropolitan centre while their child is in a neonatal intensive care unit (NICU). Regular return trips to hospital may be required for follow up. Parental experience of this unexpected event and the resultant intensive health service involvement requires further examination; most studies focus on the NICU experience. This exploratory study was undertaken from the rural paediatric allied health perspective. Because there are few accounts of rural families' experiences in the literature, this hermeneutic phenomenological qualitative study focused on the rural parent's experience of having a premature infant in a rural area during the first 12 months of the child's life. Participants were selectively recruited from the case lists of paediatricians in a rural/regional hospital. Seven parents (5 mothers and 2 fathers) of premature infants consented to participate in semi-structured interviews. Interviews were of 60-90 min duration per parent, and were audiotaped and transcribed verbatim. The transcripts were analysed thematically using a phenomenological approach. Process and reflection diaries were maintained in order to provide an audit trail. The participant group reflected a range of experiences. Parents described being initially shocked and then gradually adjusting to being the parent of a premature child. Three major themes emerged: (1) 'Coping through optimism' when parents consistently spoke positively about even stressful and difficult aspects of their experience; (2) 'Stoic survival' where parents did not emotionally deal with their experience, often citing others' needs as having higher priority; and (3) 'Striving for normal' when parents focussed on the aspects of their child's medical care or development that was closer to that of a full term child. Parents described feeling devastated if they felt their infant regressed or was progressing too slowly, and elated whenever a new milestone was achieved. Gaining insight into the experience of parents of premature infants can help health professionals ensure services more effectively meet the needs of these families. Rural families were pleased with their local services although they indicated that travelling to a metropolitan centre was extremely burdensome. While the families interviewed had access to some local specialist services, they expressed concern that if they resided in a more remote area there would be reduced access to services and greater personal strain. Further research is required to determine the experiences of Indigenous families, separated or divorced parents and families living in remote areas.


Debridement arthroplasty for primary osteoarthritis of the elbow. Surgical technique.
Formal and more aggressive debridement procedures have been described for the treatment of advanced primary osteoarthritis of the elbow. However, the literature contains little information on the results of long-term follow-up. The purpose of this study was to evaluate outcomes at an average of ten years after debridement arthroplasties performed through a posteromedial approach. Thirty-three elbows with primary osteoarthritis in thirty-two patients treated with debridement arthroplasty were available for clinical follow-up evaluation. Through a posteromedial approach, the flexor-pronator muscle origin was reflected from the medial epicondyle and the joint was opened, preserving the anterior oblique bundle of the medial collateral ligament. The ulnar nerve was decompressed in all patients. Osteophytes were removed from the anterior, medial, and posterior sides of the elbow joint. In nine elbows, osteophytes from the lateral compartment were removed through an additional lateral approach. The mean age at the time of the operation was fifty years. The mean duration of follow-up was 121 months, and nineteen elbows were followed for more than ten years. The mean preoperative limitation of extension of 31 degrees was reduced to 24 degrees , and the mean preoperative flexion of 101 degrees improved to 118 degrees (p < 0.001). The mean arc of movement improved by 24 degrees . The mean Japanese Orthopaedic Association elbow score was 83 points at the latest follow-up evaluation compared with 60 points preoperatively (p < 0.001). Of twenty-five patients who had performed heavy manual work, nineteen (76%) returned to their previous job or an equivalent job. At the latest examination of the nineteen elbows followed for more than ten years, the limitation of extension was found to have increased by 7 degrees compared with the limitation noted at one year (p < 0.009); the mean arc of flexion had remained the same. Three elbows required a reoperation. Overall, 85% of the elbows were satisfactory to the patients. Debridement arthroplasty through a posteromedial approach can provide stable and reliable long-term results with regard to relief of pain, gains in range of motion, and the patient's ability to return to his or her previous occupation. In our series, a modest loss of extension was observed at ten years, whereas the arc of flexion remained consistent.


The evidence for α-linolenic acid and cardiovascular disease benefits: Comparisons with eicosapentaenoic acid and docosahexaenoic acid.
Our understanding of the cardiovascular disease (CVD) benefits of α-linolenic acid (ALA, 18:3n-3) has advanced markedly during the past decade. It is now evident that ALA benefits CVD risk. The expansion of the ALA evidence base has occurred in parallel with ongoing research on eicosapentaenoic acid (EPA, 20:5n-3) and docosahexaenoic acid (DHA, 22:6n-3) and CVD. The available evidence enables comparisons to be made for ALA vs. EPA + DHA for CVD risk reduction. The epidemiologic evidence suggests comparable benefits of plant-based and marine-derived n-3 (omega-3) PUFAs. The clinical trial evidence for ALA is not as extensive; however, there have been CVD event benefits reported. Those that have been reported for EPA + DHA are stronger because only EPA + DHA differed between the treatment and control groups, whereas in the ALA studies there were diet differences beyond ALA between the treatment and control groups. Despite this, the evidence suggests many comparable CVD benefits of ALA vs. EPA + DHA. Thus, we believe that it is time to revisit what the contemporary dietary recommendation should be for ALA to decrease the risk of CVD. Our perspective is that increasing dietary ALA will decrease CVD risk; however, randomized controlled clinical trials are necessary to confirm this and to determine what the recommendation should be. With a stronger evidence base, the nutrition community will be better positioned to revise the dietary recommendation for ALA for CVD risk reduction.


Medicare program; Medicare prescription drug benefit. Final rule.
This final rule implements the provisions of the Social Security Act (the Act) establishing and regulating the Medicare Prescription Drug Benefit. The new voluntary prescription drug benefit program was enacted into law on December 8, 2003 in section 101 of Title I of the Medicare Prescription Drug, Improvement, and Modernization Act of 2003 (MMA) (Pub. L. 108-173). Although this final rule specifies most of the requirements for implementing the new prescription drug program, readers should note that we are also issuing a closely related rule that concerns Medicare Advantage organizations, which, if they offer coordinated care plans, must offer at least one plan that combines medical coverage under Parts A and B with prescription drug coverage. Readers should also note that separate CMS guidance on many operational details appears or will soon appear on the CMS website, such as materials on formulary review criteria, risk plan and fallback plan solicitations, bid instructions, solvency standards and pricing tools, plan benefit packages. The addition of a prescription drug benefit to Medicare represents a landmark change to the Medicare program that will significantly improve the health care coverage available to millions of Medicare beneficiaries. The MMA specifies that the prescription drug benefit program will become available to beneficiaries beginning on January 1, 2006. Generally, coverage for the prescription drug benefit will be provided under private prescription drug plans (PDPs), which will offer only prescription drug coverage, or through Medicare Advantage prescription drug plans (MA PDs), which will offer prescription drug coverage that is integrated with the health care coverage they provide to Medicare beneficiaries under Part C of Medicare. PDPs must offer a basic prescription drug benefit. MA-PDs must offer either a basic benefit or broader coverage for no additional cost. If this required level of coverage is offered, MA-PDs or PDPs, but not fallback PDPs may also offer supplemental benefits through enhanced alternative coverage for an additional premium. All organizations offering drug plans will have flexibility in the design of the prescription drug benefit. Consistent with the MMA, this final rule also provides for subsidy payments to sponsors of qualified retiree prescription drug plans to encourage retention of employer-sponsored benefits. We are implementing the drug benefit in a way that permits and encourages a range of options for Medicare beneficiaries to augment the standard Medicare coverage. These options include facilitating additional coverage through employer plans, MA-PD plans and high-option PDPs, and through charity organizations and State pharmaceutical assistance programs. See sections II.C, II.J, and II.P, and II.R of this preamble for further details on these issues. The proposed rule identified options and alternatives to the provisions we proposed and we strongly encouraged comments and ideas on our approach and on alternatives to help us design the Medicare Prescription Drug Benefit Program to operate as effectively and efficiently as possible in meeting the needs of Medicare beneficiaries.


Neuroanatomical phenotypes in mental illness: identifying convergent and divergent cortical phenotypes across autism, ADHD and schizophrenia.
There is evidence suggesting neuropsychiatric disorders share genomic, cognitive and clinical features. Here, we ask if autism-spectrum disorders (ASD), attention-deficit/hyperactivity disorder (ADHD) and schizophrenia share neuroanatomical variations. First, we used measures of cortical anatomy to estimate spatial overlap of neuroanatomical variation using univariate methods. Next, we developed a novel methodology to determine whether cortical deficits specifically target or are "enriched" within functional resting-state networks. We found cortical anomalies were preferentially enriched across functional networks rather than clustering spatially. Specifically, cortical thickness showed significant enrichment between patients with ASD and those with ADHD in the default mode network, between patients with ASD and those with schizophrenia in the frontoparietal and limbic networks, and between patients with ADHD and those with schizophrenia in the ventral attention network. Networks enriched in cortical thickness anomalies were also strongly represented in functional MRI results (Neurosynth; r = 0.64, p = 0.032). We did not account for variable symptom dimensions and severity in patient populations, and our cross-sectional design prevented longitudinal analyses of developmental trajectories. These findings suggest that common deficits across neuropsychiatric disorders cannot simply be characterized as arising out of local changes in cortical grey matter, but rather as entities of both local and systemic alterations targeting brain networks.


Stroke, myocardial infarction, acute and chronic inflammatory diseases: caspases and other apoptotic molecules as targets for drug development.
Mapping of the human and other eukaryotic genomes has provided the pharmacological industry with excellent models for drug discovery. Control of cell proliferation, differentiation, activation and cell removal is crucial for the development and existence of multicellular organisms. Each cell cycle progression, with sequences of DNA replication, mitosis, and cell division, is a tightly controlled and complicated process that, when deregulated, may become dangerous not only to a single cell, but also to the whole organism. Regulation and the proper control of the cell cycle and of programmed cell death (apoptosis) is therefore essential for mammalian development and the homeostasis of the immune system. The molecular networks that regulate these processes are critical targets for drug development, gene therapy, and metabolic engineering. In addition to the primary, intracellular apoptotic suicide machinery, components of the immune system can detect and remove cells and tissue fragments that no longer serve their defined functions. In this review we will focus on apoptotic pathways converging on caspase family proteases, summarizing pharmacological attempts that target genes, proteins, and intermolecular interactions capable of modulating apoptosis and the inflammatory response. The upcoming pharmacological development for treatment of acute pathologies, such as sepsis, SIRS, stroke, traumatic brain injury, myocardial infarction, spinal cord injury, acute liver failure, as well as chronic disorders such as Huntington's disease, Parkinson's disease, ALS, and rheumatoid arthritis, will be discussed in details. We also suggest new potential molecular targets that may prove to be effective in controlling apoptosis and the immune response in vivo.


Neurotrophins and the neuroendocrine brain: different neurotrophins sustain anatomically and functionally segregated subsets of hypothalamic dopaminergic neurons.
Hypothalamic neurons control a variety of important hormonal and behavioral functions. Little is known, however, about the neurotrophic factors that these neurons may require for survival and/or maintenance of their differentiated functions. We conducted experiments to examine this issue, utilizing a combination of immunohistochemical, in situ hybridization and cell culture approaches. We found that the low affinity receptor for nerve growth factor (p75 NGFR) is present in small subsets of hypothalamic peptidergic neurons identified as such by their content of galanin, luteinizing hormone-releasing hormone (LHRH) and vasointestinal peptide (VIP). More prominently, however, examination of hypothalamic dopaminergic (DA) neurons for the presence of p75 NGFR-like immunoreactivity revealed that the receptor was present on tyrosine hydroxylase (TH)-positive neurons of the zona incerta and periventricular region, but not on neuroendocrine DA neurons of the tuberoinfundibular region. In situ hybridization experiments using a p75 NGFR cRNA confirmed this distribution. Regardless of the presence or absence of p75 NGFR, neither DA group expresses trkA mRNA, indicating that these two major hypothalamic subsets of DNA neurons are NGF-insensitive. A substantial fraction of TH mRNA-positive cells in the zona incerta expresses trkB mRNA, which encodes the receptor for brain derived neurotrophic factor (BDNF); in turn BDNF supports the in vitro survival of hypothalamic TH neurons bearing p75-NGFR, suggesting that BDNF is trophic for DNA neurons of the zona incerta. In contrast, tuberoinfundibular DA neurons do not express trkB mRNA, but some have trkC mRNA, which encodes the receptor for neurotrophin-3 (NT-3). The in vitro survival of TH neurons devoid of p75-NGFR is supported by NT-3, implying that NT-3 may be trophic for a subset of tuberoinfundibular DA neurons. These results suggest that, in spite of expressing an identical neurotransmitter phenotype, anatomically and functionally segregated DA neurons of the neurodendocrine brain are sustained by different neurotrophic factors.


Selective adrenal necrosis and apoplexy induced by 7, 12-dimethylbenz(a)anthracene.
Invariably in every normal rat a single dose of 7, 12-dimethylbenz(a)anthracene, by mouth or injected in a vein, was found to cause apoplexy and massive necrosis in the inner zones of the adrenal cortex; the zona glomerulosa, the adrenal medulla, and a small region of cortex adjacent to the great adrenal vessels were spared from damage. DMBA caused these selective lesions in females and in males of 2 strains of rats. Hemorrhage and necrosis were observed in no organ other than the adrenal gland. Whereas adrenal glands were heavily damaged by DMBA, pituitary and ovary escaped injury by the compound. A single huge but sublethal feeding of o, p'-DDD caused degenerative changes of minor magnitude in the adrenals and only in a small percentage of rats; the property of inducing adrenal damage was not shared by other polynuclear aromatic hydrocarbons which were investigated, including strong carcinogens. Presence of adrenal medulla is not a prerequisite to damage of the adrenal cortex by DMBA. The adrenal damage occurred in rats, given DMBA, from which the pituitary had been removed but the lesions were smaller in extent and less in incidence as post-hypophysectomy atrophy of the adrenal cortex progressed. The entire DMBA molecule was necessary to induce adrenal damage; fragments of this molecule did not induce adrenal lesions. Two components which are of cardinal importance in this specific damaging effect are: (a) electronic factor; (b) steric factor. The level of isocitric dehydrogenase in adrenal is modified considerably by presence or absence of estradiol-17beta.


Virtue, flourishing, and positive psychology in psychotherapy: An overview and research prospectus.
Researchers have increasingly called for the examination of both mental health symptoms and well-being when providing and evaluating psychotherapy, and although symptoms and well-being are typically inversely related, these appear to be distinct constructs that may require distinct intervention strategies. Positive psychology interventions, virtue-based treatments, and psychotherapies explicitly focused on promoting well-being have emerged in response to, or perhaps in concert with, the calls for attention to symptoms and well-being. Our review of the relevant and vast research pockets revealed that these treatments demonstrated relative efficacy in promoting well-being, whereas evidence for relative efficacy when reducing symptoms was largely inconclusive, particularly in psychotherapy contexts. We organized our review around the virtue-ethics notion that growth in virtuousness fosters flourishing, with flourishing consisting of more than the absence of symptoms, and specifically, that flourishing also involves increased well-being. The lack of evidence for relative efficacy among active alternative treatment conditions in promoting flourishing may suggest equal effectiveness, and yet, this also suggests that there are yet-to-be-identified moderators and mechanisms of change and/or insufficient use of research designs and/or statistical procedures that could more clearly test this major tenet of the virtue-ethics tradition. Nevertheless, we know that evidence-based problem-focused psychotherapies are effective at reducing symptoms, and our review showed that positive psychology interventions, virtue-based treatments, and psychotherapies explicitly focused on well-being promote well-being and/or virtue development. We encourage researchers and psychotherapists to continue to integrate symptom reduction and well-being promotion into psychotherapy approaches aimed at fostering client flourishing. (PsycInfo Database Record (c) 2020 APA, all rights reserved).


Genomic analysis of a novel picornavirus from a migratory waterfowl, greater white-fronted goose (Anser albifrons).
The complete genome of goose picornavirus 1 (GPV-1) strain goose/NLSZK2/HUN/2013 (MF358731) was determined by RT-PCR and next-generation sequencing from a cloacal sample of a migratory waterfowl, greater white-fronted goose (Anser albifrons) in Hungary. The genome of GPV-1 shows an L-3-3-4 organization pattern with a 5'-terminal origin of replication (ORI) region, a type-IV IRES, and an Hbox/NC-type 2A protein. This virus showed the highest overall sequence identity to the members of the genus Kobuvirus, although the phylogenetic position of GPV-1 is different in the analyzed P1, 2C and 3CD phylogenetic trees, which further increases the diversity of known avian picornaviruses.


Inorganic polyphosphate is required for sustained free mitochondrial calcium elevation, following calcium uptake.
Mitochondrial free calcium is critically linked to the regulation of cellular metabolism. Free ionic calcium concentration within these organelles is determined by the interplay between two processes: exchange across the mitochondrial inner membrane and calcium-buffering within the matrix. During stimulated calcium uptake, calcium is primarily buffered by orthophosphate, preventing calcium toxicity while allowing for well-regulated yet elevated calcium loads. However, if limited to orthophosphates only, this buffering system is expected to lead to the irreversible formation of insoluble precipitates, which are not observed in living cells, under physiological conditions. Here, we demonstrate that the regulation of free mitochondrial calcium requires the presence of free inorganic polyphosphate (polyP) within the organelle. We found that the overexpression of a mitochondrial-targeted enzyme hydrolyzing polyP leads to the loss of the cellular ability to maintain elevated calcium concentrations within the organelle, following stimulated cytoplasmic signal. We hypothesize that the presence of polyP prevents the formation of calcium-phosphate insoluble clusters, allowing for the maintenance of elevated free calcium levels, during stimulated calcium uptake.


Modulation of the intestinal barrier adaptive functions in red-eared slider (Trachemys scripta elegans) invading brackish waters.
Globally, the increase in sea levels is leading to salinization of freshwater, which might influence the freshwater organisms such as red-eared slider, Trachemys scripta elegans. The turtle can invade brackish water environments, in which it must deal with elevated salinity in the gastrointestinal tract that could impact the intestinal function. The intestinal barrier provides a front-line of organismal defense against the chemical and biological environmental insults. In this study, the adaptive functions of the intestinal barrier including intestinal histomorphology, genes involved in intestinal barrier functions, and the intestinal micro-ecosystem were analyzed in the turtles exposed to freshwater (S0), 5‰ salinity (S5) and 15‰ salinity (S15) water for 30 days. The results showed that the intestine of T. s. elegans maintained normal histomorphological structure in the S5 group, whereas the villus height, crypt depth and the number of goblet cells in the S15 group were lower than that in the S5 and S0 groups. In addition, the relative expression levels of epithelial tight junction-related genes and intestinal immune-related genes in the gut were significantly upregulated in the S15 group, compared to the freshwater group. Mucin-2 gene expression was downregulated, but mucin-1 transcript levels were upregulated in salinity-treated groups. Furthermore, the abundances of phylum Proteobacteria, and genera Morganella and Aeromonas in the intestine were particularly enhanced in the S15 group than the S0 and S5 groups. Taken together, these results indicate that the intestinal barrier plays a protective role in T. s. elegans adaptation to brackish water environments. Our results provide a perspective on the evolution of salinity tolerance and help to evaluate the potential danger of the turtle to other species, and understand the challenges that other species must meet with rising sea levels.


Cerebral Revascularization for Aneurysms in the Flow-Diverter Era.
Cerebral bypass has been an important tool in the treatment of complex intracranial aneurysms. The recent advent of flow-diverting stents (FDS) has expanded the capacity for endovascular arterial reconstruction. We investigated how the advent of FDS has impacted the application and outcomes of cerebral bypass in the treatment of intracranial aneurysms. We reviewed a consecutive series of cerebral bypasses during aneurysm surgery over the course of 10 years. FDS were in active use during the last 5 years of this series. We compared the clinical characteristics, surgical technique, and outcomes of patients who required cerebral bypass for aneurysm treatment during the preflow diversion era (PreFD) with those of the postflow diversion era (PostFD). We treated 1061 aneurysms in the PreFD era (from July 2005 through June 2010) and 1348 in the PostFD era (from July 2010 through June 2015). Eighty-five PreFD patients (8%) and 45 PostFD patients (3%) were treated with cerebral bypass. PreFD patients had better baseline functional status compared to PostFD patients with average preoperative modified Rankin Scale score of 0.55 in PreFD and 1.18 in PostFD. After the introduction of FDS, cerebral bypass was performed in a lower proportion of patients with aneurysms. Patients selected for bypass in the flow-diverter era had worse preoperative modified Rankin Scale scores indicating a greater complexity of the patients. Cerebral bypass in well-selected patients and revascularization remains an important technique in vascular neurosurgery. It is also useful as a rescue technique after failed FDS treatment of aneurysms.


Risk assessment and cost-effectiveness analysis of Aujeszky's disease virus introduction through breeding and fattening pig movements into Spain.
Movement of infected animals is considered the most likely route of Aujeszky's disease virus (ADV) introduction into free areas and the main obstacle to eradicating Aujeszky's disease (AD) in those areas, which have achieved a low prevalence (>0 and < or =10%) status. For this reason, the Spanish AD control and eradication program has established measures to enhance security in animal movements in an attempt to protect areas with free or low prevalence status; however, no studies have quantified the effectiveness of the current or alternative ADV introduction prevention measures. We performed a probabilistic risk assessment and cost-effectiveness analysis, using Monte Carlo simulation, to evaluate the probability of introducing ADV-infected animals into free or low prevalence areas under the Spanish AD control and eradication program. We found the mean probability of introducing ADV-infected animals, when breeding pigs were quarantined but not tested prior to shipment, is likely (up to 21%), representing 13.6 times higher risk than when breeding pigs were tested prior to shipment. The strategy of testing pigs on fattening farms 15 days prior to shipment and using a sample size sufficient to detect a prevalence of 5% with a 95% of confidence, could reduce the probability of introducing ADV-infected animals by 91% with no additional cost. Similarly, testing pigs on breeding and fattening farms using a sample size sufficient to detect a prevalence of 1% with a 95% of confidence, could reduce the probability of introducing ADV-infected animals by 99%, but with an increased cost of 81%. Results reported in this study identify factors that contribute to risk of ADV introduction and should aid the control and eradication of AD in Spain.