Genetic polymorphisms of the beta 2-adrenergic receptor in nocturnal and nonnocturnal asthma. Evidence that Gly16 correlates with the nocturnal phenotype.
Nocturnal asthma represents a unique subset of patients with asthma who experience worsening symptoms and airflow obstruction at night. The basis for this phenotype of asthma is not known, but beta 2-adrenergic receptors (beta 2AR) are known to downregulate overnight in nocturnal asthmatics but not normal subjects or nonnocturnal asthmatics. We have recently delineated three polymorphic loci within the coding block of the beta 2AR which alter amino acids at positions 16, 27, and 164 and impart specific biochemical and pharmacologic phenotypes to the receptor. In site-directed mutagenesis/recombinant expression studies we have found that glycine at position 16 (Gly16) imparts an accelerated agonist-promoted downregulation of beta 2AR as compared to arginine at this position (Arg16). We hypothesized that Gly16 might be overrepresented in nocturnal asthmatics and thus determined the beta 2AR genotypes of two well-defined asthmatic cohorts: 23 nocturnal asthmatics with 34 +/- 2% nocturnal depression of peak expiratory flow rates, and 22 nonnocturnal asthmatics with virtually no such depression (2.3 +/- 0.8%). The frequency of the Gly16 allele was 80.4% in the nocturnal group as compared to 52.2% in the nonnocturnal group, while the Arg16 allele was present in 19.6 and 47.8%, respectively. This overrepresentation of the Gly16 allele in nocturnal asthma was significant at P = 0.007 with an odds ratio of having nocturnal asthma and the Gly16 polymorphism being 3.8. Comparisons of the two cohorts as to homozygosity for Gly16, homozygosity for Arg16, or heterozygosity were also consistent with segregation of Gly16 with nocturnal asthma. There was no difference in the frequency of polymorphisms at loci 27 (Gln27 or Glu27) and 164 (Thr164 or Ile164) between the two groups. Thus the Gly16 polymorphism of the beta 2AR, which imparts an enhanced downregulation of receptor number, is overrepresented in nocturnal asthma and appears to be an important genetic factor in the expression of this asthmatic phenotype.


Significance of intracranial pressure waveform analysis after head injury.
The authors have investigated the relationships between the amplitude of the ICP pulse wave, the mean values of ICP and CPP, and the outcome of 56 head injured ventilated patients. The ICP was monitored continuously using a Camino transducer (35 patients) or subdural catheter (21 patients). The mean Glasgow Coma Score was 6 (range 3-13; 5 patients had a GCS > 8 after resuscitation). Patients were grouped according to their Glasgow Outcome Score assessed at 12 months after injury. The amplitude of ICP pulse waveform was assessed using the fundamental harmonic of the pulse waveform (AMP) to avoid distortion caused by different frequency responses of the pressure transducers used in the study. Statistical analysis revealed that in patients with fatal outcome the ICP pulse amplitude increased when the mean ICP increased to 25 mmHg and then began to decrease. The upper breakpoint of the AMP-ICP relationship was not present in patients with good/moderate outcome. The moving correlation coefficient between the fundamental harmonic of ICP pulse wave and the mean ICP (RAP: R-symbol of correlation between A-amplitude and P-pressure) was introduced to describe the time-dependent changes in correlation between amplitude and mean ICP. The RAP was significantly lower in patients who died or remained in the vegetative state. In 7 patients who died from uncontrollable intracranial hypertension RAP was oscillating or decreased to 0 or negative values well before brain-stem herniation. The combination of an ICP above 20 mmHg for a period longer than 6 hours with low correlation between the amplitude and pressure (RAP < 0.5) was described as an predictive index of an unfavourable outcome.


Quality analysis of patient information on surgical treatment of haemorrhoids on the internet.
Haemorrhoids are the most common benign condition seen by colorectal surgeons. At clinic appointments, advice given about lifestyle modification or surgical interventions may not be understood fully by patients. Patients may use the internet for further research into their condition. However, the quality of such information has not been investigated before. This study assessed the quality of patient information on surgical treatment of haemorrhoids on the internet. Four searches were carried out using the search terms 'surgery for haemorrhoids' and 'surgery for piles' on two search engines (Google and Yahoo). The first 50 results for each search were assessed. Sites were evaluated using the DISCERN instrument. In total, 200 websites were assessed, of which 144 fulfilled the inclusion criteria. Of these, 63 (44%) were sponsored by herbal remedies for haemorrhoids. Eighty-nine (62%) mentioned conservative treatment options but eleven (8%) did not include surgery in their treatment options. Only 38 sites (27%) mentioned recurrence of haemorrhoids following surgery and 28 sites (20%) did not list any complications. Overall, 19 websites (14%) were judged as being of high quality, 66 (45%) as moderate quality and 58 (40%) as low quality. The quality of information on the internet is highly variable and a significant proportion of websites assessed are poor. The majority of websites are sponsored by private companies selling alternative treatments for haemorrhoids. Clinicians should be prepared to advise their patients which websites can provide high-quality information on the surgical treatment of haemorrhoids.


Connexin 43 expression is associated with increased malignancy in prostate cancer cell lines and functions to promote migration.
Impaired expression of connexins, the gap junction subunits that facilitate direct cell-cell communication, have been implicated in prostate cancer growth. To elucidate the crucial role of connexins in prostate cancer progression, we performed a systematic quantitative RT-PCR screening of connexin expression in four representative prostate cancer cell lines across the spectrum of malignancy. Transcripts of several connexin subunits were detected in all four cell lines, and connexin 43 (Cx43) showed marked elevation at both RNA and protein levels in cells with increased metastatic potential. Analysis of gap-junction-mediated intercellular communication revealed homocellular coupling in PC-3 cells, which had the highest C x 43 expression, with minimal coupling in LNCaP cells where C x 43 expression was very low. Treatment with the gap junction inhibitor carbenoxolone or connexin mimetic peptide ACT-1 did not impair cell growth, suggesting that growth is independent of functional gap junctions. PC-3 cells with C x 43 expression reduced by shRNA showed decreased migration in monolayer wound healing assay, as well as decreased transwell invasion capacities when compared to control cells expressing non-targeting shRNA. These results, together with the correlation between C x 43 expression levels and the metastatic capacity of the cell lines, suggest a role of C x 43 in prostate cancer invasion and metastasis.


Boron transport in plants: co-ordinated regulation of transporters.
The essentiality of boron (B) for plant growth was established > 85 years ago. In the last decade, it has been revealed that one of the physiological roles of B is cross-linking the pectic polysaccharide rhamnogalacturonan II in primary cell walls. Borate cross-linking of pectic networks serves both for physical strength of cell walls and for cell adhesion. On the other hand, high concentrations of B are toxic to plant growth. To avoid deficiency and toxicity problems, it is important for plants to maintain their tissue B concentrations within an optimum range by regulating transport processes. Boron transport was long believed to be a passive, unregulated process, but the identification of B transporters has suggested that plants sense and respond to the B conditions and regulate transporters to maintain B homeostasis. Transporters responsible for efficient B uptake by roots, xylem loading and B distribution among leaves have been described. These transporters are required under B limitation for efficient acquisition and utilization of B. Transporters important for tolerating high B levels in the environment have also been identified, and these transporters export B from roots back to the soil. Two types of transporters are involved in these processes: NIPs (nodulin-26-like intrinsic proteins), boric acid channels, and BORs, B exporters. It is demonstrated that the expression of genes encoding these transporters is finely regulated in response to B availability in the environment to ensure tissue B homeostasis. Furthermore, plants tolerant to stress produced by low B or high B in the environment can be generated through altered expression of these transporters. The identification of the first B transporter led to the discovery that B transport was a process mediated not only by passive diffusion but also by transporters whose activity was regulated in response to B conditions. Now it is evident that plants sense internal and external B conditions and regulate B transport by modulating the expression and/or accumulation of these transporters. Results obtained in model plants are applicable to other plant species, and such knowledge may be useful in designing plants or crops tolerant to soils containing low or high B.


Supplement 2003-2007 (No. 47) to the White-Kauffmann-Le Minor scheme.
This supplement reports the characterization of 70 new Salmonella serovars recognized between 2003 and 2007 by the WHO Collaborating Center for Reference and Research on Salmonella: 44 were assigned to Salmonella enterica subspecies enterica, 11 to subspecies salamae, 5 to subspecies arizonae, 8 to subspecies diarizonae, one to subspecies houtenae and one to Salmonella bongori. One new serovar, Mygdal, displayed a new H factor, H:z(91).


Synergistic Interaction of Ochratoxin A and Acrylamide Toxins in Human Kidney and Liver Cells.
Ochratoxin A (OTA) is a mycotoxin produced by Aspergillus and Penicillium, and it is found in many foods. Acrylamide (AA) can be produced in foods treated at high temperatures. In this study, we investigated the combined toxicity of OTA and AA against human renal and hepatic cells in vitro. The concentration at which the synergistic effect of OTA and AA occurs was determined using the combination index obtained from the cell viability results for OTA and AA individually or in combination. The synergistic toxicity of both substances was evaluated by cell viability and the production of reactive oxygen species. In addition, apoptosis-related markers were significantly upregulated by OTA and AA individually or in combination. To determine the combined toxic effects of OTA and AA on the cells, the levels of enzymes involved in the phase I reaction and apoptosis-related markers were determined using quantitative (q)PCR and Western blot. The expression levels of CYP enzymes CYP1A1 and CYP1A2 involved in the phase I reaction significantly increased when the cells were treated with OTA and AA in combination. The expression of apoptosis-related markers, Bcl2-associated X protein (Bax) and caspase 3, also increased when the cells were treated with OTA and AA in combination. Therefore, the synergistic toxicity of OTA and AA suggests that such effects may contribute to nephrotoxicity and hepatotoxicity.


Shuttle vectors containing a multiple cloning site and a lacZ alpha gene for conjugal transfer of DNA from Escherichia coli to gram-positive bacteria.
The mobilizable shuttle cloning vectors, pAT18 and pAT19, are composed of: (i) the replication origins of pUC and of the broad-host-range enterococcal plasmid pAM beta 1; (ii) an erythromycin-resistance-encoding gene expressed in Gram- and Gram+ bacteria; (iii) the transfer origin of the IncP plasmid RK2; and (iv) the multiple cloning site and the lacZ alpha reporter gene of pUC18 (pAT18) and pUC19 (pAT19). These 6.6-kb plasmids contain ten unique cloning sites that allow screening of derivatives containing DNA inserts by alpha-complementation in Escherichia coli carrying the lacZ delta M15 deletion, and can be efficiently mobilized by self-transferable IncP plasmids co-resident in the E. coli donors. Plasmids pAT18, pAT19 and recombinant derivatives have been successfully transferred by conjugation from E. coli to Bacillus subtilis, Bacillus thuringiensis, Listeria monocytogenes, Enterococcus faecalis, Lactococcus lactis, and Staphylococcus aureus at frequencies ranging from 10(-6) to 10(-9). The presence of a restriction system in the recipient dramatically affects (by three orders of magnitude) the efficiency of conjugal transfer of these vectors from E. coli to Gram+ bacteria.


All-optical switch and transistor gated by one stored photon.
The realization of an all-optical transistor, in which one "gate" photon controls a "source" light beam, is a long-standing goal in optics. By stopping a light pulse in an atomic ensemble contained inside an optical resonator, we realized a device in which one stored gate photon controls the resonator transmission of subsequently applied source photons. A weak gate pulse induces bimodal transmission distribution, corresponding to zero and one gate photons. One stored gate photon produces fivefold source attenuation and can be retrieved from the atomic ensemble after switching more than one source photon. Without retrieval, one stored gate photon can switch several hundred source photons. With improved storage and retrieval efficiency, our work may enable various new applications, including photonic quantum gates and deterministic multiphoton entanglement.


Pregnancy outcome in women with prosthetic heart valves.
The pregnancy outcome of 59 pregnancies in 38 women with prosthetic heart valves, managed at a tertiary referral centre from 1989-98 were reviewed. Ten women underwent valve replacement during pregnancy. The main outcome measures were major maternal complications and perinatal outcome. The maternal mortality rate for pregnancies following valve replacement surgery was 6.1%, with a 21% pregnancy loss before viability and a perinatal loss of 8%. Major morbidity in this group was as follows: haemorrhage 29.8%, cardiac failure 12.8%, thromboembolism 8.5%, infective endocarditis 6.4% and valve thrombosis 4.3%. No maternal mortality occurred among those who underwent valve replacement during pregnancy but their perinatal loss was 25%. We conclude that although maternal mortality and morbidity rates in women with prosthetic heart valves who became pregnant were high, the perinatal outcome was good except for women who underwent valve replacement during pregnancy who experienced a high perinatal loss rate.


Divergent roles for thyroid hormone receptor beta isoforms in the endocrine axis and auditory system.
Thyroid hormone receptors (TRs) modulate various physiological functions in many organ systems. The TR alpha and TR beta isoforms are products of 2 distinct genes, and the beta 1 and beta 2 isoforms are splice variants of the same gene. Whereas TR alpha 1 and TR beta 1 are widely expressed, expression of the TR beta 2 isoform is mainly limited to the pituitary, triiodothyronine-responsive TRH neurons, the developing inner ear, and the retina. Mice with targeted disruption of the entire TR beta locus (TR beta-null) exhibit elevated thyroid hormone levels as a result of abnormal central regulation of thyrotropin, and also develop profound hearing loss. To clarify the contribution of the TR beta 2 isoform to the function of the endocrine and auditory systems in vivo, we have generated mice with targeted disruption of the TR beta 2 isoform. TR beta 2-null mice have preserved expression of the TR alpha and TR beta 1 isoforms. They develop a similar degree of central resistance to thyroid hormone as TR beta-null mice, indicating the important role of TR beta 2 in the regulation of the hypothalamic-pituitary-thyroid axis. Growth hormone gene expression is marginally reduced. In contrast, TR beta 2-null mice exhibit no evidence of hearing impairment, indicating that TR beta 1 and TR beta 2 subserve divergent roles in the regulation of auditory function.


Leveraging public health nurses for disaster risk communication in Fukushima City: a qualitative analysis of nurses' written records of parenting counseling and peer discussions.
Local public health nurses (PHNs) have been recognized as the main health service providers in communities in Japan. The Fukushima nuclear disaster in 2011 has, however, created a major challenge for them in responding to mothers' concerns. This was in part due to difficulties in assessing, understanding and communicating health risks on low-dose radiation exposure. In order to guide the development of risk communication plans, this study sought to investigate mothers' primary concerns and possible solutions perceived by a core healthcare profession like the PHNs. A total of 150 records from parenting counseling sessions conducted between PHNs and mothers who have attended mandatory 18-month health checkups for their children at the Fukushima City Health and Welfare Center in 2010, 2011 (year of disaster) and 2012 were examined. Discussion notes of three peer discussions among PHNs organized in response to the nuclear disaster in 2012 and 2013 were also analyzed. All transcribed data were first subjected to text mining to list the words according to their frequencies and inter-relationships. The Steps Coding and Theorization method was then undertaken as a framework for qualitative analysis. PHNs noted mothers to have considerable needs for information on radiation risks as they impact on decisions related to relocations, concerns for child safety, and experiences with interpersonal conflicts within the family owing to differing risk perceptions. PHNs identified themselves as the information channels in the community, recommended the building of their risk communication capacities to support residents in making well-informed decisions, and advocated for self-measurement of radiation levels to increase residents' sense of control. PHNs also suggested a more standardized form of information dissemination and an expansion of community-based counseling services. Inadequate risk communication on radiation in the Fukushima nuclear incident has resulted in multiple repercussions for mothers in the community. Empowerment of local residents to assume more active roles in the understanding of their environment, increasing PHNs' capacity in communication, and an expansion of health services such as counseling will together better address risk communication challenges in post-disaster recovery efforts.


Towards coherent data policy for biomedical research with ELSI 2.0: orchestrating ethical, legal and social strategies.
As the recent inaugural Ethical, Legal, and Social Issues (ELSI) 2.0 conference made clear, the effects of information communication technology (ICT) are pervasive in biomedical research. Data initiatives are arising in all corners of biomedicine. Data sharing efforts already promised to surpass even the ambitious goals of the National Human Genome Research Institute, only 5 years after publication of its 10-year vision. ELSI research was established, in part, to address challenges of open data access and data sharing. However, by and large, ELSI research projects address particular concerns of a given population, jurisdiction, type of research practice or type of data. This does not necessarily facilitate coherent data policy for sustainable data stewardship. Forward-looking, data friendly strategies need to be considered. Orchestration strategies are needed which overcome barriers to collective action. Here we present challenges policymakers face, and suggest three basics steps towards meeting them. First, policymakers must recognise the systematic change that occurs when ICT enables dataflow itself to become an organising principle of biomedical research. Second, methods for identifying and gathering types of metadata suitable for ELSI research ought to be developed and regulated. Third, policymakers need to organise in ways that mirror the new vision for data-enabled research that data technologies are making possible, as ELSI 2.0 encourages researchers to do. Taking these steps will help ensure research evolves in ways that warrants trust of the public while still supporting widespread ethical access to necessary data, research subjects, samples and findings.


Cardiac resynchronization therapy improves functional status and cognition.
Many trials demonstrated the beneficial effects on hospitalizations and mortality of cardiac resynchronization therapy (CRT). The purpose of this study was to evaluate CRT effects on functional performance and cognition, two determinants of disability, frailty development and survival. All consecutive patients receiving a CRT device were evaluated at baseline and at the 6-month follow-up. Functional profile was assessed with the Short Physical Performance Battery (SPPB), a measure exploring balance, gait, strength and endurance, highly predictive of incident disability and mortality. The Mini-Mental State Examination (MMSE) was used to study the cognitive profile. We enrolled 54 patients; two of them died during the follow-up, two refused to continue the study. Age was 67±10years (men: 80%, LVEF: 28±5%); medical therapy was optimized (ACE-I/ARB: 84%, beta-blockers: 80%). After 6months, CRT was associated with the improvement of LVEF (35±8 vs. 28±5%, p<0.001) and NYHA Class (1.8±0.6 vs. 2.6±0.5, p<0.001), and with the reduction of left ventricular end-systolic diameter (50±9 vs. 57±9mm, p<0.001). SPPB improved in its total score (10.3±2.0 vs. 9.1±2.7, p<0.001) and in the scores exploring gait speed and strength and endurance. These changes were associated with a better cognitive profile (MMSE score: 27.0±3.5 vs. 25.9±4.8, p=0.009). Advanced age was an independent predictor of improved functional performance and cognition. CRT is associated with higher functional and cognitive profile after only 6months of therapy. These findings let us hypothesize a powerful effect of treatment to slow disability and frailty development in heart failure.


Endovascular infections caused by methicillin-resistant Staphylococcus aureus are linked to clonal complex-specific alterations in binding and invasion domains of fibronectin-binding protein A as well as the occurrence of fnbB.
Endovascular infections caused by Staphylococcus aureus involve interactions with fibronectin present as extracellular matrix or surface ligand on host cells. We examined the expression, structure, and binding activity of the two major S. aureus fibronectin-binding proteins (FnBPA, FnBPB) in 10 distinct, methicillin-resistant clinical isolates from patients with either persistent or resolving bacteremia. The persistent bacteremia isolates (n = 5) formed significantly stronger bonds with immobilized fibronectin as determined by dynamic binding measurements performed with atomic force microscopy. Several notable differences were also observed when the results were grouped by clonal complex 5 (CC5) strains (n = 5) versus CC45 strains (n = 5). Fibronectin-binding receptors on CC5 formed stronger bonds with immobilized fibronectin (P < 0.001). The fnbA gene was expressed at higher levels in CC45, whereas fnbB was found in only CC5 isolates. The fnbB gene was not sequenced because all CC45 isolates lacked this gene. Instead, comparisons were made for fnbA, which was present in all 10 isolates. Sequencing of fnbA revealed discrete differences within high-affinity, fibronectin-binding repeats (FnBRs) of FnBPA that included (i) 5-amino-acid polymorphisms in FnBR-9, FnBR-10, and FnBR-11 involving charged or polar side chains, (ii) an extra, 38-amino-acid repeat inserted between FnBR-9 and FnBR-10 exclusively seen in CC45 isolates, and (iii) CC5 isolates had the SVDFEED epitope in FnBR-11 (a sequence shown to be essential for fibronectin binding), while this sequence was replaced in all CC45 isolates with GIDFVED (a motif known to favor host cell invasion at the cost of reduced fibronectin binding). These complementary sequence and binding data suggest that differences in fnbA and fnbB, particularly polymorphisms and duplications in FnBPA, give S. aureus two distinct advantages in human endovascular infections: (i) FnBPs similar to that of CC5 enhance ligand binding and foster initiation of disease, and (ii) CC45-like FnBPs promote cell invasion, a key attribute in persistent endovascular infections.


Cell shape and division in Escherichia coli: experiments with shape and division mutants.
Double mutants which carry mutations in genes (rodA, pbpA) required for cell elongation (i.e., maintenance of rod shape) in combination with mutations in genes (ftsA, ftsI, ftsQ, or ftsZ) required for septation were constructed. Such mutants were able to grow for about two mass doublings at a normal rate at the restrictive temperature (42 degrees C). The morphology of the cells formed under these conditions was interpreted by assuming the existence of a generalized system for peptidoglycan growth together with two additional systems which modify the shape of the growing peptidoglycan layer. The results also showed that different fts genes probably control different stages in septation. ftsZ (sulB or sfiB) appears to be required for the earliest step in septation, ftsQ and ftsI (pbpB or sep) are required for a later step or steps, and ftsA is required only for the latest stages in septation.


Methylphenidate effect in children with ADHD can be measured by an ecologically valid continuous performance test embedded in virtual reality.
Continuous performance tasks (CPTs) embedded in a virtual reality (VR) classroom environment have been shown to be a sensitive and user-friendly assessment tool to detect cognitive deficits related to attention-deficit/hyperactivity disorder (ADHD). The aim of the current study was to compare the performance of children with ADHD on a VR-CPT while on and off treatment with methylphenidate (MPH) and to compare the VR-CPT to a currently used CPT, Test of Variables of Attention (TOVA). Twenty-seven children with ADHD underwent the VR-CPT, the same CPT without VR (no VR-CPT), and the TOVA, 1 hour after the ingestion of either placebo or 0.3 mg/kg MPH, in a double-blind, placebo-controlled, crossover design. Immediately following CPT, subjects described their subjective experiences on the Short Feedback Questionnaire. MPH reduced omission errors to a greater extent on the VR-CPT compared to the no VR-CPT and the TOVA, and decreased other CPT measures on all types of CPT to a similar degree. Children rated the VR-CPT as more enjoyable compared to the other types of CPT. It is concluded that the VR-CPT is a sensitive and user-friendly assessment tool in measuring the response to MPH in children with ADHD.


Chest radiography and high resolution computed tomography in the evaluation of workers exposed to silica dust: relation with functional findings.
To compare the usefulness of high resolution computed tomography (HRCT) with chest radiography (CR) in the diagnosis and assessment of severity of silicosis. 27 workers exposed to silica underwent CR, HRCT, and pulmonary function tests. Two experienced readers independently evaluated CR by International Labour Office classification, and grouped the results into four categories. HRCT categories of nodule profusion and the extent of emphysema were graded on a four point scale; in 20 subjects the percentage distribution of lung densities were measured by HRCT. Concordance between readers was higher for HRCT than for CR (K statistic = 0.49 and 0.29 respectively). There was poor concordance between CR and HRCT in the early stage of silicosis. No significant difference in pulmonary function tests was found among different CR categories, but forced expiratory volume in one second (FEV1), maximal expiratory flow at 50% and 75% of FVC (MEF50, MEF75), and diffusion capacity significantly decreased with increasing HRCT categories. Subjects with simple silicosis detected by HRCT had a lower FEV1 than subjects without silicosis, whereas subjects with conglomerated silicosis showed higher residual volume and functional residual capacity than subjects with simple silicosis. These relations were not affected by smoking or symptoms of chronic bronchitis. Different grades of emphysema detected by HRCT were significantly different in diffusion capacity. Only the HRCTs of the lowest and the highest categories of profusion of parenchymal opacities were significantly different in their distribution of density classes. HRCT is more reproducible and accurate than CR, as suggested by the higher agreement between readers and the better correlation with pulmonary function tests, irrespective of smoking and chronic bronchitis; however, these data do not support the hypothesis that HRCT is more sensitive than CR in the early detection of silicosis.


The perspective of children on factors influencing their participation in perioperative care.
To describe the experiences of participation in perioperative care of 8- to 11-year-old children. All children have the right to participate in decisions that affect them and have the right to express their views in all matters that concern them. Allowing children to be involved in their perioperative care can make a major difference in terms of their well-being by decreasing fear and anxiety and having more positive experiences. Taking the views of children into account and facilitating their participation could thus increase the quality of care. Descriptive qualitative design. The study was conducted in 2013 and data were collected by narrative interviews with 10 children with experience from perioperative care in Sweden. Qualitative content analysis was chosen to describe the variations, differences and similarities in children's experiences of participation in perioperative care. The result showed that receiving preparatory information, lack of information regarding postoperative care and wanting to have detailed information are important factors for influencing children's participation. Interaction with healthcare professionals, in terms of being listened to, being a part of the decision-making and feeling trust, is important for children's participation in the decision-making process. Poor adaptation of the care environment to the children's needs, feeling uncomfortable while waiting and needs for distraction are examples of how the environment and the care in the operating theatre influence the children's experiences of participation. Efforts should be made to improve children's opportunities for participation in the context of perioperative care and further research is needed to establish international standards for information strategies and care environment that promotes children's participation in perioperative care. Nurse anaesthetists need to acquire knowledge and develop strategies for providing preparatory visits and information to children prior to surgery as well as reducing waiting times and creating environments with meaningful and tailored opportunities for distraction in perioperative care.


Oligodendroglioma and juvenile pilocytic astrocytoma presenting as synchronous primary brain tumors. Case report with histological and molecular differentiation of the tumors and review of the literature.
Multiple metastatic brain tumors and multifocal primary brain tumors of a single histological type are well described in the literature. The concurrent presence of multiple primary brain tumors with different histological characteristics, however, is very rare. The authors describe the first known case in which an oligodendroglioma and a juvenile pilocytic astrocytoma (JPA) presented as synchronous primary brain tumors in the same patient. This 43-year-old man presented with a 2-month history of progressive headaches, nausea, and vomiting. Magnetic resonance imaging demonstrated an enhancing heterogeneous right medial cerebellar lesion and a larger calcified, nonenhancing, heterogeneous right frontal lesion with surrounding edema and a mass effect. The results of a metastatic workup were unremarkable. The patient underwent an initial right frontotemporal craniotomy and a subsequent suboccipital craniectomy 2 years later for resection of the posterior fossa lesion. Histological examination revealed the frontal and cerebellar lesions to be an oligodendroglioma and JPA, respectively. A molecular analysis detected a deletion of chromosome 1p36 in the oligodendroglioma, but not in the JPA. After the initial operation, the patient received follow-up care for his oligodendroglioma, but eventually required temozolomide for tumor progression. His condition remains stable both neurologically and according to imaging studies. The authors describe the first known case in which a low-grade oligodendroglioma and a JPA presented as synchronous primary brain tumors. They review the literature on multiple primary brain tumors with different histological characteristics and discuss potential mechanisms for the development of these lesions.


The implications of force feedback for the lambda model.
It is argued here that length and force feedback play important but distinct roles in motor coordination. Length feedback compensates for several nonlinear properties of muscle and therefore simplifies its behavior, but in addition promotes the nonlinear relationship between force and stiffness that is essential to the mechanism for modulating joint stiffness. Excitatory force feedback is also primarily autogenic. Under conditions of level treadmill stepping in cat walking, positive force feedback is restricted in the distal hindlimb to a few and perhaps only one ankle extensor, the gastrocnemius muscle group. Based on the anatomy of this group, positive force feedback provides a stiff linkage that reinforces proportional coordination between ankle and knee joints. In terms of the lambda model, excitatory force feedback can reinforce muscular force generation and stiffness, but should have no significant effect on activation threshold. Inhibitory force feedback projects mainly to muscles that span different joints and axes of rotation than the parent muscle. This heterogenic force feedback is thought to promote interjoint coordination and thought to influence stiffness of the joints and limbs. During locomotion, the inhibitory influences appear to be focused on the distal musculature. Since the inhibitory force feedback is heterogenic, it also influences the threshold for activation of relevant musculature. Threshold is therefore not entirely a control variable and independent of feedback. It is proposed that the actuators for movement consist of systems of muscles or motor units that are linked by feedback and that receive control signals from elsewhere in the nervous system.


Ecology and management of the invasive lionfish Pterois volitans/miles complex (Perciformes: Scorpaenidae) in Southern Costa Rica.
Invasive species alter ecosystem integrity and functioning and are considered one of the major threats to biodiversity on a global scale. The indopacific lionfish (Plerois volitans [Linnaeus, 1758] / miles [Bennet, 1882] complex) is the first non-native marine fish that has established itself in the Western Atlantic. It was first reported in Florida in the 1980s and then spread across the entire Caribbean in subsequent years. In Costa Rica, lionfish were first sighted by the end of 2008 and are now present in all South Caribbean reefs. Lionfish are a major problem for local fisherman by displacing native fish species. The aim of this study was to determine population density, size and diet of lionfish populations at four study sites along the Southern Caribbean coast of Costa Rica. Two of the sites were located inside the National Park Cahuita where regular lionfish removal occurs, whereas the other two study sides do not experiment this kind of management. Total length and wet weight of >450 lionfish individuals were determined between March and June 2011. Three relative metrics of prey quantity (percent number, percent frequency, and percent weight) were compared from approximately 300 lionfish caught with the polespear in shallow waters (<7 m depth). Population density was assessed weekly through visual transect surveys. Our results showed that lionfish preyed mostly upon teleosts and crustaceans. Teleosts dominated lionfish diet in percent frequency (71%) and percent weight (85%), whereas crustaceans had the highest percent number (58%). The top five teleost families of dietary importance were Pomacentridae, Acanthuridae, Blennidae, Labridae and Serranidae. The average total length (+/- SD) of lionfish was 18.7 (+/- 5.7)cm and varied significantly between sites (p<0.001). Mean density of lionfish was 92fish/ha with no significant differences between sites. Smallest fish and lowest densities were found at the two sites inside the National Park Cahuita. Despite management efforts on a regional scale, nationwide efforts are ineffective and lionfish control activities are poorly implemented. We conclude that there is an urgent need to develop an improved institutional framework for local lionfish control that promotes effective coordination among the relevant stakeholders in order to deal with invasive lionfish in Costa Rica.


Evidence that androstadienone, a putative human chemosignal, modulates women's attributions of men's attractiveness.
Considerable research effort has focused on whether specific compounds found within human body odor influence the behavior or physiology of other individuals. The most intensively studied is 4,16-androstadien-3-one, a chemical which is known to modulate mood and have activational effects in the sympathetic nervous system in a context-dependent manner, but whose action in mate-choice contexts remains largely untested. Here we present evidence that this androgen steroid may modulate women's judgments of men's attractiveness in an ecologically valid context. We tested the effects of androstadienone at a speed-dating event in which men and women interacted in a series of brief dyadic encounters. Men were rated more attractive when assessed by women who had been exposed to androstadienone, an effect that was seen in two out of three studies. The results suggest that androstadienone can influence women's attraction to men, and also that research into the modulatory effects of androstadienone should be made within ecologically valid contexts.


High-Q microwave photonic filter with a tuned modulator.
We propose the use of tuned electro-optic or electroabsorption external modulators to implement high-quality (high-Q) factor, single-bandpass photonic filters for microwave signals. Using this approach, we experimentally demonstrate a transversal finite impulse response with a Q factor of 237. This is to our knowledge the highest value ever reported for a passive finite impulse-response microwave photonic filter.


CD45 monoclonal antibody-mediated cytolysis of human NK and T lymphoma cells.
The CD45 rat monoclonal IgG2b antibodies YTH24.5 and YTH54.12 act synergistically to produce cytolysis of normal lymphocytes and have been safely given to patients in conditioning regimens for allogeneic stem cell transplantation. The antibodies are not lytic for hematopoietic stem cells, but the depletion of the lymphoid lineage cells is profound and sustained. We evaluated the YTH24.5 and YTH54.12 pair for complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC), and apoptotic and antiproliferative effects against a panel of non-Hodgkin's lymphoma (NHL) cell lines and against primary specimens. Significant CDC activity was observed against two of two NK and one of four T lymphoma cell lines; moderate activity was seen against two of four T, and four of eight B lymphoma cell lines. In the responding cell lines, the lytic activity of YTH24.5 and YTH54.12 was as least as strong as that of alemtuzumab or antithymocyte globulin. The combination of YTH24.5 and YTH54.12 also induced ADCC in one of two NK and two of four T lymphoma cell lines, as well as three primary specimens, but was ineffective in B-NHL. The antibodies decreased viability in two of two NK and one lymphoma cell line, measurable as apoptosis or direct cell death in the cell lines NK92 and CEM, respectively. In a tumor model of Jurkat lymphoma in SCID mice, administration of YTH24.5 and YTH54.12 impaired local tumor growth and delayed systemic disease progression. CD45 antibodies YTH24.5 and YTH54.12 have lytic activity against NK and T lymphoma cells via CDC and ADCC, are effective in a preclinical tumor model, and may be candidates for immunotherapeutic approaches to the treatment of human NK and T cell lymphoma.


FRET measurements on fuzzy fluorescent nanostructures.
In the last decade, fluorescence resonance energy transfer (FRET) has become a useful technique for studying intermolecular interactions applied to the analysis of biological systems. Although FRET measurements may be very helpful in the comprehension of different cellular processes, it can be difficult to obtain quantitative results, hence the necessity of studying FRET on controllable systems. Here, a fuzzy nanostructured system called a nanocapsule is presented as a nanometric-device allowing distance modulation, thus preserving photophysical properties of fluorescent dyes and exhibiting good potential features for improving quantitative FRET analysis. We evaluated the behavior of such a sample using four FRET methods (three of them based on steady-state fluorescence and one using lifetime measurements). Within some limitations that can be overcome, these nanodevices have the potential to serve as a benchmark system for characterizing new FRET couples and to develop quantitative approaches for FRET analysis.


The selfish Segregation Distorter gene complex of Drosophila melanogaster.
Segregation Distorter (SD) is an autosomal meiotic drive gene complex found worldwide in natural populations of Drosophila melanogaster. During spermatogenesis, SD induces dysfunction of SD(+) spermatids so that SD/SD(+) males sire almost exclusively SD-bearing progeny rather than the expected 1:1 Mendelian ratio. SD is thus evolutionarily "selfish," enhancing its own transmission at the expense of its bearers. Here we review the molecular and evolutionary genetics of SD. Genetic analyses show that the SD is a multilocus gene complex involving two key loci--the driver, Segregation distorter (Sd), and the target of drive, Responder (Rsp)--and at least three upward modifiers of distortion. Molecular analyses show that Sd encodes a truncated duplication of the gene RanGAP, whereas Rsp is a large pericentromeric block of satellite DNA. The Sd-RanGAP protein is enzymatically wild type but mislocalized within cells and, for reasons that remain unclear, appears to disrupt the histone-to-protamine transition in drive-sensitive spermatids bearing many Rsp satellite repeats but not drive-insensitive spermatids bearing few or no Rsp satellite repeats. Evolutionary analyses show that the Sd-RanGAP duplication arose recently within the D. melanogaster lineage, exploiting the preexisting and considerably older Rsp satellite locus. Once established, the SD haplotype collected enhancers of distortion and suppressors of recombination. Further dissection of the molecular genetic and cellular basis of SD-mediated distortion seems likely to provide insights into several important areas currently understudied, including the genetic control of spermatogenesis, the maintenance and evolution of satellite DNAs, the possible roles of small interfering RNAs in the germline, and the molecular population genetics of the interaction of genetic linkage and natural selection.


Deep vein thrombosis in Behçet's disease.
We aimed to describe the epidemiological and clinical aspects of deep vein thrombosis (DVT) in Behçet's disease (BD) and to determine the patients at high risk for this complication. Among 113 patients with BD according to the international criteria for classification of BD, those with DVT were retrospectively studied. The diagnosis of DVT was made in all cases using conventional venous angiography, venous ultrasonography and/or thoracic or abdominal computed tomography. Patients were divided in two subgroups according to the occurrence of DVT other than cerebral thromboses. The medical records of these patients were reviewed in order to investigate their past medical history and evaluate their response to the treatment prescribed. Clinical and genetic factors (HLA B51 and MICA 6) that might contribute to DVT were analysed by comparing patients with and without DVT. Results of our series were compared to those of other series in the literature. Statistical analysis was by Chi square with necessary correction and Fischer tests. Forty-four patients (38.9%) had deep vein thrombosis of various systems with 81 localisations. There were 40 men and four women (mean age 28.1 years; range 17-60). DVT appeared after the onset of disease with a mean delay of 3.8 years. In 6 cases, DVT revealed BD. When we evaluated the risk of DVT coexistence with other clinical findings and genetic factors (HLA B51 and MICA 6), we found a significant positive correlation with sex, and positive pathergy test. In our series, occurrence of DVT was significantly associated with male gender and positive pathergy test.


Dysfunctional high-density lipoprotein in patients on chronic hemodialysis.
This study examined the functionality of high-density lipoprotein (HDL) in individuals with end-stage renal disease on dialysis (ESRD-HD). The high rate of cardiovascular disease (CVD) in chronic kidney disease is not explained by standard risk factors, especially in patients with ESRD-HD who appear resistant to benefits of statin therapy. HDL is antiatherogenic because it extracts tissue cholesterol and reduces inflammation. Cellular cholesterol efflux and inflammatory response were assessed in macrophages exposed to HDL of patients with ESRD-HD or controls. HDL from patients with ESRD-HD was dramatically less effective than normal HDL in accepting cholesterol from macrophages (median 6.9%; interquartile range [IQR]: 1.4% to 10.2%) versus control (median 14.9%; IQR: 9.8% to 17.8%; p < 0.001). The profound efflux impairment was also seen in patients with ESRD-HD and diabetes compared with patients with diabetes without renal disease (median 8.1%; IQR: 3.3% to 12.9%) versus control (median 13.6%; IQR: 11.0% to 15.9%; p = 0.009). In vitro activation of cellular cholesterol transporters increased cholesterol efflux to both normal and uremic HDL. HDL of patients with ESRD-HD had reduced antichemotactic ability and increased macrophage cytokine response (tumor necrosis factor-alpha, interleukin-6, and interleukin-1-beta). HDL of patients with ESRD-HD on statin therapy had reduced inflammatory response while maintaining impaired cholesterol acceptor function. Interestingly, impaired HDL-mediated efflux did not correlate with circulating C-reactive protein levels or cellular inflammatory response. These findings suggest that abnormal HDL capacity to mediate cholesterol efflux is a key driver of excess CVD in patients on chronic hemodialysis and may explain why statins have limited effect to decrease CV events. The findings also suggest cellular cholesterol transporters as potential therapeutic targets to decrease CV risk in this population.


Self-assembly of spherical and rod-shaped nanoparticles with full positional control.
The controlled positioning of spherical gold nanoparticles and gold nanorods upon self-assembly on a substrate is of great interest for the fabrication of tailored plasmonic devices. Here, an electrostatic approach with a sequential two-step assembly protocol is presented as a cost-effective and high-yield alternative to previously presented, more complex proof of concepts. Three different geometries can be separately produced in large quantities relying on electrostatic attraction and repulsion of the charge-carrying building blocks: a single gold nanoparticle at the tip, the side or on top of a gold nanorod. DLVO theory is used to explain the electrostatic assembly strategy. The process is highly efficient and assembly yields between 79% (at the tip) and 94% (for the nanoparticle at the long side of the nanorod) are achieved.


[Evolution of clinical teaching at the medical college of Lisboa (I)].
Clinical teaching at Lisbon's Faculty of Medicine is analyzed in its two phases: 1. A period of stability and continuity of the institution (from 1911 to 1947) characterized by good rules in the selection of teachers: an impressive group of personalities (F. Gentil, Pulido Valente, Reynaldo dos Santos, Egas Moniz, A. Flores, Sobral Cid, Lopo de Carvalho, Gama Pinto, etc). At the some period a true University Hospital (of Santa Marta) provided clinical investigation (cerebral angiography and leucotomy, aortography and arteriography of the limbs, angiopneumography, endarterectomy) and the creation of new specialties (neurosurgery, vascular surgery, pneumology). 2. A period of instability due to a deleterious political intervention (from 1947 to the present day) responsible for the destruction of the structure and concept of a new teaching hospital (Hospital de Santa Maria). As a result of the socio-political situation conflicting law and vicious rules lead to an excess of non-selected teachers and an alarming increase of students, patients and medical doctors. A change from the present situation and a new concept of clinical teaching must be imagined.


Silicon Microcantilever Sensors to Detect the Reversible Conformational Change of a Molecular Switch, Spiropyan.
The high sensitivity of silicon microcantilever sensors has expanded their use in areas ranging from gas sensing to bio-medical applications. Photochromic molecules also represent promising candidates for a large variety of sensing applications. In this work, the operating principles of these two sensing methods are combined in order to detect the reversible conformational change of a molecular switch, spiropyran. Thus, arrays of silicon microcantilever sensors were functionalized with spiropyran on the gold covered side and used as test microcantilevers. The microcantilever deflection response was observed, in five sequential cycles, as the transition from the spiropyran (SP) (CLOSED) to the merocyanine (MC) (OPEN) state and vice-versa when induced by UV and white light LED sources, respectively, proving the reversibility capabilities of this type of sensor. The microcantilever deflection direction was observed to be in one direction when changing to the MC state and in the opposite direction when changing back to the SP state. A tensile stress was induced in the microcantilever when the SP to MC transition took place, while a compressive stress was observed for the reverse transition. These different type of stresses are believed to be related to the spatial conformational changes induced in the photochromic molecule upon photo-isomerisation.


Trends of Transmitted and Acquired Drug Resistance in Europe From 1981 to 2019: A Comparison Between the Populations of Late Presenters and Non-late Presenters.
The increased use of antiretroviral therapy (ART) has decreased mortality and morbidity of HIV-1 infected people but increasing levels of HIV drug resistance threatens the success of ART regimens. Conversely, late presentation can impact treatment outcomes, health costs, and potential transmission of HIV. To describe the patterns of transmitted drug resistance (TDR) and acquired drug resistance (ADR) in HIV-1 infected patients followed in Europe, to compare its patterns in late presenters (LP) vs non-late presenters (NLP), and to analyze the most prevalent drug resistance mutations among HIV-1 subtypes. Our study included clinical, socio-demographic, and genotypic information from 26,973 HIV-1 infected patients from the EuResist Integrated Database (EIDB) between 1981 and 2019. Among the 26,973 HIV-1 infected patients in the analysis, 11,581 (42.9%) were ART-naïve patients and 15,392 (57.1%) were ART-experienced. The median age was 37 (IQR: 27.0-45.0) years old and 72.6% were males. The main transmission route was through heterosexual contact (34.9%) and 81.7% of patients originated from Western Europe. 71.9% of patients were infected by subtype B and 54.8% of patients were classified as LP. The overall prevalence of TDR was 12.8% and presented an overall decreasing trend (p for trend < 0.001), the ADR prevalence was 68.5% also with a decreasing trend (p for trend < 0.001). For LP and NLP, the TDR prevalence was 12.3 and 12.6%, respectively, while for ADR, 69.9 and 68.2%, respectively. The most prevalent TDR drug resistance mutations, in both LP and NLP, were K103N/S, T215rev, T215FY, M184I/V, M41I/L, M46I/L, and L90M. Our study showed that the overall TDR (12.8%) and ADR (68.5%) presented decreasing trends during the study time period. For LP, the overall TDR was slightly lower than for NLP (12.3 vs 12.6%, respectively); while this pattern was opposite for ADR (LP slightly higher than NLP). We suggest that these differences, in the case of TDR, can be related to the dynamics of fixation of drug resistance mutations; and in the case of ADR with the more frequent therapeutic failure in LPs.


Pathogenesis of persistent lymphatic vessel hyperplasia in chronic airway inflammation.
Edema occurs in asthma and other inflammatory diseases when the rate of plasma leakage from blood vessels exceeds the drainage through lymphatic vessels and other routes. It is unclear to what extent lymphatic vessels grow to compensate for increased leakage during inflammation and what drives the lymphangiogenesis that does occur. We addressed these issues in mouse models of (a) chronic respiratory tract infection with Mycoplasma pulmonis and (b) adenoviral transduction of airway epithelium with VEGF family growth factors. Blood vessel remodeling and lymphangiogenesis were both robust in infected airways. Inhibition of VEGFR-3 signaling completely prevented the growth of lymphatic vessels but not blood vessels. Lack of lymphatic growth exaggerated mucosal edema and reduced the hypertrophy of draining lymph nodes. Airway dendritic cells, macrophages, neutrophils, and epithelial cells expressed the VEGFR-3 ligands VEGF-C or VEGF-D. Adenoviral delivery of either VEGF-C or VEGF-D evoked lymphangiogenesis without angiogenesis, whereas adenoviral VEGF had the opposite effect. After antibiotic treatment of the infection, inflammation and remodeling of blood vessels quickly subsided, but lymphatic vessels persisted. Together, these findings suggest that when lymphangiogenesis is impaired, airway inflammation may lead to bronchial lymphedema and exaggerated airflow obstruction. Correction of defective lymphangiogenesis may benefit the treatment of asthma and other inflammatory airway diseases.


Developing an effective intervention for IDU women: a harm reduction approach to collaboration.
Harm reduction is fundamentally a movement intended to empower the patient and consumer of health services. This project applied harm reduction theory as a strategy to empower collaborating community partners and researchers to overcome their preconceptions about each other in order to create a successful HIV prevention intervention and evaluation study for injection drug using women. The Women's Options for Risk Reduction through Knowledge of Self (WORKS) intervention program offered a series of four HIV prevention workshops, in conjunction with sexually transmitted infection (STI) and HIV counseling and testing to female injection drug users (IDUs) or the partners of IDUs. This community collaboration was to integrate the strengths of researchers and service providers in a comprehensive approach to prevention evaluation. In this collaborative research context, capacity building meant developing the long-term goal, explicit commitment to and integration of evaluation into the overall operation of a HIV prevention service delivery organization. The WORKS Intervention collaboration's aim was to improve the capacity of community-based organizations (CBOs) to use research-based data on HIV risk taking behavior and prevention strategies to provide effective interventions and services and effectively evaluate their efforts. Barriers to successful planning, implementation, and evaluation are presented with the strategies used to overcome them. Intervention effectiveness results from the process evaluation are presented in the context of prevention and research capacity development in CBOs.


Materials-by-Design: Computation, Synthesis, and Characterization from Atoms to Structures.
In the 50 years that succeeded Richard Feynman's exposition of the idea that there is "plenty of room at the bottom" for manipulating individual atoms for the synthesis and manufacturing processing of materials, the materials-by-design paradigm is being developed gradually through synergistic integration of experimental material synthesis and characterization with predictive computational modeling and optimization. This paper reviews how this paradigm creates the possibility to develop materials according to specific, rational designs from the molecular to the macroscopic scale. We discuss promising techniques in experimental small-scale material synthesis and large-scale fabrication methods to manipulate atomistic or macroscale structures, which can be designed by computational modeling. These include recombinant protein technology to produce peptides and proteins with tailored sequences encoded by recombinant DNA, self-assembly processes induced by conformational transition of proteins, additive manufacturing for designing complex structures, and qualitative and quantitative characterization of materials at different length scales. We describe important material characterization techniques using numerous methods of spectroscopy and microscopy. We detail numerous multi-scale computational modeling techniques that complements these experimental techniques: DFT at the atomistic scale; fully atomistic and coarse-grain molecular dynamics at the molecular to mesoscale; continuum modeling at the macroscale. Additionally, we present case studies that utilize experimental and computational approaches in an integrated manner to broaden our understanding of the properties of two-dimensional materials and materials based on silk and silk-elastin-like proteins.


Molecular interactions of porcine circoviruses type 1 and type 2 with its host.
This review discusses the molecular interaction of proteins encoded by porcine circoviruses type 1 (PCV1) and type 2 (PCV2) with respect to the putative role for disease induction. Besides protein:protein interactions also proteins binding to PCV DNA are covered. Moreover, new approaches are considered which have been generated by genomic and proteomic techniques. PCV are still an enigma, when communication with the host and induction of disease are concerned. This is remarkably, since comparison of two viruses with a size of less than 2000 nts should easily identify the molecular trigger responsible for pathogenicity of PCV2. Since scientific life isn't all beer and skittles we have to accept that this conundrum may be solved only in a long time range. The good news is that some common themes become visible and that certain aspects of the cell life cycle have been identified to be involved in interaction with the pathogen.


Choline Kinase Alpha as an Androgen Receptor Chaperone and Prostate Cancer Therapeutic Target.
The androgen receptor (AR) is a major drug target in prostate cancer (PCa). We profiled the AR-regulated kinome to identify clinically relevant and druggable effectors of AR signaling. Using genome-wide approaches, we interrogated all AR regulated kinases. Among these, choline kinase alpha (CHKA) expression was evaluated in benign (n = 195), prostatic intraepithelial neoplasia (PIN) (n = 153) and prostate cancer (PCa) lesions (n = 359). We interrogated how CHKA regulates AR signaling using biochemical assays and investigated androgen regulation of CHKA expression in men with PCa, both untreated (n = 20) and treated with an androgen biosynthesis inhibitor degarelix (n = 27). We studied the effect of CHKA inhibition on the PCa transcriptome using RNA sequencing and tested the effect of CHKA inhibition on cell growth, clonogenic survival and invasion. Tumor xenografts (n = 6 per group) were generated in mice using genetically engineered prostate cancer cells with inducible CHKA knockdown. Data were analyzed with χ(2) tests, Cox regression analysis, and Kaplan-Meier methods. All statistical tests were two-sided. CHKA expression was shown to be androgen regulated in cell lines, xenografts, and human tissue (log fold change from 6.75 to 6.59, P = .002) and was positively associated with tumor stage. CHKA binds directly to the ligand-binding domain (LBD) of AR, enhancing its stability. As such, CHKA is the first kinase identified as an AR chaperone. Inhibition of CHKA repressed the AR transcriptional program including pathways enriched for regulation of protein folding, decreased AR protein levels, and inhibited the growth of PCa cell lines, human PCa explants, and tumor xenografts. CHKA can act as an AR chaperone, providing, to our knowledge, the first evidence for kinases as molecular chaperones, making CHKA both a marker of tumor progression and a potential therapeutic target for PCa.


Adapting the Geriatric Institutional Assessment Profile for different countries and languages: A multi-language translation and content validation study.
Hospitalization can be hazardous for older people, but most hospitals in Europe are not prepared to meet the unique needs of older adult inpatients. Adaptations of the physical environment, care processes, and staff knowledge and skills in geriatric care are essential to improve the quality of care for older people. An assessment of baseline organizational approaches to older adult care is an important first step toward recognizing the challenges organizations face when delivering acute care services to older adults and attempting to improve them. The Geriatric Institutional Assessment Profile could be a promising tool for this endeavor. To describe a systematic process implemented across seven countries and languages that sought to develop valid and culturally-appropriate translations of the Geriatric Institutional Assessment Profile. Cross-cultural instrument translation and content validation study. Expert review panels comprised of 68 practicing nurses from seven European or EU associated countries (Austria (German), Belgium (Dutch), Denmark (Danish), Israel (Hebrew), Poland (Polish), Switzerland (German, French), and Turkey (Turkish)) evaluated cross-cultural relevance, including translation, of the Geriatric Institutional Assessment Profile. A systematic approach to translating and validating a cross-cultural survey instrument, including back-to-back translation, adaptation, and evaluation of content validity using content validity indexing (CVI) techniques for each country and language, assessing translation and relevance content validity separately. The item, subscale and domain content validity index scores were calculated and adjusted for chance agreement among raters for all parts of the Geriatric Institutional Assessment Profile: the four subscales of geriatric care environment, the general knowledge about older adults subscale, and the clinical geriatric knowledge subscale. Consensus discussions among the raters then finalized translations. CVI scores for relevance and translation were all in the "good" to "excellent" range. The geriatric care environment scale's CVI scores were 0.84 to 0.94 for relevance and 0.82 to 0.98 for translation. The clinical geriatric knowledge subscale's CVI scores were 0.83 to 0.97 for relevance and 0.94 to 0.98 for translation. The general knowledge about older adults subscale received high translation agreement (0.93 to 0.99) but slightly lower scores for relevance, ranging from 0.46 to 0.94. Study results provided preliminary evidence of the applicability and validity of a multi-factor measure of age-friendly care in diverse health care systems, in German, Dutch, Danish, Hebrew, Polish, French, and Turkish languages.


Comprehensive cancer control-research & development: knowing what we do and doing what we know.
Comprehensive cancer control is defined as an integrated and coordinated approach to reducing cancer incidence, morbidity, and mortality across the cancer control continuum from primary prevention to end-of-life care. This approach assumes that when the public sector, non-governmental organizations, academia, and the private sector share with each other their skills, knowledge, and resources, a country can take advantage of all its talents and resources to more quickly reduce the burden of cancer for all its population. One critical issue for comprehensive cancer control is the extent to which the private sector can contribute to cancer prevention and control programs and policies that have historically been lead by the public health sector, and similarly how can the public sector increase its investment and involvement in clinical research and practice issues that are largely driven by the private sector worldwide? In addition, building capacity to integrate research that is appropriate to the culture and context of the population will be important in different settings, in particular research related to cancer control interventions that have the capacity to influence outcomes. To whatever extent cancer control research is ultimately funded through the private and public sectors, if investments in research discoveries are ultimately to benefit the populations that bear the greatest burden of disease, then new approaches to integrating the lessons learned from science with the lessons learned from service (public health, clinical, and public policy) must be found to close the gap between what we know and what we do. Communities of practice for international cancer control, like the ones fostered by the first three International Cancer Control Congresses, represent an important forum for knowledge exchange opportunities to accelerate the translation of new knowledge into action to reduce the burden of cancer worldwide.


All inequality is not equal: children correct inequalities using resource value.
Fairness concerns guide children's judgments about how to share resources with others. However, it is unclear from past research if children take extant inequalities or the value of resources involved in an inequality into account when sharing with others; these questions are the focus of the current studies. In all experiments, children saw an inequality between two recipients-one had two more resources than another. What varied between conditions was the value of the resources that the child could subsequently distribute. When the resources were equal in value to those involved in the original inequality, children corrected the previous inequality by giving two resources to the child with fewer resources (Experiment 1). However, as the value of the resources increased relative to those initially shared by the experimenter, children were more likely to distribute the two high value resources equally between the two recipients, presumably to minimize the overall inequality in value (Experiments 1 and 2). We found that children specifically use value, not just size, when trying to equalize outcomes (Experiment 3) and further found that children focus on the relative rather than absolute value of the resources they share-when the experimenter had unequally distributed the same high value resource that the child would later share, children corrected the previous inequality by giving two high value resources to the person who had received fewer high value resources. These results illustrate that children attempt to correct past inequalities and try to maintain equality not just in the count of resources but also by using the value of resources.


Coherent dynamics of a single spin interacting with an adjustable spin bath.
Phase coherence is a fundamental concept in quantum mechanics. Understanding the loss of coherence is paramount for future quantum information processing. We studied the coherent dynamics of a single central spin (a nitrogen-vacancy center) coupled to a bath of spins (nitrogen impurities) in diamond. Our experiments show that both the internal interactions of the bath and the coupling between the central spin and the bath can be tuned in situ, allowing access to regimes with surprisingly different behavior. The observed dynamics are well explained by analytics and numerical simulations, leading to valuable insight into the loss of coherence in spin systems. These measurements demonstrate that spins in diamond provide an excellent test bed for models and protocols in quantum information.


Relationship of self-reported exercise tolerance with inflammatory markers in women with stable ischemic heart disease.
Ischemic heart disease (IHD) is associated with decreased exercise tolerance and it is subjectively reported as angina pectoris or dyspnea. Inflammation and pro- inflammatory cytokines are related to progression of IHD, but their level is seldom analyzed in association with self reported exercise tolerance. Women aged 35-75 years with stable IHD from Homocysteine Slovakia study (N=175) were analyzed for monocyte chemoatractant protein-1 (MCP-1), interleukin 6 (IL-6), transforming growth factor β1 (TGF β1), Mannan binding lectin (MBL), heat shock proteins 60 (HSP60), carbonyl protein (CP), high sensitivity C-reactive protein (hsCRP) and oxidized glutathione (GSSG) in relation to exercise induced dyspnea or angina pectoris (AP) (≤200 m). Patients with dyspnea had higher HSP60 (77.3±107.2 vs 43.7±48.9 ng/ml; p=0.014) and IL-6 (2.9±1.3 vs 1.9±0.6 pg/ml; p=0.04) levels. IL-6 and HSP60 demonstrated direct correlation with dyspnea (rho=0.39; p=0.02 resp. rho=0.22; p=0.01). AP≤200 m patients showed only decreased protein carbonyl a marker of protein oxidation and increased oxidative stress (CP 61.7±27.3 vs. 72.1±23.1 pg/ml; p=0.001). CP indirectly correlates with AP≤200 m (rho=-0.25; p=0.001). We have found associations of pro-inflammatory cytokines and inflammation markers with dyspnea or angina pectoris, but the relationship was not consistent in our patients with stable ischemic heart disease.


Chitosan and their derivatives: Antibiofilm drugs against pathogenic bacteria.
Biofilm formed by several pathogenic bacteria results in the development of resistance against antimicrobial compounds. The polymeric materials present in the biofilm architecture hinder the entry of antimicrobial compounds through the surface of bacterial cells which are embedded as well as enclosed beneath the biofilm matrix. Recent and past studies explored the alternative approaches to inhibit the formation of biofilm by different agents isolated from plants, animals, and microbes. Among these agents, chitosan and its derivatives have got more attention due to their properties such as biodegradability, biocompatibility, non-allergenic and non-toxicity. Recent researches have focused on employing chitosan and its derivatives as effective agents to inhibit biofilm formation and attenuate virulence properties by various pathogenic bacteria. Such antibiofilm activity of chitosan and its derivatives can be further enhanced by conjugation with a wide range of bioactive compounds. The present review describes the antibiofilm properties of chitosan and its derivatives against the pathogenic bacteria. This review also summarizes the mechanisms of biofilm inhibition exhibited by these molecules. The knowledge of the antibiofilm activities of chitosan and its derivatives as well as their underlying mechanisms provides essential insights for widening their applications in the future.


Comparison of different irrigation activation regimens and conventional irrigation techniques for the removal of modified triple antibiotic paste from root canals.
The aim of this study was to compare the efficacy of irrigation activation regimens and conventional syringe irrigation technique in the removal of modified triple antibiotic paste (mTAP) from root canal walls. Fifty-six extracted human mandibular premolars were prepared using ProTaper rotary files (Dentsply Maillefer, Ballaigues, Switzerland) up to size F4. The root canals were filled with mTAP medicament, and after 21 days, the roots were randomly assigned to 5 groups (n = 10) according to the irrigation regimens used: conventional syringe irrigation (CI), Self-Adjusting File (SAF; ReDent-Nova, Ra'anana, Israel), EndoVac (Discus Dental, Culver City, CA), EndoActivator (Dentsply, Tulsa, OK), and passive ultrasonic irrigation (PUI). In 3 teeth, mTAP was not removed (positive controls), and another 3 teeth were not filled with mTAP (negative controls). The roots were sectioned, and the amount of remaining medicament at each root half (n = 20) was evaluated at 30× magnification using a 4-grade scoring system. Data were evaluated using the Kruskal-Wallis and Mann-Whitney U tests. There were statistically significant differences among all experimental groups; of which, the CI group was the significantly least efficient in removing mTAP from the root canal (P < .05). At the apical and middle third, the PUI, SAF, EndoVac, and EndoActivator groups removed significantly more mTAP medicament than the CI group (P < .05); however, there were no significant differences between these groups (P > .05). The SAF and PUI showed significantly better performances in removing mTAP from the coronal third (P < .05). The use of irrigation activation regimens significantly improves the removal of mTAP from root canals when compared with CI.


Condom use for disease prevention among unmarried U.S. women.
Among a nationally representative sample of 932 sexually experienced unmarried women aged 17-44, 41% reported using condoms for protection against sexually transmitted diseases, and 30% said they used condoms for this reason every time or most times they had intercourse. While 67% of unmarried condom users cited disease prevention as their primary motivation for choosing this method, only 4% said contraception was their sole reason for using condoms; the remaining 29% gave both reasons. Condom use for disease prevention appeared most common among young women, never-married women, those with the highest incomes, women at an early stage of their reproductive career, women who had not been surgically sterilized and were not using oral contraceptives, those who believed in the effectiveness of condoms and women who had intercourse infrequently. Results of logistic regression analysis showed that black women and those who believed condoms and spermicides are effective in protecting against disease were about twice as likely as their counterparts to use condoms for disease prevention every time or most times they had sex; women who had intercourse two or more times a week, who used the pill or who had been pregnant were about half as likely as others to do so.


Allelic genealogy and human evolution.
Genetic variation at most loci examined in human populations indicates that the (effective) population size has been approximately 10(4) for the past 1 Myr and that individuals have been genetically united rather tightly. Also suggested is that the population size has never dropped to a few individuals, even in a single generation. These impose important requirements for the hypotheses for the origin of modern humans: a relatively large population size and frequent migration if populations were geographically subdivided. Any hypothesis that assumes a small number of founding individuals throughout the late Pleistocene can be rejected. Extraordinary polymorphism at some loci of the major histocompatibility complex (Mhc) rules out the past action of severe bottlenecks, or the so-called founder principle, which invokes only a small number of founding individuals when a new species emerges. This conclusion may be extended to the 35-Myr-old history of the human lineage, because some polymorphism at Mhc loci seems to have lasted that long. Furthermore, although the population structure prior to the late Pleistocene is less clear, owing to the insensitivity of Mhc alleles, even to low levels of migration, the nature of Mhc polymorphism suggests that the effective size of populations leading to humans was as large as 10(5). Hence, the effective population size of humans might have become somewhat smaller in most of the late Pleistocene. The reduction could be due either to the then adverse environment in the Old World and/or to the increased migration rate. It is also argued that population explosion fostered by the agriculture revolution has had significant effects on incorporating new alleles into human populations.


The splicing factor crooked neck associates with the RNA-binding protein HOW to control glial cell maturation in Drosophila.
In both vertebrates and invertebrates, glial cells wrap axonal processes to ensure electrical conductance. Here we report that Crooked neck (Crn), the Drosophila homolog of the yeast Clf1p splicing factor, is directing peripheral glial cell maturation. We show that crooked neck is expressed and required in glial cells to control migration and axonal wrapping. Within the cytoplasm, Crn interacts with the RNA-binding protein HOW and then translocates to the nucleus where the Crn/HOW complex controls glial differentiation by facilitating splicing of specific target genes. By using a GFP-exon trap approach, we identified some of the in vivo target genes that encode proteins localized in autocellular septate junctions. In conclusion, here we show that glial cell differentiation is controlled by a cytoplasmic assembly of splicing components, which upon translocation to the nucleus promote the splicing of genes involved in the assembly of cellular junctions.


Efficacy and safety of prescription omega-3 fatty acids for the prevention of recurrent symptomatic atrial fibrillation: a randomized controlled trial.
Atrial fibrillation (AF) is common, yet there remains an unmet medical need for additional treatment options. Current pharmacological treatments have limited efficacy and significant adverse events. Limited data from small trials suggest omega-3 polyunsaturated fatty acids may provide a safe, effective treatment option for AF patients. To evaluate the safety and efficacy of prescription omega-3 fatty acids (prescription omega-3) for the prevention of recurrent symptomatic AF. Prospective, randomized, double-blind, placebo-controlled, parallel-group multicenter trial involving 663 US outpatient participants with confirmed symptomatic paroxysmal (n = 542) or persistent (n = 121) AF, with no substantial structural heart disease, and in normal sinus rhythm at baseline were recruited from November 2006 to July 2009 (final follow-up was January 2010). Prescription omega-3 (8 g/d) or placebo for the first 7 days; prescription omega-3 (4 g/d) or placebo thereafter through week 24. The primary end point was symptomatic recurrence of AF (first recurrence) in participants with paroxysmal AF. Secondary analyses included first recurrence in the persistent stratum and both strata combined. Participants were followed up for 6 months. At 24 weeks, in the paroxysmal AF stratum, 129 of 269 participants (48%) in the placebo group and 135 of 258 participants (52%) in the prescription group had a recurrent symptomatic AF or flutter event. In the persistent AF stratum, 18 participants (33%) in the placebo group and 32 (50%) in the prescription group had documented symptomatic AF or flutter events. There was no difference between treatment groups for recurrence of symptomatic AF in the paroxysmal stratum (hazard ratio [HR], 1.15; 95% confidence interval [CI], 0.90-1.46; P = .26), in the persistent stratum (HR, 1.64; 95% CI, 0.92-2.92; P = .09), and both strata combined (HR, 1.22; 95% CI, 0.98-1.52; P = .08). Other, secondary end points were supportive of the primary result. A total of 5% of those receiving placebo and 4% of those receiving prescription omega-3 discontinued due to adverse events. Eicosapentaenoic and docosahexaenoic acid blood levels were significantly higher in the prescription group than in the placebo group at weeks 4 and 24. Among participants with paroxysmal AF, 24-week treatment with prescription omega-3 compared with placebo did not reduce recurrent AF over 6 months. clinicaltrials.gov Identifier: NCT00402363.


Cellular transformation and malignancy induced by ras require c-jun.
ras is an important oncogene in experimental animals and humans. In addition, activated ras proteins are potent inducers of the transcription factor AP-1, which is composed of heterodimeric complexes of Fos and Jun proteins. Together with the fact that deregulated expression of some AP-1 proteins can cause neoplastic transformation, this finding suggests that AP-1 may function as a critical ras effector. We have tested this hypothesis directly by analyzing the response to activated ras in cells that harbor a null mutation in the c-jun gene. The transcriptional response of AP-1-responsive genes to activated ras is severely impaired in c-jun null fibroblasts. Compared with wild-type cells, the c-jun null cells lack many characteristics of ras transformation, including loss of contact inhibition, anchorage independence, and tumorigenicity in nude mice; these properties are restored by forced expression of c-jun. Rare tumorigenic variants of ras-expressing c-jun null fibroblasts do arise. Analysis of these variants reveals a consistent restoration of AP-1 activity. The results provide genetic evidence that c-jun is a crucial effector for transformation by activated ras proteins.


Prion protein misfolding.
The crucial event in the development of transmissible spongiform encephalopathies (TSEs) is the conformational change of a host-encoded membrane protein - the cellular PrP(C) - into a disease associated, fibril-forming isoform PrP(Sc). This conformational transition from the alpha-helix-rich cellular form into the mainly beta-sheet containing counterpart initiates an 'autocatalytic' reaction which leads to the accumulation of amyloid fibrils in the central nervous system (CNS) and to neurodegeneration, a hallmark of TSEs. The exact molecular mechanisms which lead to the conformational change are still unknown. It also remains to be brought to light how a polypeptide chain can adopt at least two stable conformations. This review focuses on structural aspects of the prion protein with regard to protein-protein interactions and the initiation of prion protein misfolding. It therefore highlights parts of the protein which might play a notable role in the conformational transition from PrP(C) to PrP(Sc) and consequently in inducing a fatal chain reaction of protein misfolding. Furthermore, features of different proteins, which are able to adopt insoluble fibrillar states under certain circumstances, are compared to PrP in an attempt to understand the unique characteristics of prion diseases.


First Report of Colletotrichum gloeosporioides Causing Anthracnose of Banana (Musa spp.) in Malaysia.
Banana is the second largest cultivated fruit crop in Malaysia, and is cultivated for both the domestic market and also for export. Anthranose is a well-known postharvest disease of banana and with high potential for damaging market value, as infection commonly occurs during storage. Anthracnose symptoms were observed on several varieties of banana such as mas, berangan, awak, nangka, and rastali in the states of Perak and Penang between August and October 2011. Approximately 80% of the fruits became infected with initial symptoms characterized as brown to black spots that later became sunken lesions with orange or salmon-colored conidial masses. Infected tissues (5 × 5 mm) were surface sterilized by dipping in 1% sodium hypochlorite (NaOCl) for 3 to 5 min, rinsed with sterile distilled water, and plated onto potato dextrose agar (PDA). Direct isolation was done by transferring the conidia from conidial masses using an inoculation loop and plating onto PDA. For both methods, the PDA plates were incubated at 27 ± 1°C with cycles of 12 h light and 12 h darkness. Visible growth of mycelium was observed after 4 to 5 days of incubation. Twenty isolates with conidial masses were recovered after 7 days of incubation. The isolates produced grayish white to grayish green and grey to moss dark green colony on PDA, pale orange conidial masses, and fusiform to cylindrical and hyaline conidia with an average size of 15 to 19 × 5 to 6 μm. Appresoria were ovate to obovate, dark brown, and 9 to 15 × 7 to 12 μm and setae were present, slightly swollen at the base, with a tapered apex, and brown. The cultural and morphological characteristics of the isolates were similar to those described for C. gleosporioides (1,2,3). All the C. gloeosporioides isolates were deposited in culture collection at Plant Pathology Lab, University Sains Malaysia. For confirmation of the identity of the isolates, ITS regions were sequenced using ITS4 and ITS5 primers. The isolates were deposited in GenBank with accessions JX163228, JX163231, JX163201, JX163230, JX163215, JX163223, JX163219, JX163202, JX163225, JX163222, JX163206, JX163218, JX163208, JX163209, JX163210, JX431560, JX163212, JX163213, JX431540, and JX431562. The resulting sequences showed 99% to 100% similarity with multiple C. gloeosporioides isolates in GenBank. Pathogenicity tests were conducted using mas, berangan, awak, nangka, and rastali bananas. Fruit surfaces were sterilized with 70% ethanol and wounded using a sterile scalpel. Two inoculation techniques were performed separately: mycelia plug and conidial suspension. Mycelial disc (5 mm) and a drop of 20 μl spore suspension (106 conidia/ml) were prepared from 7-day-old culture and placed on the fruit surface. The inoculated fruits were incubated at 27 ± 1°C for 10 days at 96.1% humidity. After 3 to 4 days of inoculation, brown to black spotted lesions were observed and coalesced to become black sunken lesions. Similar anthracnose symptoms were observed on all banana varieties tested. C. gloeosporioides was reisolated from the anthracnose lesions of all the inoculated fruit in which the cultural and morphological characteristics were the same as the original isolates. To our knowledge, this is the first report of C. gloeosporioides causing anthracnose of Musa spp. in Malaysia. References: (1) P. F. Cannon et al. Mycotaxon 104:189, 2008. (2) J. E. M. Mordue. Glomerella cingulata. CMI Description of Pathogenic Fungi and Bacteria, No. 315. CAB International,1971. (3) H. Prihastuti et al. Fungal Diversity 39:89, 2009.


Lactate and microcirculation as suitable targets for hemodynamic optimization in resuscitation of circulatory shock.
A discussion of recent research exploring the feasibility of perfusion-guided resuscitation of acute circulatory failure with a focus on lactate and microcirculation. Upon diagnosis of shock, hyperlactemia is associated with poor outcome and, under appropriate clinical circumstances, may reflect inadequate tissue perfusion. Persistent hyperlactemia despite resuscitation is even more strongly correlated with morbidity and mortality. Importantly, there is minimal coherence between lactate trends and static hemodynamic measures such as blood pressure, especially after the initial, hypovolemic phase of shock. During this early period, lactate guided-resuscitation is effective and possibly superior to hemodynamic-guided resuscitation. Similar to hyperlactemia, impaired microcirculation is ubiquitous in shock and is evident even in the setting of hemodynamic compensation (i.e., occult shock). Moreover, persistent microcirculatory derangement is associated with poor outcome and may reflect ongoing shock and/or long-lasting damage. Although the wait continues for a microcirculation-guided resuscitation trial, there is progress toward this goal. Although questions remain, a multimodal perfusion-based approach to resuscitation is emerging with lactate and microcirculation as core measures. In this model, hyperlactemia and microcirculatory derangement support the diagnosis of shock, may help guide resuscitation during the initial period, and may reflect resuscitation efficacy and iatrogenic harm (e.g., fluid overload).


Prophylactic antibiotic regimen and dental implant failure: a meta-analysis.
The aim of this meta-analysis was to investigate whether there are any positive effects of prophylactic antibiotic regimen on implant failure rates and post-operative infection when performing dental implant treatment in healthy individuals. An electronic search without time or language restrictions was undertaken in March 2014. Eligibility criteria included clinical human studies, either randomised or not. The search strategy resulted in 14 publications. The I(2) statistic was used to express the percentage of the total variation across studies due to heterogeneity. The inverse variance method was used with a fixed- or random-effects model, depending on the heterogeneity. The estimates of relative effect were expressed in risk ratio (RR) with 95% confidence interval. Six studies were judged to be at high risk of bias, whereas one study was considered at moderate risk, and six studies were considered at low risk of bias. The test for overall effect showed that the difference between the procedures (use versus non-use of antibiotics) significantly affected the implant failure rates (P = 0.0002), with a RR of 0.55 (95% CI 0.41-0.75). The number needed to treat (NNT) to prevent one patient having an implant failure was 50 (95% CI 33-100). There were no apparent significant effects of prophylactic antibiotics on the occurrence of post-operative infections in healthy patients receiving implants (P = 0.520). A sensitivity analysis did not reveal difference when studies judged as having high risk of bias were not considered. The results have to be interpreted with caution due to the presence of several confounding factors in the included studies.


Utilization of diets containing graded levels of ethanol production co-products by Nile tilapia.
A feeding trial was performed to investigate inclusion levels of distillers dried grains with solubles (DDGS) as a fishmeal replacement for juvenile Nile tilapia (Oreochromis niloticus). On a dry matter basis, five isocaloric [19.3 ± 0.4 kJ/g (mean ± SE)], isonitrogenous (39.1 ± 0.5% crude protein) diets were formulated to contain 17.5%, 20%, 22.5%, 25%, and 27.5% DDGS and compared against a 0% DDGS, reference diet (gross energy = 14.5 kJ/g; crude protein = 39.8%). The reference diet resulted in significantly higher body weight gain (BWG), food conversion ratio (FCR), and protein efficiency ratio (PER) than experimental diets except that 17.5% DDGS provided similar FCR and PER. The diet containing 27.5% DDGS had significantly lower FCR and PER values than all other diets even though apparent digestibility did not significantly differ among experimental diets. Although DDGS can be incorporated at higher levels, 20% DDGS provided the highest apparent BWG among experimental diets, while 17.5% promoted the best FCR and PER. Fishmeal may be replaced with low levels of fuel-based DDGS to reduce feeding cost; however, additional supplements should be considered to enhance fish performance.


The genetic architecture of blood pressure variability: A genome-wide association study of 9370 participants from UK Biobank.
Long-term blood pressure variability (BPV) is a risk factor for cardiovascular diseases, dementia, and stroke. However, its genetic architecture is not fully understood. This study aims to explore its genetic factors and provide more evidence on the mechanisms and further pathological study of BPV. The genome-wide association study (GWAS) is based on the UK Biobank cohort. There were four data collection rounds from 2006 to 2020, and 9370 participants with more than three blood pressure measurements were included. They had a median age of 55 and a male percentage of 50.1%. The phenotypes (BPV) were calculated by four methods and the genetic data contains 6 884 260 single nucleotide polymorphisms (SNPs) after imputation and quality control. A linear regression model was performed with adjustments for sex, age, genotype array, and a significant principal component. Subgroup analysis was performed on hypertension-free participants. The significant and suggestive significant P thresholds were set as 5 × 10-8 and 1 × 10-6 . Six genetic loci (BAD, CCDC88B, GPR137, PLCB3, RPS6KA4 for systolic BPV, and WWC2 for diastolic BPV) were identified by coding region SNPs at the suggestive significant P threshold (1 × 10-6 ). Among them, gene CCDC88B and RPS6KA4 reached the significant P threshold (5 × 10-8 ), with the strongest signal of SNP rs1229536170 (P = 6.36 × 10-8 , β = -.29). The annotation results indicate that genes CCDC88B, GPR137, RPS6KA4, and BAD are associated with long-term SBPV. Their functions of inflammation, epithelial dysfunction, and apoptosis are related to artery stiffness, which was reported as potential mechanisms of BPV.


Model Organisms Facilitate Rare Disease Diagnosis and Therapeutic Research.
Efforts to identify the genetic underpinnings of rare undiagnosed diseases increasingly involve the use of next-generation sequencing and comparative genomic hybridization methods. These efforts are limited by a lack of knowledge regarding gene function, and an inability to predict the impact of genetic variation on the encoded protein function. Diagnostic challenges posed by undiagnosed diseases have solutions in model organism research, which provides a wealth of detailed biological information. Model organism geneticists are by necessity experts in particular genes, gene families, specific organs, and biological functions. Here, we review the current state of research into undiagnosed diseases, highlighting large efforts in North America and internationally, including the Undiagnosed Diseases Network (UDN) (Supplemental Material, File S1) and UDN International (UDNI), the Centers for Mendelian Genomics (CMG), and the Canadian Rare Diseases Models and Mechanisms Network (RDMM). We discuss how merging human genetics with model organism research guides experimental studies to solve these medical mysteries, gain new insights into disease pathogenesis, and uncover new therapeutic strategies.


New Jersey's efforts to improve postpartum depression care did not change treatment patterns for women on medicaid.
Identification and treatment of postpartum depression are the increasing focus of state and national legislation, including portions of the Affordable Care Act. Some state policies and proposals are modeled directly on programs in New Jersey, the first state to require universal screening for postpartum depression among mothers who recently delivered babies. We examined the impact of these policies on a particularly vulnerable population, Medicaid recipients, and found that neither the required screening nor the educational campaign that preceded it was associated with improved treatment initiation, follow-up, or continued care. We argue that New Jersey's policies, although well intentioned, were predicated on an inadequate base of evidence and that efforts should now be undertaken to build that base. We also argue that to improve detection and treatment, policy makers contemplating or implementing postpartum depression mandates should consider additional measures. These could include requiring mechanisms to monitor and enforce the screening requirement; paying providers to execute screening and follow-up; and preliminary testing of interventions before policy changes are enacted.


Several groups among human herpesvirus 6 strains can be distinguished by Southern blotting and polymerase chain reaction.
Eight human herpesvirus 6 (HHV-6) strains were studied by Southern blot and polymerase chain reaction. DNA from infected cells was digested by a panel of restriction enzymes and hybridized with cloned BamHI fragments corresponding to about 30% of the HHV-6 strain SIE genome. In parallel, this DNA was amplified by polymerase chain reaction using pairs of primers derived from the strain SIE nucleotide sequence. Subsequently, amplification products were analyzed by hybridization, digestion with restriction endonucleases, and partial nucleotide sequencing. Overall results indicated that all strains were closely related to one another. However, concordant differences in restriction patterns allowed at least two groups to be distinguished, typified by strains SIE and HST, respectively. Differences between the two groups were found to reflect a limited number of punctual changes in nucleotide sequences. These results strengthen the idea of a unique HHV-6 species with genetic polymorphism. In addition, this study provides useful markers for the diagnosis and molecular epidemiology of HHV-6 infections.


The wheat durable, multipathogen resistance gene Lr34 confers partial blast resistance in rice.
The wheat gene Lr34 confers durable and partial field resistance against the obligate biotrophic, pathogenic rust fungi and powdery mildew in adult wheat plants. The resistant Lr34 allele evolved after wheat domestication through two gain-of-function mutations in an ATP-binding cassette transporter gene. An Lr34-like fungal disease resistance with a similar broad-spectrum specificity and durability has not been described in other cereals. Here, we transformed the resistant Lr34 allele into the japonica rice cultivar Nipponbare. Transgenic rice plants expressing Lr34 showed increased resistance against multiple isolates of the hemibiotrophic pathogen Magnaporthe oryzae, the causal agent of rice blast disease. Host cell invasion during the biotrophic growth phase of rice blast was delayed in Lr34-expressing rice plants, resulting in smaller necrotic lesions on leaves. Lines with Lr34 also developed a typical, senescence-based leaf tip necrosis (LTN) phenotype. Development of LTN during early seedling growth had a negative impact on formation of axillary shoots and spikelets in some transgenic lines. One transgenic line developed LTN only at adult plant stage which was correlated with lower Lr34 expression levels at seedling stage. This line showed normal tiller formation and more importantly, disease resistance in this particular line was not compromised. Interestingly, Lr34 in rice is effective against a hemibiotrophic pathogen with a lifestyle and infection strategy that is different from obligate biotrophic rusts and mildew fungi. Lr34 might therefore be used as a source in rice breeding to improve broad-spectrum disease resistance against the most devastating fungal disease of rice.