Efficacy of omega 3 fatty acid as an adjunct in the management of chronic periodontitis: A randomized controlled trial.
: Periodontitis is conventionally treated with both surgical and nonsurgical methods. Various adjuncts have been used previously with compromised efficacy. Recently omega-3(ώ-3) polyunsaturated fatty acids (PUFA) including docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) were shown to have therapeutic anti-inflammatory and protective actions in inflammatory diseases including periodontitis. The purpose of the present study was to evaluate and compare the clinical efficacy of ώ-3 fatty acids as an adjunct to scaling and root planing in the treatment of periodontitis. 110 Patients were selected for the study out of which 20 were excluded (12 not meeting the inclusion criteria and 8 refused to participate). 90 patients (48 in test and 42 in the control group) after randomisation through a coin toss method were enrolled in a single-blind randomised controlled trial conducted in the Periodontics department of a dental college. Full mouth subgingival scaling and root planing and ώ-3 fatty acid 500 mg (EPA/DHA 180/120 mg), BD daily for 1 month was given to the test group and subgingival scaling and root planing only was given to the control group. Clinical parameters like probing pocket depth, clinical attachment level, plaque index and gingival index were recorded at baseline, 1 and 3 months and were compared. Statistical analyses demonstrated a significant reduction in probing pocket depth (t = 65.56, P = 0.000) and (t = 51.69, P = 0.000) at 1 and 3 months, respectively, in test group compared to baseline and control group. There was a significant gain in clinical attachment level (t = 63.29, P = 0.000) and (t = 31.03, P = 0.000) at 1 and 3 months, respectively, in test group compared to baseline and control group. The gingival index shows an appreciable reduction in both groups, and in test group, it is statistically significant at 3 months (t = 2.15, P = 0.03). There was no statistical significant reduction in plaque index at 3 months (t = 0, P = 0.997). The present study showed that adjunctive use of ώ-3 fatty acids proved to be beneficial over scaling and root planing alone in the treatment of chronic moderate periodontitis. The beneficial effects were in terms of significant improvements in clinical parameters, probing pocket depth, and clinical attachment level and gingival index. Dietary modulation is now emerging as an adjunct to periodontal therapy. Hence, omega-3 fatty acid may be used routinely in the management of chronic periodontitis.


Lingual frenulum protocol with scores for infants.
An experimental protocol model for frenulum evaluation was first designed, and administered to ten infants in 2010. After obtaining the data and statistical analysis, the protocol was re-designed and administered to 100 infants. The aim of this study is to present an efficient and effective lingual frenulum protocol with scores for infants. From the experimental protocol model, a new protocol was designed. One speech-language pathologist, and specialist in orofacial myology, administered the new protocol to 100 full-term infants. All steps of the protocol were recorded and photographed. The data collected was sent to two specialists in the area, who evaluated the cases based on the recordings and photographs. The data from the three evaluations were compared. A two-part protocol was designed to evaluate the lingual frenulum in infants. The first part consists of clinical history with specific questions about family history and breastfeeding. The second part consists of clinical examination: anatomo-functional, non-nutritive and nutritive sucking evaluations. A new lingual frenulum protocol with scores for infants was designed, and has proved to be an effective tool for health professionals to assess and diagnose anatomical alterations of the lingual frenulum, and its possible interference with breastfeeding.


Characterization and expression of AmphiBMP3 /3b gene in amphioxus Branchiostoma japonicum.
Bone morphogenetic proteins (BMPs) are responsible for regulating embryo development and tissue homeostasis beyond osteogenesis. However, the precise biological roles of BMP3 and BMP3b remain obscure to a certain extent. In the present study, we cloned an orthologous gene (AmphiBMP3/3b) from amphioxus (Branchiostoma japonicum) and found its exon/intron organization is highly conserved. Further, in situ hybridization revealed that the gene was strongly expressed in the dorsal neural plate of the embryos. The gene also appeared in Hatschek's left diverticulum, neural tube, preoral ciliated pit and gill slit of larvae, and adult tissues including ovary, neural tube and notochordal sheath. Additionally, real-time quantitative polymerase chain reaction (RTqPCR) analysis revealed that the expression displayed two peaks at gastrula and juvenile stages. These results indicated that AmphiBMP3/3b, a sole orthologue of vertebrate BMP3 and BMP3b, might antagonize ventralizing BMP2 orthologous signaling in embryonic development, play a role in the evolutionary precursors of adenohypophysis, as well as act in female ovary physiology in adult.


Cost-effectiveness study of three antimalarial drug combinations in Tanzania.
As a result of rising levels of drug resistance to conventional monotherapy, the World Health Organization (WHO) and other international organisations have recommended that malaria endemic countries move to combination therapy, ideally with artemisinin-based combinations (ACTs). Cost is a major barrier to deployment. There is little evidence from field trials on the cost-effectiveness of these new combinations. An economic evaluation of drug combinations was designed around a randomised effectiveness trial of combinations recommended by the WHO, used to treat Tanzanian children with non-severe slide-proven malaria. Drug combinations were: amodiaquine (AQ), AQ with sulfadoxine-pyrimethamine (AQ+SP), AQ with artesunate (AQ+AS), and artemether-lumefantrine (AL) in a six-dose regimen. Effectiveness was measured in terms of resource savings and cases of malaria averted (based on parasitological failure rates at days 14 and 28). All costs to providers and to patients and their families were estimated and uncertain variables were subjected to univariate sensitivity analysis. Incremental analysis comparing each combination to monotherapy (AQ) revealed that from a societal perspective AL was most cost-effective at day 14. At day 28 the difference between AL and AQ+AS was negligible; both resulted in a gross savings of approximately US1.70 dollars or a net saving of US22.40 dollars per case averted. Varying the accuracy of diagnosis and the subsistence wage rate used to value unpaid work had a significant effect on the number of cases averted and on programme costs, respectively, but this did not change the finding that AL and AQ+AS dominate monotherapy. In an area of high drug resistance, there is evidence that AL and AQ+AS are the most cost-effective drugs despite being the most expensive, because they are significantly more effective than other options and therefore reduce the need for further treatment. This is not necessarily the case in parts of Africa where recrudescence following SP and AQ treatment (and their combination) is lower so that the relative advantage of ACTs is smaller, or where diagnostic services are not accurate and as a result much of the drug goes to those who do not have malaria.


Inoculation- and nitrate-induced CLE peptides of soybean control NARK-dependent nodule formation.
Systemic autoregulation of nodulation in legumes involves a root-derived signal (Q) that is perceived by a CLAVATA1-like leucine-rich repeat receptor kinase (e.g. GmNARK). Perception of Q triggers the production of a shoot-derived inhibitor that prevents further nodule development. We have identified three candidate CLE peptide-encoding genes (GmRIC1, GmRIC2, and GmNIC1) in soybean (Glycine max) that respond to Bradyrhizobium japonicum inoculation or nitrate treatment. Ectopic overexpression of all three CLE peptide genes in transgenic roots inhibited nodulation in a GmNARK-dependent manner. The peptides share a high degree of amino acid similarity in a 12-amino-acid C-terminal domain, deemed to represent the functional ligand of GmNARK. GmRIC1 was expressed early (12 h) in response to Bradyrhizobium-sp.-produced nodulation factor while GmRIC2 was induced later (48 to 72 h) but was more persistent during later nodule development. Neither GmRIC1 nor GmRIC2 were induced by nitrate. In contrast, GmNIC1 was strongly induced by nitrate (2 mM) treatment but not by Bradyrhizobium sp. inoculation and, unlike the other two GmCLE peptides, functioned locally to inhibit nodulation. Grafting demonstrated a requirement for root GmNARK activity for nitrate regulation of nodulation whereas Bradyrhizobium sp.-induced regulation was contingent on GmNARK function in the shoot.


A randomized, double-blind, placebo-controlled trial of camicinal in Parkinson's disease.
Delayed gastric emptying may impair l-dopa absorption, contributing to motor fluctuations. We evaluated the effect of camicinal (GSK962040), a gastroprokinetic, on the absorption of l-dopa and symptoms of PD. Phase II, double-blind, placebo-controlled trial. Participants were randomized to receive camicinal 50 mg once-daily (n = 38) or placebo (n = 20) for 7 to 9 days. l-dopa exposure was similar with coadministration of camicinal compared to placebo. Median time to maximum l-dopa concentration was reduced, indicating more rapid absorption of l-dopa. Camicinal resulted in significant reduction in OFF time (-2.31 hours; 95% confidence interval: -3.71, -0.90), significant increase in ON time (+1.88 hours; 95% confidence interval: 0.28, 3.48) per day, and significant decrease in mean total MDS-UPDRS score (-12.5; 95% confidence interval: -19.67, -5.29). Camicinal treatment was generally well tolerated. PD symptom improvement with camicinal occurred in parallel with more rapid absorption of l-dopa. This study provides evidence of an improvement of the motor response to l-dopa in people with PD treated with camicinal 50 mg once-daily compared with placebo, which will require further evaluation. © 2017 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.


Phase I and pharmacological studies of pentamethylmelamine administered by 24-hour intravenous infusion.
A Phase I study of pentamethylmelamine (PMM) was conducted, administering the drug as a 24-hr i.v. infusion once weekly for 3 weeks. Doses ranged from 80 to 3000 mg/sq m/week. Twenty-six evaluable patients received a total of 30 courses of PMM. The median performance status of the patients was 60% (range, 40 to 90%), and the median age was 58 years (range, 43 to 72 years). The highest tolerated dose was 2000 mb/sq m/week. Nausea and vomiting were the dose-limiting toxicities; myelosuppression was neither consistent nor severe. One objective response lasting 10 months was noted in a patient with renal cancer. Pharmacokinetic studies using [ring-14C]PMM demonstrated a postinfusion half-life of 14C of approximately 12 hr, with the majority of the radiolabel excreted in the urine. PMM was introduced as a parenteral form of hexamethylmelamine. The present schedule does not permit administration of PMM in a dose greater than the tolerated dose of hexamethylmelamine and does not appear to offer an advantage over the p.o. use of the parent compound.


Impaired spatial and non-spatial configural learning in patients with hippocampal pathology.
The hippocampus has been proposed to play a critical role in memory through its unique ability to bind together the disparate elements of an experience. This hypothesis has been widely examined in rodents using a class of tasks known as "configural" or "non-linear", where outcomes are determined by specific combinations of elements, rather than any single element alone. On the basis of equivocal evidence that hippocampal lesions impair performance on non-spatial configural tasks, it has been proposed that the hippocampus may only be critical for spatial configural learning. Surprisingly few studies in humans have examined the role of the hippocampus in solving configural problems. In particular, no previous study has directly assessed the human hippocampal contribution to non-spatial and spatial configural learning, the focus of the current study. Our results show that patients with primary damage to the hippocampus bilaterally were similarly impaired at configural learning within both spatial and non-spatial domains. Our data also provide evidence that residual configural learning can occur in the presence of significant hippocampal dysfunction. Moreover, evidence obtained from a post-experimental debriefing session suggested that patients acquired declarative knowledge of the underlying task contingencies that corresponded to the best-fit strategy identified by our strategy analysis. In summary, our findings support the notion that the hippocampus plays an important role in both spatial and non-spatial configural learning, and provide insights into the role of the medial temporal lobe (MTL) more generally in incremental reinforcement-driven learning.


What mothers say about why poor children fall behind on immunizations. A summary of focus groups in North Carolina.
To develop a more thorough understanding of the factors that impede poor parents' utilization of health care services for their children and to refine interventions to improve immunization rates. We conducted focus group sessions with mothers whose children received care at the health departments in five North Carolina counties. Mothers were uninsured or were receiving Medicaid. A total of 50 women participated; group size varied from three to seven mothers. Socially disadvantaged mothers faced barriers at multiple points in the process of obtaining preventive care for their children. Organizational barriers, such as a lack of flexibility in scheduling and long waiting times, were exacerbated by personal barriers, such as a lack of reliable transportation, chaotic home environments, and employment conflicts. Lack of knowledge regarding the timing of childhood immunizations and misperceptions about the safety of immunizations were also important obstacles. Mothers made several suggestions, such as changes in scheduling, greater assistance with transportation, improved waiting facilities, and increased health education. Our study suggests that even with improved financing of well-child care, many important barriers to adequate immunization will remain. Many of the changes that mothers in our focus groups advocated are not related to insurance coverage and would be simple and inexpensive to implement. To help with these changes, we developed a checklist for use by health departments to determine which organizational barriers exist at their facility and suggest strategies to overcome the problems. Organizational, personal, and attitudinal barriers pose serious problems for socioeconomically disadvantaged families. To improve vaccination rates for children, new personnel and programs are probably less important than careful strategies to maximize existing resources.


Disruption of rhythms of molecular clocks in primary synovial fibroblasts of patients with osteoarthritis and rheumatoid arthritis, role of IL-1β/TNF.
Circadian rhythms play an important role in the body and in single cells. Rhythms of molecular clocks have not been investigated in synovial fibroblasts (SF) of patients with osteoarthritis (OA) and rheumatoid arthritis (RA). The study was initiated to fill this gap and to study effects of interleukin (IL)-1β/tumor necrosis factor (TNF) on rhythmicity in synovial fibroblasts of RA and OA patients. The presence of BMAL-1, CLOCK, Period 1 and Period 2 proteins in synovial tissue was investigated by immunofluorescence. The presence of mRNA of molecular clocks was studied during 72 h by qPCR. Characteristics of rhythms were studied with time series analysis. BMAL-1, CLOCK, Period 1 and Period 2 proteins were abundantly present in synovial tissue of OA, RA and controls. Receiving synovial tissue at different operation time points during the day (8:00 am to 4:00 pm) did not reveal a rhythm of BMAL-1 or Period 1 protein. In OASF and RASF, no typical rhythm curve of molecular clock mRNA was observed. Time series analysis identified a first peak between 2 and 18 hours after synchronization but a period was not detectable due to loss of rhythm. TNF inhibited mRNA of CLOCK, Period 1 and Period 2 in OASF, while IL-1β and TNF increased these factors in RASF. This was supported by dose-dependently increased levels in MH7A RA fibroblasts. In RASF, IL-1β and TNF shifted the first peak of BMAL-1 mRNA to later time points (8 h to 14 h). Rhythmicity is not present in primary OASF and RASF, which is unexpected because fibroblasts usually demonstrate perfect rhythms during several days. This might lead to uncoupling of important cellular pathways.


Couples becoming parents: Trajectories for psychological distress and buffering effects of social support.
Becoming a parent is a time of both joy and stress. Associations between exposure to postnatal depression and negative child outcomes underscore the importance of understanding trajectories and correlates of perinatal depression and anxiety. In a study of 438 expectant couples (from the UK, USA and Netherlands) tracked across four time-points (third trimester, 4, 14 and 24 months), we used dyadic latent growth curve modeling (LGCM) of self-reported symptoms of anxiety and depression (CES-D, GHQ, STAI) to investigate the affective impact of becoming a parent. Confirmatory factor analyses of anxious-depressive symptoms revealed a single latent factor with measurement invariance across time and parent. Dyadic LGCM intercepts showed greater prenatal problems in mothers compared with fathers. LGCM slopes revealed stable maternal problems but worsening paternal problems. Both intercepts and slopes showed significant within-couple associations. Controlling for prenatal salivary cortisol levels and perinatal couple relationship quality, support from friends attenuated mothers' psychological distress and support from family reduced fathers' psychological distress across the transition to parenthood. Our sample was low risk (i.e., predominantly well-educated and affluent and no history of serious mental illness), limiting the generalizability of findings. In addition, the inverse association between psychological distress and social support may, in part, reflect the use of self-report for both measures. The international dyadic longitudinal design strengthens conclusions regarding variation in trajectories of psychological distress in both mothers and fathers. Crucially, social support appears pivotal in enabling new parents to flourish.


Vagal nerve stimulation modulates gut injury and lung permeability in trauma-hemorrhagic shock.
Hemorrhagic shock is known to disrupt the gut barrier leading to end-organ dysfunction. The vagus nerve can inhibit detrimental immune responses that contribute to organ damage in hemorrhagic shock. Therefore, we explored whether stimulation of the vagus nerve can protect the gut and recover lung permeability in trauma-hemorrhagic shock (THS). Male Sprague-Dawley rats were subjected to left cervical vagus nerve stimulation at 5 V for 10 minutes. The right internal jugular and femoral artery were cannulated for blood withdrawal and blood pressure monitoring, respectively. Animals were then subjected to hemorrhagic shock to a mean arterial pressure between 30 mm Hg and 35 mm Hg for 90 minutes then reperfused with their own whole blood. After observation for 3 hours, gut permeability was assessed with fluorescein dextran 4 in vivo injections in a ligated portion of distal ileum followed by Evans blue dye injection to assess lung permeability. Pulmonary myeloperoxidase levels were measured and compared. Vagal nerve stimulation abrogated THS-induced lung injury (mean [SD], 8.46 [0.36] vs. 4.87 [0.78]; p < 0.05) and neutrophil sequestration (19.39 [1.01] vs. 12.83 [1.16]; p < 0.05). Likewise, THS gut permeability was reduced to sham levels. Neuromodulation decreases injury in the THS model as evidenced by decreased gut permeability as well as decreased lung permeability and pulmonary neutrophil sequestration in a rat model.


Representation of the visual field in the striate cortex: comparison of MR findings with visual field deficits in organic mercury poisoning (Minamata disease).
To compare MR imaging findings of the striate cortex with visual field deficits in patients with Minamata disease and to reestimate the classical Holmes retinotopic map by using the data obtained from comparing visual field abnormalities with degree of visual cortex atrophy. MR imaging was performed in eight patients with Minamata disease who had been given a full neuroophthalmic examination, including Goldmann dynamic perimetry. The atrophic portions of the calcarine area were measured in the sagittal plane next to the midsagittal image and represented as a percentage of atrophy of the total length of the calcarine fissure. MR findings were compared with results of a visual field test. The visual field test revealed moderate to severe concentric constriction of the visual fields, with central vision ranging from 7 degrees to 42 degrees (mean, 19 degrees). The ventral portion of the calcarine sulcus was significantly dilated on MR images in all patients. A logarithmic correlation was found between the visual field defect and the extent of dilatation of the calcarine fissure. The central 10 degrees and 30 degrees of vision seemed to fill about 20% and 50% of the total surface area of the calcarine cortex, respectively. Visual field deficits in patients with Minamata disease correlated well with MR findings of the striate cortex. Our data were consistent with the classical Holmes retinotopic map.


Regulation of Amino Acid Transport in Saccharomyces cerevisiae.
We review the mechanisms responsible for amino acid homeostasis in Saccharomyces cerevisiae and other fungi. Amino acid homeostasis is essential for cell growth and survival. Hence, the de novo synthesis reactions, metabolic conversions, and transport of amino acids are tightly regulated. Regulation varies from nitrogen pool sensing to control by individual amino acids and takes place at the gene (transcription), protein (posttranslational modification and allostery), and vesicle (trafficking and endocytosis) levels. The pools of amino acids are controlled via import, export, and compartmentalization. In yeast, the majority of the amino acid transporters belong to the APC (amino acid-polyamine-organocation) superfamily, and the proteins couple the uphill transport of amino acids to the electrochemical proton gradient. Although high-resolution structures of yeast amino acid transporters are not available, homology models have been successfully exploited to determine and engineer the catalytic and regulatory functions of the proteins. This has led to a further understanding of the underlying mechanisms of amino acid sensing and subsequent downregulation of transport. Advances in optical microscopy have revealed a new level of regulation of yeast amino acid transporters, which involves membrane domain partitioning. The significance and the interrelationships of the latest discoveries on amino acid homeostasis are put in context.


Quantitative 3D-OCT motion correction with tilt and illumination correction, robust similarity measure and regularization.
Variability in illumination, signal quality, tilt and the amount of motion pose challenges for post-processing based 3D-OCT motion correction algorithms. We present an advanced 3D-OCT motion correction algorithm using image registration and orthogonal raster scan patterns aimed at addressing these challenges. An intensity similarity measure using the pseudo Huber norm and a regularization scheme based on a pseudo L0.5 norm are introduced. A two-stage registration approach was developed. In the first stage, only axial motion and axial tilt are coarsely corrected. This result is then used as the starting point for a second stage full optimization. In preprocessing, a bias field estimation based approach to correct illumination differences in the input volumes is employed. Quantitative evaluation was performed using a large set of data acquired from 73 healthy and glaucomatous eyes using SD-OCT systems. OCT volumes of both the optic nerve head and the macula region acquired with three independent orthogonal volume pairs for each location were used to assess reproducibility. The advanced motion correction algorithm using the techniques presented in this paper was compared to a basic algorithm corresponding to an earlier version and to performing no motion correction. Errors in segmentation-based measures such as layer positions, retinal and nerve fiber thickness, as well as the blood vessel pattern were evaluated. The quantitative results consistently show that reproducibility is improved considerably by using the advanced algorithm, which also significantly outperforms the basic algorithm. The mean of the mean absolute retinal thickness difference over all data was 9.9 um without motion correction, 7.1 um using the basic algorithm and 5.0 um using the advanced algorithm. Similarly, the blood vessel likelihood map error is reduced to 69% of the uncorrected error for the basic and to 47% of the uncorrected error for the advanced algorithm. These results demonstrate that our advanced motion correction algorithm has the potential to improve the reliability of quantitative measurements derived from 3D-OCT data substantially.


Presence of Germ Cells in Disorders of Sex Development: Implications for Fertility Potential and Preservation.
We sought to determine the presence of germ cells in the gonads of patients with disorders of sex development to establish whether preservation of germ cells for future fertility potential is possible. We hypothesized that germ cells are present but vary by age and diagnosis. We reviewed histology from patients with disorders of sex development who underwent gonadectomy/biopsy from 2002 to 2014 at a single institution for pathological classification of the gonad, composition of gonadal stroma and germ cell presence. A total of 44 patients were identified and germ cells were present in 68%. The presence and average number of germ cells per mm2 were analyzed by gonad type and diagnosis. By gonad type all ovotestes, most testes, ovaries and dysgenetic testes, and 15% of streak gonads had germ cells present. By diagnosis germ cells were present in all patients with complete androgen insensitivity syndrome, Denys-Drash syndrome, SRY mutation, mixed gonadal dysgenesis, ovotesticular conditions and StAR (steroid acute regulatory protein) deficiency, in some patients with persistent müllerian duct syndrome, XO/XY Turner syndrome and disorders of sex development not otherwise specified, and in none with complete or partial gonadal dysgenesis. Germ cells were present in the gonads of 88% of patients 0 to 3 years old, 50% of those 4 to 11 years old and 43% of those older than 12 years. Germ cells were present in the majority of our cohort and the presence decreased with age. This novel, fertility driven evaluation of germ cell quantity in a variety of disorders of sex development suggests that fertility potential may be greater than previously thought. Further studies must be done to evaluate a larger population and examine germ cell quality to determine the viability of these germ cells.


Reproductive factors and risk of estrogen receptor positive, triple-negative, and HER2-neu overexpressing breast cancer among women 20-44 years of age.
Aspects of reproductive history are among the most well-established breast cancer risk factors. However, relatively little is known about how they influence risk of different molecular subtypes of breast cancer, particularly among younger women. Using data from a population-based case-control study of women 20-44 years of age, we assessed the relationships between various reproductive factors and risk of estrogen receptor positive (ER+), triple-negative, and HER2-overexpressing breast cancers. Detailed reproductive histories were obtained through structured interviewer administered in-person questionnaires. Reproductive histories among control women (n = 941) were compared to those of ER+ cases (n = 781), triple-negative cases (n = 180), and HER2-overexpressing cases (n = 60) using polytomous logistic regression. Age at menarche, parity, and number of full-term pregnancies were similarly associated with risk of all three breast cancer subtypes. In contrast, age at first live birth, the interval between age at menarche and age at first birth, and breastfeeding were inversely associated with risk of triple-negative breast cancer (P values for trend 0.002, 0.006 and 0.018, respectively), but were not associated with risk of ER+ or HER2-overexpressing cancers. A strong inverse association between breastfeeding and risk of triple-negative breast cancer has now been consistently observed across numerous studies, and at present it is the most well-established protective factor for this aggressive and lethal form of breast cancer. Further studies clarifying the biological mechanisms underlying this relationship and confirming our results with respect to age at first birth and the interval between age at menarche and age at first birth are needed.


Fabrication and characterization of an inorganic gold and silica nanoparticle mediated drug delivery system for nitric oxide.
Nitric oxide (NO) plays an important role in inhibiting the development of hepatic fibrosis and its ensuing complication of portal hypertension by inhibiting human hepatic stellate cell (HSC) activation. Here we have developed a gold nanoparticle and silica nanoparticle mediated drug delivery system containing NO donors, which could be used for potential therapeutic application in chronic liver disease. The gold nanoconjugates were characterized using several physico-chemical techniques such as UV-visible spectroscopy and transmission electron microscopy. Silica nanoconjugates were synthesized and characterized as reported previously. NO released from gold and silica nanoconjugates was quantified under physiological conditions (pH = 7.4 at 37 degrees C) for a substantial period of time. HSC proliferation and the vascular tube formation ability, manifestations of their activation, were significantly attenuated by the NO released from these nanoconjugates. This study indicates that gold and silica nanoparticle mediated drug delivery systems for introducing NO could be used as a strategy for the treatment of hepatic fibrosis or chronic liver diseases, by limiting HSC activation.


Restricted replication of simian immunodeficiency virus strain 239 in macrophages is determined by env but is not due to restricted entry.
Virus derived from the infectious, pathogenic, molecular clone of simian immunodeficiency virus (SIV) called SIVmac239 replicates poorly in primary rhesus monkey alveolar macrophage cultures. Variants with three to nine amino acid changes in the envelope replicate 100 to 1,000 times more efficiently in these macrophage cultures than parental SIVmac239. Early events, including virus entry into cells, were analyzed by measuring the amounts of newly synthesized viral DNA 14 to 16 h after infection of macrophages by using a quantitative polymerase chain reaction method. SIVmac239 ws found to enter macrophages with an efficiency similar to that of the macrophage-tropic derivatives. The assay indeed measured newly synthesized viral DNA since detection was inhibited by the reverse transcriptase inhibitors azidothymidine and foscarnet and by heat inactivation of the virus stock prior to infection. Furthermore, entry of SIVmac239 and macrophage-tropic variant into macrophages was inhibited by monoclonal antibody against CD4. Analysis of the time course of viral DNA accumulation showed that although initial entry of SIVmac239 into cells occurred normally, subsequent logarithmic increases in the amounts of viral DNA associated with spread of virus through the macrophage cultures was blocked. Increasing the amount of SIVmac239 incubated with macrophages increased the amount of virus entering the cell, but this could not overcome the block to replication. Thus, restricted replication of SIVmac239 in macrophages is determined by the envelope, but surprisingly it is not due to restricted virus entry.


A new technique for meatal stenosis in patients with lichen sclerosus.
A novel technique is described to relieve stenosis of a ventrally placed or pinhole external urinary meatus in men and boys with lichen sclerosus. A total of 19 patients underwent the new operation in a 5-year period. Mean patient age was 42.2 years (range 6 to 74) and mean followup was 3 years 9 months (range 18 months to 6 years 7 months). The operation involves dorsal and ventral meatotomies with an inverted V-shaped relieving incision to correct puckering caused by dorsal meatotomy. Patients were mailed a questionnaire asking if they were pleased with the cosmetic results, and how often and how much they sprayed when passing urine. Two patients died of unrelated causes and 2 were lost to followup. There were no recurrences or major complications. A total of 13 patients replied to the questionnaires. All patients were pleased or very pleased with the cosmetic result. Most patients (11 of 13 or 85%) did not spray at all or, if they did, only sprayed occasionally. No patient found it constant or severe. The technique relieves stenosis of the external urinary meatus in the medium term. It is rapid and easy to perform on an outpatient basis and it provides good cosmesis with a low incidence of a spraying stream. Because the main axis of the operation is dorsal, it does not create a hypospadiac meatus.


Frontostriatal functional connectivity correlates with repetitive behaviour across autism spectrum disorder and obsessive-compulsive disorder.
Autism spectrum disorder (ASD) and obsessive-compulsive disorder (OCD) are neurodevelopmental disorders with considerable overlap in terms of their defining symptoms of compulsivity/repetitive behaviour. Little is known about the extent to which ASD and OCD have common versus distinct neural correlates of compulsivity. Previous research points to potentially common dysfunction in frontostriatal connectivity, but direct comparisons in one study are lacking. Here, we assessed frontostriatal resting-state functional connectivity in youth with ASD or OCD, and healthy controls. In addition, we applied a cross-disorder approach to examine whether repetitive behaviour across ASD and OCD has common neural substrates. A sample of 78 children and adolescents aged 8-16 years was used (ASD n = 24; OCD n = 25; healthy controls n = 29), originating from the multicentre study COMPULS. We tested whether diagnostic group, repetitive behaviour (measured with the Repetitive Behavior Scale-Revised) or their interaction was associated with resting-state functional connectivity of striatal seed regions. No diagnosis-specific differences were detected. The cross-disorder analysis, on the other hand, showed that increased functional connectivity between the left nucleus accumbens (NAcc) and a cluster in the right premotor cortex/middle frontal gyrus was related to more severe symptoms of repetitive behaviour. We demonstrate the fruitfulness of applying a cross-disorder approach to investigate the neural underpinnings of compulsivity/repetitive behaviour, by revealing a shared alteration in functional connectivity in ASD and OCD. We argue that this alteration might reflect aberrant reward or motivational processing of the NAcc with excessive connectivity to the premotor cortex implementing learned action patterns.


Molecular cloning and expression of chicken cardiac troponin C.
We have isolated a full length complementary DNA clone (pCTnC1) from a 19-day embryonic chicken heart library corresponding to cardiac troponin C (TnC). Sequence analysis demonstrated varying homologies with TnC complementary DNA clones isolated from developing chick skeletal muscle. Using pCTnC1 as a hybridization probe, we have determined that cardiac TnC is constitutively expressed in both atria and ventricles of the developing and adult heart. These data along with previous immunochemical studies of TnC expression demonstrate that the slow skeletal and cardiac muscle isoform is the only TnC expressed in the heart. In contrast, expression of slow skeletal and cardiac muscle TnC is developmentally regulated in skeletal muscles of the chicken. The tightly controlled expression of slow skeletal and cardiac muscle TnC in the varying myocyte types of the heart suggests a physiologically significant role of this regulatory protein.


Patterns of intraneural ganglion cyst descent.
On the basis of the principles of the unifying articular theory, predictable patterns of proximal ascent have been described for fibular (peroneal) and tibial intraneural ganglion cysts in the knee region. The mechanism underlying distal descent into the terminal branches of the fibular and tibial nerves has not been previously elucidated. The purpose of this study was to demonstrate if and when cyst descent distal to the articular branch-joint connection occurs in intraneural ganglion cysts to understand directionality of intraneural cyst propagation. In Part I, the clinical records and MRIs of 20 consecutive patients treated at our institution for intraneural ganglion cysts (18 fibular and two tibial) arising from the superior tibiofibular joint were retrospectively analyzed. These patients underwent cyst decompression and disconnection of the articular branch. Five of these patients developed symptomatic cyst recurrence after cyst decompression without articular branch disconnection which was done elsewhere prior to our intervention. In Part II, five additional patients with intraneural ganglion cysts (three fibular and two tibial) treated at other institutions without disconnection of the articular branch were compared. These patients in Parts I and II demonstrated ascent of intraneural cyst to differing degrees (12 had evidence of sciatic nerve cross-over). In addition, all of these patients demonstrated previously unrecognized MRI evidence of intraneural cyst extending distally below the level of the articular branch to the joint of origin: cyst within the proximal most portions of the deep fibular and superficial fibular branches in fibular intraneural ganglion cysts and descending tibial branches in tibial intraneural ganglion cysts. The patients in Part I had complete resolution of their cysts at follow-up MRI examination 1 year postoperatively. The patients in Part II had intraneural recurrences postoperatively within the articular branch, the parent nerve, and the terminal branches, although in three cases they were subclinical. The authors demonstrate that cyst descent distal to the take-off of the articular branch to the joint of origin occurs regularly in patients with fibular and tibial intraneural ganglion cysts. The authors believe that parent terminal branch descent follows ascent up the articular branch from an affected joint of origin. This mechanism for bidirectional flow explains cyst within terminal branches of the fibular and tibial nerves and is dependent on pressure fluxes and resistances. This new pattern is consistent with principles previously described in a unified (articular) theory, is generalizable to other intraneural ganglion cysts arising from joints, and has important implications for pathogenesis and treatment of these intraneural cysts.


Strengthening the influenza vaccine virus selection and development process: Report of the 3rd WHO Informal Consultation for Improving Influenza Vaccine Virus Selection held at WHO headquarters, Geneva, Switzerland, 1-3 April 2014.
Despite long-recognized challenges and constraints associated with their updating and manufacture, influenza vaccines remain at the heart of public health preparedness and response efforts against both seasonal and potentially pandemic influenza viruses. Globally coordinated virological and epidemiological surveillance is the foundation of the influenza vaccine virus selection and development process. Although national influenza surveillance and reporting capabilities are being strengthened and expanded, sustaining and building upon recent gains has become a major challenge. Strengthening the vaccine virus selection process additionally requires the continuation of initiatives to improve the timeliness and representativeness of influenza viruses shared by countries for detailed analysis by the WHO Global Influenza Surveillance and Response System (GISRS). Efforts are also continuing at the national, regional, and global levels to better understand the dynamics of influenza transmission in both temperate and tropical regions. Improved understanding of the degree of influenza seasonality in tropical countries of the world should allow for the strengthening of national vaccination policies and use of the most appropriate available vaccines. There remain a number of limitations and difficulties associated with the use of HAI assays for the antigenic characterization and selection of influenza vaccine viruses by WHOCCs. Current approaches to improving the situation include the more-optimal use of HAI and other assays; improved understanding of the data produced by neutralization assays; and increased standardization of serological testing methods. A number of new technologies and associated tools have the potential to revolutionize influenza surveillance and response activities. These include the increasingly routine use of whole genome next-generation sequencing and other high-throughput approaches. Such approaches could not only become key elements in outbreak investigations but could drive a new surveillance paradigm. However, despite the advances made, significant challenges will need to be addressed before next-generation technologies become routine, particularly in low-resource settings. Emerging approaches and techniques such as synthetic genomics, systems genetics, systems biology and mathematical modelling are capable of generating potentially huge volumes of highly complex and diverse datasets. Harnessing the currently theoretical benefits of such bioinformatics ("big data") concepts for the influenza vaccine virus selection and development process will depend upon further advances in data generation, integration, analysis and dissemination. Over the last decade, growing awareness of influenza as an important global public health issue has been coupled to ever-increasing demands from the global community for more-equitable access to effective and affordable influenza vaccines. The current influenza vaccine landscape continues to be dominated by egg-based inactivated and live attenuated vaccines, with a small number of cell-based and recombinant vaccines. Successfully completing each step in the annual influenza vaccine manufacturing cycle will continue to rely upon timely and regular communication between the WHO GISRS, manufacturers and regulatory authorities. While the pipeline of influenza vaccines appears to be moving towards a variety of niche products in the near term, it is apparent that the ultimate aim remains the development of effective "universal" influenza vaccines that offer longer-lasting immunity against a broad range of influenza A subtypes.


Facilitating access to evidence: Primary Health Care Search Filter.
The evidence base developed by, and relevant to, primary health care (PHC) is rapidly increasing. With the wealth of literature available, searchers trying to find PHC-specific citations can feel overwhelmed. Flinders Filters and the Primary Health Care Research & Information Service collaborated to develop a search filter enabling efficient and effective retrieval of relevant PHC literature. Stage 1 involved developing a PHC Search Filter in the OvidSP Medline platform using a rigorous experimental methodology. The search filter was then translated for Web-based 'one-click searching' in PubMed during Stage 2. Stage 3 involved planning and implementing a mixed-methods evaluation. The search filter sensitivity was 77.0% with a post hoc relevance assessment of 78.3%. Four months after its launch, a mixed-methods study evaluated the PHC Search Filter. With 90 respondents, analysis of data from the online survey demonstrated overarching benefits, a positive response to the tool and directions for further refinement of the PHC Search Filter. Designing the PHC Search Filter followed an established method that ensures the tool offers a validated search strategy. Evaluation results suggest that the PHC Search Filter is a useful tool that is easy to navigate. Challenges for the Filter relate to access to full text articles, while challenges for the evaluation relate to the small sample size. The PHC Search Filter reduces the burden associated with literature searching, increases the value of the results that are received and provides a useful resource to improve the likelihood of incorporating relevant evidence into policy and practice.


Cheaters must prosper: reconciling theoretical and empirical perspectives on cheating in mutualism.
Cheating is a focal concept in the study of mutualism, with the majority of researchers considering cheating to be both prevalent and highly damaging. However, current definitions of cheating do not reliably capture the evolutionary threat that has been a central motivation for the study of cheating. We describe the development of the cheating concept and distill a relative-fitness-based definition of cheating that encapsulates the evolutionary threat posed by cheating, i.e. that cheaters will spread and erode the benefits of mutualism. We then describe experiments required to conclude that cheating is occurring and to quantify fitness conflict more generally. Next, we discuss how our definition and methods can generate comparability and integration of theory and experiments, which are currently divided by their respective prioritisations of fitness consequences and traits. To evaluate the current empirical evidence for cheating, we review the literature on several of the best-studied mutualisms. We find that although there are numerous observations of low-quality partners, there is currently very little support from fitness data that any of these meet our criteria to be considered cheaters. Finally, we highlight future directions for research on conflict in mutualisms, including novel research avenues opened by a relative-fitness-based definition of cheating.


Effect of granulocyte colony-stimulating factor (G-CSF)-supported chemotherapy on MR imaging of normal red bone marrow in breast cancer patients with focal bone metastases.
To investigate the effect of granulocyte colony-stimulating factor (G-CSF)-supported chemotherapy on normal red bone marrow MR imaging in breast cancer patients with focal bone metastases. Fifteen breast cancer patients who were examined before and after chemotherapy with T1-weighted-SE and long echo-time inversion-recovery turbo-spin-echo (long TE IR-TSE) sequences in the thoracolumbar spine and pelvis were retrospectively studied. Nine of them received G-CSF therapy after the administration of each chemotherapy course. Of these 9 patients, the MR follow-ups were performed during G-CSF in 4 patients and after G-CSF therapy in 5 patients. Six patients did not receive G-CSF. Signal intensity (SI) changes in normal bone marrow were evaluated visually in all patients and quantitatively in 13 patients. In all 4 patients investigated during G-CSF therapy a diffuse, homogeneous SI increase on long TE IR-TSE was observed visually and quantitatively in initially normal bone marrow. This change obscured some focal lesions in 2 patients. No such SI change was visible after G-CSF therapy (p = 0.008) or in patients not receiving G-CSF. On T1-weighted images an SI decrease was found both during and after G-CSF therapy, but an increase occurred in patients not receiving G-CSF. G-CSF-supported chemotherapy can induce diffuse SI changes in normal red bone marrow on MR imaging. On long TE IR-TSE, the changes are visible during G-CSF treatment and can lead to misinterpretations in the response evaluation of bone metastases to therapy.


Oxidative stress-mediated hemolytic activity of solvent exchange-prepared fullerene (C60) nanoparticles.
The present study investigated the hemolytic properties of fullerene (C(60)) nanoparticles prepared by solvent exchange using tetrahydrofuran (nC(60)THF), or by mechanochemically assisted complexation with macrocyclic oligosaccharide gamma-cyclodextrin (nC(60)CDX) or the copolymer ethylene vinyl acetate-ethylene vinyl versatate (nC(60)EVA-EVV). The spectrophotometrical analysis of hemoglobin release revealed that only nC(60)THF, but not nC(60)CDX or nC(60)EVA-EVV, was able to cause lysis of human erythrocytes in a dose- and time-dependent manner. Atomic force microscopy revealed that nC(60)THF-mediated hemolysis was preceded by erythrocyte shrinkage and increase in cell surface roughness. A flow cytometric analysis confirmed a decrease in erythrocyte size and demonstrated a significant increase in reactive oxygen species production in red blood cells exposed to nC(60)THF. The nC(60)THF-triggered hemolytic activity was efficiently reduced by the antioxidants N-acetylcysteine and butylated hydroxyanisole, as well as by serum albumin, the most abundant protein in human blood plasma. These data indicate that nC(60)THF can cause serum albumin-preventable hemolysis through oxidative stress-mediated damage of the erythrocyte membrane.


A novel group of diverse Polinton-like viruses discovered by metagenome analysis.
The rapidly growing metagenomic databases provide increasing opportunities for computational discovery of new groups of organisms. Identification of new viruses is particularly straightforward given the comparatively small size of viral genomes, although fast evolution of viruses complicates the analysis of novel sequences. Here we report the metagenomic discovery of a distinct group of diverse viruses that are distantly related to the eukaryotic virus-like transposons of the Polinton superfamily. The sequence of the putative major capsid protein (MCP) of the unusual linear virophage associated with Phaeocystis globosa virus (PgVV) was used as a bait to identify potential related viruses in metagenomic databases. Assembly of the contigs encoding the PgVV MCP homologs followed by comprehensive sequence analysis of the proteins encoded in these contigs resulted in the identification of a large group of Polinton-like viruses (PLV) that resemble Polintons (polintoviruses) and virophages in genome size, and share with them a conserved minimal morphogenetic module that consists of major and minor capsid proteins and the packaging ATPase. With a single exception, the PLV lack the retrovirus-type integrase that is encoded in the genomes of all Polintons and the Mavirus group of virophages. However, some PLV encode a newly identified tyrosine recombinase-integrase that is common in bacteria and bacteriophages and is also found in the Organic Lake virophage group. Although several PLV genomes and individual genes are integrated into algal genomes, it appears likely that most of the PLV are viruses. Given the absence of protease and retrovirus-type integrase, the PLV could resemble the ancestral polintoviruses that evolved from bacterial tectiviruses. Apart from the conserved minimal morphogenetic module, the PLV widely differ in their genome complements but share a gene network with Polintons and virophages, suggestive of multiple gene exchanges within a shared gene pool. The discovery of PLV substantially expands the emerging class of eukaryotic viruses and transposons that also includes Polintons and virophages. This class of selfish elements is extremely widespread and might have been a hotbed of eukaryotic virus, transposon and plasmid evolution. New families of these elements are expected to be discovered.


Maternal and perinatal death surveillance and response: a systematic review of qualitative studies.
To understand the experiences and perceptions of people implementing maternal and/or perinatal death surveillance and response in low- and middle-income countries, and the mechanisms by which this process can achieve its intended outcomes. In June 2022, we systematically searched seven databases for qualitative studies of stakeholders implementing maternal and/or perinatal death surveillance and response in low- and middle-income countries. Two reviewers independently screened articles and assessed their quality. We used thematic synthesis to derive descriptive themes and a realist approach to understand the context-mechanism-outcome configurations. Fifty-nine studies met the inclusion criteria. Good outcomes (improved quality of care or reduced mortality) were underpinned by a functional action cycle. Mechanisms for effective death surveillance and response included learning, vigilance and implementation of recommendations which motivated further engagement. The key context to enable effective death surveillance and response was a blame-free learning environment with good leadership. Inadequate outcomes (lack of improvement in care and mortality and discontinuation of death surveillance and response) resulted from a vicious cycle of under-reporting, inaccurate data, and inadequate review and recommendations, which led to demotivation and disengagement. Some harmful outcomes were reported, such as inappropriate referrals and worsened staff shortages, which resulted from a fear of negative consequences, including blame, disciplinary action or litigation. Conditions needed for effective maternal and/or perinatal death surveillance and response include: separation of the process from litigation and disciplinary procedures; comprehensive guidelines and training; adequate resources to implement recommendations; and supportive supervision to enable safe learning.


Computed tomography of partial anomalous pulmonary venous connection in adults.
To systematically describe the imaging features and clinical correlates of a partial anomalous pulmonary venous connection diagnosed on computed tomography (CT) in adults. Twenty-nine adults with a partial anomalous pulmonary venous connection on CT were retrospectively identified. There were 19 women and 10 men, with a mean age of 53 (range: 19-83) years. Four cases were identified by review of 1825 consecutive chest CT reports from July 2000-July 2001, and 25 cases were culled from chest radiology teaching files at 3 institutions. Inclusion criteria were availability of CT images and medical charts. Chest radiographs (25 of 29 cases) were reviewed for mediastinal contour abnormalities, heart size, and pulmonary vascular pattern. Chest CT scans were reviewed for location, size, and drainage site of the anomalous vein; presence or absence of a pulmonary vein in the normal location; cardiac size and configuration; and pulmonary vasculature. Charts were reviewed for evidence of pulmonary and cardiovascular disease, history of congenital heart disease, and results of other cardiac imaging. The prevalence of a partial anomalous pulmonary venous connection was 0.2% (4 of 1825 chest CT reports). Seventy-nine percent (23 of 29 patients) had an anomalous left upper lobe vein connecting to a persistent left vertical vein, only 5% (1 of 23 patients) of whom had a left upper lobe vein in the normal location. Seventeen percent (5 of 29 patients) had an anomalous right upper lobe vein draining into the superior vena cava, 60% (3 of 5 patients) of whom also had a right upper lobe pulmonary vein in the normal location. One patient (3%) had an anomalous right lower lobe vein draining into the suprahepatic inferior vena cava. Chest radiographic findings were abnormal left mediastinal contour in 64% (15 of 25 patients), abnormal right mediastinal contour in 8% (2 of 25 patients), and cardiomegaly in 24% (6 of 25 patients). Computed tomography findings were cardiomegaly in 48% (14 of 29 patients), right atrial enlargement in 31% (9 of 29 patients), right ventricular enlargement in 31% (9 of 29 patients), and pulmonary artery enlargement in 14% (4 of 29 patients). Pulmonary or cardiovascular symptoms were present in 69% (20 of 29 patients), 55% (11 of 20 patients) of whom had specific alternative diagnoses (excluding congestive heart failure and pulmonary hypertension) to explain the symptoms. Only 1 patient (3%) was diagnosed with a secundum atrial septal defect. A partial anomalous pulmonary venous connection was seen in 0.2% of adults on CT. In contrast to previous series focusing on children, the anomalous vein in adults was most commonly from the left upper lobe, in women, and infrequently associated with atrial septal defects.


Potential impact of Dare County landfills on Alligator River National Wildlife Refuge.
Runoff of leachate from East Lake and Dare County Construction and Demolition Debris landfills has the potential to impact wildlife resources at Alligator River National Wildlife Refuge, Dare and Hyde Counties, North Carolina. Sediment quality of samples collected in August 2000 at 14 locations down-gradient from the landfills was assessed by measuring metal and organic contaminants in the sediments, chronic toxicity of solid-phase sediment (28-d static-renewal exposures; survival and growth as test endpoints) and acute toxicity of sediment porewater (96-h static exposures) to Hyalella azteca (Crustacea: Amphipoda). In addition, contaminant bioaccumulation from 4 sediments was determined using 28-d exposures of Lumbriculus variegatus (freshwater oligochaete). Although survival was not impaired, length of H. azteca was significantly reduced in sediments from 5 locations. Pore water from 4 locations was acutely toxic to H. azteca. Metals and a few polycyclic aromatic hydrocarbons (PAHs) were bioaccumulated by L. variegatus from the sediments. Several metals and PAHs exceeded sediment quality guidelines, and metals in porewater from several sites exceeded water quality criteria for the protection of aquatic wildlife. Runoff of leachate from the landfills has reduced sediment quality and has the potential to adversely affect wildlife resources at Alligator River National Wildlife Refuge.


Absorption and metabolism of acetaminophen by the in situ perfused rat small intestine preparation.
The in situ perfused rat small intestine preparation was used to examine the extents of segmental absorption and metabolism of acetaminophen (A). Additionally, the preparation was employed to investigate any intestinal excretion of A and its conjugates from the circulation to the intestinal lumen. In this preparation, blood perfusate (300 ml) recirculated the intestinal preparation at 7.5 ml/min, entering via the superior mesenteric artery and returned to the reservoir via the portal vein. To demonstrate the extent of segmental absorption, metabolism, and excretion by different segments of the intestine, tracer doses of 3H-A (0.41 to 0.55 mumol in 0.3 ml of saline) were administered into the (a) entire intestine; (b) segments (first, second, and third) of one-third the length of the intestine, by instillation of the dose into the lumens of the segments; and (c) reservoir of perfusate. Exudates of luminal fluid from the injected segment and segments not exposed to drug were monitored for A and its conjugates during the experiment and at the end of 2 hr. Absorption of A was usually complete by 60 min; the extent of absorption of A at the end of 2 hr by the entire length of the intestine and by its three (first, second, and third) individual segments were 71.7 +/- 2.6, 50.5 +/- 4.0, 73.9 +/- 2.1, and 58.8 +/- 6.1% of dose (mean +/- SE), respectively. At the end of 2 hr, the total amount of acetaminophen glucuronide in perfusate and luminal fluid accounted for 3.1-5.5% and 0.14-0.1% of dose, respectively, among these preparations; acetaminophen sulfate was present only as a small percentage of dose in the lumen. Glucuronidation activity, when expressed as a percentage of the absorbed dose, was fairly constant for the entire intestine and first and second segments (8%) but decreased slightly for the third segment (7%). When A was present in blood perfusing the intestine, no metabolite was detected in perfusate or luminal fluid. Instead, unchanged A was excreted (5.6% dose) into the lumen. The effect of dose and vehicle on the extents of absorption and metabolism of A in the preparation was investigated by the instillation of different doses of A (0.16, 99.2, and 396.9 mumol in 0.3 ml of polyethene glycol 400) into the entire intestine at the duodenum.(ABSTRACT TRUNCATED AT 400 WORDS)


PAK4 crystal structures suggest unusual kinase conformational movements.
In order for protein kinases to exchange nucleotide they must open and close their catalytic cleft. These motions are associated with rotations of the N-lobe, predominantly around the 'hinge region'. We conducted an analysis of 28 crystal structures of the serine-threonine kinase, p21-activated kinase 4 (PAK4), including three newly determined structures in complex with staurosporine, FRAX486, and fasudil (HA-1077). We find an unusual motion between the N-lobe and C-lobe of PAK4 that manifests as a partial unwinding of helix αC. Principal component analysis of the crystal structures rationalizes these movements into three major states, and analysis of the kinase hydrophobic spines indicates concerted movements that create an accessible back pocket cavity. The conformational changes that we observe for PAK4 differ from previous descriptions of kinase motions, and although we observe these differences in crystal structures there is the possibility that the movements observed may suggest a diversity of kinase conformational changes associated with regulation. Protein kinases are key signaling proteins, and are important drug targets, therefore understanding their regulation is important for both basic research and clinical points of view. In this study, we observe unusual conformational 'hinging' for protein kinases. Hinging, the opening and closing of the kinase sub-domains to allow nucleotide binding and release, is critical for proper kinase regulation and for targeted drug discovery. We determine new crystal structures of PAK4, an important Rho-effector kinase, and conduct analyses of these and previously determined structures. We find that PAK4 crystal structures can be classified into specific conformational groups, and that these groups are associated with previously unobserved hinging motions and an unusual conformation for the kinase hydrophobic core. Our findings therefore indicate that there may be a diversity of kinase hinging motions, and that these may indicate different mechanisms of regulation.


Social cognition and psychopathology: a critical overview.
The philosophical and interdisciplinary debate about the nature of social cognition, and the processes involved, has important implications for psychiatry. On one account, mindreading depends on making theoretical inferences about another person's mental states based on knowledge of folk psychology, the so-called "theory theory" (TT). On a different account, "simulation theory" (ST), mindreading depends on simulating the other's mental states within one's own mental or motor system. A third approach, "interaction theory" (IT), looks to embodied processes (involving movement, gesture, facial expression, vocal intonation, etc.) and the dynamics of intersubjective interactions (joint attention, joint action, and processes not confined to an individual system) in highly contextualized situations to explain social cognition, and disruptions of these processes in some psychopathological conditions. In this paper, we present a brief summary of these three theoretical frameworks (TT, ST, IT). We then focus on impaired social abilities in autism and schizophrenia from the perspective of the three approaches. We discuss the limitations of such approaches in the scientific studies of these and other pathologies, and we close with a short reflection on the future of the field. In this regard we argue that, to the extent that TT, ST and IT offer explanations that capture different (limited) aspects of social cognition, a pluralist approach might be best.


Restriction of Legionella pneumophila growth in macrophages requires the concerted action of cytokine and Naip5/Ipaf signalling pathways.
Macrophages from the C57BL/6 (B6) mouse strain restrict intracellular growth of Legionella pneumophila, whereas A/J macrophages are highly permissive. The mechanism by which B6 macrophages restrict Legionella growth remains poorly understood, but is known to require the cytosolic microbe sensors Naip5 (Birc1e) and Ipaf. We hypothesized that Naip5 and Ipaf may act in partnership with other antimicrobial signalling pathways in macrophages. Indeed, we found that macrophages lacking either tumour necrosis factor (TNF)-alpha or type I interferon (IFN) signalling are permissive for growth of L. pneumophila, even in the presence of functional Naip5 and Ipaf alleles. Similarly, macrophages lacking Naip5 and/or Ipaf signalling were permissive even though we found that Naip5 or Ipaf were not required for induction of TNF-alpha and type I IFN. Therefore, our data suggest that the mechanism by which B6 macrophages restrict intracellular replication of L. pneumophila is more complex than previously appreciated, and involves the concerted action of cytokine and intracellular microbe sensor signalling pathways.


Area-Type Electronic Bipolar Switching Al/TiO1.7/TiO2/Al Memory with Linear Potentiation and Depression Characteristics.
In electronic bipolar resistive switching (eBRS), the electron trapping and detrapping at the defect sites within the switching layer, such as the highly defective TiO1.7 in this study, constitute the switching mechanism. It is an appealing candidate solution to the nonuniformity issue of resistive switching memory. However, TiO1.7-based eBRS has suffered from a lack of endurance and retention. In this study, a 7 nm-thick stoichiometric TiO2 layer is interposed between an Al bottom electrode and a 50 nm-thick TiO1.7 layer, which is in contact with an Al top electrode. Despite the minimal structural modification, improvements in the electrical performance were substantial. The off-to-on state resistance ratio of 20 and the resistance values could be retained up to 30 000 direct current sweep cycles and 106 alternating current pulse switching cycles. Data retention also significantly improves. Moreover, the device is electroforming-free and shows fully area-type switching characteristics. Such notable improvements are attributed to the favorable energy band structure of the Al/TiO1.7/TiO2/Al structure. The device shows almost linear potentiation and depression characteristics after the repeated pulse voltage applications, which significantly improves the accuracy of the neural network, the synapses of which are composed of the Al/TiO1.7/TiO2/Al memory cells.


Platelet decline as a predictor of brain injury in HIV infection.
An association between platelet decline and increased risk of progression to dementia has been observed in an advanced HIV infection cohort study. This investigation evaluated the prognostic significance of platelet decline for dementia, for psychomotor slowing, and for brain injury, as quantified in vivo, in a much larger population of HIV+ men. Platelet counts and neurocognitive data were available from biannual visits of 2,125 HIV+ men participating in the prospective, Multicenter AIDS Cohort Study from 1984 to 2009. Brain volumetric data were also available from an imaging substudy of 83 seropositive participants aged 50 and older. The association of platelet counts with neurocognitive outcome was assessed using Cox proportional hazard models where change in platelet count from baseline was a time-updated variable. Marked platelet decline was associated with increased risk of dementia in univariate analysis (hazard ratio [HR] = 2.5, 95% confidence interval [CI] = 1.8-3.5), but not after adjustment for CD4 cell count, HIV viral load, age, study site, hemoglobin, race, education, smoking, and alcohol use (HR = 1.4, 95% CI = 0.78-2.5). Platelet decline did not predict psychomotor slowing in either univariate (HR = 0.79, 95% CI = 0.58-1.08) or multivariate (HR = 1.10, 95% CI = 0.73-1.67) analysis. Analysis of brain volumetric data, however, indicated a relationship between platelet decline and reduced gray matter volume fraction in univariate (p = 0.06) and multivariate (p < 0.05) analyses. Platelet decline was not an independent predictor of dementia or psychomotor slowing, after adjusting for stage of disease. Findings from a structural brain imaging substudy of older participants, however, support a possible relationship between platelet decline and reduced gray matter.


Naive T lymphocytes and recent thymic emigrants are associated with HIV-1 disease history in french adolescents and young adults infected in the perinatal period: the ANRS-EP38-IMMIP study.
Children born at the start of the human immunodeficiency virus (HIV) epidemic and infected during the perinatal period are now young adults living with the virus. Naive T-lymphocyte restoration is essential for the maintenance of a diverse T-cell receptor repertoire and for immunity to pathogens. The ANRS-EP38-IMMIP study included 93 patients infected with HIV type 1 (HIV-1) during the perinatal period. Naive CD4 (CD4N) and CD8 (CD8N) T lymphocytes and CD4 recent thymic emigrants (CD4RTE) were quantified in the peripheral blood by flow cytometry. Wilcoxon tests, Pearson correlation coefficients, and linear regressions were used to study their associations with HIV disease parameters. Median CD4N, CD8N, and CD4RTE percentages were 56% (interquartile range [IQR], 44-64), 31% (IQR, 22-44), and 79% (IQR, 74-83), respectively. The three T-lymphocyte subsets were positively correlated with CD4 T-cell count. Patients aviremic at the time of the study tended to have a lower CD4N percentage (55% vs 58%; P = .10), a significantly higher CD8N percentage (39% vs 22%; P < .0001), and a significantly lower CD4RTE percentage (77% vs 81%; P = .003) than viremic patients. In aviremic patients, CD4N percentages were positively associated with cumulative viremia over the last 10 years (r = 0.335; P = .01) and were significantly higher in patients harboring X4R5 viruses than in those harboring R5 viruses (61% vs 44%; P = .001). After at least 15 years of HIV infection, perinatally infected youths had preserved CD4N and CD4RTE levels. This persistence of high levels of thymic activity potentially compensating for the deleterious effects of current and past HIV replication is remarkable.


Specific localization and imaging of amyloid deposits in vivo using 123I-labeled serum amyloid P component.
Highly specific, high-resolution scintigraphic images of amyloid-laden organs in mice with experimentally induced amyloid A protein (AA) amyloidosis were obtained after intravenous injection of 123I-labeled serum amyloid P component (SAP). Interestingly, a much higher proportion (up to 40%) of the injected dose of heterologous human SAP localized to amyloid and was retained there than was the case with isologous mouse SAP, indicating that human SAP binds more avidly to mouse AA fibrils than does mouse SAP. Specificity of SAP localization was established by the failure of the related proteins, human C-reactive protein and Limulus C-reactive protein, to deposit significantly in amyloid and by the absence of human SAP deposition in nonamyloidotic organs. However, only partial correlations were observed between the quantity of SAP localized and two independent estimates, histology and RIA for AA of the amount of amyloid in particular organs. It is not clear which of the three methods used reflects better the extent or clinical significance of the amyloid deposits but in vivo localization of radiolabeled SAP, detectable and quantifiable by gamma camera imaging, is apparently extremely sensitive. These findings establish the use of labeled SAP as a noninvasive in vivo diagnostic probe in experimental amyloidosis, potentially capable of revealing the natural history of the condition, and suggest that it may also be applicable generally as a specific targeting agent for diagnostic and even therapeutic purposes in clinical amyloidosis.


Biochemical and Pharmacokinetic Properties of PEGylated Cystathionine γ-Lyase from Aspergillus carneus KF723837.
Cystathionine γ-lyase (CGL) was purified to its electrophoretic homogeneity from Aspergillus carneus by various chromatographic approaches. The purified enzyme has four identical subunits of 52 kDa based on SDS and native PAGE analyses. To improve its structural stability, purified CGL was modified by covalent binding to polyethylene glycol moieties. The specific activity of free-CGL and PEG-CGL was 59.71 and 48.71 U/mg, respectively, with a PEGylation yield of 81.5 and 70.7% modification of surface ε-amino groups. Free- and modified CGL have the same pattern of pH stability (8.0-9.0). At 50 °C, the thermal stability [half-life time (T1/2)] of PEG-CGL was increased by 40% in comparison to free-CGL. The activity of CGL was completely inhibited by hydroxylamine and Hg(+2), with no effect by EDTA. Free-CGL (0.04 mM(-1)s(-1)) and PEG-CGL (0.03 mM(-1)s(-1)) have a similar catalytic efficiency to L-cystathionine as a substrate. The inhibition constant values of propargylglycine were 0.31 and 0.52 µM for the free- and PEG-CGL, respectively. By in vitro proteolysis, PEG-CGL retains >50% of its initial activity compared to <10% of the free-CGL for acid protease for 30 min. From in vivo pharmacokinetics in New Zealand white rabbits, the T1/2 was 19.1 and 28.9 h for the Holo free-CGL and PEG-CGL, respectively, ensuring the role of PEGylation on shielding the CGL surface from proteolytic attack, reducing its antigenicity, and stabilizing its internal Schiff base. By external infusion of pyridoxal 5'-phosphate (10 µM), the T1/2 of free- and PEG-CGL was prolonged to 24 and 33 h, respectively, so dissociation of pyridoxal 5'-phosphate was one of the main causes of loss of enzyme activity. The biochemical and hematological responses of rabbits to free- and PEG-CGL were assessed, with relative similarity to the negative control, confirming the nil toxicity of enzymes. The titer of IgG was duplicated in response to free- versus PEG-CGL after 45 days. To the best of our knowledge, this is the first report concerned with purification and PEGylation of CGL from fungi, with higher affinity for L-cystathionine. With further molecular studies, CGL will be a promising enzyme against various cardiovascular diseases and antioxidant deficiency, as well as for generation of a neurotransmitter (H2S).


(1)H, (13)C, and (15)N resonance assignments for the tandem PHD finger motifs of human CHD4.
The plant homeodomain (PHD) zinc finger is a structural motif of about 40-60 amino acid residues found in many eukaryotic proteins that are involved in chromatin-mediated gene regulation. The human chromodomain helicase DNA binding protein 4 (CHD4) is a multi-domain protein that harbours, at its N-terminal end, a pair of PHD finger motifs (dPHD) connected by a ~30 amino acid linker. This tandem PHD motif is thought to be involved in targeting CHD4 to chromatin via its interaction with histone tails. Here we report the (1)H, (13)C and (15)N backbone and side-chain resonance assignment of the entire dPHD by heteronuclear multidimensional NMR spectroscopy. These assignments provide the starting point for the determination of the structure, dynamics and histone-binding properties of this tandem domain pair.


Sleep quality in the general population: psychometric properties of the Pittsburgh Sleep Quality Index, derived from a German community sample of 9284 people.
The Pittsburgh Sleep Quality Index (PSQI) is frequently used to assess sleep problems in patients. The aim of this study was to provide reference values for this questionnaire, to test psychometric properties, and to analyze associations with psychological, sociodemographic, and behavioral factors. A German community sample comprising 9284 adult residents (aged 18-80 years) was surveyed using the PSQI and several other questionnaires. According to the generally accepted cut-off (PSQI > 5), 36% of the general population slept badly. Females reported significantly more sleep problems than males (mean scores: M = 5.5 vs. M = 4.4, respectively; effect size d = 0.35), but there was no linear association between age and sleep quality. Sleep problems were correlated with fatigue, quality of life (physical as well as mental), physical complaints, anxiety, and lack of optimism. Sleep quality was also strongly associated with socioeconomic status, professional situation (poorest sleep quality in unemployed people), and obesity. In addition to the results of the PSQI total score, mean scores of specific components of sleep quality were presented (sleep latency, sleep duration, and use of sleep medication). The PSQI proved to be a suitable instrument for measuring sleep quality. Gender differences, psychological factors, and obesity should be taken into account when groups of patients are compared with respect to sleep problems.


Implementing lifestyle medicine with medication therapy management services to improve patient-centered health care.
To describe a patient-centered medication therapy management (MTM) program that focuses on lifestyle medicine. Community pharmacy in Omaha, NE, from August 2008 to September 2010. Traditional MTM services are combined with lifestyle medicine interventions for employees of a self-insured organization who have dyslipidemia, hypertension, and/or diabetes. Program participants meet one-on-one with a pharmacist 12 times during the first year of the program to ensure proper drug therapy and modify lifestyle behaviors (physical activity, nutrition, weight control, sleep, stress, and alcohol and tobacco use) through individualized programming. Several patient-centered activities have been developed for the program with an emphasis on modifying lifestyle behaviors in conjunction with medications to manage participants' chronic condition. In addition, a new specialty position in health care is being developed (the ambulatist) that focuses on maintaining the ambulatory status of individuals with chronic medical conditions through appropriate drug therapy, lifestyle medicine, and care coordination. Biometric data collection and participant survey data at baseline and after 12 months. Pilot data for 15 participants showed improvements in all measurements, including blood cholesterol, low-density lipoprotein cholesterol, blood glucose, body weight, physical activity level, fruit and vegetable intake, risk for myocardial infarction, risk for any cardiovascular disease event, self-reported unhealthy days, and qualitative survey data. Pharmacists are in an ideal position to implement lifestyle medicine strategies in combination with MTM services to enhance patient-centered health care in a community pharmacy setting.


Early diagnosis and treatment of discoid lupus erythematosus.
Discoid lupus erythematosus is a chronic dermatological disease that can lead to scarring, hair loss, and hyperpigmentation changes in skin if it is not treated early and promptly. It has a prolonged course and can have a considerable effect on quality of life. Early recognition and treatment improves the prognosis. The diagnosis is usually made by clinical examination. In some cases histopathology may be required to confirm the diagnosis. The histology is that of an inflammatory interface dermatosis. There is insufficient evidence for which treatment is most effective. Because lesions are induced or exacerbated by ultraviolet exposure, photoprotective measures are important. Potent topical steroids and antimalarials are the mainstay of treatment. Some cases of discoid lupus erythematosus can be refractory to standard therapy; in these cases retinoids, thalidomide, and topical tacrolimus offer alternatives, as do immunosuppressives like azathioprine, cyclosporine, mycophenolate mofetil, and methotrexate.


Trif is not required for immune complex glomerulonephritis: dying cells activate mesangial cells via Tlr2/Myd88 rather than Tlr3/Trif.
Viral RNA or bacterial products can activate glomerular mesangial cells via a subset of Toll-like receptors (Tlr). Because Tlr2-deficient mice were recently found to have attenuated nephrotoxic serum nephritis (NSN), we hypothesized that endogenous Tlr agonists can activate glomerular mesangial cells. Primary mesangial cells from C57BL/6 mice expressed Tlr1-6 and Tlr11 mRNA at considerable levels and produced Il-6 when being exposed to the respective Tlr ligands. Exposure to necrotic cells activated cultured primary mesangial cells to produce Il-6 in a Tlr2/Myd88-dependent manner. Apoptotic cells activated cultured mesangial cells only when being enriched to high numbers. Apoptotic cell-induced Il-6 release was Myd88 dependent, and only purified apoptotic cell RNA induced Trif signaling in mesangial cells. Does Trif signaling contribute to disease activity in glomerulonephritis? To answer this question, we induced autologous NSN by injection of NS raised in rabbits in Trif-mutant and wild-type mice. Lack of Trif did not alter the functional and histomorphological abnormalities of NSN, including the evolution of anti-rabbit IgG and anti-rabbit-specific nephritogenic T cells. We therefore conclude that apoptotic cell RNA is a poor activator of Trif signaling in mesangial cells and that necrotic cells' releases rather activate mesangial cells via the Tlr2/Myd88 signaling pathway.


Gibbs free energy of protein-protein interactions correlates with ATP production in cancer cells.
In this paper, we analyze several cancer cell types from two seemingly independent angles: (a) the over-expression of various proteins participating in protein-protein interaction networks and (b) a metabolic shift from oxidative phosphorylation to glycolysis. We use large data sets to obtain a thermodynamic measure of the protein-protein interaction network, namely the associated Gibbs free energy. We find a strong inverse correlation between the percentage of energy production via oxidative phosphorylation and the Gibbs free energy of the protein networks. The latter is a measure of functional dysregulation within the cell. Our findings corroborate earlier indications that signaling pathway upregulation in cancer cells is linked to the metabolic shift known as the Warburg effect; hence, these two seemingly independent characteristics of cancer phenotype may be interconnected.


Segmental duplications and monosomies are linked to in vitro developmental arrest.
To verify which genetic abnormalities prevent embryos to blastulate in a stage-specific time. A single center retrospective study was performed between April 2016 and January 2017. Patients requiring Preimplantation Genetic Testing for Aneuploidies (PGT-A) by Next Generation Sequencing (NGS) were included. All embryos were cultured in a time-lapse imaging system and single blastomere biopsy was performed on day 3 of development. Segmental duplications and deletions as well as whole chromosome monosomies and trisomies were registered. Embryo arrest was defined if the embryo failed to blastulate 118 h post-injection. A logistic regression model was applied using the time to blastulate as the response variable and the different mutations as explanatory variables. A p value < 0.05 was considered significant. Of the 285 biopsied cleavage stage embryos, 103 (36.1%) were euploid, and 182 (63.9%) were aneuploid. There was a significant difference in the developmental arrest between euploid and aneuploid embryos (8.7% versus 42.9%; p = 0.0001). Segmental duplications and whole chromosome monosomies were found to have a significant effect on developmental arrest (p = 0.0163 and p = 0.0075), while trisomies and segmental deletions had no effect on developmental arrest. In case of segmental duplications, an increase of one extra segmental duplication increases the odd of arrest by 159%. For whole chromosome monosomies, the odd will only increase by 29% for every extra chromosomal monosomy. Both chromosomal abnormalities remained significant after adding age as an explanatory variable to the model (p = 0.014 and p = 0.009). Day 3 cleavage stage embryos with segmental duplications or monosomies have a significantly decreased chance to reach the blastocyst stage.


Effectiveness of pharmacotherapy for body dysmorphic disorder: a chart-review study.
Research on the pharmacotherapy of body dysmorphic disorder (BDD) is limited. No placebo-controlled, continuation, maintenance, or discontinuation studies have been published. Only one augmentation study has been published. In this chart-review study of 90 patients with DSM-IV BDD treated for up to 8 years by the first 2 authors (K.A.P., R.S.A.) in their clinical practice, response to a variety of medications, including augmentation strategies, was assessed. The relapse rate with medication discontinuation was also determined. All subjects received a serotonin reuptake inhibitor (SRI), with 63.2% (55/87) of adequate SRI trials resulting in improvement in BDD symptoms; similar response rates were obtained for each type of SRI. Discontinuation of an effective SRI resulted in relapse in 83.8% (31/37) of cases. Response rates to selective SRI augmentation were clomipramine, 44.4% (4/9) of trials; buspirone, 33.3% (12/36) of trials; lithium, 20.0% (1/5); methylphenidate, 16.7% (1/6); and antipsychotics, 15.4% (2/13) of trials. These findings from a clinical setting suggest that a majority of BDD patients improve with an SRI and that all SRIs appear effective. Certain SRI augmentation strategies may be beneficial. The high relapse rate with SRI discontinuation suggests that long-term treatment is often necessary. These preliminary findings require confirmation in placebo-controlled efficacy studies and effectiveness studies.


Explicit finite difference methods for the delay pseudoparabolic equations.
Finite difference technique is applied to numerical solution of the initial-boundary value problem for the semilinear delay Sobolev or pseudoparabolic equation. By the method of integral identities two-level difference scheme is constructed. For the time integration the implicit rule is being used. Based on the method of energy estimates the fully discrete scheme is shown to be absolutely stable and convergent of order two in space and of order one in time. The error estimates are obtained in the discrete norm. Some numerical results confirming the expected behavior of the method are shown.


Genotoxicity of alcohol is linked to DNA replication-associated damage and homologous recombination repair.
Although alcohol consumption is related to increased cancer risk, its molecular mechanism remains unclear. Here, we demonstrate that an intake of 10% alcohol for 4 weeks in rats is genotoxic due to induction of micronuclei. Acetaldehyde (AA), the first product of ethanol metabolism, is believed to be responsible for DNA damage induced by alcohol. Here, we observe that AA effectively blocks DNA replication elongation in mammalian cells, resulting in DNA double-strand breaks associated with replication. AA-induced DNA damage sites colocalize with the homologous recombination (HR) repair protein RAD51. HR measured in the hypoxhantineguaninefosforibosyltransferase (HPRT) gene is effectively induced by AA and recombination defective mammalian cells are hypersensitive to AA, clearly demonstrating that HR is essential in the repair of AA-induced DNA damage. Altogether, our data indicate that alcohol genotoxicity related to AA produces replication lesions on DNA triggering HR repair.


Early hematopoietic and vascular development in the chick.
The field of hematopoietic and vascular developmental research owes its origin to the chick embryo. Many key concepts, such as the hematopoietic stem cell, hemangioblast and hemogenic endothelium, were first proposed in this model organism. Genetically tractable models have gradually replaced the chick in the past two decades. However, advances in comparative genomics, transcriptomics and promoteromics promise a re-emergence of the chick embryo as a powerful model for hematopoietic/vascular research. This review summarizes the current status of our understanding of early blood/vascular development in the chick, focusing primarily on the processes of primitive hematopoiesis and early vascular network formation in the extraembryonic and lateral plate mesoderm territories. Emphasis is given to ontological and molecular association between the blood and endothelial cells and to the evolutionary relationship between the hemangioblasts, common precursors for the blood and endothelial lineages, and the coelomic epithelial lining cells. Links between early blood/vascular development and later definitive hematopoiesis are also discussed. Finally, potential applications of the chick model for comparative and omics-level studies of the blood/vascular system are highlighted.


C1q Modulates the Response to TLR7 Stimulation by Pristane-Primed Macrophages: Implications for Pristane-Induced Lupus.
The complement component C1q is known to play a controversial role in the pathogenesis of systemic lupus erythematosus, but the underlying mechanisms remain poorly understood. Intraperitoneal injection of pristane induces a lupus-like syndrome whose pathogenesis implicates the secretion of type I IFN by CD11b(+) Ly6C(high) inflammatory monocytes in a TLR7-dependent fashion. C1q was also shown to influence the secretion of IFN-α. In this study, we explored whether C1q deficiency could affect pristane-induced lupus. Surprisingly, C1qa(-/-) mice developed lower titers of circulating Abs and milder arthritis compared with the controls. In keeping with the clinical scores, 2 wk after pristane injection the peritoneal recruitment of CD11b(+) Ly6C(high) inflammatory monocytes in C1qa(-/-) mice was impaired. Furthermore, C1q-deficient pristane-primed resident peritoneal macrophages secreted significantly less CCL3, CCL2, CXCL1, and IL-6 when stimulated in vitro with TLR7 ligand. Replenishing C1q in vivo during the pristane-priming phase rectified this defect. Conversely, pristane-primed macrophages from C3-deficient mice did not show impaired cytokine production. These findings demonstrate that C1q deficiency impairs the TLR7-dependent chemokine production by pristane-primed peritoneal macrophages and suggest that C1q, and not C3, is involved in the handling of pristane by phagocytic cells, which is required to trigger disease in this model.


The relationship between rejection sensitivity and compliant condom use.
Those who are rejection sensitive anxiously expect and readily perceive rejection. Rejection sensitivity is hypothesized to predict behavior; however, this link may be more evident in some contexts than others. The current study examined the link between rejection sensitivity and condom use. Australian young adults in romantic (n = 649, 70% female) and casual (n = 144, 76.2% female) relationship contexts completed measures on rejection sensitivity, condom use preferences, and condom use. Regression analysis showed that rejection sensitivity predicted condom use when participants' condom use preferences were at odds with those they thought their partner held. Specifically, highly rejection-sensitive individuals who preferred more frequent condom use reported using condoms less often, if that was what they thought their partners wanted. The results lend support to the model of rejection sensitivity in that individuals comply more with their perceived partner's preferences if they are more rejection-sensitive. The results also highlight the need to take the situational context into consideration when examining links between personality dispositions and behavior.


Controlled clinical trials of drug treatment for hypertension. A review.
We reviewed the designs and major results of 17 large-scale, controlled, clinical trials that reported the effects of drug treatment for hypertension on morbidity or mortality. Seven trials conducted in study populations with more-severe hypertension (diastolic blood pressures 100-120 mm Hg or higher), including the more-severe stratum of the Veterans Administration Trial, showed large reductions in stroke, other "hypertensive" events, and, in one trial, total mortality. Of 11 trials in populations with less-severe hypertension (diastolic blood pressures predominantly below 105 mm Hg), including the less-severe stratum of the Veterans Administration Trial, nine met the criteria for pooling of results. Among the aggregate 43,000 patients in the nine trials who were followed up for an average of 5.6 years, mean diastolic blood pressure reduction was 5.8 mm Hg, and a significant 11% reduction in total mortality was observed. This benefit was largely attributable to a 38% reduction in fatal strokes; nonfatal strokes were similarly reduced. Coronary heart disease mortality was 8% lower in drug treatment than in control groups, but this difference was not significant. A similar result was observed for combined coronary mortality and nonfatal myocardial infarction. A possible explanation for the inconclusive result regarding coronary end points was an adverse trend, observed in several trials, in a subgroup with baseline resting electrocardiographic abnormalities. Because all the trials except the propranolol arm of the Medical Research Council trial used drug regimens based on thiazide-like diuretic agents, and because there are now several new drug classes proposed as initial therapy, additional large-scale clinical trials may need to be considered.


Molecular simulation of conformational transitions in biomolecules using a combination of structure-based potential and empirical valence bond theory.
The functions of biological macromolecules are inherently linked to their complex conformational behaviour. As a consequence of this complexity, the corresponding potential energy landscapes encompass multiple minima. Some of the intermediate structures between initial and final states can be characterized by experimental techniques. Computer simulations can explore the dynamics of individual states and bring these together to rationalize the overall process. Here, we show that the experimental structures can be exploited to define simple yet accurate atomistic structure-based potentials (SBP) that describe individual conformational states. These individual states can then be coupled by using the empirical valence bond (EVB) model. The overall energy landscape can easily be parameterised to reproduce available kinetic and thermodynamic data. We illustrate the procedure by applying the EVB-SBP method to study base flipping in B-DNA. Simple SBP is shown to reproduce structural ensembles obtained by using more refined force field simulations. Umbrella sampling in conjunction with the general energy gap reaction coordinate enables us to study alternative molecular pathways efficiently. We find that base rotation takes place via both grooves of the B-DNA with a marked preference for the major groove pathway. We also identify an unusual high-energy off-pathway intermediate that may appear if the base closing process is initiated from a syn base.


Review of the impact of donor characteristics on pediatric heart transplant outcomes.
Heart transplantation (HTx) is a treatment option for end-stage heart failure in children. HTx is limited by the availability and acceptability of donor hearts. Refusal of donor hearts has been reported to be common with reasons for refusal including preexisting donor characteristics. This review will focus on the impact of donor characteristics and comorbidities on outcomes following pediatric HTx. A literature review was performed to identify articles on donor characteristics and comorbidities and pediatric HTx outcomes. There are many donor characteristics to consider when accepting a donor heart. Weight-based matching is the most common form of matching in pediatric HTx with a donor-recipient weight ratio between 0.7 and 3 having limited impact on outcomes. From an age perspective, donors <50 years can be carefully considered, but the impact of ischemic time needs to be understood. To increase the donor pool, with minimal impact on outcomes, ABO-incompatible donors should be considered in patients that are eligible. Other factors to be considered when accepting an organ is donor comorbidities. Little is known about donor comorbidities in pediatric HTx, with most of the data available focusing on infections. Being aware of the potential infections in the donor, understanding the testing available and risks of transmission, and treatment options for the recipient is essential. There are a number of donor characteristics that potentially impact outcomes following pediatric HTx, but these need to be taken into consideration along with their interactions with recipient factors when interpreting the outcomes following HTx.