[Reaction of microorganisms to the digestive fluid of the earthworms].
The reaction of soil bacteria and fungi to the digestive fluid of the earthworm Aporrectodea caliginosa was studied. The fluid was obtained by centrifugation of the native enzymes of the digestive tract. The inhibition of growth of certain bacteria, spores, and fungal hyphae under the effect of extracts from the anterior and middle sections of the digestive tract of A. caliginosa was discovered for the first time. In bacteria, microcolony formation was inhibited as early as 20-30 s after the application of the gut extracts, which may indicate the nonenzymatic nature of the effect. The digestive fluid exhibited the same microbicidal activity whether the earthworms were feeding on soil or sterile sand. This indicates that the microbicidal agents are formed within the earthworm's body, rather than by soil microorganisms. The effect of the digestive fluid from the anterior and middle divisions is selective in relation to different microorganisms. Of 42 strains of soil bacteria, seven were susceptible to the microbicidal action of the fluid (Alcaligenes.faecalis 345-1, Microbacterium sp. 423-1, Arthrobacter sp. 430-1, Bacillus megaterium 401-1, B. megaterium 413-1, Kluyvera ascorbata 301-1, Pseudomonas reactans 387-2). The remaining bacteria did not die in the digestive fluid. Of 13 micromycetes, the digestive fluid inhibited spore germination in Aspergillus terreus and Paecilomyces lilacinus and the growth of hyphae in Trichoderma harzianum and Penicillium decumbens. The digestive fluid stimulated spore germination in Alternaria alternata and the growth of hyphae in Penicillium chrysogenum. The reaction of the remaining micromycetes was neutral. The gut fluid from the posterior division of the abdominal tract did not possess microbicidal activity. No relation was found between the reaction of microorganisms to the effects of the digestive fluid and the taxonomic position of the microorganisms. The effects revealed are similar to those shown earlier for millipedes and wood lice in the following parameters: quick action of the digestive fluid on microorganisms, and the selectivity of the action on microorganisms revealed at the strain level. The selective effect of the digestive gut fluid of the earthworms on soil microorganisms is important for animal feeding, maintaining the homeostasis of the gut microbial community, and the formation of microbial communities in soils.


Relationship dynamics and teenage pregnancy in South Africa.
Teenage pregnancy is extremely common in South Africa. Whilst its 'problematic' nature is a subject of debate, it reflects a pattern of sexual activity which puts teenagers at risk of HIV. Currently one in five pregnant teenagers is infected with the virus. This creates a new imperative to understand teenage pregnancy and the pattern of high risk sexual activity of which it is one consequence. This was an exploratory study undertaken to investigate factors associated with teenage pregnancy amongst sexually active adolescents in an urban and peri-urban context. The study used a matched case control design, with 191 cases and 353 school or neighbourhood, age-matched controls. Subjects were under 19 years and recruited from township areas of Cape Town. A structured questionnaire was used to obtain information on socio-economic factors, contraceptive knowledge and use, and sexual behaviour. Conditional logistic regression was used to analyse the relationship between teenage pregnancy and the factors investigated. The results presented focus on relationship dynamics and their association with the risk of pregnancy. Both groups of teenagers had been dating for a mean of two and a half years and about half were still with their first sexual partner. The partners of the pregnant teenagers were significantly older, less likely to be in school and less likely to have other girlfriends. The pregnant teenagers were significantly more likely to have experienced forced sexual initiation and were beaten more often. They were much less likely to have confronted their boyfriend when they discovered he had other girlfriends. Multiple modelling shows that both forced sexual initiation and unwillingness to confront an unfaithful partner are strongly associated with pregnancy and also related to each other. We argue that the associations are mediated through unequal power relations within the relationship which are reinforced by violence. We further discuss indicators of greater intimacy within relationships of the pregnant teenagers which may suggest that more of the pregnancies were wanted than was suggested. Both of these conclusions pose critical challenges for health promoters.


Development and initial validation of the Stress of Conscience Questionnaire.
Stress in health care is affected by moral factors. When people are prevented from doing 'good' they may feel that they have not done what they ought to or that they have erred, thus giving rise to a troubled conscience. Empirical studies show that health care personnel sometimes refer to conscience when talking about being in ethically difficult everyday care situations. This study aimed to construct and validate the Stress of Conscience Questionnaire (SCQ), a nine-item instrument for assessing stressful situations and the degree to which they trouble the conscience. The items were based on situations previously documented as causing negative stress for health care workers. Content and face validity were established by expert panels and pilot studies that selected relevant items and modified or excluded ambiguous ones. A convenience sample of 444 health care personnel indicated that the SCQ had acceptable validity and internal consistency (Cronbach's alpha exceeded 0.83 for the overall scale). Explorative factor analysis identified and labelled two factors: 'internal demands' and 'external demands and restrictions'. The findings suggest that the SCQ is a concise and practical instrument for use in various health care contexts.


On the magnitude of the electrostatic contribution to ligand-DNA interactions.
A model based on the nonlinear Poisson-Boltzmann equation is used to study the electrostatic contribution to the binding free energy of a simple intercalating ligand, 3,8-diamino-6-phenylphenanthridine, to DNA. We find that the nonlinear Poisson-Boltzmann model accurately describes both the absolute magnitude of the pKa shift of 3,8-diamino-6-phenylphenanthridine observed upon intercalation and its variation with bulk salt concentration. Since the pKa shift is directly related to the total electrostatic binding free energy of the charged and neutral forms of the ligand, the accuracy of the calculations implies that the electrostatic contributions to binding are accurately predicted as well. Based on our results, we have developed a general physical description of the electrostatic contribution to ligand-DNA binding in which the electrostatic binding free energy is described as a balance between the coulombic attraction of a ligand to DNA and the disruption of solvent upon binding. Long-range coulombic forces associated with highly charged nucleic acids provide a strong driving force for the interaction of cationic ligands with DNA. These favorable electrostatic interactions are, however, largely compensated for by unfavorable changes in the solvation of both the ligand and the DNA upon binding. The formation of a ligand-DNA complex removes both charged and polar groups at the binding interface from pure solvent while it displaces salt from around the nucleic acid. As a result, the total electrostatic binding free energy is quite small. Consequently, nonpolar interactions, such as tight packing and hydrophobic forces, must play a significant role in ligand-DNA stability.


Social embeddedness in an online weight management programme is linked to greater weight loss.
The obesity epidemic is heightening chronic disease risk globally. Online weight management (OWM) communities could potentially promote weight loss among large numbers of people at low cost. Because little is known about the impact of these online communities, we examined the relationship between individual and social network variables, and weight loss in a large, international OWM programme. We studied the online activity and weight change of 22,419 members of an OWM system during a six-month period, focusing especially on the 2033 members with at least one friend within the community. Using Heckman's sample-selection procedure to account for potential selection bias and data censoring, we found that initial body mass index, adherence to self-monitoring and social networking were significantly correlated with weight loss. Remarkably, greater embeddedness in the network was the variable with the highest statistical significance in our model for weight loss. Average per cent weight loss at six months increased in a graded manner from 4.1% for non-networked members, to 5.2% for those with a few (two to nine) friends, to 6.8% for those connected to the giant component of the network, to 8.3% for those with high social embeddedness. Social networking within an OWM community, and particularly when highly embedded, may offer a potent, scalable way to curb the obesity epidemic and other disorders that could benefit from behavioural changes.


Crystal and melt inclusion timescales reveal the evolution of magma migration before eruption.
Volatile element concentrations measured in melt inclusions are a key tool used to understand magma migration and degassing, although their original values may be affected by different re-equilibration processes. Additionally, the inclusion-bearing crystals can have a wide range of origins and ages, further complicating the interpretation of magmatic processes. To clarify some of these issues, here we combined olivine diffusion chronometry and melt inclusion data from the 2008 eruption of Llaima volcano (Chile). We found that magma intrusion occurred about 4 years before the eruption at a minimum depth of approximately 8 km. Magma migration and reaction became shallower with time, and about 6 months before the eruption magma reached 3-4 km depth. This can be linked to reported seismicity and ash emissions. Although some ambiguities of interpretation still remain, crystal zoning and melt inclusion studies allow a more complete understanding of magma ascent, degassing, and volcano monitoring data.


HIV-specific ADCC improves after antiretroviral therapy and correlates with normalization of the NK cell phenotype.
Natural killer (NK) cell phenotype and function have recently gained much attention as playing crucial roles in antibody-dependent cellular cytotoxicity (ADCC). We investigated NK cell function, as measured by ADCC, in HIV-1-positive individuals before and 6 months after highly active antiretroviral therapy (HAART) initiation. The ability of antibodies and NK cells to mediate ADCC was investigated separately and in combination in an autologous model. The NK cell subset distribution and NK cell phenotype (ie, expression of maturation and activation markers within NK cell subsets) were analyzed. The ability of NK cells to mediate ADCC was significantly increased after only 6 months of HAART and was not explained by a normalization of NK cell subsets (CD56 CD16 and CD56 CD16 NK cells) but rather by normalization in the frequency of NK cells expressing CCR7 and CD27. For individuals with no increase in ADCC after 6 months of HAART, the frequency of NK cells expressing NKp46 was downregulated. The ability of antibodies to mediate ADCC alone and in combination in an autologous model was not improved. HAART improves the ability of NK cells to mediate ADCC after 6 months. This improvement does not correlate with general immune restoration, as measured by CD4 T-cell counts, but rather to a decrease in the frequency of NK cells expressing CCR7 and CD27.


Evaluation of the effect of the 2011 Tsunami on coastal forests by means of multiple isotopic analyses of tree-rings.
The March 2011 Mega-Tsunami in eastern Japan damaged at different degrees the black pine (Pinus thunbergii) forests along the coast. In order to evaluate the recovery of black pine four years later, tree-ring samples from 9 trees for the period 2002-2014 were analyzed for ring growth and stable isotopes (δ13C, δ15N and δ18O). The results showed that annual tree-ring width decreased approximately 70 % from the year 2011 to 2014 compared to the period previous to the tsunami (2002-2010). The multiple isotopic analyses showed that the reduction in growth was caused by soil salinity that prompted stomatal closure and an abrupt increase of tree-ring δ13C. Sea water deposition in the soil did not affect tree-ring δ18O values. Two years after the tsunami, decreasing tree-ring δ13C values caused by apparently photosynthetic recovery did not translate into radial tree-growth, indicating a possible shift in carbon allocation to foliage and mainly roots as a defense mechanism to sodium toxicity. The dual δ13C-δ18O model explains neither the limited growth nor the subsequent recovery in δ13C. Similarly tree-ring δ15N indicated that there was no difference in nitrogen availability before and after the tsunami, suggesting that nutrients were not a limitation but rather soil salinity.


Breast cancer screening in France: results of the EDIFICE survey.
The EDIFICE survey aimed to investigate the compliance of the general population to the screening tests available in France for the 4 most common cancers: breast, colorectal, prostate and lung. Implementation of breast cancer screening has been generalized in France since 2003: women aged between 50 and 74 years are systematically invited to perform a mammography every second year. Results pertaining to breast cancer are reported hereafter. This nationwide observational survey was carried out in France from 18 January to 2 February 2005 among representative samples of 773 women aged between 40 and 75 years and 600 general practitioners (GPs). Information collected included socio-demographic characteristics, attitude towards cancer screening and actual experience of cancer screening, as well as GPs' practice regarding screening. The precision of the results is +/- 4.3% for a 95% confidence interval. Among the 507 participating women aged between 50 and 74 years, 92.5% (469/507) had undergone at least one mammography: 54.6% (256/469) underwent this test on their own initiative and 44.6% (209/469) of women performed it in the framework of a systematic screening plan. Most women participating in the systematic screening (89.0% i.e. 186/209) had a mammography within the last dating from less than 2 years versus 73.8% (189/256) of those who performed it outside the screening program (Chi(2) test; p<0.01). Interestingly, 422 women (61.9% i.e. 422/682 women aged between 40-75 years with at least one mammography) had performed a mammography before the recommended age for screening. There was a significant correlation (p = 0.009) between the existence of a first mammography before 50 years of age and subsequent screening on women's own initiative (54.6% of 469 screened women). Main reasons for not performing the screening test every second year (77 women aged between 50-74 years) included: feeling unconcerned and/or unmotivated (p = 0.0001), no cancer anxiety (p = 0.020) and no recommendation by the GP (p = 0.015); Of the 600 participating GPs, 68.6% (412/600) systematically recommended a mammography to their patients. GPs' perceptions of the reasons for women's avoidance of the screening test were unwillingness to be aware of mammography results (44.4% - 266/600) and the belief that mammography was painful (52.5% - 315/600). The main result of the EDIFICE survey is the high rate of women's attendance at mammography screening. The EDIFICE survey pointed out that systematic and organized screening played a major role in the regularity of screening tests for breast cancer every second year. GPs and gynaecologist are key actors in heightening public awareness.


4E10-resistant HIV-1 isolated from four subjects with rare membrane-proximal external region polymorphisms.
Human antibody 4E10 targets the highly conserved membrane-proximal external region (MPER) of the HIV-1 transmembrane glycoprotein, gp41, and has extraordinarily broad neutralizing activity. It is considered by many to be a prototype for vaccine development. In this study, we describe four subjects infected with viruses carrying rare MPER polymorphisms associated with resistance to 4E10 neutralization. In one case resistant virus carrying a W680G substitution was transmitted from mother to infant. We used site-directed mutagenesis to demonstrate that the W680G substitution is necessary for conferring the 4E10-resistant phenotype, but that it is not sufficient to transfer the phenotype to a 4E10-sensitive Env. Our third subject carried Envs with a W680R substitution causing variable resistance to 4E10, indicating that residues outside the MPER are required to confer the phenotype. A fourth subject possessed a F673L substitution previously associated with 4E10 resistance. For all three subjects with W680 polymorphisms, we observed additional residues in the MPER that co-varied with position 680 and preserved charged distributions across this region. Our data provide important caveats for vaccine development targeting the MPER. Naturally occurring Env variants described in our study also represent unique tools for probing the structure-function of HIV-1 envelope.


Implementation of patient-reported outcome measures in U.S. Total joint replacement registries: rationale, status, and plans.
In the U.S. and abroad, the use of patient-reported outcome measures to evaluate the impact of total joint replacement surgery on patient quality of life is increasingly common. Analyses of patient-reported outcomes have documented substantial pain relief and functional gain among the vast majority of patients managed with total joint replacement. In addition, postoperative patient-reported outcomes are useful to identify persistent pain and suboptimal outcomes in the minority of patients who have them. The leaders of five U.S. total joint replacement registries report the rationale, current status, and vision for the use of patient-reported outcome measures in U.S. total joint replacement registries. Surgeon leaders of the Function and Outcomes Research for Comparative Effectiveness in Total Joint Replacement registry, American Joint Replacement Registry, California Joint Replacement Registry, Michigan Arthroplasty Registry Collaborative Quality Initiative, and Virginia Joint Registry report the rationale supporting the adoption of patient-reported outcome measures, factors associated with the selection and successful implementation of patient-reported outcome measures, and barriers to complete and valid data. U.S. registries are at varied stages of implementation of preoperative surveys and postoperative total joint replacement outcome measures. Surgeon leaders report unified rationales for adopting patient-reported outcome measures: to capture data on pain relief and functional gain following total joint replacement as well as to identify suboptimal implant performance. Key considerations in the selection of a patient-reported outcome measure include its ability to measure both joint pain and physical function while limiting any burden on patients and surgeons related to its use. Complete patient-reported outcomes data will be associated with varied modes of survey completion, including options for home-based completion, to ensure consistent timing and data capture. The current stage of implementation of patient-reported outcome measures varies widely among U.S. registries. Nonetheless, evidence from the Function and Outcomes Research for Comparative Effectiveness in Total Joint Replacement registry supports the feasibility of successful implementation of patient-reported outcome measures with careful attention to the selection of the outcome measure, mode and timing of postoperative administration, and minimization of any burden on the patient and surgeon.


When to start antiretroviral therapy in resource-limited settings: a human rights analysis.
Recent evidence from developed and developing countries shows clear clinical and public health benefit to starting antiretroviral therapy (ART) earlier. While discussions about when to start ART have often focused on the clinical risks and benefits, the main issue is one of fair limit-setting. We applied a human rights framework to assess a policy of early treatment initiation according to the following criteria: public-health purpose; likely effectiveness; specificity; human rights burdens and benefits; potential for less restrictive approaches; and fair administration. According to our analysis, a policy of earlier ART initiation would better serve both public health and human rights objectives. We highlight a number of policy approaches that could be taken to help meet this aim, including increased international financial support, alternative models of care, and policies to secure the most affordable sources of appropriate antiretroviral drugs. Widespread implementation of earlier ART initiation is challenging in resource-limited settings. Nevertheless, rationing of essential medicines is a restriction of human rights, and the principle of least restriction serves to focus attention on alternative measures such as adapting health service models to increase capacity, decreasing costs, and seeking additional international funding. Progressive realisation using well-defined steps will be necessary to allow for a phased implementation as part of a framework of short-term targets towards nationwide policy adoption, and will require international technical and financial support.


The role of the estrogen receptor in diethylstilbestrol toxicity.
The site and specificity of the tissue response to a toxicant are of central importance; it is in this area of diethylstilbestrol (DES) toxicity that the estrogen receptor would appear to play its primary role. Compilation of the various sites of DES toxicity in humans and experimental animals indicates that lesions appear predominantly in estrogen responsive target tissues suggesting that the presence of the estrogen receptor in such target tissues may help govern the tissue specificity of the toxic insult. DES and many of its oxidative metabolites interact with high affinity with the estrogen receptor. Such an interaction may be responsible for localizing DES to target tissues. Autoradiographic and biochemical studies have supported the localization of radiolabeled DES in susceptible tissues. The intracellular mechanism of receptor binding of DES and certain metabolites could then result in mobilization of these compounds to the nucleus. Experimental evidence has shown that DES and a number of its metabolites are able to translocate receptor to the nucleus of uterine cells. Such an action by the receptor results in an increased probability of potential chemical interactions with the genome. The actual induction of a chemical lesion in the target cell may, at this point, proceed by non-receptor mediated mechanisms. For example, studies using in vitro cell culture systems which contain no estrogen receptors have shown that DES can induce neoplastic cell transformation, mutagenesis, irreversible binding to DNA and protein and unscheduled DNA synthesis. These results raise the possibility that a part of DES toxicity may follow pharmacologic principles established for chemical carcinogens. Following induction of the molecular lesion, the role of the receptor continues in this process by mediating increased protein synthesis and mitogenesis in responsive target tissues which ultimately permits a more extensive expression of the toxic effects. It has been demonstrated that DES is a potent mitogen in vivo in both uterine and pituitary tissues, subsequently, the lesion will perpetuate itself through this receptor mediated biological response. This is particularly important since a number of DES induced reproductive tract tumors are expressed only after additional estrogen exposure. While other tumors have been shown to be estrogen sensitive and will regress without continued estrogen stimulation. Therefore, it should be considered that the presence of the estrogen receptor and the estrogen receptor mediated biological responsiveness of a particular tissue are most important in explaining the specificity of DES toxicity.


[Effects of acupuncture of Jianjing (GB 21) on gallbladder volume and symptoms of cholecystitis patients].
To observe the effect of acupuncture of Jianjing (GB 21) and non-acupoint on gallbladder volume and clinical symptoms of chronic cholecystitis patients. Sixty cases of chronic cholecystitis patients were equally randomized into Jianjing (GB 21) group and non-acupoint group. A filiform needle was inserted into Jianjing (GB 21) or non-acupoint (2 cun lateral to the mid-point between the spinous processes of the 6th and 7th cervical vertebrae) on the right side, manipulated for a while till "Deqi", and retained for 30 min. A color Doppler ultrasound scanner was used to detect the volume of the gallbladder before and 15 min after acupuncture stimulation and 30 min after withdrawal of the acupuncture needle. Changes of the patients symptoms of shoulder-back pain, stomachache, distension and nausea were evaluated according to the patients' complaints. After acupuncture intervention, the remission rates of shoulder-back pain and stomachache in non-acupoint and GB 21 groups were 56.67% and 90.00% respectively, while the effective rates of the patients' gastric distention and nausea in non-acupoint and GB 21 groups were 16.67% and 23.33%, respectively. The therapeutic effect of Jianjing (GB 21) was apparently superior to that of non-acupoint in pain relief (P < 0.05). Fifteen min following acupuncture stimulation and 30 min after withdrawal of the acupuncture needle, the gallbladder volume in cholecystitis patients with deflated gallbladder was increased apparently in GB 21 group (P < 0.01), and that in patients with expanded gallbladder was decreased significantly (P < 0.01). No significant differences were found among pre-, during and post-treatment in the non-acupoint group in the effects of acupuncture on regulation of the deflated and expanded gallbladder volume (P > 0.05). Acupuncture stimulation of Jianjing (GB 21) can effectively relieve shoulder-back pain and stomachache, and regulate the volume of the deflated and expanded gallbladder in cholecystitis patients. The effect of acupuncture of non-acupoint is relatively poorer in relieving the cholecystitis patients' symptoms and regulating the gallbladder volume.


Systemic immune unresponsiveness induced in adult mice by anterior chamber presentation of minor histocompatibility antigens.
The ability to introduce carefully controlled numbers of viable cells into the anterior chamber of mouse eyes made it possible to examine the interrelationship between presentation of antigens into the anteior chamber and into conventional body sites and their synergistic/antagonistic effects on the immune system. P815 mastocytoma (DBA/2; H-2d) cells are syngeneic with BALB/c hosts at the major histocompatibility locus, but differ at multiple minor histocompatibility loci. When P815 cells were injected subcutaneously, they were rejected by BALB/c recipients who became specifically immune. By contrast, when P815 cells were injected intracamerally, they grew progressively into massive intraocular tumors; moreover, these BALB/c hosts proved subsequently unable to reject subcutaneously injected P815 cells, and, more impressively, failed to reject DBA/2 skin allografts placed orthotopically. Minor histocompatibility antigens, presented first through the anterior chamber of mouse eyes, elicit a suppressive rather than an aggressive host immune response that protects cells that bear these antigens from a destructive alloimmune reaction at both intracameral and systemic sites.


Romantic relationship transitions and changes in health among rural, White young adults.
A growing body of research examines how the presence and quality of romantic relationships, from dating to marriage, contribute to health. However, this work oftentimes fails to consider instability in the relationship supports and stressors thought to affect health. This is particularly important during the transition to adulthood when instability in romantic relationships is expected to be common. Barr, Culatta, and Simons (2013) put forth a new model that has shown promise for assessing the degree of this instability and its implications for young adult health. They tested their model, however, with an African American sample, and it remains unclear whether it is generalizable to other groups of young adults. The current study considers the generality of their model by applying it to a rural, White sample drawn from the Iowa Youth and Families Project, the only extant data set able to assess both their proposed measurement of relationship instability and its relation to multidimensional measures of health across the transition to adulthood. Findings lend support to their model, yet the degree of instability found among the rural, White young adults in the current study was less than that found in Barr et al.'s (2013) study. (PsycINFO Database Record


Pathologic accumulation of α-synuclein and Aβ in Parkinson disease patients with dementia.
To determine the relative contributions of individual pathologic protein deposits associated with dementia in patients with Parkinson disease (PD). Autopsied patients were analyzed from February 24, 2005, through July 25, 2010, to determine the distribution and severity of individual pathologic protein deposits (α-synuclein, Aβ, and tau) using routine protocols for histologic and immunohistochemical analysis and established neuropathologic staging criteria. Clinical data were extracted from an electronic medical record system used for all patients with PD. Thirty-two consecutive autopsied patients treated at the Washington University Movement Disorders Center who had neuropathologic confirmation of PD and a history of dementia, regardless of the timing of the onset of dementia with respect to motor symptoms. Three pathologic subgroups of dementia associated with PD were identified: (1) predominant synucleinopathy (Braak Lewy body stages 5-6) (12 [38%]), (2) predominant synucleinopathy with Aβ deposition (Braak amyloid stages B-C) but minimal or no cortical tau deposition (19 [59%]), and (3) synucleinopathy and Aβ deposition with at least moderate neocortical tauopathy (Braak tau stages 5-6; 1 [3%]). Kaplan-Meier and Cox regression analyses revealed that patients with synucleinopathy plus Aβ deposition had significantly shorter survival (years from PD onset until death and years from dementia onset until death) than patients with synucleinopathy only. Dementia associated with PD has 2 major pathologic subgroups: neocortical synucleinopathy and neocortical synucleinopathy with Aβ deposition. Alzheimer disease with neocortical Aβ and tau deposition does not commonly cause dementia with PD. Furthermore, accumulation of Aβ is associated with lower survival rates in PD patients with dementia. Additional studies are needed to prospectively determine the association between α-synuclein and Aβ accumulation and the role of Aβ in the development and progression of cognitive impairment in PD.


The myelodysplastic syndromes: a personal recollection of four decades of classification and prognostic scoring systems.
In 1976 the French-American-British (FAB) Leukemia Working Group proposed the first definitions of patients with myelodysplastic syndromes (MDS), namely refractory anemia with excess blasts (RAEB) and chronic myelomonocytic leukemia (CMML). Subsequent publications resulted in additional subgroups that had prognostic significance. Incorporation of the subgroupings by the World Health Organization and additional fine tuning of the degrees of morphologic dysplasia and percentage of blasts have enhanced the classification. Several prognostic scoring systems have added degrees of cytopenia, cytogenetic aberrations and molecular genetic mutations that allow care providers to subdivide cases into lower, intermediate and higher grade categories.


Construction of a correlated physical and genetic map of the Klebsiella pneumoniae hisDGO region using transposon Tn5 mutagenesis.
Multicopy plasmids containing the hisDG region of Klebsiella pneumoniae were mutagenized with transposon Tn5. The resulting plasmids were examined for their ability to complement hisD and hisG mutations in Escherichia coli. The physical location of Tn5 on each of the hisD::Tn5 and hisG::Tn5 plasmids was determined by restriction endonuclease analysis. By combining the two types of data, a precise correlated physical and genetic map of the K. pneumoniae hisDG region was constructed. Based on this analysis, the minimum sizes of the hisD and the hisG genes were calculated to be 1100 bp and 900 bp, respectively. The hisO(P) region was also identified. The insertional specificity of transposon Tn5 was shown to be very low. One unanticipated result was obtained: Tn5 insertions in the plasmid-borne hisG gene were not polar on hisD.


Effect of growth hormone and resistance exercise on muscle growth and strength in older men.
The purpose of this study was to determine whether growth hormone (GH) administration enhances the muscle protein anabolism associated with heavy-resistance exercise training in older men. Twenty-three healthy, sedentary men (67 +/- 1 yr) with low serum insulin-like growth factor I levels followed a 16-wk progressive resistance exercise program (75-90% max strength, 4 days/wk) after random assignment to either a GH (12.5-24 micrograms.kg-1.day-1; n = 8) or placebo (n = 15) group. Fat-free mass (FFM) and total body water increased more in the GH group. Whole body protein synthesis and breakdown rates increased in the GH group after treatment. However, increments in vastus lateralis muscle protein synthesis rate, urinary creatinine excretion, and training-specific isotonic and isokinetic muscle strength were similar in both groups, while 24-h urinary 3-methylhistidine excretion was unchanged after treatment. These observations suggest that resistance exercise training improved muscle strength and anabolism in older men, but these improvements were not enhanced when exercise was combined with daily GH administration. The greater increase in FFM with GH treatment may have been due to an increase in noncontractile protein and fluid retention.


Biomimetic drug-delivery systems for the management of brain diseases.
Acting as a double-edged sword, the blood-brain barrier (BBB) is essential for maintaining brain homeostasis by restricting the entry of small molecules and most macromolecules from blood. However, it also largely limits the brain delivery of most drugs. Even if a drug can penetrate the BBB, its accumulation in the intracerebral pathological regions is relatively low. Thus, an optimal drug-delivery system (DDS) for the management of brain diseases needs to display BBB permeability, lesion-targeting capability, and acceptable safety. Biomimetic DDSs, developed by directly utilizing or mimicking the biological structures and processes, provide promising approaches for overcoming the barriers to brain drug delivery. The present review summarizes the biological properties and biomedical applications of the biomimetic DDSs including the cell membrane-based DDS, lipoprotein-based DDS, exosome-based DDS, virus-based DDS, protein template-based DDS and peptide template-based DDS for the management of brain diseases.


GroPBS: Fast Solver for Implicit Electrostatics of Biomolecules.
Knowledge about the electrostatic potential on the surface of biomolecules or biomembranes under physiological conditions is an important step in the attempt to characterize the physico-chemical properties of these molecules and, in particular, also their interactions with each other. Additionally, knowledge about solution electrostatics may also guide the design of molecules with specified properties. However, explicit water models come at a high computational cost, rendering them unsuitable for large design studies or for docking purposes. Implicit models with the water phase treated as a continuum require the numerical solution of the Poisson-Boltzmann equation (PBE). Here, we present a new flexible program for the numerical solution of the PBE, allowing for different geometries, and the explicit and implicit inclusion of membranes. It involves a discretization of space and the computation of the molecular surface. The PBE is solved using finite differences, the resulting set of equations is solved using a Gauss-Seidel method. It is shown for the example of the sucrose transporter ScrY that the implicit inclusion of a surrounding membrane has a strong effect also on the electrostatics within the pore region and, thus, needs to be carefully considered, e.g., in design studies on membrane proteins.


Almost there: transmission routes of bacterial symbionts between trophic levels.
Many intracellular microbial symbionts of arthropods are strictly vertically transmitted and manipulate their host's reproduction in ways that enhance their own transmission. Rare horizontal transmission events are nonetheless necessary for symbiont spread to novel host lineages. Horizontal transmission has been mostly inferred from phylogenetic studies but the mechanisms of spread are still largely a mystery. Here, we investigated transmission of two distantly related bacterial symbionts--Rickettsia and Hamiltonella--from their host, the sweet potato whitefly, Bemisia tabaci, to three species of whitefly parasitoids: Eretmocerus emiratus, Eretmocerus eremicus and Encarsia pergandiella. We also examined the potential for vertical transmission of these whitefly symbionts between parasitoid generations. Using florescence in situ hybridization (FISH) and transmission electron microscopy we found that Rickettsia invades Eretmocerus larvae during development in a Rickettsia-infected host, persists in adults and in females, reaches the ovaries. However, Rickettsia does not appear to penetrate the oocytes, but instead is localized in the follicular epithelial cells only. Consequently, Rickettsia is not vertically transmitted in Eretmocerus wasps, a result supported by diagnostic polymerase chain reaction (PCR). In contrast, Rickettsia proved to be merely transient in the digestive tract of Encarsia and was excreted with the meconia before wasp pupation. Adults of all three parasitoid species frequently acquired Rickettsia via contact with infected whiteflies, most likely by feeding on the host hemolymph (host feeding), but the rate of infection declined sharply within a few days of wasps being removed from infected whiteflies. In contrast with Rickettsia, Hamiltonella did not establish in any of the parasitoids tested, and none of the parasitoids acquired Hamiltonella by host feeding. This study demonstrates potential routes and barriers to horizontal transmission of symbionts across trophic levels. The possible mechanisms that lead to the differences in transmission of species of symbionts among species of hosts are discussed.


High Intensity Aerobic Exercise Training Improves Deficits of Cardiovascular Autonomic Function in a Rat Model of Type 1 Diabetes Mellitus with Moderate Hyperglycemia.
Indices of cardiovascular autonomic neuropathy (CAN) in experimental models of Type 1 diabetes mellitus (T1DM) are often contrary to clinical data. Here, we investigated whether a relatable insulin-treated model of T1DM would induce deficits in cardiovascular (CV) autonomic function more reflective of clinical results and if exercise training could prevent those deficits. Sixty-four rats were divided into four groups: sedentary control (C), sedentary T1DM (D), control exercise (CX), or T1DM exercise (DX). Diabetes was induced via multiple low-dose injections of streptozotocin and blood glucose was maintained at moderate hyperglycemia (9-17 mM) through insulin supplementation. Exercise training consisted of daily treadmill running for 10 weeks. Compared to C, D had blunted baroreflex sensitivity, increased vascular sympathetic tone, increased serum neuropeptide Y (NPY), and decreased intrinsic heart rate. In contrast, DX differed from D in all measures of CAN (except NPY), including heart rate variability. These findings demonstrate that this T1DM model elicits deficits and exercise-mediated improvements to CV autonomic function which are reflective of clinical T1DM.


Effects of lead-contaminated sediment on Rana sphenocephala tadpoles.
We exposed larval southern leopard frogs (Rana sphenocephala) to lead-contaminated sediments to determine the lethal and sublethal effects of this metal. Tadpoles were laboratory-raised from early free-swimming stage through metamorphosis at lead concentrations of 45, 75, 180, 540, 2360, 3940, 5520, and 7580 mg/kg dry weight in sediment. Corresponding pore water lead concentrations were 123, 227, 589, 1833, 8121, 13,579, 19,038, and 24,427 microg/L. Tadpoles exposed to lead concentrations in sediment of 3940 mg/kg or higher died within 2 to 5 days of exposure. At lower concentrations, mortality through metamorphosis ranged from 3.5% at 45 mg/kg lead to 37% at 2360 mg/kg lead in sediment. The LC50 value for lead in sediment was 3728 mg/kg (95% CI = 1315 to 72,847 mg/kg), which corresponded to 12,539 microg/L lead in pore water (95% CI = 4000 to 35,200 microg/L). Early growth and development were depressed at 2,360 mg/kg lead in sediment (8100 microg/L in pore water) but differences were not evident by the time of metamorphosis. The most obvious effect of lead was its pronounced influence on skeletal development. Whereas tadpoles at 45 mg/kg lead in sediment did not display permanent abnormalities, skeletal malformations increased in frequency and severity at all higher lead concentrations. By 2360 mg/kg, 100% of surviving metamorphs displayed severe spinal problems, reduced femur and humerus lengths, deformed digits, and other bone malformations. Lead concentrations in tissues correlated positively with sediment and pore water concentrations.


Application of a method used to deconstruct a single dose pharmacokinetic profile from multiple dose data.
With traditional non-compartmental methods, it is challenging to deconstruct plasma concentration versus time curves to assess the influence of individual doses. This study describes the application of a mathematical approach used to deconstruct a single dose curve using data derived from the second, third, fourth or nth dosing interval. Using data from a prospective clinical trial it is demonstrated that this approach reliably estimates pharmacokinetic parameters measured following two doses of zolpidem tartrate. Additionally, the study demonstrates the application of this approach using previously published data from a single- and multiple-dose pharmacokinetic study of the antibiotic gatifloxacin. Copyright © 2015 John Wiley & Sons, Ltd.


Intraoperative assessment of cerebral aqueduct patency and cisternal scarring: impact on success of endoscopic third ventriculostomy in 403 African children.
In the setting of a developing country where preoperative imaging may be limited, the authors wished to determine whether cisternal scarring or aqueduct patency at the time of surgery was sufficiently predictive of the failure of endoscopic third ventriculostomy (ETV) to justify shunt placement at the time of the initial operation. The status of the prepontine cistern and aqueduct at the time of ventriculoscopy was prospectively recorded in 403 children in whom an ETV had been completed. Kaplan-Meier methods were used to construct survival curves. A Cox proportional hazards model was used to provide estimates of HRs for the time to ETV failure. Several independent variables were tested in a single multivariable model, including those previously shown to be associated with ETV survival, that is, age, hydrocephalus etiology, and extent of choroid plexus cauterization (CPC). In addition, intraoperative variables of particular interest were included in the analysis: status of the aqueduct at surgery (closed vs open) and status of the prepontine cistern at surgery (scarred vs clean/unscarred). Multicollinearity was not a concern since the variance inflation factors for all variables were < 2. The examination of stratified survival curves confirmed the appropriateness of the proportional hazards assumption for each variable. Overall actuarial 3-year success was 57%. Consistent with previous results, age, hydrocephalus etiology, and extent of CPC were significantly associated with ETV success. A closed aqueduct and an unscarred cistern were each independently associated with significantly better ETV success (HRs of 0.66 and 0.44, respectively). The presence of cisternal scarring more than doubled the risk of ETV failure, and an open aqueduct increased the risk of failure by 50%. Intraoperative observations of the aqueduct and prepontine cistern are independent predictors of the risk of ETV failure and can be used to further refine outcome predictions based on age, hydrocephalus etiology, and extent of CPC. Further studies will test validity in several African centers and determine what threshold of failure risk should prompt shunt placement at the initial operation.


Microbial functional diversity: From concepts to applications.
Functional diversity is increasingly recognized by microbial ecologists as the essential link between biodiversity patterns and ecosystem functioning, determining the trophic relationships and interactions between microorganisms, their participation in biogeochemical cycles, and their responses to environmental changes. Consequently, its definition and quantification have practical and theoretical implications. In this opinion paper, we present a synthesis on the concept of microbial functional diversity from its definition to its application. Initially, we revisit to the original definition of functional diversity, highlighting two fundamental aspects, the ecological unit under study and the functional traits used to characterize it. Then, we discuss how the particularities of the microbial world disallow the direct application of the concepts and tools developed for macroorganisms. Next, we provide a synthesis of the literature on the types of ecological units and functional traits available in microbial functional ecology. We also provide a list of more than 400 traits covering a wide array of environmentally relevant functions. Lastly, we provide examples of the use of functional diversity in microbial systems based on the different units and traits discussed herein. It is our hope that this paper will stimulate discussions and help the growing field of microbial functional ecology to realize a potential that thus far has only been attained in macrobial ecology.


Progress in deciphering the genetics of multiple sclerosis.
Multiple sclerosis is the most common neurological disease affecting young adults. The aetiology is unknown, although many clues point to an autoimmune inflammatory nature. Family studies of multiple sclerosis have shown familial aggregation, and therefore suggest that the disease entails a genetic component that has been widely studied. Some of the studies from the extensive literature in the field of multiple sclerosis genetics published in the past year are discussed here. A number of the recent publications considered in this review have reconfirmed the well-known association with the major histocompatibility complex as well as identifying that there are at least two important loci within this region. These findings add further complexity to the role of the major histocompatibility complex in multiple sclerosis. Links to other diseases have been few for multiple sclerosis, but the association with diabetes in the Sardinian population and, perhaps, a 'protective' effect of Down's syndrome can now be added. Numerous candidate genes for susceptibility and disease-modifying effect have also been studied in the literature, but with few replications. Associations with components of the endocrine and the neuro-endocrine system have also been considered in this review along with the potential value of microarray analysis. Multiple sclerosis is a complex trait that is associated with the major histocompatibility complex, although the form of this association may not be as straightforward as previously thought. Recent findings raise the possibility of an association with haplotype blocks rather than with single alleles. The finding of allelic heterogeneity within the major histocompatibility complex, as with the Sardinians, adds an additional layer of complexity. Genome scans for this and other autoimmune diseases have often been notably disappointing despite many claims for linkages. The reasons for the difficulty may encompass locus heterogeneity, small effects and phenocopies, among others. A variety of attempts to study more restricted populations are in progress, including rare individual pedigrees with high recurrence risk.


Contextual effects of prekindergarten classrooms for disadvantaged children on cognitive development: the case of Chapter 1.
This study explores the effects of the social context of Chapter 1 prekindergarten classrooms on children's learning. Chapter 1 (also called Title I) is a federal government preschool program directed at children in low-income schools who are at risk of later school failure. Using hierarchical linear modeling (HLM) and a sample of 677 4-year-olds in 55 1990-91 Chapter 1 prekindergarten classes in 5 states, the study explores factors that influence gains on the Preschool Inventory (PSI) over the preschool year. Social context is defined here mainly in terms of the cognitive and social composition of the classroom. Contextual factors defined in terms of demographics are shown to be related to learning, but the average cognitive level of the class is not. On average, children learn less in classrooms with high concentrations of minorities, children with special needs, recent immigrants, and children whose mothers have little education. The study explores differential effects of racial concentration on race differences in learning. Policy implications are discussed.


Colchicine for acute gout.
This is an update of a Cochrane review first published in 2006. Gout is one of the most common rheumatic diseases worldwide. Despite the use of colchicine as one of the first-line therapies for the treatment of acute gout, evidence for its benefits and harms is relatively limited. To evaluate the benefits and harms of colchicine for the treatment of acute gout. We searched the following electronic databases from inception to April 2014: Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE. We did not impose any date or language restrictions in the search. We also handsearched conference proceedings of the American College of Rheumatology and the European League against Rheumatism (2010 until 2013) and reference lists of identified studies. We searched the clinical trials register clinicaltrials.gov and the WHO trials register. We considered published randomised controlled trials (RCTs) and controlled clinical trials (CCTs) evaluating colchicine therapy compared with another therapy (active or placebo) in acute gout. The primary benefit outcome of interest was pain, defined as a proportion with 50% or greater decrease in pain, and the primary harm outcome was study participants withdrawal due to adverse events. Two authors independently screened search results for relevant studies, extracted data into a standardised form and assessed the risk of bias of included studies. We pooled data if deemed to be sufficiently clinically homogeneous. We assessed the quality of the body of evidence for each outcome using the GRADE approach. Two RCTs (124 participants) were included in this updated review, including one new RCT. We considered one trial to be at low risk of bias, while we considered the newly included trial to be at unclear risk of bias. Both trials included a placebo and a high-dose colchicine arm, although the colchicine regimens varied. In one trial 0.5 mg colchicine was given every two hours until there was either complete relief of symptoms or toxicity and the total doses were not specified. In the other trial a total of 4.8 mg colchicine was given over six hours. The newly identified trial also included a low-dose colchicine arm (total 1.8 mg over one hour).Based upon pooled data from two trials (124 participants), there is low-quality evidence that a greater proportion of people receiving high-dose colchicine experience a 50% or greater decrease in pain from baseline up to 32 to 36 hours compared with placebo (35/74 in the high-dose colchicine group versus 12/50 in the placebo group (risk ratio (RR) 2.16, 95% confidence interval (CI) 1.28 to 3.65), with a number needed to treat to benefit (NNTB) of 4 (95% CI 3 to 12). However, the total number of adverse events (diarrhoea, vomiting or nausea) is greater in those who receive high-dose colchicine versus placebo (62/74 in the high-dose colchicine group versus 11/50 in the placebo group (RR 3.81, 95% CI 2.28 to 6.38), with a number needed to treat to harm (NNTH) of 2 (95% CI 2 to 5). Only one trial included reduction of inflammation as part of a composite measure comprising pain, tenderness, swelling and erythema, each graded on a four-point scale (none 0 to severe 3) to derive a maximum score for any one joint of 12. They reported the proportion of people who achieved a 50% reduction in this composite score. Based upon one trial (43 participants), there was low-quality evidence that more people in the high-dose colchicine group had a 50% or greater decrease in composite score from baseline up to 32 to 36 hours than people in the placebo group (11/22 in the high-dose colchicine group versus 1/21 in the placebo group (RR 10.50, 95% CI 1.48 to 74.38) and 45% absolute difference).Based upon data from one trial (103 participants), there was low-quality evidence that low-dose colchicine is more efficacious than placebo with respect to the proportion of people who achieve a 50% or greater decrease in pain from baseline to 32 to 36 hours (low-dose colchicine 31/74 versus placebo 5/29 (RR 2.43, 95% CI 1.05 to 5.64)), with a NNTB of 5 (95% CI 2 to 20). There are no additional harms in terms of adverse events (diarrhoea, nausea or vomiting) with low-dose colchicine compared to placebo (19/74 and 6/29 respectively (RR 1.24, 95% CI 0.55 to 2.79)).Based upon data from one trial (126 participants), there is low-quality evidence that there are no additional benefits in terms of the proportion of people achieving 50% or greater decrease in pain from baseline up to 32 to 36 hours with high-dose colchicine compared to low-dose (19/52 and 31/74 respectively (RR 0.87, 95% CI 0.56 to 1.36). However, there were statistically significantly more adverse events in those who received high-dose colchicine (40/52 versus 19/74 in the low-dose group (RR 3.00, 95% CI 1.98 to 4.54)), with a NNTH of 2 (95% CI 2 to 3).No trials reported function of the target joint, patient-reported global assessment of treatment success, health-related quality of life or withdrawals due to adverse events. We identified no studies comparing colchicine to non-steroidal anti-inflammatory drugs (NSAIDs) or other active treatments such as glucocorticoids (by any route). Based upon only two published trials, there is low-quality evidence that low-dose colchicine is likely to be an effective treatment for acute gout. We downgraded the evidence because of a possible risk of selection and reporting biases and imprecision. Both high and low-dose colchicine improve pain when compared to placebo. While there is some uncertainty around the effect estimates, compared with placebo, high-dose but not low-dose colchicine appears to result in a statistically significantly greater number of adverse events. Therefore low-dose colchicine may be the preferred treatment option. There are no trials about the effect of colchicine in populations with comorbidities or in comparison with other commonly used treatments, such as NSAIDs and glucocorticoids.


Where are we now? A multicountry qualitative study to explore access to pre-antiretroviral care services: a precursor to antiretroviral therapy initiation.
To explore barriers and facilitators to accessing postdiagnosis HIV care in five sub-Saharan African countries. In-depth interviews were conducted with 77 people living with HIV (PLHIV) in pre-antiretroviral therapy care or not-yet-in care and 46 healthcare workers. Participants were purposely selected from health and demographic surveillance sites in Karonga (Malawi), Manicaland (Zimbabwe), uMkhanyakude (South Africa), Kisesa (Tanzania) and Rakai and Kyamulibwa (Uganda). Thematic content analysis was conducted, guided by the constructs of affordability, availability and acceptability of care.- RESULTS: Affordability: Transport and treatment costs were a barrier to HIV care, although some participants travelled to distant clinics to avoid being seen by people who knew them or for specific services. Broken equipment and drug stock-outs in local clinics could also necessitate travel to other facilities. Availability: Some facilities did not offer full HIV care, or only offered all services intermittently. PLHIV who frequently travelled complained that care was seldom available to them in places they visited. Acceptability: Severe pain or sickness was a key driver for accessing postdiagnosis care, whereas asymptomatic PLHIV often delayed care-seeking. A belief in witchcraft was a deterrent to accessing clinical care following diagnosis. Changing antiretroviral therapy guidelines generated uncertainty among PLHIV about when to start treatment and delayed postdiagnosis care. PLHIV reported that healthcare workers' knowledge, attitudes and behaviours, and their ability to impart health education, also influenced whether they accessed HIV care. Despite efforts to decentralise services over the past decade, many barriers to accessing HIV care persist. There is a need to increase sustained access to care for PLHIV not yet on treatment, with initiatives that encompass biomedical aspects of care alongside considerations for individual and collective challenges they faced. A failure to do so may undermine efforts to achieve universal access to antiretroviral therapy.


A prospective evaluation of the management of bleeding peptic ulcer.
Bleeding from a peptic ulcer is associated with significant morbidity and mortality, particularly in the elderly. The results of a management policy of early endoscopy and close monitoring of patients were prospectively evaluated to assess whether major stigmata of recent haemorrhage (SRH) helped to identify patients who were likely to rebleed. Early endoscopy allowed the diagnosis of the most likely site of haemorrhage in 94% of the 190 patients. The nature and site of SRH (visible vessel, fresh clot, red or black spot) was recorded. Ninety-three of 167 patients in whom the presence or absence of SRH were recorded, had major SRH (visible vessel, fresh clot) and 51% of these patients rebled while only 10 of 74 (14%) patients without major SRH rebled. Overall, 80% of those with further haemorrhage had major SRH. Operation was performed on 28% of patients and the main indication for operation was further haemorrhage. Major morbidity in the surgical patients was strongly correlated with vascular instability at the time of further haemorrhage. Significant morbidity occurred in 16 of 28 patients (57%) with vascular instability, compared with only 1 of 18 patients (6%) without vascular instability (P less than 0.001). The overall low mortality of 5.3% was attributed to an approach of joint medical and surgical management with early operation for further haemorrhage. Although major SRH identified a group of patients most likely to suffer further haemorrhage, the positive predictive value of major SRH was only 51%.


Cancer growth and metastasis as a metaphor of Go gaming: An Ising model approach.
This work aims for modeling and simulating the metastasis of cancer, via the analogy between the cancer process and the board game Go. In the game of Go, black stones that play first could correspond to a metaphor of the birth, growth, and metastasis of cancer. Moreover, playing white stones on the second turn could correspond the inhibition of cancer invasion. Mathematical modeling and algorithmic simulation of Go may therefore benefit the efforts to deploy therapies to surpass cancer illness by providing insight into the cellular growth and expansion over a tissue area. We use the Ising Hamiltonian, that models the energy exchange in interacting particles, for modeling the cancer dynamics. Parameters in the energy function refer the biochemical elements that induce cancer birth, growth, and metastasis; as well as the biochemical immune system process of defense.


Non-small-cell lung cancer dimensions: CT-pathological correlation and interobserver variation.
The aim of the study was to identify the most accurate CT window level setting for the measurement of non-small-cell lung cancer to optimise CT planning for radiotherapy treatment. 27 patients who underwent resection for non-small-cell lung cancer in a single institution were studied. The maximal superior-inferior, anteroposterior and mediolateral dimensions of the resected tumours were measured by a consultant pathologist. Two radiologists made corresponding measurements using pre-operative CT scans independently of each other and of the pathologist's findings. The measurements were obtained using four different CT window settings. The mean pathological size of the superior-inferior tumours, the anteroposterior tumours and the mediolateral tumours was 32 mm, 28 mm and 25 mm, respectively. A total of 648 CT measurements were taken, of which 321 were within +/-5 mm of the pathological size (49.5%). There was significant interobserver variability between the two radiologists. There was poor correlation between the pathological and radiological measurements of tumour size. Significant interobserver variability was noted between the two radiologists and no window setting could be identified as being superior in accurately assessing the tumour size.


Deleted mitochondrial DNA in human luteinized granulosa cells.
The rearrangement of mitochondrial DNA in luteinized granulosa cells was determined in order to evaluate the fertilization capacity of oocytes and the development of embryos. Multiple deletions of mtDNA were found in luteinized granulosa cells from in vitro fertilization (IVF) patients. The 4977-base pair (bp) deletion was the most frequent deletion found in human granulosa cells. No significant difference was noted between mtDNA deletions of granulosa cells based on the fertilization capacity of oocytes and the development of embryos. To determine the relationship of proportions of mtDNA rearrangements with the aging process, granulosa cells were grouped into three different cohorts according to maternal age: younger than 32 years, between 32 and 37 years, and older than 37 years. No statistical correlation was noted between patient age and the frequency of occurrence of multiple mtDNA deletions. However, an increase in granulosa cell apoptosis was associated with an increase in mtDNA deletions. Accumulation of mtDNA deletions may contribute to mitochondrial dysfunction and impaired ATP production. We concluded that the accumulation of rearranged mtDNA in granulosa cells might not interfere with fertilization of human oocytes and further embryonic development; it was, however, associated with apoptosis processes.


Clinical evaluation of probucol in hypercholesteremia: individual lipoprotein responses and inhibitory effect on carotid atherosclerosis progression.
Probucol treatment has been evaluated in 140 patients with hypercholesterolemia attending a single Lipid Clinic, in an attempt to identify the relations between lipid/lipoprotein responses and patient characteristics. Probucol was administered as a single drug at the standard dose (0.5 g tablets b.i.d.) for at least 6 months. One-hundred (71%) patients displayed a reduction of low-density lipoprotein cholesterol (LDL-C), which was significantly correlated with the baseline LDL-C level (r = 0.64; p < 0.0001). Most of the patients (90%) also responded with a reduction of high-density lipoprotein cholesterol (HDL-C); the HDL-C reduction was also directly related to baseline HDL cholesterolemia (r = 0.67, p < 0.0001). A highly significant correlation was found between the individual LDL-C and HDL-C responses. Eleven patients who continued with probucol treatment had a B-mode ultrasonographic investigation performed at baseline and after 24 months. No changes in carotid mean and maximal intimal-medial thickness were recorded, in contrast to an increase (i.e., indicative of atherosclerosis progression) in matched patients with hypercholesterolemia receiving other lipid-lowering regimens. Our report underlines that probucol can still provide a valuable option for the treatment for hypercholesterolemia, being particularly effective in patients with a combined increase of LDL-C and HDL-C levels.


Long-Term Exposure to Road Traffic Noise and Incident Heart Failure: Evidence From UK Biobank.
Evidence on road traffic noise and heart failure (HF) is limited, and little is known on the potential mediation roles of acute myocardial infarction (AMI), hypertension, or diabetes. The purpose of this study was to evaluate the impacts of long-term road traffic noise exposure on the risk of incident HF considering air pollution, and explore the mediations of the previously mentioned diseases. This prospective study included 424,767 participants without HF at baseline in UK Biobank. The residential-level noise and air pollution exposure was estimated, and the incident HF was identified through linkages with medical records. Cox proportional hazard models were used to estimate HRs. Furthermore, time-dependent mediation was performed. During a median 12.5 years of follow-up, 12,817 incident HF were ascertained. The HRs were 1.08 (95% CI: 1.00-1.16) per 10 dB[A] increase in weighted average 24-hour road traffic noise level (Lden), and 1.15 (95% CI: 1.02-1.31) for exposure to Lden >65 dB[A] compared with the reference category (Lden ≤55 dB[A]), respectively. Furthermore, the strongest combined effects were found in those with both high exposures to road traffic noise and air pollution including fine particles and nitrogen dioxide. Prior AMI before HF within 2 years' time interval mediated 12.5% of the association of road traffic noise with HF. More attention should be paid and a preventive strategy should be considered to alleviate the disease burden of HF related to road traffic noise exposure, especially in participants who survived AMI and developed HF within 2 years.


Parallel self-mixing imaging system based on an array of vertical-cavity surface-emitting lasers.
In this paper we investigate the feasibility of a massively parallel self-mixing imaging system based on an array of vertical-cavity surface-emitting lasers (VCSELs) to measure surface profiles of displacement, distance, velocity, and liquid flow rate. The concept of the system is demonstrated using a prototype to measure the velocity at different radial points on a rotating disk, and the velocity profile of diluted milk in a custom built diverging-converging planar flow channel. It is envisaged that a scaled up version of the parallel self-mixing imaging system will enable real-time surface profiling, vibrometry, and flowmetry.


Paleoclimatic modeling and phylogeography of least killifish, Heterandria formosa: insights into Pleistocene expansion-contraction dynamics and evolutionary history of North American Coastal Plain freshwater biota.
Climatic and sea-level fluctuations throughout the last Pleistocene glacial cycle (~130-0 ka) profoundly influenced present-day distributions and genetic diversity of Northern Hemisphere biotas by forcing range contractions in many species during the glacial advance and allowing expansion following glacial retreat ('expansion-contraction' model). Evidence for such range dynamics and refugia in the unglaciated Gulf-Atlantic Coastal Plain stems largely from terrestrial species, and aquatic species Pleistocene responses remain relatively uninvestigated. Heterandria formosa, a wide-ranging regional endemic, presents an ideal system to test the expansion-contraction model within this biota. By integrating ecological niche modeling and phylogeography, we infer the Pleistocene history of this livebearing fish (Poeciliidae) and test for several predicted distributional and genetic effects of the last glaciation. Paleoclimatic models predicted range contraction to a single southwest Florida peninsula refugium during the Last Glacial Maximum, followed by northward expansion. We inferred spatial-population subdivision into four groups that reflect genetic barriers outside this refuge. Several other features of the genetic data were consistent with predictions derived from an expansion-contraction model: limited intraspecific divergence (e.g. mean mtDNA p-distance = 0.66%); a pattern of mtDNA diversity (mean Hd = 0.934; mean π = 0.007) consistent with rapid, recent population expansion; a lack of mtDNA isolation-by-distance; and clinal variation in allozyme diversity with higher diversity at lower latitudes near the predicted refugium. Statistical tests of mismatch distributions and coalescent simulations of the gene tree lent greater support to a scenario of post-glacial expansion and diversification from a single refugium than to any other model examined (e.g. multiple-refugia scenarios). Congruent results from diverse data indicate H. formosa fits the classic Pleistocene expansion-contraction model, even as the genetic data suggest additional ecological influences on population structure. While evidence for Plio-Pleistocene Gulf Coast vicariance is well described for many freshwater species presently codistributed with H. formosa, this species demography and diversification departs notably from this pattern. Species-specific expansion-contraction dynamics may therefore have figured more prominently in shaping Coastal Plain evolutionary history than previously thought. Our findings bolster growing appreciation for the complexity of phylogeographical structuring within North America's southern refugia, including responses of Coastal Plain freshwater biota to Pleistocene climatic fluctuations.


The importance of angiogenesis markers in the outcome of patients with diffuse large B cell lymphoma: a retrospective study of 97 patients.
The role of angiogenesis has been extensively evaluated in solid tumors and more recently in hematologic malignancies. Several surrogate markers of angiogenesis including tumor VEGF, VEGF receptors, and microvessel density have correlated with outcome in some lymphoma studies. This is a single institution retrospective study evaluating the role of angiogenesis markers in the clinical outcome of patients with diffuse large B cell lymphoma (DLBCL). A total of 97 patients with DLBCL diagnosed and managed at Indiana University between 1993 and 2001 were included. Archived tumor samples were stained for VEGF-A, VEGF-C, VEGF-R1, and CD31 and graded as negative or positive (1+, 2+, 3+). The relationship between the expression of these markers and the international prognostic variables as well as the progression free survival (PFS) and the overall survival (OS) was evaluated. VEGF-A, VEGF-C, VEGF-R1 were expressed in 77, 98, and 18% of tumors, respectively. VEGF-A negative patients had an improved OS compared to VEGF-A (1+) (P = 0.0502). VEGF-C correlated with both LDH (r = 0.28, P = 0.0502) and IPI score (r = 0.25, P = 0.013). VEGF-R1 negative patients had a superior survival compared to those with VEGF-R1 (2+) (P = 0.0154). The presence of tumor associated angiogenesis may alter the outcome of patients with DLBCL and could be a prognostic factor. Further clinical studies are needed to correlate the degree of angiogenesis with response to anti-angiogenesis agents.


Lumenal calcification and microvasculopathy in fetuin-A-deficient mice lead to multiple organ morbidity.
The plasma protein fetuin-A mediates the formation of protein-mineral colloids known as calciprotein particles (CPP)-rapid clearance of these CPP by the reticuloendothelial system prevents errant mineral precipitation and therefore pathological mineralization (calcification). The mutant mouse strain D2,Ahsg-/- combines fetuin-A deficiency with the calcification-prone DBA/2 genetic background, having a particularly severe compound phenotype of microvascular and soft tissue calcification. Here we studied mechanisms leading to soft tissue calcification, organ damage and death in these mice. We analyzed mice longitudinally by echocardiography, X-ray-computed tomography, analytical electron microscopy, histology, mass spectrometry proteomics, and genome-wide microarray-based expression analyses of D2 wildtype and Ahsg-/- mice. Fetuin-A-deficient mice had calcified lesions in myocardium, lung, brown adipose tissue, reproductive organs, spleen, pancreas, kidney and the skin, associated with reduced growth, cardiac output and premature death. Importantly, early-stage calcified lesions presented in the lumen of the microvasculature suggesting precipitation of mineral containing complexes from the fluid phase of blood. Genome-wide expression analysis of calcified lesions and surrounding (not calcified) tissue, together with morphological observations, indicated that the calcification was not associated with osteochondrogenic cell differentiation, but rather with thrombosis and fibrosis. Collectively, these results demonstrate that soft tissue calcification can start by intravascular mineral deposition causing microvasculopathy, which impacts on growth, organ function and survival. Our study underscores the importance of fetuin-A and related systemic regulators of calcified matrix metabolism to prevent cardiovascular disease, especially in dysregulated mineral homeostasis.


Steroid hormones controlling the life cycle of the nematode Caenorhabditis elegans: stereoselective synthesis and biology.
Cholesterol-derived hormones, the dafachronic acids, play a major role in controlling the life cycle and initiating dauer larva formation of the nematode Caenorhabditis elegans. This Perspective describes recent progress in the synthesis of these steroid hormones and their biological function.


Genomic and karyotypic variation in Drosophila parasitoids (Hymenoptera, Cynipoidea, Figitidae).
Drosophila melanogaster Meigen, 1830 has served as a model insect for over a century. Sequencing of the 11 additional Drosophila Fallen, 1823 species marks substantial progress in comparative genomics of this genus. By comparison, practically nothing is known about the genome size or genome sequences of parasitic wasps of Drosophila. Here, we present the first comparative analysis of genome size and karyotype structures of Drosophila parasitoids of the Leptopilina Förster, 1869 and Ganaspis Förster, 1869 species. The gametic genome size of Ganaspis xanthopoda (Ashmead, 1896) is larger than those of the three Leptopilina species studied. The genome sizes of all parasitic wasps studied here are also larger than those known for all Drosophila species. Surprisingly, genome sizes of these Drosophila parasitoids exceed the average value known for all previously studied Hymenoptera. The haploid chromosome number of both Leptopilina heterotoma (Thomson, 1862) and Leptopilina victoriae Nordlander, 1980 is ten. A chromosomal fusion appears to have produced a distinct karyotype for Leptopilina boulardi (Barbotin, Carton et Keiner-Pillault, 1979)(n = 9), whose genome size is smaller than that of wasps of the Leptopilina heterotoma clade. Like Leptopilina boulardi, the haploid chromosome number for Ganaspis xanthopoda is also nine. Our studies reveal a positive, but non linear, correlation between the genome size and total chromosome length in Drosophila parasitoids. These Drosophila parasitoids differ widely in their host range, and utilize different infection strategies to overcome host defense. Their comparative genomics, in relation to their exceptionally well-characterized hosts, will prove to be valuable for understanding the molecular basis of the host-parasite arms race and how such mechanisms shape the genetic structures of insectcommunities.


E2F mediates induction of the Sp1-controlled promoter of the human DNA polymerase epsilon B-subunit gene POLE2.
The B-subunits of replicative DNA polymerases from Archaea to humans belong to the same protein family, suggesting that they share a common fundamental function. We report here the gene structure for the B-subunit of human DNA polymerase epsilon (POLE2), whose expression and transcriptional regulation is typical for replication proteins with some unique features. The 75 bp core promoter region, located within exon 1, contains an Sp1 element that is a critical determinant of promoter activity as shown by the luciferase reporter, electrophoretic mobility shift and DNase I footprinting assays. Two overlapping E2F elements adjacent to the Sp1 element are essential for full promoter activity and serum response. Binding sites for E2F1 and NF-1 reside immediately downstream from the core promoter region. Our results suggest that human POLE2 is regulated by two E2F-pocket protein complexes, one associated with Sp1 and the other with NF-1. So far, only one replicative DNA polymerase B-subunit gene promoter, POLA2 encoding the B-subunit of DNA polymerase alpha, has been characterized. Mitogenic activation of the POLE2 promoter by an E2F-mediated mechanism resembles that of POLA2, but the regulation of basal promoter activity is different between these two genes.


Automated benchmarking of peptide-MHC class I binding predictions.
Numerous in silico methods predicting peptide binding to major histocompatibility complex (MHC) class I molecules have been developed over the last decades. However, the multitude of available prediction tools makes it non-trivial for the end-user to select which tool to use for a given task. To provide a solid basis on which to compare different prediction tools, we here describe a framework for the automated benchmarking of peptide-MHC class I binding prediction tools. The framework runs weekly benchmarks on data that are newly entered into the Immune Epitope Database (IEDB), giving the public access to frequent, up-to-date performance evaluations of all participating tools. To overcome potential selection bias in the data included in the IEDB, a strategy was implemented that suggests a set of peptides for which different prediction methods give divergent predictions as to their binding capability. Upon experimental binding validation, these peptides entered the benchmark study. The benchmark has run for 15 weeks and includes evaluation of 44 datasets covering 17 MHC alleles and more than 4000 peptide-MHC binding measurements. Inspection of the results allows the end-user to make educated selections between participating tools. Of the four participating servers, NetMHCpan performed the best, followed by ANN, SMM and finally ARB. Up-to-date performance evaluations of each server can be found online at http://tools.iedb.org/auto_bench/mhci/weekly. All prediction tool developers are invited to participate in the benchmark. Sign-up instructions are available at http://tools.iedb.org/auto_bench/mhci/join. email@example.com or firstname.lastname@example.com Supplementary data are available at Bioinformatics online.


Amino acid sequence and crystal structure of BaP1, a metalloproteinase from Bothrops asper snake venom that exerts multiple tissue-damaging activities.
BaP1 is a 22.7-kD P-I-type zinc-dependent metalloproteinase isolated from the venom of the snake Bothrops asper, a medically relevant species in Central America. This enzyme exerts multiple tissue-damaging activities, including hemorrhage, myonecrosis, dermonecrosis, blistering, and edema. BaP1 is a single chain of 202 amino acids that shows highest sequence identity with metalloproteinases isolated from the venoms of snakes of the subfamily Crotalinae. It has six Cys residues involved in three disulfide bridges (Cys 117-Cys 197, Cys 159-Cys 181, Cys 157-Cys 164). It has the consensus sequence H(142)E(143)XXH(146)XXGXXH(152), as well as the sequence C(164)I(165)M(166), which characterize the "metzincin" superfamily of metalloproteinases. The active-site cleft separates a major subdomain (residues 1-152), comprising four alpha-helices and a five-stranded beta-sheet, from the minor subdomain, which is formed by a single alpha-helix and several loops. The catalytic zinc ion is coordinated by the N(epsilon 2) nitrogen atoms of His 142, His 146, and His 152, in addition to a solvent water molecule, which in turn is bound to Glu 143. Several conserved residues contribute to the formation of the hydrophobic pocket, and Met 166 serves as a hydrophobic base for the active-site groups. Sequence and structural comparisons of hemorrhagic and nonhemorrhagic P-I metalloproteinases from snake venoms revealed differences in several regions. In particular, the loop comprising residues 153 to 176 has marked structural differences between metalloproteinases with very different hemorrhagic activities. Because this region lies in close proximity to the active-site microenvironment, it may influence the interaction of these enzymes with physiologically relevant substrates in the extracellular matrix.


Dermatomyositis.
Dermatomyositis is an idiopathic inflammatory myopathy with characteristic skin manifestations. Although the disorder is rare, with a prevalence of one to 10 cases per million in adults and one to 3.2 cases per million in children, early recognition and treatment are important ways to decrease the morbidity of systemic complications. An association with other connective tissue disorders (overlap syndrome) and malignancy make this diagnosis particularly important to primary care physicians. Patient management includes careful evaluation for underlying malignancy and liberal use of physical therapy, antihistamines, sunscreen and oral corticosteroids. Poor prognostic indicators include poorly responsive disease, delay in diagnosis and the presence of malignancy. The therapeutic goal is to maintain function and prevent or minimize sequelae.


Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version (K-SADS-PL): initial reliability and validity data.
To describe the psychometric properties of the Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime version (K-SADS-PL) interview, which surveys additional disorders not assessed in prior K-SADS, contains improved probes and anchor points, includes diagnosis-specific impairment ratings, generates DSM-III-R and DSM-IV diagnoses, and divides symptoms surveyed into a screening interview and five diagnostic supplements. Subjects were 55 psychiatric outpatients and 11 normal controls (aged 7 through 17 years). Both parents and children were used as informants. Concurrent validity of the screen criteria and the K-SADS-PL diagnoses was assessed against standard self-report scales. Interrater (n = 15) and test-retest (n = 20) reliability data were also collected (mean retest interval: 18 days; range: 2 to 36 days). Rating scale data support the concurrent validity of screens and K-SADS-PL diagnoses. Interrater agreement in scoring screens and diagnoses was high (range: 93% to 100%). Test-retest reliability kappa coefficients were in the excellent range for present and/or lifetime diagnoses of major depression, any bipolar, generalized anxiety, conduct, and oppositional defiant disorder (.77 to 1.00) and in the good range for present diagnoses of posttraumatic stress disorder and attention-deficit hyperactivity disorder (.63 to .67). Results suggest the K-SADS-PL generates reliable and valid child psychiatric diagnoses.


e-Fungi: a data resource for comparative analysis of fungal genomes.
The number of sequenced fungal genomes is ever increasing, with about 200 genomes already fully sequenced or in progress. Only a small percentage of those genomes have been comprehensively studied, for example using techniques from functional genomics. Comparative analysis has proven to be a useful strategy for enhancing our understanding of evolutionary biology and of the less well understood genomes. However, the data required for these analyses tends to be distributed in various heterogeneous data sources, making systematic comparative studies a cumbersome task. Furthermore, comparative analyses benefit from close integration of derived data sets that cluster genes or organisms in a way that eases the expression of requests that clarify points of similarity or difference between species. To support systematic comparative analyses of fungal genomes we have developed the e-Fungi database, which integrates a variety of data for more than 30 fungal genomes. Publicly available genome data, functional annotations, and pathway information has been integrated into a single data repository and complemented with results of comparative analyses, such as MCL and OrthoMCL cluster analysis, and predictions of signaling proteins and the sub-cellular localisation of proteins. To access the data, a library of analysis tasks is available through a web interface. The analysis tasks are motivated by recent comparative genomics studies, and aim to support the study of evolutionary biology as well as community efforts for improving the annotation of genomes. Web services for each query are also available, enabling the tasks to be incorporated into workflows. The e-Fungi database provides fungal biologists with a resource for comparative studies of a large range of fungal genomes. Its analysis library supports the comparative study of genome data, functional annotation, and results of large scale analyses over all the genomes stored in the database. The database is accessible at http://www.e-fungi.org.uk, as is the WSDL for the web services.


Long-term seizure remission in childhood absence epilepsy: might initial treatment matter?
Examine the possible association between long-term seizure outcome in childhood absence epilepsy (CAE) and the initial treatment choice. Children with CAE were prospectively recruited at initial diagnosis and followed in a community-based cohort study. Children presenting with convulsive seizures, significant imaging abnormalities, or who were followed <5 years were excluded. Early outcomes included success of initial medication, early remission, and pharmacoresistance. The primary long-term outcome was complete remission: ≥5 years both seizure free and medication free. Survival methods were used for analyses. The first medication was ethosuximde (ESM) in 41 (69%) and valproic acid (VPA) in 18 (31%). Initial success rates were 59% (ESM) and 56% (VPA). Early remission and pharmacoresistance were similar in each group. Apart from atypical electroencephalography (EEG) features (61% [VPA], 17% [ESM]), no clinical features varied substantially between the treatment groups. Complete remission occurred in 31 children (76%) treated with ESM and 7 (39%) who received VPA (p = 0.007). Children with versus without atypical EEG features were less likely to enter complete remission (50% vs. 71%, p = 0.03). In a Cox regression, ESM was associated with a higher rate of complete remission than VPA (hazards ratio [HR] 2.5, 95% confidence interval [CI] 1.1-6.0; p = 0.03). Atypical EEG features did not independently predict outcome (p = 0.15). Five-year and 10-year remission, regardless of continued treatment, occurred more often in children initially treated with ESM versus VPA. These findings are congruent with results of studies in genetic absence models in rats and provide preliminary evidence motivating a hypothesis regarding potential disease-modifying effects of ESM in CAE. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.


A CD46-like molecule functional in teleost fish represents an ancestral form of membrane-bound regulators of complement activation.
In the complement system, the regulators of complement activation (RCA) play crucial roles in controlling excessive complement activation and in protecting host cell from misdirected attack of complement. Several members of RCA family have been cloned from cyclostome and bony fish species and classified into soluble and membrane-bound type as in mammalian RCA factors. Complement-regulatory functions have been described only for soluble RCA of lamprey and barred sand bass; however, little is known on the biological function of the membrane-bound RCA proteins in the lower vertebrates. In this study, a membrane-bound RCA protein, designated teleost complement-regulatory membrane protein (Tecrem), was cloned and characterized for its complement-regulatory roles. Carp Tecrem, an ortholog of a zebrafish type 2 RCA, ZCR1, consists of four short consensus repeat modules, a serine/threonine/proline-rich domain, a transmembrane region, and a cytoplasmic domain, from the N terminus, as does mammalian CD46. Tecrem showed a ubiquitous mRNA expression in carp tissues, agreeing well with the putative regulatory role in complement activation. A recombinant Chinese hamster ovary cell line bearing carp Tecrem showed a significantly higher tolerance against lytic activity of carp complement and less deposition of C3-S, the major C3 isotypes acting on the target cell, than control Chinese hamster ovary (mock transfectant). Anti-Tecrem mAb enhanced the depositions of carp C3 and two C4 isotypes on autologous erythrocytes. Thus, the present findings provide the evidence of complement regulation by a membrane-bound group 2 RCA in bony fish, implying the host-cell protection is an evolutionarily conserved mechanism in regulation of the complement system.


Intracranial mass lesions: dynamic contrast-enhanced susceptibility-weighted echo-planar perfusion MR imaging.
Dynamic contrast agent-enhanced perfusion magnetic resonance (MR) imaging provides physiologic information that complements the anatomic information available with conventional MR imaging. Analysis of dynamic data from perfusion MR imaging, based on tracer kinetic theory, yields quantitative estimates of cerebral blood volume that reflect the underlying microvasculature and angiogenesis. Perfusion MR imaging is a fast and robust imaging technique that is increasingly used as a research tool to help evaluate and understand intracranial disease processes and as a clinical tool to help diagnose, manage, and understand intracranial mass lesions. With the increasing number of applications of perfusion MR imaging, it is important to understand the principles underlying the technique. In this review, the essential underlying physics and methods of dynamic contrast-enhanced susceptibility-weighted echo-planar perfusion MR imaging are described. The clinical applications of cerebral blood volume maps obtained with perfusion MR imaging in the differential diagnosis of intracranial mass lesions, as well as the pitfalls and limitations of the technique, are discussed. Emphasis is on the clinical role of perfusion MR imaging in providing insight into the underlying pathophysiology of cerebral microcirculation.


Bactericidal and Bioresorbable Calcium Phosphate Cements Fabricated by Silver-Containing Tricalcium Phosphate Microspheres.
Bacterial adhesion to the calcium phosphate surface is a serious problem in surgery. To prevent bacterial infection, the development of calcium-phosphate cements (CPCs) with bactericidal properties is indispensable. The aim of this study was to fabricate antibacterial CPCs and evaluate their biological properties. Silver-containing tricalcium phosphate (Ag-TCP) microspheres consisting of α/β-TCP phases were synthesized by an ultrasonic spray-pyrolysis technique. The powders prepared were mixed with the setting liquid to fabricate the CPCs. The resulting cements consisting of β-TCP and hydroxyapatite had a porous structure and wash-out resistance. Additionally, silver and calcium ions could be released into the culture medium from Ag-TCP cements for a long time accompanied by the dissolution of TCP. These data showed the bioresorbability of the Ag-TCP cement. In vitro antibacterial evaluation demonstrated that both released and immobilized silver suppressed the growth of bacteria and prevented bacterial adhesion to the surface of CPCs. Furthermore, histological evaluation by implantation of Ag-TCP cements into rabbit tibiae exhibited abundant bone apposition on the cement without inflammatory responses. These results showed that Ag-TCP cement has a good antibacterial property and good biocompatibility. The present Ag-TCP cements are promising for bone tissue engineering and may be used as antibacterial biomaterials.


Direct comparison of prefrontal cortex regions engaged by working and long-term memory tasks.
Neuroimaging studies have suggested the involvement of ventrolateral, dorsolateral, and frontopolar prefrontal cortex (PFC) regions in both working (WM) and long-term memory (LTM). The current study used functional magnetic resonance imaging (fMRI) to directly compare whether these PFC regions show selective activation associated with one memory domain. In a within-subjects design, subjects performed the n-back WM task (two-back condition) as well as LTM encoding (intentional memorization) and retrieval (yes-no recognition) tasks. Additionally, each task was performed with two different types of stimulus materials (familiar words, unfamiliar faces) in order to determine the influence of material-type vs task-type. A bilateral region of dorsolateral PFC (DL-PFC; BA 46/9) was found to be selectively activated during the two-back condition, consistent with a hypothesized role for this region in active maintenance and/or manipulation of information in WM. Left frontopolar PFC (FP-PFC) was also found to be selectively engaged during the two-back. Although FP-PFC activity has been previously associated with retrieval from LTM, no frontopolar regions were found to be selectively engaged by retrieval. Finally, lateralized ventrolateral PFC (VL-PFC) regions were found to be selectively engaged by material-type, but uninfluenced by task-type. These results highlight the importance of examining PFC activity across multiple memory domains, both for functionally differentiating PFC regions (e.g., task-selectivity vs material-selectivity in DL-PFC and VL-PFC) and for testing the applicability of memory domain-specific theories (e.g., FP-PFC in LTM retrieval).


Genome mapping of quantitative trait loci (QTL) controlling domestication traits of intermediate wheatgrass (Thinopyrum intermedium).
Allohexaploid (2n = 6x = 42) intermediate wheatgrass (Thinopyrum intermedium), abbreviated IWG, is an outcrossing perennial grass belonging to the tertiary gene pool of wheat. Perenniality would be valuable option for grain production, but attempts to introgress this complex trait from wheat-Thinopyrum hybrids have not been commercially successful. Efforts to breed IWG itself as a dual-purpose forage and grain crop have demonstrated useful progress and applications, but grain yields are significantly less than wheat. Therefore, genetic and physical maps have been developed to accelerate domestication of IWG. Herein, these maps were used to identify quantitative trait loci (QTLs) and candidate genes associated with IWG grain production traits in a family of 266 full-sib progenies derived from two heterozygous parents, M26 and M35. Transgressive segregation was observed for 17 traits related to seed size, shattering, threshing, inflorescence capacity, fertility, stem size, and flowering time. A total of 111 QTLs were detected in 36 different regions using 3826 genotype-by-sequence markers in 21 linkage groups. The most prominent QTL had a LOD score of 15 with synergistic effects of 29% and 22% over the family means for seed retention and percentage of naked seeds, respectively. Many QTLs aligned with one or more IWG gene models corresponding to 42 possible domestication orthogenes including the wheat Q and RHT genes. A cluster of seed-size and fertility QTLs showed possible alignment to a putative Z self-incompatibility gene, which could have detrimental grain-yield effects when genetic variability is low. These findings elucidate pathways and possible hurdles in the domestication of IWG.


Impaired functional capacity predicts mortality in patients with obstructive sleep apnea.
Obstructive sleep apnea (OSA) is associated with increased mortality, for which impaired functional capacity (IFC) has been established as a surrogate. We sought to assess whether IFC is associated with increased mortality in patients with OSA and whether IFC is predictive of increased mortality after accounting for coronary artery disease. Patients with OSA who underwent both polysomnography testing and exercise stress echocardiogram were selected. Records were reviewed retrospectively for demographics, comorbidities, stress echocardiographic parameters, and polysomnography data. Univariable and multivariable logistic regression analysis was used to evaluate the association between IFC and overall mortality. We then evaluated the variables associated with IFC in the overall population and in the subgroup with normal Duke treadmill score (DTS). In our cohort, 404 (26%) patients had IFC. The best predictors of IFC were female sex, history of smoking, ejection fraction less than 55, increased body mass index, presence of comorbidities, abnormal exercise echocardiogram, abnormal heart rate recovery, and abnormal DTS. Compared with those without IFC, patients with IFC were 5.1 times more likely to die (odds ratio [OR], 5.1; 95% confidence interval [CI], 2.5-10.5; P < 0.0001) by univariate analysis and 2.7 times more likely to die (OR, 2.7; 95% CI, 1.2-6.1; P = 0.02) by multivariate analysis, when accounting for heart rate recovery, DTS, and sleep apnea severity. Among those without coronary artery disease, patients with IFC were at significantly increased risk of mortality (OR, 4.3; 95% CI, 1.35-13.79; P = 0.0088) compared with those with preserved functional capacity. In our OSA population, IFC was a strong predictor of increased mortality. Among those with normal DTS, IFC identified a cohort at increased risk of mortality.