Creating Acceptable Tablets 3D (CAT 3D): A Feasibility Study to Evaluate the Acceptability of 3D Printed Tablets in Children and Young People.
3D printing (3DP) has been proposed as a novel approach for personalising dosage forms for children and young people (CYP). Owing to its low cost and the lack of need for finishing steps, fused deposing modelling (FDM) 3DP has been heavily researched in solid dosage forms (SDFs) manufacturing. However, the swallowability and overall acceptability of 3D printed dosage forms are yet to be established. This work is the first to evaluate the acceptability of different sized 3D printed placebo SDFs in CYP (aged 4-12 years). All participants had previously participated in a feasibility study (CAT study) that assessed the swallowability and acceptability of different sized GMP manufactured placebo conventional film-coated tablets, and therefore only attempted to swallow one 3D printed tablet. The participants assessed the swallowability, acceptability, mouthfeel, volume of water consumed, and taste of the sample using a 5-point hedonic facial scale on a participant questionnaire. A total of 30 participants were recruited, 87% of whom successfully swallowed the 3D printed tablet that they attempted to take. Attributes of the 3D printed tablets were scored as acceptable by the following percentage of participants-swallowability (80%), mouthfeel/texture (87%), the volume of water consumed (80%), taste (93%), and overall acceptability (83%). Overall, 77% of children reported they would be happy to take the tablet every day if it was a medicine. Participants were also asked which tablets felt better in the mouth-the film-coated tablets or the 3D printed tablets, and the most popular response (43%) was that both were acceptable. This study shows that FDM-based 3D printed SDFs may be a suitable dosage form for children aged 4-12 years. The results from this feasibility study will be used to inform a larger, definitive study looking at the acceptability of 3D printed tablets in children.


Biodegradable polyester elastomers in tissue engineering.
Tissue engineering often makes use of biodegradable scaffolds to guide and promote controlled cellular growth and differentiation in order to generate new tissue. There has been significant research regarding the effects of scaffold surface chemistry and degradation rate on tissue formation and the importance of these parameters is widely recognised. Nevertheless, studies describing the role of mechanical stimuli during tissue development and function suggest that the mechanical properties of the scaffold will also be important. In particular, scaffold mechanics should be taken into account if mechanical stimulation, such as cyclic strain, will be incorporated into strategies to grow improved tissues or the target tissue to be replaced has elastomeric properties. Biodegradable polyesters, such as polyglycolide, polylactide and poly(lactide-co-glycolide), although commonly used in tissue engineering, undergo plastic deformation and failure when exposed to long-term cyclic strain, limiting their use in engineering elastomeric tissues. This review will cover the latest advances in the development of biodegradable polyester elastomers for use as scaffolds to engineer tissues, such as heart valves and blood vessels.


Cogan's syndrome.
Work originating in the 1940s led to the characterization of a rare, chronic inflammatory disorder with a unique predilection for the cornea and vestibuloauditory apparatus, now called Cogan's syndrome (CS) after the ophthalmologist who first described it. CS occurs primarily in young adults and typically presents with interstitial keratitis (IK) and Ménière's-like episodes developing within several months of each other. The inflammatory process may target other ocular sites, and the disease itself may be accompanied by aortitis or a Takayasu's-like or medium-sized vessel vasculitis. Morbidity in CS results from deafness and complications from cardiovascular disease. Most evidence suggests that the ocular and vestibuloauditory manifestations are not a consequence of vasculitis but rather mediated by other immunologic mechanisms, possibly organ-specific autoimmunity. The cornerstone of treatment in CS is corticosteroids, topically for IK and systemically for inner ear dysfunction. Early corticosteroid therapy appears to be critical for reversing hearing loss. Cochlear implants can partially restore auditory function and have been a salvation for patients who suffer from deafness as a result of permanent cochlear damage.


[Treatment of immunological infertility with Chinese medicinal herbs of ziyin jianghuo].
According to the microcosmic Syndrome Differentiation, immunological infertility is recognised as Kidney Yin Deficiency-Hyperactivity of Fire Syndrome. Zhibai Dihuang Pills, a recipe of Chinese medicinal herbs, was used to treat the infertile couples with antisperm and/or antizona pellucida antibodies in their blood serum. It was found that after the treatment, the antibodies were converted to negativeness in 81.3% of immunological infertile couples. All 8 cases of successful pregnancy occurred in 1-9 months after antibodies negative conversion and the negative status was maintained throughout the course of pregnancy.


Prorenin induces vascular smooth muscle cell proliferation and hypertrophy via epidermal growth factor receptor-mediated extracellular signal-regulated kinase and Akt activation pathway.
It is widely acknowledged that the (pro)renin receptor mediates angiotensin (Ang) II-dependent and Ang II-independent effects of prorenin. We examined the effect of prorenin on vascular smooth muscle cell (VSMC) signal transduction, proliferation, and hypertrophy. Recombinant rat prorenin dose-dependently increased extracellular signal-regulated kinase (ERK) 1/2 and Akt phosphorylation in rat VSMCs. Prorenin also significantly increased cell number, and [H]-thymidine and [H]-leucine incorporation, which were attenuated by pretreatment with inhibitors for ERK kinase and phosphatidylinositol 3 kinase. Prorenin was also found to stimulate epidermal growth factor (EGF) receptor and Src phosphorylation. Pretreatment of VSMCs with an EGF receptor tyrosine kinase inhibitor and a Src inhibitor significantly attenuated the prorenin-induced increase in ERK 1/2 and Akt phosphorylation, as well as DNA and protein synthesis. Prorenin-induced phosphorylation of the EGF receptor, ERK 1/2, and Akt, as well as DNA and protein synthesis were all blocked by (pro)renin receptor siRNA, but not by an Ang II type 1 receptor blocker, candesartan, nor an Ang-converting enzyme inhibitor, captopril. These results reveal that prorenin directly stimulates VSMC proliferative and hypertrophic changes, dependent on the (pro)renin receptor, independent of Ang II. Furthermore, EGF receptor-mediated ERK 1/2 and Akt activation contributes to prorenin-dependent proliferative and hypertrophic effects in VSMCs.


Dissociable Neural Systems Support the Learning and Transfer of Hierarchical Control Structure.
Humans can draw insight from previous experiences to quickly adapt to novel environments that share a common underlying structure. Here we combine functional imaging and computational modeling to identify the neural systems that support the discovery and transfer of hierarchical task structure. Human subjects (male and female) completed multiple blocks of a reinforcement learning task that contained a global hierarchical structure governing stimulus-response action mapping. First, behavioral and computational evidence showed that humans successfully discover and transfer the hierarchical rule structure embedded within the task. Next, analysis of fMRI BOLD data revealed activity across a frontoparietal network that was specifically associated with the discovery of this embedded structure. Finally, activity throughout a cingulo-opercular network supported the transfer and implementation of this discovered structure. Together, these results reveal a division of labor in which dissociable neural systems support the learning and transfer of abstract control structures.SIGNIFICANCE STATEMENT A fundamental and defining feature of human behavior is the ability to generalize knowledge from the past to support future action. Although the neural circuits underlying more direct forms of learning have been well established over the last century, we still lack a solid framework from which to investigate more abstract, higher-order human learning and knowledge generalization. We designed a novel behavioral paradigm to specifically isolate a learning process in which previous knowledge, rather than directly indicating the correct action, instead guides the search for the correct action. Moreover, we identify that this learning process is achieved via the coordinated and temporally specific activity of two prominent cognitive control brain networks.


Quantitative trait mapping in Diversity Outbred mice identifies two genomic regions associated with heart size.
Heart size is an important factor in cardiac health and disease. In particular, increased heart weight is predictive of adverse cardiovascular outcomes in multiple large community-based studies. We use two cohorts of Diversity Outbred (DO) mice to investigate the role of genetics, sex, age, and diet on heart size. DO mice (n = 289) of both sexes from generation 10 were fed a standard chow diet, and analyzed at 12-15 weeks of age. Another cohort of female DO mice (n = 258) from generation 11 were fed either a high-fat, cholesterol-containing (HFC) diet or a low-fat, high-protein diet, and analyzed at 24-25 weeks. We did not observe an effect of diet on body or heart weight in generation 11 mice, although we previously reported an effect on other cardiovascular risk factors, including cholesterol, triglycerides, and insulin. We do observe a significant genetic effect on heart weight in this population. We identified two quantitative trait loci for heart weight, one (Hwtf1) at a genome-wide significance level of p ≤ 0.05 on MMU15 and one (Hwtf2) at a genome-wide suggestive level of p ≤ 0.1 on MMU10, that together explain 13.3% of the phenotypic variance. Hwtf1 contained collagen type XXII alpha 1 chain (Col22a1), and the NZO/HlLtJ and WSB/EiJ haplotypes were associated with larger hearts. This is consistent with heart tissue Col22a1 expression in DO founders and SNP patterns within Hwtf1 for Col22a1. Col22a1 has been previously associated with cardiac fibrosis in mice, suggesting that Col22a1 may be involved in pathological cardiac hypertrophy.


Immunoglobulin with complementary paratope and idiotope.
A hybridoma antibody (11E7-1) was isolated from a myeloma fusion with nu/nu BALB/c immunized against the T15 idiotype. This IgM antibody exhibited a dual specificity, binding both to PC and to anti-PC antibodies from two idiotype families. Binding to PC and anti-PC antibodies are completely inhibited by PC analogs. Furthermore, the hybridoma antibody binds to itself. Self-binding is also inhibited by PC analogs. From these data, we suggest that 11E7-1 hybridoma antibody has a PC-specific paratope site, and at same time expresses the internal PC antigen idiotope. The term autobody is proposed to signify its self-binding and potential role in autoimmunity. Autobodies may have a unique role in the network of immune system. Furthermore, it may be a model for designing idiotype vaccines.


The Effects of Cold Stress on Photosynthesis in Hibiscus Plants.
The present work studies the effects of cold on photosynthesis, as well as the involvement in the chilling stress of chlororespiratory enzymes and ferredoxin-mediated cyclic electron flow, in illuminated plants of Hibiscus rosa-sinensis. Plants were sensitive to cold stress, as indicated by a reduction in the photochemistry efficiency of PSII and in the capacity for electron transport. However, the susceptibility of leaves to cold may be modified by root temperature. When the stem, but not roots, was chilled, the quantum yield of PSII and the relative electron transport rates were much lower than when the whole plant, root and stem, was chilled at 10°C. Additionally, when the whole plant was cooled, both the activity of electron donation by NADPH and ferredoxin to plastoquinone and the amount of PGR5 polypeptide, an essential component of the cyclic electron flow around PSI, increased, suggesting that in these conditions cyclic electron flow helps protect photosystems. However, when the stem, but not the root, was cooled cyclic electron flow did not increase and PSII was damaged as a result of insufficient dissipation of the excess light energy. In contrast, the chlororespiratory enzymes (NDH complex and PTOX) remained similar to control when the whole plant was cooled, but increased when only the stem was cooled, suggesting the involvement of chlororespiration in the response to chilling stress when other pathways, such as cyclic electron flow around PSI, are insufficient to protect PSII.


Testicular cancer incidence to rise by 25% by 2025 in Europe? Model-based predictions in 40 countries using population-based registry data.
Testicular cancer mainly affects White Caucasian populations, accounts for 1% of all male cancers, and is frequently the most common malignancy among young adult men. In light of the escalating rates of testicular cancer incidence in Europe, and in support of future planning to ensure optimal care of patients with what can be a curable disease, we predict the future burden in 40 European countries around 2025. Current observed trends were extrapolated with the NORDPRED model to estimate the future burden of testicular cancer in the context of changes in risk versus changes in demographics. Despite substantial heterogeneity in the rates, the vast majority of European countries will see an increasing burden over the next two decades. We estimate there will be 23,000 new cases of testicular cancer annually in Europe by 2025, a rise of 24% from 2005. Some of the most rapid increases in testicular cancer are observed in Croatia, Slovenia, Italy and Spain, and a transition is underway, whereby recent attenuations and declines in rates in certain high-risk countries in Northern Europe contrast with the increasing trends and escalating burden in Southern Europe. According to our estimates for 2025, around one in 100 men will be diagnosed with the disease annually in the highest risk countries of Europe (Croatia, Slovenia and Norway). Elucidating the key determinants of testicular cancer and the equitable provision of optimal care for patients across Europe are priorities given the steady rise in the number of patients by 2025, and an absence of primary prevention opportunities. None.


Detection of endometrial cancer via molecular analysis of DNA collected with vaginal tampons.
We demonstrate the feasibility of detecting EC by combining minimally-invasive specimen collection techniques with sensitive molecular testing. Prior to hysterectomy for EC or benign indications, women collected vaginal pool samples with intravaginal tampons and underwent endometrial brushing. Specimens underwent pyrosequencing for DNA methylation of genes reported to be hypermethylated in gynecologic cancers and recently identified markers discovered by profiling over 200 ECs. Methylation was evaluated individually across CpGs and averaged across genes. Differences between EC and benign endometrium (BE) were assessed using two-sample t-tests and area under the curve (AUC). Thirty-eight ECs and 28 BEs were included. We evaluated 97 CpGs within 12 genes, including previously reported markers (RASSF1, HSP2A, HOXA9, CDH13, HAAO, and GTF2A1) and those identified in discovery work (ASCL2, HTR1B, NPY, HS3ST2, MME, ADCYAP1, and additional CDH13 CpG sites). Mean methylation was higher in tampon specimens from EC v. BE for 9 of 12 genes (ADCYAP1, ASCL2, CDH13, HS3ST2, HTR1B, MME, HAAO, HOXA9, and RASSF1) (all p<0.05). Among these genes, relative hypermethylation was observed in EC v. BE across CpGs. Endometrial brush and tampon results were similar. Within tampon specimens, AUC was highest for HTR1B (0.82), RASSF1 (0.75), and HOXA9 (0.74). This is the first report of HOXA9 hypermethylation in EC. DNA hypermethylation in EC tissues can also be identified in vaginal pool DNA collected via intravaginal tampon. Identification of additional EC biomarkers and refined collection methods are needed to develop an early detection tool for EC.


The intestinal parasite Pomphorhynchus laevis as a sensitive accumulation indicator for the platinum group metals Pt, Pd, and Rh.
Concentrations of the platinum group elements Pt, Pd, and Rh were analyzed by adsorptive cathodic stripping voltammetry (Pt, Rh) and total-reflection X-ray fluorescence (Pd) in the intestinal helminth Pomphorhynchus laevis and its host Barbus barbus. The fish were caught in the Danube river south of the city of Budapest (Hungary) and were exposed to ground catalytic material for 28 days. Following exposure all three precious metals were taken up and accumulated in host organs and the parasites. Interestingly, in all tissues of the unexposed controls Pt was found, whereas Pd was not present in the muscle of the controls and Rh was not detectable in muscle and intestine of unexposed barbel. All metals were found at significantly higher concentrations in the acanthocephalan than in the tissues of barbel. These results are discussed with respect to the application of P. laevis as an accumulation indicator for metals.


Oxidative stress in ageing of hair.
Experimental evidence supports the hypothesis that oxidative stress plays a major role in the ageing process. Reactive oxygen species are generated by a multitude of endogenous and environmental challenges. Reactive oxygen species or free radicals are highly reactive molecules that can directly damage cellular structural membranes, lipids, proteins, and DNA. The body possesses endogenous defence mechanisms, such as antioxidative enzymes and non-enzymatic antioxidative molecules, protecting it from free radicals by reducing and neutralizing them. With age, the production of free radicals increases, while the endogenous defence mechanisms decrease. This imbalance leads to the progressive damage of cellular structures, presumably resulting in the ageing phenotype. Ageing of hair manifests as decrease of melanocyte function or graying, and decrease in hair production or alopecia. There is circumstantial evidence that oxidative stress may be a pivotal mechanism contributing to hair graying and hair loss. New insights into the role and prevention of oxidative stress could open new strategies for intervention and reversal of the hair graying process and age-dependent alopecia.


Dynamic changes in the secondary structure of ECE-1 and XCE account for their different substrate specificities.
X-converting enzyme (XCE) involved in nervous control of respiration, is a member of the M13 family of zinc peptidases, for which no natural substrate has been identified yet. In contrast, it's well characterized homologue endothelin-converting enzyme-1 (ECE-1) showed broad substrate specificity and acts as endopeptidase as well as dipeptidase. To explore the structural differences between XCE and ECE-1, homology model of XCE was built using the complex structure of ECE-1 with phosphoramidon (pdb-id: 3DWB) as template. Phosphoramidon was docked into the binding site of XCE whereas phosphate oxygen of the inhibitor was used as water molecule to design the apo forms of both enzymes. Molecular dynamics simulation of both enzymes was performed to analyze the dynamic nature of their active site residues in the absence and presence of the inhibitor. Homology model of XCE explained the role of non-conserved residues of its S2' subsite. Molecular dynamics (MD) simulations identified the flexible transitions of F149/I150, N566/N571, W714/W719, and R145/R723 residues of ECE-1/XCE for the strong binding of the inhibitor. Secondary structure calculations using DSSP method reveals the folding of R145/R723 residue of ECE-1/XCE into β-sheet structure while unfolding of the S2' subsite residues in aECE-1 and sustained compact folding of that of aXCE. The results evaluated are in good agreement with available experimental data, thus providing detailed molecular models which can explain the structural and specificities differences between both zinc peptidases. Secondary structure changes of both enzymes during the simulation time revealed the importance of β-sheet structure of R145/R723 for its binding with the terminal carboxylate group of the inhibitor. Unfolding of the α-helix comprising the S2' subsite residues in aECE-1 correlate well with its endopeptidase activity while their compact folding in aXCE may account for the inactivity of the enzyme towards large C-terminal containing substrates.


Active learning and leadership in an undergraduate curriculum: How effective is it for student learning and transition to practice?
Nurses are being increasingly asked to develop leadership skills in their practice and to be actively involved in continuous change processes in the workplace. Nursing students need to be developing leadership skills prior to entering the workplace to ensure they are able to meet the challenges associated with organisations and the cultures present in nursing, along with having highly tuned communication skills and leadership attributes that contribute to best patient care and outcomes. This paper looks at how the use of Active Learning in an undergraduate setting enabled the development and implementation of a leadership subject for nursing students preparing for professional practice. Through the use of a specific model of Active Learning, incorporating multiple intelligences into education allows students to bring deeper learning to their conscience so that whole person learning is an engaged experience. It seems apparent that Active Learning is an effective means of learning about leadership in undergraduate students who are developing towards a career as a health professional.


Dose-Dependent Effect of Granulocyte Transfusions in Hematological Patients with Febrile Neutropenia.
It is still under debate whether granulocyte transfusions (GTs) substantially increase survival in patients with febrile neutropenia. We retrospectively examined data relative to 96 patients with hematological malignancies receiving 491 GTs during 114 infectious episodes (IE). Patients were grouped according to the median doses of granulocytes transfused during the infectious episode (low-dose group: <1.5-x108 cells/Kg; standard-dose group: 1.5-3.0x108 cells/Kg and high-dose group: >3.0x108 cells/Kg). The impact of clinical, microbiological and GT-related variables on the infection-related mortality (IRM) was investigated. The IRM was not influenced by the number of GTs or by the total amount of granulocytes received, whereas a dose-related effect of the median dose received for IE was detected at univariate analysis (IRM of 18.4% in the standard-dose group, 44.4% in the low-dose group and 48.4% in the high-dose group, p = 0.040) and confirmed at multivariate analysis (OR 3.7, IC 95% 1.5-8.9; 0.004 for patients not receiving standard doses of GTs). Moreover, patients receiving GTs at doses lower or greater than standard had increased risk for subsequent ICU admission and reduced overall survival. The dose-related effect of GTs was confirmed in bacterial but not in fungal infections. Preliminary findings obtained from a subgroup of patients candidate to GTs revealed that levels of inflammatory response mediators increase in a dose-related manner after GTs, providing a possible explanation for the detrimental effect exerted by high-dose transfusions. GTs can constitute a valuable tool to improve the outcome of infections in neutropenic patients, provided that adequate recipient-tailored doses are supplied. Further investigations of the immunomodulatory effects of GTs are recommended.


Consultations with complementary and alternative medicine practitioners by older Australians: results from a national survey.
The use of complementary and alternative medicines (CAM) and CAM practitioners is common, most frequently for the management of musculoskeletal conditions. Knowledge is limited about the use of CAM practitioners by older people, and specifically those with other long term or chronic conditions. In 2011 we conducted an Australia wide survey targeting older adults aged over 50 years (n = 2540). Participants were asked to identify their chronic conditions, and from which health professionals they had 'received advice or treatment from in the last 3 months', including 'complementary health practitioners, e.g. naturopath'. Descriptive analyses were undertaken using SPSS and STATA software. Overall, 8.8% of respondents reported seeing a CAM practitioner in the past three months, 12.1% of women and 3.9% of men; the vast majority also consulting medical practitioners in the same period. Respondents were more likely to report consulting a CAM practitioner if they had musculoskeletal conditions (osteoporosis, arthritis), pain, or depression/anxiety. Respondents with diabetes, hypertension and asthma were least likely to report consulting a CAM practitioner. Those over 80 reported lower use of CAM practitioners than younger respondents. CAM practitioner use in a general older population was not associated with the number of chronic conditions reported, or with the socio-economic level of residence of the respondent. Substantial numbers of older Australians with chronic conditions seek advice from CAM practitioners, particularly those with pain related conditions, but less often with conditions where there are clear treatment guidelines using conventional medicine, such as with diabetes, hypertension and asthma. Given the policy emphasis on better coordination of care for people with chronic conditions, these findings point to the importance of communication and integration of health services and suggest that the concept of the 'treating team' needs a broad interpretation.


Increased prevalence of dental caries and poor oral hygiene in juvenile idiopathic arthritis.
Recent decades have seen a trend to treat juvenile idiopathic arthritis (JIA) with increasing immunosuppression to improve the long-term outcome. Poor oral hygiene and dental decay cause significant morbidity, and patients with chronic disease (who may be further immunocompromised by treatment) are at greater risk. This study investigated patients with JIA using standard measures of oral health. One hundred and forty-nine patients with JIA were included. The children were attending a regional paediatric rheumatology service and the adults were attending an adult rheumatology clinic. Random age- and sex-matched healthy controls were recruited from a dental teaching hospital. The structured dental examination included standard epidemiological indices of oral hygiene (gingival index, plaque index, oral cleanliness index) and dental decay [DMFT (decayed, missing or filled teeth) index]. JIA patients, at all ages, had increased levels of dental decay and poor oral hygiene. This increased level of decay was statistically significant in the patients aged 0-11 yr. Significant levels of untreated caries and increased levels of missing teeth were found in JIA, suggesting that patients with JIA had less restorative dental treatment, with tooth extraction often the chosen option for the treatment of dental decay. This is the largest study of oral health in JIA and is cross-sectional with non-diseased controls. It shows significantly increased levels of poor oral hygiene and dental decay in patients with JIA. The high levels of untreated dental decay suggest barriers to dental care. These results emphasize the role of regular dental care in the multidisciplinary management of JIA.


Midazolam does not inhibit association formation, just its storage and strengthening.
Although there have been many studies examining the effects of benzodiazepines on memory performance, their effects on working memory are equivocal and little is known about whether they affect the efficacy of practice of already learned material. The objectives in two experiments were to examine (a) whether midazolam impairs performance on a working memory task designed to minimize mnemonic strategies such as rehearsal or chunking of information to be recalled and (b) the effect of midazolam on repeated practice of paired associates that were learned before drug administration. Both experiments involved subcutaneous administration of 0.03 mg of saline or midazolam per kilogram of bodyweight in within-subject, placebo-controlled designs, involving 23 subjects in (a) and 31 in (b). The drug had no effect on the ability to recall the digits in serial order even though the encoding task prevented the digits from being rehearsed or maintained in an articulatory buffer. Paired associates that were learned before the injection showed a benefit of subsequent practice under saline but not under midazolam. The results suggest that (a) midazolam does not affect the formation of new associations in short-term memory provided that the presentation rate is not too fast to form these associations when sedated, despite the evidence that the drug blocks long-term memory (LTM) retention of associations; and (b) the potential for over-learning with practice of learned associations in LTM is adversely affected by midazolam such that repeated exposures do not strengthen new learning.


Effects of oxygen on autonomic nervous system dysfunction in patients with chronic obstructive pulmonary disease.
Chronic hypoxaemia can play a pathological role in abnormalities of the autonomic nervous system (ANS). In patients with chronic obstructive pulmonary disease (COPD), chronic hypoxaemia is associated with increased mortality and only long-term oxygen therapy is able to improve their survival. Normoxaemic COPD patients have been shown to suffer from abnormalities in ANS function. The aims of this study were to evaluate ANS function in COPD patients with chronic hypercapnic respiratory insufficiency and to test whether oxygen supplementation could reverse any ANS dysfunction. Eleven stable COPD patients with chronic hypercapnic respiratory insufficiency underwent evaluation of ANS by analysis of variability in cardiac frequency at rest and during both vagal (controlled breathing) and sympathetic (tilting) stimuli breathing with and without oxygen supplementation. Thirteen male, healthy, nonsmoking volunteers served as controls. Evaluation of ANS in COPD patients during hypoxic conditions showed alterations both at rest and in response to vagal and sympathetic stimuli. Oxygen supply reversed hypoxaemia without significant changes in arterial carbon dioxide tension and, therefore, ANS alterations were corrected during sympathetic stimulus only. Breathing room air and oxygen, the resting low-frequency (LF) powers were 45+/-15 and 148+/-55 ms2 x Hz(-1), respectively, and controlled breathing LF were 107+/-41 and 141+/-113 ms2 x Hz(-1), respectively. In stable patients with chronic obstructive pulmonary disease with chronic respiratory insufficiency, hypoxaemia is associated with derangements in the autonomic nervous system which may be partially reversed by oxygen administration.


Antigens of human trophoblast. Effects of heterologous anti-trophoblast sera on lymphocyte responses in vitro.
This report describes the inhibition of human mixed lymphocyte culture (MLC) reactions by rabbit antisera to intact and detergent solubilized, fractionated, human trophoblast membranes. Heat-inactivated antisera were passed through solid-phase immunoabsorption columns of normal human serum and extensively absorbed with human erythrocytes, lymphocytes and liver powder. Immunohistological experiments with these absorbed antisera showed that they reacted brilliantly with syncytiotrophoblast in cryostat sections of human but not baboon or monkey placentae, and not with other normal adult tissues including peripheral blood lymphocytes (PBL). Addition of these antisera to MLC reactions produced significant and reproducible suppression of responses without affecting cell viability. Absorption studies demonstrated complete removal of MLC inhibition and trophoblast membranes but not with PBL or suspensions of HEp-2 cells. Timed experiments showed that optimal inhibition occurred when the antisera were added between 2 and 6 h after culture initiation, and that little suppression was achieved after 18 h. Lymphocytes harvested from MLC reactions after 2 h showed that 3--5% of the cells reacted with PBL/liver-absorbed anti-trophoblast sera, and that unstimulated PBL were negative. Cultures of subhuman primate lymphocytes in the presence of heterologous antisera to human trophoblast membranes showed total inhibition of rhesus:human and human:rhesus MLC, and no suppression of baboon:human or human:baboon reactions, whereas human lymphocytes responded in an exagerated manner when stimulated by baboon cells. Modulated MLC responses to human, rhesus, or baboon lymphocytes, in the presence of anti-trophoblast sera indicate that the antisera recognize trophoblast cross-reactive lymphocytes antigens. We propose that these antigens are reaction products of cell-cell interactions, and that the nature of the antigens is determined by the specificity of the recognition signals which initiate the reaction.


Heterogeneous mechanics of the mouse pulmonary arterial network.
Individualized modeling and simulation of blood flow mechanics find applications in both animal research and patient care. Individual animal or patient models for blood vessel mechanics are based on combining measured vascular geometry with a fluid structure model coupling formulations describing dynamics of the fluid and mechanics of the wall. For example, one-dimensional fluid flow modeling requires a constitutive law relating vessel cross-sectional deformation to pressure in the lumen. To investigate means of identifying appropriate constitutive relationships, an automated segmentation algorithm was applied to micro-computerized tomography images from a mouse lung obtained at four different static pressures to identify the static pressure-radius relationship for four generations of vessels in the pulmonary arterial network. A shape-fitting function was parameterized for each vessel in the network to characterize the nonlinear and heterogeneous nature of vessel distensibility in the pulmonary arteries. These data on morphometric and mechanical properties were used to simulate pressure and flow velocity propagation in the network using one-dimensional representations of fluid and vessel wall mechanics. Moreover, wave intensity analysis was used to study effects of wall mechanics on generation and propagation of pressure wave reflections. Simulations were conducted to investigate the role of linear versus nonlinear formulations of wall elasticity and homogeneous versus heterogeneous treatments of vessel wall properties. Accounting for heterogeneity, by parameterizing the pressure/distention equation of state individually for each vessel segment, was found to have little effect on the predicted pressure profiles and wave propagation compared to a homogeneous parameterization based on average behavior. However, substantially different results were obtained using a linear elastic thin-shell model than were obtained using a nonlinear model that has a more physiologically realistic pressure versus radius relationship.


Extracellular DNA-induced antimicrobial peptide resistance in Salmonella enterica serovar Typhimurium.
The Salmonella enterica serovar Typhimurium PhoPQ two component system (TCS) is activated by low Mg2+ levels, low pH and by antimicrobial peptides (AP). Under Mg2+ limitation, the PhoPQ system induces pmrD expression, which post-translationally activates the PmrAB TCS. PhoPQ and PmrAB control many genes required for intracellular survival and pathogenesis. These include the polymyxin resistance (pmr) operon, which is required for aminoarabinose modification of LPS and protecting the outer membrane from antimicrobial peptide disruption and killing. Extracellular DNA is a ubiquitous polymer in the matrix of biofilms and accumulates in some infection sites. Extracellular DNA chelates cations and thus activates the Pseudomonas aeruginosa PhoPQ/PmrAB systems, leading to expression of the orthologous arn (pmr) operon. Here we show that extracellular DNA induces expression of the S. Typhimurium pmr antimicrobial peptide resistance operon in a PhoPQ and PmrAB-dependent manner. Induction of the pmr genes by DNA was blocked when present with excess Mg2+. Exogenous DNA led to increased resistance of planktonic cultures to aminoglycosides, antimicrobial peptides (AP) and ciprofloxacin, but only AP resistance was PhoPQ/PmrAB-dependent. Extracellular DNA was shown to be a matrix component of S. Typhimurium biofilms cultivated in flow chambers and on glass surfaces. A pmrH-gfp fusion was highly expressed in flow chamber biofilms cultivated in medium with repressing levels of 10 mM Mg2+ and co-localized with eDNA. Expression of pmrH-lux was monitored in plastic peg biofilms and shown to require PhoPQ and PmrAB. Biofilms had higher levels of pmrH expression compared to planktonic cultures. We propose that DNA accumulation in biofilms contributes to the increased pmrH-lux expression in biofilms. The Salmonella PhoPQ/PmrAB systems and antimicrobial peptide resistance are activated by the cation chelating properties of extracellular DNA. DNA-induced AP resistance may allow immune evasion and increased survival of S. Typhimurium biofilms formed during extracellular growth stages of an infection or outside the host.


HIV-1 reactivation induced by the periodontal pathogens Fusobacterium nucleatum and Porphyromonas gingivalis involves Toll-like receptor 2 [corrected] and 9 activation in monocytes/macrophages.
Although oral coinfections (e.g., periodontal disease) are highly prevalent in human immunodeficiency virus type 1-positive (HIV-1(+)) patients and appear to positively correlate with viral load levels, the potential for oral bacteria to induce HIV-1 reactivation in latently infected cells has received little attention. We showed that HIV-1 long terminal repeat (LTR) promoter activation can be induced by periodontopathogens in monocytes/macrophages; nevertheless, the mechanisms involved in this response remain undetermined. Since Toll-like receptor 2 (TLR2), TLR4, and TLR9 activation have been involved in HIV-1 recrudescence, we sought to determine the role of these TLRs in HIV-1 reactivation induced by the periodontal pathogens Fusobacterium nucleatum and Porphyromonas gingivalis using BF24 monocytes/macrophages stably transfected with the HIV-1 promoter driving chloramphenicol acetyltransferase (CAT) expression and THP89GFP cells, a model of HIV-1 latency. We demonstrated that TLR9 activation by F. nucleatum and TLR2 activation by both bacteria appear to be involved in HIV-1 reactivation; however, TLR4 activation had no effect. Moreover, the autocrine activity of tumor necrosis factor alpha (TNF-alpha) but not interleukin-1beta (IL-1beta) produced in response to bacteria could impact viral reactivation. The transcription factors NF-kappaB and Sp1 appear to be positively regulating HIV-1 reactivation induced by these oral pathogens. These results suggest that oral Gram-negative bacteria (F. nucleatum and P. gingivalis) associated with oral and systemic chronic inflammatory disorders enhance HIV-1 reactivation in monocytes/macrophages through TLR2 and TLR9 activation in a mechanism that appears to be transcriptionally regulated. Increased bacterial growth and emergence of these bacteria or their products accompanying chronic oral inflammatory diseases could be risk modifiers for viral replication, systemic immune activation, and AIDS progression in HIV-1(+) patients.


Counting cations involved in cationic clusters of hydroxy-functionalized ionic liquids by means of infrared and solid-state NMR spectroscopy.
In hydroxy-functionalized ionic liquids, two types of hydrogen bonding coexist: the conventional H-bonds between cation and anion (c-a) and those between cation and cation (c-c), although the interaction between like-charged ions is supposed to be much weaker due to the repulsive Coulomb forces. Counting the cations involved in either (c-a) or (c-c) clusters is a challenge. For that purpose, we recently performed neutron diffraction (ND) measurements and molecular dynamics (MD) simulations at and above room temperature accompanied by NMR solid-state experiments in the glassy state of the ILs. In principle, these methods are suitable for determining the populations of (c-a) and (c-c) cluster species. For different reasons we could only address single temperatures and/or small temperature intervals above 300 K. The by far largest temperature range with reasonable efforts is accessible by simple infrared (IR) spectroscopy. However, counting (c-a) or (c-c) hydrogen bonds is a difficult task due to the different transition dipole moments resulting in varying intensities and broad vibrational bands. Here we present a method for deriving the number of cations involved in (c-a) ion pairs from IR spectra in the OH stretch region. This procedure provides access to the equilibria of (c-a) and (c-c) hydrogen bonds as a function of temperature allowing derivation of the transition enthalpy.


Nanoparticles for imaging: top or flop?
Nanoparticles are frequently suggested as diagnostic agents. However, except for iron oxide nanoparticles, diagnostic nanoparticles have been barely incorporated into clinical use so far. This is predominantly due to difficulties in achieving acceptable pharmacokinetic properties and reproducible particle uniformity as well as to concerns about toxicity, biodegradation, and elimination. Reasonable indications for the clinical utilization of nanoparticles should consider their biologic behavior. For example, many nanoparticles are taken up by macrophages and accumulate in macrophage-rich tissues. Thus, they can be used to provide contrast in liver, spleen, lymph nodes, and inflammatory lesions (eg, atherosclerotic plaques). Furthermore, cells can be efficiently labeled with nanoparticles, enabling the localization of implanted (stem) cells and tissue-engineered grafts as well as in vivo migration studies of cells. The potential of using nanoparticles for molecular imaging is compromised because their pharmacokinetic properties are difficult to control. Ideal targets for nanoparticles are localized on the endothelial luminal surface, whereas targeted nanoparticle delivery to extravascular structures is often limited and difficult to separate from an underlying enhanced permeability and retention (EPR) effect. The majority of clinically used nanoparticle-based drug delivery systems are based on the EPR effect, and, for their more personalized use, imaging markers can be incorporated to monitor biodistribution, target site accumulation, drug release, and treatment efficacy. In conclusion, although nanoparticles are not always the right choice for molecular imaging (because smaller or larger molecules might provide more specific information), there are other diagnostic and theranostic applications for which nanoparticles hold substantial clinical potential.


Analysis of 3D plasmonic circuits by using surface impedance models.
Novel and accurate global and local surface impedance models have been developed to analyze plasmonic circuits fast and efficiently. In the analysis procedure, first the metal strip in the plasmonic circuit is modeled by a surface impedance. Then, the calculated surface impedance is employed in the surface integral equation to analyze the plasmonic circuit such as a through line and line coupler. Accuracy of the numerical results is shown in comparison with a commercial simulation software. The number of unknowns as well as the computational time are also compared with the volume integral equation, and it is obvious that, using our proposed surface impedance models, the analysis will be much faster and more efficient. This could have been evident from the beginning because usage of the surface impedance model helps bring the unknowns to the boundary of the structure, which reduces the number of unknowns.


Path curvature discrimination: dependence on gaze direction and optical flow speed.
Many experimental approaches to the control of steering rely on the tangent point (TP) as major source of information. The TP is a good candidate to control self-motion. It corresponds to a singular and salient point in the subject's visual field, and its location depends on the road geometry, the direction of self-motion relative to the road and the position of the driver on the road. However, the particular status of the TP in the optical flow, as a local minimum of flow speed, has often been left aside. We therefore assume that the TP is actually an optimal location in the dynamic optical array to perceive a change in the trajectory curvature. In this study, we evaluated the ability of human observers to detect variations in their path curvature from optical flow patterns, as a function of their gaze direction in a virtual environment. We simulated curvilinear self-motion parallel to a ground plane. Using random-dot optic flow stimuli of brief duration and a two-alternative forced-choice adaptive procedure, we determined path curvature discrimination thresholds, as a function of gaze direction. The discrimination thresholds are minimal for a gaze directed toward a local minimum of optical flow speed. A model based on Weber fraction of the foveal velocities (ΔV/V) correctly predicts the relationship between experimental thresholds and local flow velocities. This model was also tested for an optical flow computation integrating larger circular areas in central vision. Averaging the flow over five degrees leads to an even better fit of the model to experimental thresholds. We also found that the minimal optical flow speed direction corresponds to a maximal sensitivity of the visual system, as predicted by our model. The spontaneous gazing strategies observed during driving might thus correspond to an optimal selection of relevant information in the optical flow field.


Management of adults and children undergoing chimeric antigen receptor T-cell therapy: best practice recommendations of the European Society for Blood and Marrow Transplantation (EBMT) and the Joint Accreditation Committee of ISCT and EBMT (JACIE).
Chimeric antigen receptor (CAR) T cells are a novel class of anti-cancer therapy in which autologous or allogeneic T cells are engineered to express a CAR targeting a membrane antigen. In Europe, tisagenlecleucel (Kymriah™) is approved for the treatment of refractory/relapsed acute lymphoblastic leukemia in children and young adults as well as relapsed/refractory diffuse large B-cell lymphoma, while axicabtagene ciloleucel (Yescarta™) is approved for the treatment of relapsed/refractory high-grade B-cell lymphoma and primary mediastinal B-cell lymphoma. Both agents are genetically engineered autologous T cells targeting CD19. These practical recommendations, prepared under the auspices of the European Society of Blood and Marrow Transplantation, relate to patient care and supply chain management under the following headings: patient eligibility, screening laboratory tests and imaging and work-up prior to leukapheresis, how to perform leukapheresis, bridging therapy, lymphodepleting conditioning, product receipt and thawing, infusion of CAR T cells, short-term complications including cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, antibiotic prophylaxis, medium-term complications including cytopenias and B-cell aplasia, nursing and psychological support for patients, long-term follow-up, post-authorization safety surveillance, and regulatory issues. These recommendations are not prescriptive and are intended as guidance in the use of this novel therapeutic class.


Establishing a pharmacist-prescriber partnership in publicly funded primary healthcare clinics to optimise antibiotic prescribing in the Western Cape: An exploratory study.
Promoting evidence-based antibiotic prescribing through successful antimicrobial stewardship (AMS) programmes is critical to preserving the effectiveness of antibiotics for common infections in primary care. This requires a coordinated multidisciplinary effort. Such pharmacist-prescriber partnerships have been effective in high-income countries (HICs). Yet, evidence generated in such countries is not always applicable because of different social determinants of health. A multidisciplinary workshop was conducted with pharmacists and clinicians (doctors, nurses) on community-based antibiotic stewardship, the purpose of which was to explore how and where such partnerships might work in publicly funded primary care clinics in the greater Cape Metro region. Participants perceived that promoting effective AMS was a priority for South African primary healthcare. However, it was clear that there are many hurdles to overcome working in settings that are relatively resource-poor. Prescribing guidelines needed to be harmonised. Participants felt that staff training on the principles of AMS should be mandatory. Research was urgently needed to better understand their community's understanding of antibiotic use and AMS, and to champion outreach projects in the community. Important stakeholder perspectives in the community were highlighted to promote a multidisciplinary approach to AMS initiatives in primary care. These will need to be addressed to optimise antibiotic prescribing in the community.


Peak bone mass and osteoporosis prevention.
The incidence of osteoporotic fractures increases with advancing age. Despite advances in therapy, reversal of bone loss in established osteoporosis remains problematic and deformities and disability due to fractures often persist. Therefore the logical approach to osteoporosis treatment is preventive. Risk of fracture is determined largely by bone density, which is the end result of peak value achieved at skeletal maturity and subsequent age- and menopause-related bone loss. Thus the determinants of peak bone density and bone loss require full characterization. Environmental and lifestyle factors are important determinants of bone density, particularly physical activity and diet. For example, muscle strength and physical fitness predict bone density, so that regular moderate exercise may help maintain bone mass but probably does not reverse loss. Long-term calcium intake appears to be important for achievement and maintenance of peak bone density, especially in males. Smoking and excessive alcohol intake are deleterious to bone mass. Cultural norms in diet, lifestyle and physical activity obviously have an impact on bone density. Genetic factors have a strong role in determining the wide range in 'normal' peak bone mass. Moreover we have found strong genetic determinants of rates of change of bone mass in the lumbar spine and similar trends for sites in the femoral neck. We have shown previously that genetic factors influence bone turnover indices, particularly osteocalcin. Investigating these relationships with restriction fragment length polymorphisms, we have identified variants of the vitamin D receptor gene which predict osteocalcin levels and presumably bone turnover.(ABSTRACT TRUNCATED AT 250 WORDS)


Cellular telephone use and time trends in brain tumour mortality in Switzerland from 1969 to 2002.
A rising concern exists that with the widespread use of mobile communication technologies, the incidence of brain tumours may increase. On the basis of data from the Swiss national mortality registry from 1969 to 2002, annual age-standardized brain tumour mortality rates per 100,000 person-years were calculated using the European standard population. Time trend analyses were performed by the Poisson regression for six different age groups in men and women separately. The study period was divided into two intervals: before and after 1987, when the analogue mobile technology was introduced in Switzerland. Age-standardized brain tumour mortality rates ranged between 3.7 and 6.7 for men and 2.5 and 4.4 for women per 100,000 person-years. For the whole study period, a significant increase in brain tumour mortality was observed for men and women in the older age groups (60-74 and 75+ years) but not in the younger ones in whom mobile phone use was more prevalent. Time trend analyses restricted to data from 1987 onwards revealed relatively stable brain tumour mortality rates in all age groups. For instance, the annual change in brain tumour mortality rate for the 45-59-year age group was -0.3% (95% confidence interval: -1.7; 1.1) for men and -0.4% (95% confidence interval:-2.2; 1.3) for women. We conclude that after the introduction of mobile phone technology in Switzerland, brain tumour mortality rates remained stable in all age groups. Our results suggest that mobile phone use is not a strong risk factor in the short term for mortality from brain tumours. Ecological analyses like this, however, are limited in their ability to reveal potentially small increases in risk for diseases with a long latency period.


The eMERGE Network: a consortium of biorepositories linked to electronic medical records data for conducting genomic studies.
The eMERGE (electronic MEdical Records and GEnomics) Network is an NHGRI-supported consortium of five institutions to explore the utility of DNA repositories coupled to Electronic Medical Record (EMR) systems for advancing discovery in genome science. eMERGE also includes a special emphasis on the ethical, legal and social issues related to these endeavors. The five sites are supported by an Administrative Coordinating Center. Setting of network goals is initiated by working groups: (1) Genomics, (2) Informatics, and (3) Consent & Community Consultation, which also includes active participation by investigators outside the eMERGE funded sites, and (4) Return of Results Oversight Committee. The Steering Committee, comprised of site PIs and representatives and NHGRI staff, meet three times per year, once per year with the External Scientific Panel. The primary site-specific phenotypes for which samples have undergone genome-wide association study (GWAS) genotyping are cataract and HDL, dementia, electrocardiographic QRS duration, peripheral arterial disease, and type 2 diabetes. A GWAS is also being undertaken for resistant hypertension in ≈ 2,000 additional samples identified across the network sites, to be added to data available for samples already genotyped. Funded by ARRA supplements, secondary phenotypes have been added at all sites to leverage the genotyping data, and hypothyroidism is being analyzed as a cross-network phenotype. Results are being posted in dbGaP. Other key eMERGE activities include evaluation of the issues associated with cross-site deployment of common algorithms to identify cases and controls in EMRs, data privacy of genomic and clinically-derived data, developing approaches for large-scale meta-analysis of GWAS data across five sites, and a community consultation and consent initiative at each site. Plans are underway to expand the network in diversity of populations and incorporation of GWAS findings into clinical care. By combining advanced clinical informatics, genome science, and community consultation, eMERGE represents a first step in the development of data-driven approaches to incorporate genomic information into routine healthcare delivery.


ATP-mediated Erk1/2 activation stimulates bacterial capture by filopodia, which precedes Shigella invasion of epithelial cells.
Shigella, the causative agent of bacillary dysentery in humans, invades epithelial cells, using a type III secretory system (T3SS) to inject bacterial effectors into host cells and remodel the actin cytoskeleton. ATP released through connexin hemichanels on the epithelial membrane stimulates Shigella invasion and dissemination in epithelial cells. Here, we show that prior to contact with the cell body, Shigella is captured by nanometer-thin micropodial extensions (NMEs) at a distance from the cell surface, in a process involving the T3SS tip complex proteins and stimulated by ATP- and connexin-mediated signaling. Upon bacterial contact, NMEs retract, bringing bacteria in contact with the cell body, where invasion occurs. ATP stimulates Erk1/2 activation, which controls actin retrograde flow in NMEs and their retraction. These findings reveal previously unappreciated facets of interaction of an invasive bacterium with host cells and a prominent role for Erk1/2 in the control of filopodial dynamics.


Keratanase digestion of keratan sulphates: characterization of large oligosaccharides from the N-acetyllactosamine repeat sequence and from the non-reducing terminal chain caps.
Keratan sulfate (KS) chains prepared from both bovine tracheal rings and bovine femoral head cartilage were digested with the enzyme keratanase from Pseudomonas species; large repeat-sequence and non-reducing terminal oligosaccharides were fractionated and purified using high-performance ion-exchange chromatography. The main beta-linked pentasulfated hexasaccharide repeat segment, [R6], GlcNAc(6S)1-1-3Gal(6S)1-4GlcNAc(6S)1-3Gal(6S)1-4GlcNAc(6S)1-3Gal-ol and the asialo beta-linked capping pentasulfated heptasaccharide, [C7], Gal1-4GlcNAc(6S)1-3Gal(6S)1-4GlcNAc(6S)1-3Gal(6S)1-4GlcNAc(6S) 1-3Gal-ol have been completely characterized by high-field NMR spectroscopy using one- and two-dimensional methods. Partial 1H assignments are summarized for three homologous series of higher oligosaccharides: GlcNAc(6S)[1-3Gal(6S)1-4GlcNAc(6S)]2-5(1-3)Gal-0l [R8,R10,R12] Gal1-4GlcNAc(6S)[1-3Gal(6S)1-4GlcNAc(6S)]3-5(1-3)Gal-ol [C9,C11,C13] NeuAc alpha 2-3Gal1-4GlcNAc(6S)[1-3Gal(6S)1-4GlcNAc(6S)]2-4(1-3)Gal-ol [C8,C10,C12] obtained from keratan sulfate by keratanase cleavage. The first shows that the unsulfated galactose residues within the repeat sequence region of KS may be separated by fully sulfated segments which have a wide distribution of lengths. The others, viz. those with sialylated caps, and the related galactose capped asialo-segments (derived from a KS digestion in which the keratanase also exhibited sialidase activity) represent an homologous series of epitopes in which the first internal unsulfated galactose is located at a position which may be up to five or more fully sulfated N-acetyllactosamine disaccharide repeat units along from the non-reducing terminus of the KS polymer.


Physician roles in the cancer-related follow-up care of cancer survivors.
Information about primary care physicians' (PCPs) and oncologists' involvement in cancer-related follow-up care, and care coordination practices, is lacking but essential to improving cancer survivors' care. This study assesses PCPs' and oncologists' self-reported roles in providing cancer-related follow-up care for survivors who are within 5 years of completing cancer treatment. In 2009, the National Cancer Institute and the American Cancer Society conducted a nationally representative survey of PCPs (n=1,014) and medical oncologists (n=1,125) (response rate=57.6%, cooperation rate=65.1%). Mailed questionnaires obtained information on physicians' roles in providing cancer-related follow-up care to early-stage breast and colon cancer survivors, personal and practice characteristics, beliefs about and preferences for follow-up care, and care coordination practices. More than 50% of PCPs reported providing cancer-related follow-up care for survivors, mainly by co-managing with an oncologist. In contrast, more than 70% of oncologists reported fulfilling these roles by providing the care themselves. In adjusted analyses, PCP co-management was associated with specialty, training in late or long-term effects of cancer, higher cancer patient volume, favorable attitudes about PCP care involvement, preference for a shared model of survivorship care, and receipt of treatment summaries from oncologists. Among oncologists, only preference for a shared care model was associated with co-management with PCPs. PCPs and oncologists differ in their involvement in cancer-related follow-up care of survivors, with co-management more often reported by PCPs than by oncologists. Given anticipated national shortages of PCPs and oncologists, study results suggest that improved communication and coordination between these providers is needed to ensure optimal delivery of follow-up care to cancer survivors.


Muscle balance at the knee--moment arms for the normal knee and the ACL-minus knee.
Forces, moments and stresses at the knee are dependent upon external and internal loading factors including muscle forces, segmental position and velocity, load carried, and the moment arms (mechanical advantage) of the muscle-tendon units. Requisite to prediction of forces and moments is a detailed understanding of effective moment arms throughout the knee range-of-motion (ROM). Existing muscle models for the knee are based upon limited static studies of only a few preserved specimens. The objectives of this report are to develop a comprehensive description of muscle-tendon moment arms for the normal knee and the anterior cruciate ligament (ACL)-minus knee during flexion-extension motion. Recent research results describe two nonorthogonal, nonintersecting axes of motion for the knee--one describing flexion-extension (FE) and the other longitudinal rotation (LR, equivalent to internal-external rotation). The effective flexion-extension moment arms of the muscles crossing the knee were developed with respect to the FE axis in 15 fresh, hemi-pelvis cadaver specimens. The normal moment arms for each of 13 muscles plus the patellar tendon exhibited variable, yet repeatable and recognizable patterns throughout the ROM. For most muscles there was no significant difference between the normal and ACL-minus moment arms. The results provide a basis for more accurate predictions of joint reaction forces and moments as well as useful knowledge for practitioners and therapists to assist in the assessment of muscle balance at the knee following injury, repair, and throughout rehabilitation.


Marked telomere shortening in mobilized peripheral blood progenitor cells (PBPC) following two tightly spaced high-dose chemotherapy courses with G-CSF.
The purpose of the study was to compare telomere length (TL) in peripheral blood progenitor cells (PBPC) collected after two tightly spaced high-dose (hd) chemotherapy courses. We assessed 37 previously untreated lymphoma patients undergoing a hd-chemotherapy program with autografting. They sequentially received hd-cyclophosphamide (CY) and hd-Ara-C, both followed by PBPC harvesting. Both post-CY and post-Ara-C harvests were assessed for TL by Southern blot analysis. In 12 patients, the assay was also performed on purified CD34+ cells. All patients displayed high PBPC mobilization following both hd-CY and hd-Ara-C. In all but one patient, TL was shorter in PBPC collected after Ara-C compared to CY: 7226bp (range: 4135-9852) vs 8282 bp (range 4895-14860) (P < 0.0001). This result was confirmed on CD34+ cells. Platelet recovery in patients receiving post-Ara-C PBPC was significantly slower compared to those receiving post-CY PBPC. In conclusion, (i) administration of tightly spaced hd-chemotherapy courses induces marked telomere shortening on harvested PBPC; (ii) engraftment kinetics seem slower, with delayed platelet recovery, in patients autografted with PBPC suffering marked TL erosion; (iii) long-term follow-up is required to verify whether PBPC with shortened telomeres display defective engraftment stability and/or risk of secondary leukemia; (iv) TL evaluation is advisable whenever new mobilization procedures are developed.


Polarimetric ghost imaging.
For conventional ghost imaging (GI) systems, the object image is obtained based on the reflective or transmissive character of the object. When the object and its background have the same reflectivity or transmittance, conventional GI is helpless in detecting the object from the background. An improvement is to use the polarization components of the reflected or transmitted light. We propose a polarimetric GI system that employs a polarization state generator and a polarization state analyzer. This feature allows for the first time, to the best of our knowledge, imaging the object buried in the same reflectivity or transmittance background, which represents a breakthrough for GI applications. Using a combination of intensity and polarization information, we are better able to distinguish between the background and the different material objects.


Disability status, mortality, and leading causes of death in the United States community population.
We examined the effect of functional disability on all-cause mortality and cause-specific deaths among community-dwelling US adults. We used data from 142,636 adults who participated in the 1994-1995 National Health Interview Survey-Disability Supplement eligible for linkage to National Death Index records from 1994 to 2006 to estimate the effects of disability on mortality and leading causes of death. Adults with any disability were more likely to die than adults without disability (19.92% vs. 10.94%; hazard ratio=1.51, 95% confidence interval, 1.45-1.57). This association was statistically significant for most causes of death and for most types of disability studied. The leading cause of death for adults with and without disability differed (heart disease and malignant neoplasms, respectively). Our results suggest that all-cause mortality rates are higher among adults with disabilities than among adults without disabilities and that significant associations exist between several types of disability and cause-specific mortality. Interventions are needed that effectively address the poorer health status of people with disabilities and reduce the risk of death.


Changes in expectations to marry and to divorce across the transition to adulthood.
Marriage and divorce expectations predict family life and personal outcomes. Understanding how expectations are associated with varying characteristics over emerging adulthood (ages 18-28) will inform understanding of emerging adult development. Panel Study of Income Dynamics Transition into Adulthood 2005-2015 data were used in hybrid-effects ordinal logistic regression to parse interindividual and intraindividual variation associated with relationship experiences, socioeconomic and contextual characteristics, and mental and emotional wellbeing. Partnerships were associated with optimistic expectations: both dating and cohabiting predicted greater marriage expectations and lower divorce expectations within individuals. Between individuals, greater time in full-time employment predicted more positive marital expectations, greater responsibility was associated with lower marital expectations, stronger religious identity predicted higher marital expectations and lower divorce expectations, having been arrested predicted greater divorce expectations, greater wellbeing predicted greater marriage expectations, and older age predicted lower marriage expectations. Both between and within individuals, greater worry predicted lower marriage expectations.


A prospective study of the effectiveness of group and individual psychotherapy for women CSA survivors.
There is little empirical evidence to guide clinical practice in treating adult patients presenting to adult mental health and primary care services with severe psychological difficulties consequent on childhood sexual abuse. The aim of this study was to determine the effectiveness of a model of short term, focal, integrative psychotherapy with this population of patients and to compare outcomes when the model is delivered on an individual or group basis. This study used a patient preference design with random allocation to one of two treatment modalities (individual or group treatment). There was a waiting list control. A group of 48 women patients were assessed on 4 psychological measures when entering a waiting list condition, immediately before treatment and after completion of 12 sessions of psychotherapy, either in a group or individually. Follow-up data were collected at 4 months and 8 months. Both individual and group patients showed highly statistically and clinically significant improvements after treatment. These gains were maintained at follow-up with the exception of one measure that indicated a significant decline from post-treatment levels for the group patients. This model of psychotherapy is highly effective, when delivered by chartered clinical psychologists to patients whose preferences for individual or group therapy have been met.


Delayed presentation of a right-sided diaphragmatic hernia and group B streptococcal sepsis. Two case reports and a review of the literature.
Group B streptococcal sepsis was associated with delayed presentation of an unsuspected right-sided diaphragmatic hernia in two neonates. These unusual clinical observations and a review of 24 similar cases from the literature form the basis of this report. Infants present with respiratory distress during the first few hours of life and have group B streptococcal sepsis confirmed by results of blood cultures. The right side of the diaphragm appears normal on the initial chest roentgenogram in the majority of cases. After initial improvement with antibiotic therapy and ventilatory support, sudden deterioration of respiratory status may occur. Subsequent chest roentgenograms often demonstrate herniated viscera in half of the cases, while ultrasound examination, isotopic liver scan, and peritoneography are useful in achieving a diagnosis in the other cases. If recognized, survival is 100% following hernia repair. Persistent respiratory symptoms in a neonate who is recovering from group B streptococcal sepsis should prompt a careful evaluation of the right side of the diaphragm for the presence of an unsuspected posterolateral hernia.


Biological activity, membrane-targeting modification, and crystallization of soluble human decay accelerating factor expressed in E. coli.
Decay-accelerating factor (DAF, CD55) is a glycophosphatidyl inositol-anchored glycoprotein that regulates the activity of C3 and C5 convertases. In addition to understanding the mechanism of complement inhibition by DAF through structural studies, there is also an interest in the possible therapeutic potential of the molecule. In this report we describe the cloning, expression in Escherichia coli, isolation and membrane-targeting modification of the four short consensus repeat domains of soluble human DAF with an additional C-terminal cysteine residue to permit site-specific modification. The purified refolded recombinant protein was active against both classical and alternative pathway assays of complement activation and had similar biological activity to soluble human DAF expressed in Pichia pastoris. Modification with a membrane-localizing peptide restored cell binding and gave a large increase in antihemolytic potency. These data suggested that the recombinant DAF was correctly folded and suitable for structural studies as well as being the basis for a DAF-derived therapeutic. Crystals of the E. coli-derived protein were obtained and diffracted to 2.2 A, thus permitting the first detailed X-ray crystallography studies on a functionally active human complement regulator protein with direct therapeutic potential.


Anisotropic Flow of Charged Particles in Pb-Pb Collisions at √[s{NN}]=5.02 TeV.
We report the first results of elliptic (v_{2}), triangular (v_{3}), and quadrangular (v_{4}) flow of charged particles in Pb-Pb collisions at a center-of-mass energy per nucleon pair of sqrt[s_{NN}]=5.02 TeV with the ALICE detector at the CERN Large Hadron Collider. The measurements are performed in the central pseudorapidity region |η|<0.8 and for the transverse momentum range 0.2<p_{T}<5 GeV/c. The anisotropic flow is measured using two-particle correlations with a pseudorapidity gap greater than one unit and with the multiparticle cumulant method. Compared to results from Pb-Pb collisions at sqrt[s_{NN}]=2.76 TeV, the anisotropic flow coefficients v_{2}, v_{3}, and v_{4} are found to increase by (3.0±0.6)%, (4.3±1.4)%, and (10.2±3.8)%, respectively, in the centrality range 0%-50%. This increase can be attributed mostly to an increase of the average transverse momentum between the two energies. The measurements are found to be compatible with hydrodynamic model calculations. This comparison provides a unique opportunity to test the validity of the hydrodynamic picture and the power to further discriminate between various possibilities for the temperature dependence of shear viscosity to entropy density ratio of the produced matter in heavy-ion collisions at the highest energies.


Effect of platelet-rich plasma on healing tissues in acute ruptured Achilles tendon: a human immunohistochemistry study.
Platelet-rich plasma (PRP), an autologous derivative of whole blood that contains a supraphysiological concentration of platelets, is thought to invoke an earlier and improved tissue healing response. This notion has been supported by in-vitro and animal studies in bone, cartilage, tendon, and muscle. To our knowledge no published study exists of the effects of PRP in human tissues in vivo. The aim of our study was to investigate the response of ruptured Achilles tendon treated with PRP. Tendon tissue biopsy samples were obtained from 20 patients with ruptured Achilles tendon by means of ultrasound-guided needle biopsies from the healing area of the Achilles tendon 6 weeks after treatment with PRP or placebo controls (10 patients each). All samples were embedded in paraffin wax, sectioned, and stained with haematoxylin and eosin and alcian blue. Immunohistochemistry markers were used to identify collagen I and III, lymphocytes (CD45), proliferation (KI67), and blood vessels (CD34). All images were masked and analysed with Image J software. Cellularity and glycosaminoglycans content were significantly higher in PRP-treated tendons than in controls (p=0·01 and p<0·001, respectively). Fibre structure of the tissue was significantly better in the PRP group than in the control tissue (p<0·001). Although both groups showed high collagen I staining, content of collagen I was significantly higher in PRP-treated tendons than in control tendons (p=0·0079), whereas collagen III content was not different (p=1·0). The ratio of collagen III to collagen I was significantly lower in PRP samples (p=0·007). There was no significant difference in CD45 expression (p=0·33). However, PRP samples had fewer blood vessels than did control samples (p=0·023). The overall modified Bonar score was significantly lower in PRP samples, which indicates improved early tendon healing. This is the first study, to our knowledge, to report the immunohistochemical response of ruptured human Achilles tendon to PRP. The findings reveal that locally applied PRP enhanced the maturity of the healing tendon tissues by promoting better collagen I deposition, decreased cellularity, less vascularity, and higher glycosaminoglycan content when compared with control samples. Further work is required to determine the longer term effects of the use of PRP in musculoskeletal diseases. National Institute for Health Research.


At the second glance: stability of neural responses toward visual sexual stimuli.
Studies investigating the neural responses toward sexual stimuli can provide an important basis for further understanding disorders of sexual functioning. Although our knowledge of the neural correlates of sexual stimulus processing has increased considerably in the last decade, the stability of the observed effects in studies on neural sexual responses has been rather neglected. The current study aimed to test the stability of behavioral and neural responses to visual sexual stimuli in men and women over a time span of 1 to 1.5 years. To disentangle valence and arousal-related aspects of sexual stimulus processing, we employed not only sexual and neutral, but also positive and negative emotional stimuli. A sample of 56 subjects (24 women) was assessed twice, with an interval of 1 to 1.5 years between assessments. During a functional magnetic resonance imaging (fMRI) session, participants passively viewed sexual, neutral, positive, and negative emotional pictures. Pictures were presented in 24 blocks of five pictures each. Every block was rated immediately after its presentation with respect to valence, arousal, and sexual arousal. Blood oxygen level dependent (BOLD) responses measured by fMRI and stimulus ratings. fMRI analyses revealed a distributed network involved in the processing of sexual stimuli, with large parts of this network being consistently activated at both assessment points. Nucleus accumbens, anterior cingulate, occipital and parietal cortex showed the most robust results with respect to group stability. Responses of anterior cingulate, orbitofrontal, parietal and occipital cortex showed interindividual stability. Gender differences were restricted to a few regions of interest. Our data indicate stability of neural responses toward sexual stimuli not only on the group but also on the individual level. Activation of parietal and occipital cortex might reflect a trait like character of attention related responses toward sexual stimuli.


The profile of hematinic deficiencies in patients with oral lichen planus: a case-control study.
Oral lichen planus (OLP) is a relatively common mucocutaneous disorder, and its causative factors and pathogenesis are not fully understood. Existing studies on the association between hematinic deficiencies and OLP are limited and inconsistent. The aim of this study was to assess the hematinic deficiencies in a cohort of OLP patients and evaluate the correlation between hematinic deficiencies and OLP. A total of 236 OLP patients and 226 age-and-gender-matched healthy controls were enrolled in this study. The levels of hemoglobin (Hb), serum folate, vitamin B12 and ferritin were measured and compared between OLP patients and healthy controls. An REU (reticular/hyperkeratotic, erosive/erythematous, ulcerative) scoring system was adopted and compared between the OLP patients with and without hematinic deficiencies. The correlation between hematinic deficiencies and OLP was analyzed. The frequencies of serum ferritin and vitamin B12 deficiency in OLP patients were both significantly higher than those of the healthy controls. According to gender and age, the profiles of hematinic deficiencies in OLP patients were significantly different. As for the REU score, no significant difference existed between OLP patients with and without hematinic deficiencies. Both serum ferritin deficiency and serum vitamin B12 deficiency were significantly correlated with OLP. The present study suggested a significant association between hematinic deficiencies and OLP. Iron, folate, and vitamin B12 levels in OLP patients should be monitored routinely. Further studies are warranted to explore the interactions between OLP and hematinic deficiencies.


Thyrotropin receptor signaling deficiency impairs spatial learning and memory in mice.
Subclinical hyperthyroidism, a condition characterized by decreased thyroid-stimulating hormone (TSH) and normal concentration of thyroid hormone, is associated with an elevated risk for cognitive impairment. TSH is the major endogenous ligand of the TSH receptor (TSHR) and its role is dependent on signal transduction of TSHR. It has not, however, been established whether TSHR signaling is involved in the regulation of cognition. Here, we utilized Tshr knockout mice and found that Tshr deletion led to significantly compromised performance in learning and memory tests. Reduced dendritic spine density and excitatory synaptic density as well as altered synaptic structure in CA1 subfield of the hippocampus were also noted. Furthermore, the synapse-related gene expression was altered in the hippocampus of Tshr -/- mice. These findings suggest that TSHR signaling deficiency impairs spatial learning and memory, which discloses a novel role of TSHR signaling in brain function.


Functional small-diameter neovessels created using endothelial progenitor cells expanded ex vivo.
Arterial conduits are increasingly preferred for surgical bypass because of inherent functional properties conferred by arterial endothelial cells, especially nitric oxide production in response to physiologic stimuli. Here we tested whether endothelial progenitor cells (EPCs) can replace arterial endothelial cells and promote patency in tissue-engineered small-diameter blood vessels (4 mm). We isolated EPCs from peripheral blood of sheep, expanded them ex vivo and then seeded them on decellularized porcine iliac vessels. EPC-seeded grafts remained patent for 130 days as a carotid interposition graft in sheep, whereas non-seeded grafts occluded within 15 days. The EPC-explanted grafts exhibited contractile activity and nitric-oxide-mediated vascular relaxation that were similar to native carotid arteries. These results indicate that EPCs can function similarly to arterial endothelial cells and thereby confer longer vascular-graft survival. Due to their unique properties, EPCs might have other general applications for tissue-engineered structures and in treating vascular diseases.


Patients' perceptions of fatigue in rheumatoid arthritis: overwhelming, uncontrollable, ignored.
Fatigue is commonly reported by patients with rheumatoid arthritis (RA) but is rarely a treatment target. The aim of this study was to explore the concept of fatigue as experienced by patients with RA. Fifteen patients with RA and fatigue (> or =7 on a 10-cm visual analog scale) were individually interviewed and asked about the description, cause, consequence, and management of fatigue. Transcripts were systematically analyzed by 2 researchers independently, relevant phrases were coded, and earlier transcripts were checked for the emerging codes. A random sample of analyses were independently reviewed. A total of 191 codes arising from the data were grouped into 46 categories and overarching themes. Vivid descriptions reflect 2 types of fatigue: severe weariness and dramatic overwhelming fatigue. RA fatigue is different from normal tiredness because it is extreme, often not earned, and unresolving. Participants described physical, cognitive, and emotional components and attributed fatigue to inflammation, working the joints harder, and unrefreshing sleep. Participants described far-reaching effects on physical activities, emotions, relationships, and social and family roles. Participants used self-management strategies but with limited success. Most did not discuss fatigue with clinicians but when they did, they felt it was dismissed. Participants held negative views on the management of fatigue. The data show that RA fatigue is important, intrusive, and overwhelming, and patients struggle to manage it alone. These data on the complexity of fatigue experiences will help clinicians design measures, interventions, and self-managment guidance.


DNA polymorphism detectable by restriction endonucleases.
Data on DNA polymorphisms detected by restriction endonucleases are rapidly accumulating. With the aim of analyzing these data, several different measures of nucleon (DNA segment) diversity within and between populations are proposed, and statistical methods for estimating these quantities are developed. These statistical methods are applicable to both nuclear and nonnuclear DNAs. When evolutionary change of nucleons occurs mainly by mutation and genetic drift, all the measures can be expressed in terms of the product of mutation rate per nucleon and effective population size. A method for estimating nucleotide diversity from nucleon diversity is also presented under certain assumptions. It is shown that DNA divergence between two populations can be studied either by the average number of restriction site differences or by the average number of nucleotide differences. In either case, a large number of different restriction enzymes should be used for studying phylogenetic relationships among related organisms, since the effect of stochastic factors on these quantities is very large. The statistical methods developed have been applied to data of Shah and Langley on mitochondrial (mt)DNA from Drosophila melanogaster, simulans and virilis. This application has suggested that the evolutionary change of mtDNA in higher animals occurs mainly by nucleotide substitution rather than by deletion and insertion. The evolutionary distances among the three species have also been estimated.


Evaluation of underlying mechanisms in the link between childhood ADHD symptoms and risk for early initiation of substance use.
Although there has been support for attention-deficit/hyperactivity disorder (ADHD) as a risk for early substance use, this link is not fully established or understood. Furthermore, the potential mechanisms explaining these associations are unclear. The current study examined peer rejection, school bonding, and internalizing problems as potential mediators of the association between childhood ADHD symptoms and risk for early initiation of substance use. The sample included a control group of 126 students with problematic aggression (79% African American, 66% male) from an intervention study following children from fourth to ninth grade. Results suggested that ADHD symptoms follow a path to early initiation of tobacco use through the combined effects of peer rejection and internalizing problems as well as through internalizing problems alone. ADHD symptoms were also associated with the cubic slope of marijuana use initiation, such that increased ADHD symptoms were associated with a strong cubic trend (e.g., a more rapid acceleration of risk for initiation). ADHD symptoms were not associated with risk for early initiation of alcohol use. Identification of important vulnerability factors in children with ADHD symptoms highlight the need for primary prevention and psychological interventions that target these factors and decrease the likelihood of early tobacco and marijuana use initiation.


Reliability and validity of the Orofacial Esthetic Scale in prosthodontic patients.
This study evaluated the reliability and validity of the Orofacial Esthetic Scale (OES)-an instrument assessing self-reported orofacial esthetics in prosthodontic patients. The OES has seven items addressing direct esthetic impacts in the orofacial region, as well as an eighth global assessment item. The response format was a 0 to 10 numeric rating scale (very dissatisfied to very satisfied with appearance, respectively). OES summary scores ranged from 0 (worst score) to 70 (best score). Test-retest reliability (n = 27) and internal consistency (n = 119) were assessed. Content validation (asking patients about their satisfaction with the questionnaire content, n = 119) and discriminative validation (comparing OES scores between patients and healthy controls, n = 119) were performed. Convergent validity was assessed by correlating patients' own OES scores (n = 29) with ratings from a consensus expert group (n = 4) and with the Oral Health Impact Profile (OHIP) esthetic-item summary score (n = 119). Test-retest reliability was excellent for the OES scores (intraclass correlation coefficient = .96). Internal consistency was satisfactory for esthetically impaired patients (n = 27, Cronbach alpha = .86). Patients rated their satisfaction with the questionnaire content as 7.8 +/- 1.3 units on a 0 to 10 numeric rating scale (0 = very dissatisfied, 10 = very satisfied). OES scores discriminated esthetically impaired patients (31.4 units) from healthy controls (45.9 units, P < .001). OES scores correlated well with other measures of the same construct (r = .43 for patients' own assessment with an assessment by experts using the OES, r = -.72 for a correlation with the OHIP's three esthetic-related items). The OES, developed especially for prosthodontic patients, exhibited good score reliability and validity.


Interaction of Escherichia coli DbpA with 23S rRNA in different functional states of the enzyme.
DEx(D)/(H) proteins catalyze structural rearrangements in RNA by coupling ATP hydrolysis to the destabilization of RNA helices or RNP complexes. The Escherichia coli DEx(D)/(H) protein DbpA specifically recognizes a region within the catalytic core of 23S rRNA. To better characterize the interaction of DbpA with this region and to identify changes in the complex between different nucleotide-bound states of the enzyme, RNase T1, RNase T2, kethoxal and DMS footprinting of DbpA on a 172 nt fragment of 23S rRNA were performed. A number of protections identified in helices 90 and 92 were consistent with biochemical experiments measuring the RNA binding and ATPase activity of DbpA with truncated RNAs. When DbpA was bound with AMPPNP, but not ADP, several additional footprints were detected in helix 93 and the single-stranded region 5' of helix 90, suggesting binding of the helicase domains of DbpA at these sites. These results propose that DbpA can act at multiple sites and hint at the targets of its biological activity on rRNA.


Opposing effects of CTLA4 insufficiency on regulatory versus conventional T cells in autoimmunity converge on effector memory in target tissue.
Quantitative variations in CTLA4 expression, because of genetic polymorphisms, are associated with various human autoimmune conditions, including type 1 diabetes (T1D). Extensive studies have demonstrated that CTLA4 is not only essential for the suppressive role of regulatory T cells (T(reg)) but also required for intrinsic control of conventional T (T(conv)) cells. We report that a modest insufficiency of CTLA4 in mice, which mimics the effect of some human CTLA4 genetic polymorphisms, accompanied by a T1D-permissive MHC locus, was sufficient to induce juvenile-onset diabetes on an otherwise T1D-resistant genetic background. Reduction in CTLA4 levels had an unanticipated effect in promoting Treg function both in vivo and in vitro. It led to an increase in T(reg) memory in both lymphoid and nonlymphoid target tissue. Conversely, modulating CTLA4 by either RNA interference or Ab blockade promoted conventional effector memory T cell formation in the T(conv) compartment. The CD4(+) conventional effector memory T cells, including those within target tissue, produced IL-17 or IFN-γ. Blocking IL-7 signaling reduced the Th17 autoimmune compartment but did not suppress the T1D induced by CTLA4 insufficiency. Enhanced effector memory formation in both T(conv) and T(reg) lineages may underpin the apparently dichotomized impact of CTLA4 insufficiency on autoimmune pathogenesis. Therefore, although the presence of CTLA4 plays a critical role in controlling homeostasis of T cells, its quantitative variation may impose diverse or even opposing effects on distinct lineages of T cells, an optimal sum of which is necessary for preservation of T cell immunity while suppressing tissue damage.


Clinical characteristics and therapeutic outcomes of paroxysmal nocturnal hemoglobinuria patients in Turkey: a multicenter experience.
The aim of this study is to collect paroxysmal nocturnal hemoglobinuria (PNH) patient data from hematology centers all over Turkey in order to identify clinical features and management of PNH patients. Patients with PNH were evaluated by a retrospective review of medical records from 19 different institutions around Turkey. Patient demographics, medical history, laboratory findings, and PNH-specific information, including symptoms at the diagnosis, complications, erythrocyte, and granulocyte clone size, treatment, and causes of death were recorded. Sixty patients (28 males, 32 females) were identified. The median age was 33 (range; 17-77) years. Forty-six patients were diagnosed as classic PNH and 14 as secondary PNH. Fatigue and abdominal pain were the most frequent presenting symptoms. After eculizumab became available in Turkey, most of the patients (n = 31/46, 67.4%) were switched to eculizumab. Three patients with classic PNH underwent stem cell transplantation. The median survival time was 42 (range; 7-183 months) months. This study is the first and most comprehensive review of PNH cases in Turkey. It provided us useful information to find out the differences between our patients and literature, which may help us understand the disease.


The UniProt-GO Annotation database in 2011.
The GO annotation dataset provided by the UniProt Consortium (GOA: http://www.ebi.ac.uk/GOA) is a comprehensive set of evidenced-based associations between terms from the Gene Ontology resource and UniProtKB proteins. Currently supplying over 100 million annotations to 11 million proteins in more than 360,000 taxa, this resource has increased 2-fold over the last 2 years and has benefited from a wealth of checks to improve annotation correctness and consistency as well as now supplying a greater information content enabled by GO Consortium annotation format developments. Detailed, manual GO annotations obtained from the curation of peer-reviewed papers are directly contributed by all UniProt curators and supplemented with manual and electronic annotations from 36 model organism and domain-focused scientific resources. The inclusion of high-quality, automatic annotation predictions ensures the UniProt GO annotation dataset supplies functional information to a wide range of proteins, including those from poorly characterized, non-model organism species. UniProt GO annotations are freely available in a range of formats accessible by both file downloads and web-based views. In addition, the introduction of a new, normalized file format in 2010 has made for easier handling of the complete UniProt-GOA data set.


A genome-wide screen for identifying all regulators of a target gene.
We have developed a new screening methodology for identifying all genes that control the expression of a target gene through genetic or metabolic interactions. The screen combines mutant libraries with luciferase reporter constructs, whose expression can be monitored in vivo and over time in different environmental conditions. We apply the method to identify the genes that control the expression of the gene acs, encoding the acetyl coenzyme A synthetase, in Escherichia coli. We confirm most of the known genetic regulators, including CRP-cAMP, IHF and components of the phosphotransferase system. In addition, we identify new regulatory interactions, many of which involve metabolic intermediates or metabolic sensing, such as the genes pgi, pfkA, sucB and lpdA, encoding enzymes in glycolysis and the TCA cycle. Some of these novel interactions were validated by quantitative reverse transcriptase-polymerase chain reaction. More generally, we observe that a large number of mutants directly or indirectly influence acs expression, an effect confirmed for a second promoter, sdhC. The method is applicable to any promoter fused to a luminescent reporter gene in combination with a deletion mutant library.


Variation in parent-offspring kinship in socially monogamous systems with extra-pair reproduction and inbreeding.
Female extra-pair reproduction in socially monogamous systems is predicted to cause cuckolded socially-paired males to conditionally reduce paternal care, causing selection against extra-pair reproduction and underlying polyandry. However, existing models and empirical studies have not explicitly considered that cuckolded males might be related to their socially-paired female and/or to her extra-pair mate, and therefore be related to extra-pair offspring that they did not sire but could rear. Selection against paternal care, and hence against extra-pair reproduction, might then be weakened. We derive metrics that quantify allele-sharing between within-pair and extra-pair offspring and their mother and her socially-paired male in terms of coefficients of kinship and inbreeding. We use song sparrow (Melospiza melodia) paternity and pedigree data to quantify these metrics, and thereby quantify the joint effects of extra-pair reproduction and inbreeding on a brood's total allelic value to its socially-paired parents. Cuckolded male song sparrows were almost always detectably related to extra-pair offspring they reared. Consequently, although brood allelic value decreased substantially following female extra-pair reproduction, this decrease was reduced by within-pair and extra-pair reproduction among relatives. Such complex variation in kinship within nuclear families should be incorporated into models considering coevolutionary dynamics of extra-pair reproduction, parental care, and inbreeding.


How can we improve healthcare access and general self-rated health among orphans and vulnerable children? Findings from a Kenyan cross-sectional study.
This study analyzes healthcare access and general self-rated health (GSRH) among orphan and vulnerable child (OVC) households enrolled in an empowerment program in Eastern Province, Kenya. Analyses investigate whether reported monthly income mediates the association between program participation and medical security. Predictors of GSRH are also investigated. Cross-sectional survey data on families (n = 707) participating in a multisectoral empowerment program were collected in June 2012. Regression methods were used to investigate study aims. Monthly income mediated 14.3 % of the total effect of program participation on healthcare accessibility. Program participation was not significantly associated with higher GSRH. Increased reported monthly income predicted improved healthcare access, but only explained a portion of improved healthcare access in the study population. Partnerships between community-based empowerment programs and clinical providers might successfully target multiple outcomes among OVC, including improved healthcare access, though further research on potential synergies is required. GSRH was associated with increased access to food, medical care, literacy, safe drinking water and household income. Further research on GSRH among OVC should target measurement validity, potential sources of disparity in GSRH between OVC and non-OVC, and targets for improving GSRH among OVC.