"…the availability of contraceptives is everywhere.": coordinated and integrated public family planning service delivery in Rwanda.
Contraceptive use in Rwanda tripled since 2005. This study aims to understand the role of coordinated and integrated public family planning service delivery in achieving this increase in contraceptive use in Rwanda. This qualitative study in 2018 included eight focus group discussions with family planning providers and 32 in-depth interviews with experienced family planning users. Results indicate a well-coordinated public family planning service delivery system with community health workers and nurses filling different and complementary roles in meeting family planning client needs at the local level. In addition, integration of family planning into other maternal and child health services is the norm. The coordination and integration of family planning across both providers and services may help explain the rapid increase in Rwanda's contraceptive use and has potential applications for enhancing family planning service delivery in other settings.


Epidermal growth factor induces matrix metalloproteinase-1 (MMP-1) expression and invasion in glioma cell lines via the MAPK pathway.
Glioblastoma multiforme (GBM) is an aggressive cancer with a poor survival rate. A key component that contributes to the poor prognosis is the capacity of glioma cells to invade local brain tissue in a diffuse manner. Among various proteases that aid in the process of invasion, matrix metalloproteinase-1 (MMP-1) has been identified as an important contributory factor in various cancers. Apart from its traditional role in cleaving its primary extracellular matrix (ECM) substrates, and like other members of the matrix metalloproteinase family, MMP-1 can activate latent forms of bio-active molecules initiating downstream pro-invasive and pro-oncogenic signaling mechanisms. MMP-1 expression is regulated by several growth factors including epidermal growth factor (EGF). Due to the fact that the epidermal growth factor receptor (EGFR) is aberrantly overexpressed in GBM, we wanted to examine in greater detail the signaling mechanisms by which MMP-1 expression and invasion is driven by EGF in GBM cells. T98G cells treated with EGF resulted in an induction of MMP-1 expression following EGFR activation. Inhibition of EGFR by both pharmacologic and genetic approaches abrogated this induction. Repression of the mitogen activated protein kinase (MAPK) signaling led to the inhibition of EGF-induced MMP-1 whereas the PI3-kinase/AKT signaling was not associated with EGFR-mediated MMP-1 induction. Inhibition of EGFR signaling also led to a decrease in T98G invasion. These data suggest that EGFR mediated MMP-1 regulation is mainly via the MAPK pathway in T98G cells and inhibition of EGFR and MMP-1 results in a decrease in T98G cell invasion.


Dynamics of evidence-informed health policy making in Pakistan.
Incorporating evidence is fundamental to maintaining the general acceptance and efficiency in public policies. In Pakistan, different actors-local and global-strive to facilitate the development of evidence-informed health policies. Effective involvement however, requires knowledge of the country-context, i.e. knowing the intricacies of how policies are formulated in Pakistan. Obtaining this knowledge is one of the key steps to making interventions impactful. We carried out a qualitative study to explore the environment of evidence-informed health policy in Pakistan. The study involved 89 participants and comprised three phases including: (1) literature review followed by a consultative meeting with key informants to explore the broad contours of policy formulation, (2) in-depth interviews with participants belonging to various levels of health system to discuss these contours and (3) a roundtable with experts to share and solidify the findings. Policy development is a slow, non-linear process with variable room for incorporation of evidence. Political actors dominate decisions that impact all aspects of policy, i.e. context, process and content. Research contributions are mostly influenced by the priorities of donor agencies-the usual proponents and sponsors of the generation of evidence. Since the devolution of health system in 2012, Pakistan's provinces continue to follow the same processes as before 2012, with little capacity to generate evidence and incorporate it into health policy. This study highlights the non-systematic, nearly ad hoc way of developing health policy in the country, overly dominated by political actors. Health advocates need to understand the policy process and the actors involved if they are to identify points of impact where their interaction with policy brings the maximum leverage. Moreover, an environment is needed where generation of data gains the importance it deserves and where capacities are enhanced for communicating and understanding evidence, as well as its incorporation into policy.


Iron-deficiency anemia associated with Helicobacter pylori gastritis.
Recent studies have suggested an association of Helicobacter pylori and iron-deficiency anemia (IDA). This is a report of six cases of IDA associated with H. pylori gastritis. Six patients with IDA were studied (5 boys and 1 girl; mean age 13.6 years; range 13-15 years). Five had a medical history of long-standing IDA and of oral iron supplementation at outpatient clinics. The anemia recurred after the iron therapy had been discontinued. The sixth patient was admitted to the hospital with severe IDA. An extensive work-up was ordered that included technetium-99m (99mTc) scans for Meckel's diverticulum, total colonoscopy, and gastrointestinal endoscopy. After biopsy-based H. pylori test results were confirmed to be positive, anti-H. pylori therapy consisting of lansoprazole, clarithromycin, and metronidazole was administered for 2 weeks with no iron supplementation. The hematologic profile and iron status were assessed periodically after the end of the eradication regimen. Upper gastrointestinal endoscopy revealed a marked antral nodularity but no evidence of bleeding lesions in all the patients. Given the histology and the fact that rapid urease test results were positive, chronic active gastritis with H. pylori was diagnosed in all these cases. H. pylori was successfully eradicated in all the patients. There was no evidence of IDA in any of the follow-up examinations between 27 and 50 months after anti-H. pylori therapy. H. pylori infection may be involved in cases of IDA of unknown origin, and the eradication of H. pylori can be associated with the resolution of anemia.


Muscle activity, cross-sectional area, and density following passive standing and whole body vibration: A case series.
To investigate the effects of intermittent passive standing (PS) and whole body vibration (WBV) on the electromyography (EMG) activity, cross-sectional area, and density of lower extremity muscles in individuals with chronic motor complete spinal cord injury (SCI). Case series. Seven adult men with chronic (≥2 years), thoracic motor complete (AIS A-B) SCI completed a 40-week course of thrice-weekly intermittent PS-WBV therapy, in a flexed knee posture (160°), for 45 minutes per session at a frequency of 45 Hz and 0.6-0.7 mm displacement using the WAVE(®) Pro Plate, with an integrated EasyStand™ standing frame. EMG was measured in major lower extremity muscles to represent muscle activity during PS-WBV. The cross-sectional area and density of the calf muscles were measured using peripheral quantitative computed tomography at the widest calf cross-section (66% of the tibia length) at pre- and post-intervention. All measured variables were compared between the pre- and post-intervention measurements to assess change after the PS-WBV intervention. PS-WBV acutely induced EMG activity in lower extremity muscles of SCI subjects. No significant changes in lower extremity EMG activity, muscle cross-sectional area, or density were observed following the 40-week intervention. Although acute exposure to PS-WBV can induce electrophysiological activity of lower extremity muscles during PS in men with motor complete SCI, the PS-WBV intervention for 40 weeks was not sufficient to result in enhanced muscle activity, or to increase calf muscle cross-sectional area or density.


A parallel approach to the discovery of carrier delivery vehicles to enhance antigen immunogenicity.
As part of an ongoing effort to generate human and murine monoclonal antibodies against poorly immunogenic tumor-associated antigens we have merged the rapidly expanding disciplines of parallel polymer synthesis and controlled-release technology with immunology to produce a rapid and generic approach to improve the immunogenicity of carrier-bound antigens. The process involves three stages: An array of cross-linked hydrogel materials containing a carrier protein (at various concentrations) is prepared in parallel in one step. The array is then screened in mice to determine the most effective hydrogel at enhancing the immunogenicity of the encapsulated versus nonencapsulated carrier. Finally, the most efficient hydrogel is prepared containing the critical carrier-antigen conjugate and is used for immunization protocols. The strategy was successful for the BSA-glycoconjugate of the tumor-associated antigen GM3 analogue 4. When encapsulated within the hydrogel array member most efficient at elevating BSA immunogenicity, the BSA-4 glycoconjugate was significantly more immunogenic that when administered as a free antigen.


[Intraoperative manometry during functional surgery of the esophagus].
The purpose of this investigation was to verify the suitability of intra-operative manometry in the course of functional surgery of the esophagus, especially with reference to the results obtained in terms of sphincter functionality, related to the overall changes in symptoms and pH-metry. The practice disclosed herein refers solely to the Heller-Dor operation for esophageal achalasia and to the Nissen Rossetti operation for gastro-esophageal reflux. The promising results obtained using this method to achieve a complete myotomy during Heller's operation, in our opinion testify in favor of its usefulness with this type of surgical procedure. On the contrary, for preparing a fundoplication we feel that method is of orientative value only, since there is no correspondence between the values obtained at the end of the fundoplication and those recorded 18 to 24 months after surgery. The predictive nature of the examination is thus denied.


Immunization against coccidiosis in fowls.
Immunity plays a major role in the control of coccidiosis. With the presently practised system of "protected exposure" under chemoprophylactic medication, problems are encountered because of seasonal variation in litter moisture and coccidial challenge. The alternative, "controlled exposure" or "vaccination" products a more solid immunity and more reliable results. This was found to be the method of choice in coccidiosis control in replacement pullets in the semi-arid subtropical climate of Rhodesia.


Safety of fenbendazole in Chinese ring-necked pheasants (Phasianus colchicus).
Ring-necked pheasants raised on propagation farms can be severely parasitized with Syngamus trachea (gapeworm) and other parasitic worms. Fenbendazole is a highly effective benzimidazole-class anthelmintic that is not currently approved for game bird species in the United States. The objective of this work was to provide target animal safety data to support a label claim for fenbendazole in pheasants at 100 parts per million (ppm) in the feed for 7 consecutive days. Demonstration of safety in young pheasants and a separate demonstration of reproductive safety in adult birds were required. In the young bird study, 160 Chinese ring-necked pheasants (Phasianus colchicus, 80 males and 80 females) were fed a commercial game bird starter ration containing no antibiotics, growth promoters, or coccidiostats until day 0 of the study (approximately 21 days of age). On day 0 the birds were placed on their respective study diets containing fenbendazole at 0, 100, 300, and 500 ppm for 21 days (three times the normal treatment duration). Clinical observations were recorded twice daily. Feed consumption, feed conversion rate, and body weights were determined for each pen. Three birds from each pen were randomly selected for necropsy, histopathology, and clinical pathology. Birds were carefully examined for feathering abnormalities immediately following euthanasia. The remaining birds in each pen were submitted for drug concentration analysis so that concentrations (for low vs. high treatment levels) could be correlated with clinical observations, clinical pathology, and histologic findings. There no morbidities or mortalities after study day--1. There were no statistically significant treatment-related differences in feed consumption, feed conversion rates, body weights, serum biochemistry profiles, hematologic profiles, gross necropsy findings, histopathologic examination, and feathering. Allowable liver and muscle concentrations of fenbendazole sulfone in turkeys are 6 and 2 ppm, respectively, with a 6-hr feed withdrawal. Analysis of fenbendazole concentrations in kidney, liver, leg/thigh, and breast muscle and skin with associated fat revealed that, even at the highest dose level used and with no feed withdrawal, fenbendazole concentrations were relatively low in these tissues. These findings indicate that fenbendazole has a relatively wide margin of safety in young pheasants and that the proposed dose of 100 ppm in the feed for 7 consecutive days is well within the margin of safety. In the reproductive safety study, two large game bird farms fed fendbendazole at 100 ppm for 7 days and collected data on hatching percentage of pheasant eggs before and after treatment. Reproductive performance in hen pheasants was not adversely affected.


Staff well-being in UK children's hospices: a national survey.
Poor psychological well-being among healthcare workers can have numerous negative impacts, but evidence about levels of burnout in children's hospice care staff is limited. This study aimed to determine the prevalence of burnout and to explore the association between staff characteristics and support mechanisms with burnout among children's hospice care staff in the UK. Two national online surveys collecting data on hospice care staff psychological well-being and hospice organisational characteristics. All children's hospices in the UK were invited.Thirty-one hospices (out of 52) responded to the hospice survey and 583 staff responded to the staff survey. Data collection took place between May and December 2020 and measures included the Copenhagen Burnout Inventory, Work Engagement and the Health and Safety Executive Management Standards Indicator Tool. Burnout prevalence was 11% and mean burnout score was 32.5 (SD: 13.1). Burnout levels were independent of working arrangements (eg, working from home or at the hospice) during the COVID-19 pandemic. Hospices performed well in most management standards, but poorly on the 'Control' domain. The average Work Engagement score for staff was 7.5 (SD: 1.5). Burnout levels for staff in children's hospices in the UK were lower than in other healthcare settings, with this comparing to 17.3% among palliative care staff generally. Overall, hospices performed well in management standards and there was no indication of urgent action needed. Work Engagement in our sample was higher compared with other National Health Service workers during the COVID-19 pandemic.


[Effect of histamine on motor and vascular effects on the small intestine induced by acetylcholine].
In acute experiments on cats, an isolated portion of the small intestine was perfused with a constant blood flow pump. Contractile activity of the intestine was estimated by means of isometric tension. Arterial vessel reactions were reflected in perfusion pressure shifts. Responses of the venous section of the perfused vascular bed were recorded by means of accumulography technique. The subthreshold dose of histamine (10(-9) or 10(-7) g/ml, 0.8 ml/min) potentiated the contractile responses of the jejunum induced with i. a. administration of acetylcholine (0.1 X 10(-4) g). Blockade of nicotinic receptors with benzohexonium and H1-histamine receptors with suprastin did not affect the potentiating effect of histamine. Dilatatory responses of arterial vessels induced by acetylcholine could be either increased or decreased against the background of histamine. The drug did not modulate responses of the intestinal venous vessels however. The modulating effect of histamine on the acetylcholine-induced contractile responses of the jejunum seems to be actualized through the participation of H2-histamine receptors.


Sleep disturbances and childhood sexual abuse.
This longitudinal, prospective study examined the relationship between childhood sexual abuse and later sleep problems in adolescence while taking into account cooccurring psychopathology that is closely related to sleep disruption [e.g., depression and posttraumatic stress disorder (PTSD)]. Sleep disturbances in 147 females (78 sexually abused; 69 comparison) were assessed 10 years after disclosure of substantiated abuse. The follow-up protocol included self-report questions regarding typical sleeping patterns and sleep disturbances as well as measures of depression, PTSD, and lifetime victimization histories. Sleep disturbances correlated significantly with both depression and PTSD. Hierarchical regression analysis showed that sexually abused participants reported significantly greater rates of sleep disturbances than comparison participants above and beyond depression and PTSD. Sleep disturbances were related to revictimization rates independent of sexual abuse, depression, and PTSD. Assessments of sleep disturbances should be integrated into standard of care for adolescents who have experienced sexual abuse.


Nature of the hormonal influence in mouse mammary cancer.
New findings indicate that hormones may play a permissive role, rather than an inductive one, in mammary tumorigenesis. Hormones supporting normal gland development may result in the emergence of precancerous lesions; hormones maintaining such hyperplastic lesions may result in the emergence of tumors. The "inherited hormonal influence" may rest in genetically determined sensitivity of mammary tissue to somatotropin.


Congenital cervical teratoma in neonates. Case report and review.
Cervical teratomas are uncommon neoplasms. Although these lesions are histologically benign they are usually large and may cause airway obstruction. Cervical teratomas are usually diagnosed at birth. In-utero diagnosis is possible by prenatal ultrasound which assists in planning early airway management and surgical intervention. Mortality is significant but prognosis is good with airway control and complete surgical excision. However, pressure injury of contiguous structures can limit resectability and adversely affect outcome. Malignant cervical teratoma with metastasis has been reported mostly arising in adults with poor outcome. We present nine cases of neonatal cervical teratoma identified at two institutions between 1984 and 1996. One patient died before surgical intervention. All others underwent resection. There was one intraoperative death and one postoperative death. The remaining six patients did well postoperatively with no significant sequelae with 3 to 14 years follow-up.


Atherosclerosis and diabetes mellitus.
Diabetes mellitus occurred most frequently in Prague (8.4%) and Malmö (8.6%), and less often in Tallin (3.4%), Yalta (3.3%), and Ryazan (2.1%), these differences not being connected with differences in age distribution. The extent of raised and calcified lesions in the coronary arteries and calcified lesions in the aorta in the pure diabetes group was similar to that in the high atherosclerosis group and significantly higher than in the standardized average atherosclerosis group. Raised and calcified lesions in the aorta and raised lesions in the coronary arteries were more extensive in the diabetes group than in the high atherosclerosis group. In all diabetes groups, stenosis of the coronary arteries and myocardial lesions occurred much more frequently than in the average atherosclerosis group but were less common than in the high atherosclerosis group. Coronary thrombosis also occurred more frequently in the high atherosclerosis group. Diabetes per se and hypertension were found to have approximately the same effect on the development of atherosclerosis, but hypertension had a greater effect than diabetes on the development of aortic atherosclerosis. There were no significant differences in the frequency of coronary stenosis and myocardial lesions in diabetics and hypertensives. Diabetics of more than 10 years' standing generally showed more coronary but not more aortic atherosclerosis than those who had had diabetes for less than 10 years. In insulin-treated diabetics coronary atherosclerosis tended to be more extensive than in those treated by diet or by tablets, but there was no difference in the frequency of coronary stenosis and thrombosis and myocardial and cerebrovascular lesions.


Pharmacokinetics and absolute bioavailability of intramuscular tranexamic acid in man.
The bioavailability of tranexamic acid after the administration of a single intramuscular dose was estimated in three healthy male volunteers. 500 mg tranexamic acid were given intramuscularly and intravenously, as a bolus injection, to each subject on separate occasions. Following intramuscular administration, the peak plasma concentrations were attained after approximately one hour and the apparent elimination half-life was about two hours. The absolute bioavailability was 105.2 +/- 10.7% (mean +/- SD). At the dose given, the bioavailability of tranexamic acid after intramuscular administration is fast and complete.


[Transgenic mice overexpressing PACAP in pancreatic beta-cells: acute and chronic effects on insulin and glucose homeostasis].
PACAP belongs to the vasoactive intestinal polypeptide (VIP)/secretin/glucagon superfamily, which also includes glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP). PACAP shares an insulinotropic property with the latter two peptides; for instance, it stimulates insulin secretion from islets in a glucose-dependent manner at femtomolar concentrations. However, the pathophysiological significance of PACAP in diabetes remains largely unknown, for several reasons, including a lack of low-molecular weight PACAP ligands and a lack of suitable animal models. As an approach to understanding PACAP's pancreatic function in vivo, we have recently generated transgenic mice overexpressing PACAP in islet beta cells under the control of human insulin promoter (Tg mice). As a consequence, it has been demonstrated that in addition to stimulating insulin secretion, PACAP has long-term effects on pancreatic endocrine cells, including proliferation of beta cells during streptozotocin-induced diabetes development as well as aging. These observations provide additional information to support the possibility that drugs associated with PACAP-signaling pathways might be of therapeutic value for the treatment of diabetes. In this review, we briefly summarize these previous studies using Tg mice and also focus on the physiological and pathophysiological roles mediated by PACAP during diabetes development.


Uterine artery embolization with trisacryl gelatin microspheres in women treated for leiomyomas: a clinicopathologic analysis of alterations in gynecologic surgical specimens.
To characterize the histologic range of alterations due to uterine artery embolization with trisacryl gelatin microspheres in gynecologic specimens containing leiomyomas in detail, we report our clinicopathologic experience with 26 cases (longest postuterine artery embolization interval, 1.9 yr). Microspheres were observed in 85% of cases and could be seen up to 1.9 years after embolization. They were mainly present in leiomyomas and nonneoplastic myometrium but could be found in other nontargeted sites, such as the cervix, endometrium, ovaries, and fallopian tubes; however, infarction (present in 96% of cases) was confined to leiomyomas and did not involve other nonneoplastic tissues. The appearance of the infarcts was correlated with time after embolization, and coagulative necrosis/necrosis of indeterminate type was restricted to the early period after uterine artery embolization (before 10 wk postuterine artery embolization) whereas hyaline necrosis was seen predominantly in the late period (mostly after 10 wk, up to 1.9 yr). Of the 14 hysterectomy specimens with microspheres in extravascular spaces (almost all of which were in close proximity to the arteries), pseudoaneurysms were also focally present in 8 (57%) specimens. Microspheres were usually associated with mild inflammatory reactions, which persisted >1 year after embolization but did not become more severe over time. Morphologic and histochemical features of trisacryl gelatin microspheres were compared with other embolization agents, which can also be encountered in surgical specimens [polyvinyl alcohol (PVA) particles and PVA microspheres]. Trisacryl gelatin microspheres were negative with periodic acid-Schiff and orange-pink with Movat stains whereas PVA was positive with periodic acid-Schiff and black with Movat. Our study, the largest histologic analysis to date, confirms and extends the observations of earlier studies of trisacryl gelatin microspheres. In addition, we conclude that, as expected, the histologic appearance of microsphere-induced infarcts is a function of time, similar to healing of infarcts in nongynecologic sites. Pseudoaneurysms are a likely mechanism for the production of microspheres in extravascular spaces. Inflammation associated with microspheres can persist in gynecologic tissues but does not seem to result in the destruction of nontargeted sites. Finally, trisacryl gelatin microspheres can be distinguished from PVA particles and PVA microspheres based on a combination of morphologic features and histochemical stains.


Effect of storage temperature and duration on the behavior of Escherichia coli O157:H7 on packaged fresh-cut salad containing romaine and iceberg lettuce.
This study investigated the impact of storage temperature and duration on the fate of Escherichia coli O157:H7 on commercially packaged lettuce salads, and on product quality. Fresh-cut Romaine and Iceberg lettuce salads of different commercial brands were obtained from both retail and wholesale stores. The packages were cut open at one end, the lettuce salad inoculated with E. coli O157:H7 via a fine mist spray, and resealed with or without an initial N(2) flush to match the original package atmospheric levels. The products were stored at 5 and 12 °C until their labeled "Best If Used By" dates, and the microbial counts and product quality were monitored periodically. The results indicate that storage at 5 °C allowed E. coli O157:H7 to survive, but limited its growth, whereas storage at 12 °C facilitated the proliferation of E. coli O157:H7. There was more than 2.0 log CFU/g increase in E. coli O157:H7 populations on lettuce when held at 12 °C for 3 d, followed by additional growth during the remainder of the storage period. Although there was eventually a significant decline in visual quality of lettuce held at 12 °C, the quality of this lettuce was still fully acceptable when E. coli O157:H7 growth reached a statistically significant level. Therefore, maintaining fresh-cut products at 5 °C or below is critical for reducing the food safety risks as E. coli O157:H7 grows at a rapid, temperature-dependent rate prior to significant quality deterioration. Specific information regarding the effect of temperature on pathogen growth on leafy greens is needed to develop science-based food safety guidelines and practices by the regulatory agencies and produce industry. Temperature control is commonly thought to promote quality of leafy greens, not safety, based at least partially on a theory that product quality deterioration precedes pathogen growth at elevated temperatures. This prevalent attitude results in temperature abuse incidents being frequently overlooked in the supply chain. This study demonstrates that human pathogens, such as E. coli O157:H7, can grow significantly on commercially packaged lettuce salads while the product's visual quality is fully acceptable. Packaged fresh-cut salads are marketed as "ready-to-eat" while lacking an effective pathogen kill step during their preparation. Thus, maintaining storage temperature at 5 °C or below is critical to prevent pathogen proliferation and mitigate food safety risks should pathogen contamination inadvertently occur during crop growth or postharvest fresh-cut processing.


Ballistic dynamics of flexural thermal movements in a nanomembrane revealed with subatomic resolution.
Flexural oscillations of freestanding films, nanomembranes, and nanowires are attracting growing attention for their importance to the fundamental physical and optical properties and device applications of two-dimensional and nanostructured (meta)materials. Here, we report on the observation of short-time scale ballistic motion in the flexural mode of a nanomembrane cantilever, driven by thermal fluctuation of flexural phonons, including measurements of ballistic velocities and displacements performed with subatomic resolution, using a free electron edge-scattering technique. Within intervals <10 μs, the membrane moves ballistically at a constant velocity, typically ~300 μm/s, while Brownian-like dynamics emerge for longer observation periods. Access to the ballistic regime provides verification of the equipartition theorem and Maxwell-Boltzmann statistics for flexural modes and can be used in fast thermometry and mass sensing during atomic absorption/desorption processes on the membrane.


Actions of estrogens and progestins on nerve cells.
Estrogens and progestins alter electrical and chemical features of nerve cells, particularly in hypothalamus. Temporally, these events follow nuclear receptor occupation by these steroids, although not all effects have been proved to depend on translocation of receptors to the nucleus. Narrowing studies to focus on particular medial hypothalamic cells has been useful for understanding some of the actions of these steroids in brain. The variety of morphological, chemical, and electrical effects allow for a multiplicity in the cellular functions controlled by these hormones.


Rhodopsin exhibits a preference for solvation by polyunsaturated docosohexaenoic acid.
An all-atom molecular dynamics simulation of rhodopsin in a membrane environment has been carried out with lipid composition similar to that of the retinal membrane. The initial conformation of the protein was taken from the X-ray crystallographic structure (1F88), while those of the lipids came from a previous molecular dynamics simulation. During the course of the 12.5 ns simulation, the initially randomly placed lipids adopt an anisotropic solvation structure around the protein. The lipids, having one saturated stearic acid chain and one polyunsaturated docosohexaenoic acid chain with a zwitterionic phosphatidylcholine headgroup, arrange themselves to maximize contact between the polyunsaturated chain and the protein surface. This organization is driven by energetically favorable interactions between the transmembrance helices and the docosohexaenoyl chains that are largely of the van der Waals type. These observations are consistent with various experimental studies on rhodopsin and other G-protein coupled receptors and with the picture of extreme flexibility in polyunsaturated fatty acid chains that has arisen from recent NMR and computational work.


Effect of Graphite Nanoplate Morphology on the Dispersion and Physical Properties of Polycarbonate Based Composites.
The influence of the morphology of industrial graphite nanoplate (GNP) materials on their dispersion in polycarbonate (PC) is studied. Three GNP morphology types were identified, namely lamellar, fragmented or compact structure. The dispersion evolution of all GNP types in PC is similar with varying melt temperature, screw speed, or mixing time during melt mixing. Increased shear stress reduces the size of GNP primary structures, whereby the GNP aspect ratio decreases. A significant GNP exfoliation to individual or few graphene layers could not be achieved under the selected melt mixing conditions. The resulting GNP macrodispersion depends on the individual GNP morphology, particle sizes and bulk density and is clearly reflected in the composite's electrical, thermal, mechanical, and gas barrier properties. Based on a comparison with carbon nanotubes (CNT) and carbon black (CB), CNT are recommended in regard to electrical conductivity, whereas, for thermal conductive or gas barrier application, GNP is preferred.


Effects of whole-body vibration therapy on body functions and structures, activity, and participation poststroke: a systematic review.
Whole-body vibration (WBV) has gained increasing popularity in rehabilitation. Recent studies have investigated the application of WBV in individuals with chronic illnesses, including stroke. The purpose of this study was to compare WBV exercise with the same exercise condition without WBV and with other types of physical exercise in enhancing body functions and structures, activity, and participation in individuals with stroke and examine its safety. Electronic searches were conducted on MEDLINE, CINAHL, PEDro, PubMed, PsycINFO, and Science Citation Index. Randomized controlled trials (RCTs) that investigated the effects of WBV among individuals with stroke were identified by 2 independent researchers. Ten articles (9 studies, totaling 333 study participants) satisfied the selection criteria and were included in this review. The methodological quality was rated using the PEDro scale. The results were extracted by 2 independent researchers and confirmed with the principal investigator. Only 2 RCTs were considered as demonstrating level 1 evidence (PEDro score ≥6 and sample size >50). Two RCTs examined the effects of a single WBV session, and 7 RCTs examined the effects of WBV programs spanning 3 to 12 weeks. No consistent benefits on bone turnover, leg motor function, balance, mobility, sensation, fall rate, activities of daily living, or societal participation were found, regardless of the nature of the comparison group. Adverse events were minor. A broad approach was used, with stroke as an inclusion criterion for review. No solid evidence was found concerning the effects of WBV on subgroups of people with specific stroke-related deficits due to the heterogeneity of patient groups. Based on the review, there is insufficient evidence to support clinical use of WBV in enhancing body functions and structures, activity, and participation after stroke.


Proposal for the recognition of minimally differentiated acute myeloid leukaemia (AML-MO)
We describe a form of acute myeloid leukaemia (AML), designated AML-MO, with minimal myeloid differentiation, not included previously in the FAB classification. AML-MO cannot be diagnosed on morphological grounds alone as the blast cells are large and agranular, sometimes resembling L2 or, rarely, L1 lymphoblasts, and should be identified by the following features: negative myeloperoxidase (MPO) and Sudan Black B reaction (or positive in less than 3% of blasts), negative B and T lineage markers and expression of myeloid antigens recognized by at least one monoclonal antibody, CD13 or CD33. Other myeloid markers are also often positive and these include CD11b and the enzyme MPO demonstrated by immunocytochemistry and/or electron microscopy analysis. The findings in a group of 10 cases satisfying the criteria for AML-MO are described. AML-MO represents 2-3% of all cases of AML and 1-1.5% of all acute leukaemias. Its clinical and biological significance is not yet apparent but its identification in a larger number of cases may achieve this aim.


KLHL5 knockdown increases cellular sensitivity to anticancer drugs.
KLHL family genes are noted for their involvement in the E3 ligase ubiquitination pathway through binding with Cullin-3 (CUL3) resulting in degradation of specific binding partners. KLHLs are thus intriguing genes for cancer as they can directly influence the degradation of therapeutically relevant cell cycle regulators such as Aurora Kinase, PLK1, or CDK1. However, most KLHL family members remain understudied within the literature. This study explores the relationship of expression of KLHL member, KLHL5, with the pharmacologic effect of anti-cancer drugs. KLHL5 knockdown decreased the proliferation and viability of cancer cells and sensitized cancer cells to numerous anti-cancer drugs. Drugs related to cell cycle including Akt/PI3K/mTOR inhibitors were especially sensitized by KLHL5 knockdown. The potential of KLHL5 as a prognostic or diagnostic cancer marker was compared to other KLHLs through a pan-cancer study of The Cancer Genome Atlas (TCGA) tumor groups. While KLHL5 expression shows marginal dysregulation in cancer, other KLHLs exhibit significant dysregulation in all cancer types, and exceptionally in renal carcinomas. This study advocates for further study of KLHLs as potential alternative therapeutic targets, since while KLHL5 is a novel gene impacting anticancer drug effects, others may have a similar impact on drug effect while having greater potential as diagnostic or prognostic markers.


Lipid-laden foam cells in the pathology of atherosclerosis: shedding light on new therapeutic targets.
Lipid-laden foam cells within atherosclerotic plaques are key players in all phases of lesion development including its progression, necrotic core formation, fibrous cap thinning, and eventually plaque rupture. Manipulating foam cell biology is thus an attractive therapeutic strategy at early, middle, and even late stages of atherosclerosis. Traditional therapies have focused on prevention, especially lowering plasma lipid levels. Despite these interventions, atherosclerosis remains a major cause of cardiovascular disease, responsible for the largest numbers of death worldwide. Foam cells within atherosclerotic plaques are comprised of macrophages, vascular smooth muscle cells, and other cell types which are exposed to high concentrations of lipoproteins accumulating within the subendothelial intimal layer. Macrophage-derived foam cells are particularly well studied and have provided important insights into lipid metabolism and atherogenesis. The contributions of foam cell-based processes are discussed with an emphasis on areas of therapeutic potential and directions for drug development. As key players in atherosclerosis, foam cells are attractive targets for developing more specific, targeted therapies aimed at resolving atherosclerotic plaques. Recent advances in our understanding of lipid handling within these cells provide insights into how they might be manipulated and clinically translated to better treat atherosclerosis.


Replication of lactate dehydrogenase-elevating virus in C58 mice and quantification of antiviral antibodies and of tissue virus levels as a function of development of paralytic disease.
Infection with the lactate dehydrogenase-elevating virus (LDV) triggers a generally fatal paralytic disease in old immunosuppressed C58 mice, but not in comparable mice of many other strains. We have compared the replication of LDV and the humoral immune response to it in C58 mice and mice of various resistant strains. Plasma LDV titres of persistently infected C58 mice were about tenfold higher than in other strains of mice and the proportion of LDV-permissive macrophages in peritoneal exudates of C58 mice was about twice as high as that observed in other mouse strains. C58 mice developed normal levels of anti-LDV IgG, as measured by ELISA, and normal levels of IgG that sensitized LDV to neutralization by rabbit anti-mouse IgG. C58 mice also developed normal IgM and IgG responses to human gamma-globulin and sheep erythrocytes. The antibody responses to LDV were similarly inhibited by cyclophosphamide in C58 and resistant strains of mice, which enhanced the incidence of signs of paralysis only in C58 mice. Thus, the sensitivity of C58 mice to LDV-induced paralytic disease is not due to an inherent inability of the mice to mount a humoral antibody response to LDV, and a suppression of the antibody response by cyclophosphamide is not the only prerequisite for development of the disease. We have quantified LDV in various tissues of immunosuppressed and non-immunosuppressed, 8- or 9-month-old C58 mice as a function of time after LDV infection and in relation to the development of paralytic disease. Changes in tissue LDV titres as a function of time after infection paralleled those found in the plasma; LDV titres were highest 1 day post-infection, and then decreased to a lower persistent level during the next 1 to 2 weeks. Tissue LDV titres, including those of the spinal cord, were lower than those in the plasma, and our results indicate that most of the LDV in tissue homogenates may be attributable to blood contamination, even though the animals were extensively perfused before removal of the tissues.


Expansion on stromal cells preserves the undifferentiated state of human hematopoietic stem cells despite compromised reconstitution ability.
Lack of HLA-matched hematopoietic stem cells (HSC) limits the number of patients with life-threatening blood disorders that can be treated by HSC transplantation. So far, insufficient understanding of the regulatory mechanisms governing human HSC has precluded the development of effective protocols for culturing HSC for therapeutic use and molecular studies. We defined a culture system using OP9M2 mesenchymal stem cell (MSC) stroma that protects human hematopoietic stem/progenitor cells (HSPC) from differentiation and apoptosis. In addition, it facilitates a dramatic expansion of multipotent progenitors that retain the immunophenotype (CD34+CD38-CD90+) characteristic of human HSPC and proliferative potential over several weeks in culture. In contrast, transplantable HSC could be maintained, but not significantly expanded, during 2-week culture. Temporal analysis of the transcriptome of the ex vivo expanded CD34+CD38-CD90+ cells documented remarkable stability of most transcriptional regulators known to govern the undifferentiated HSC state. Nevertheless, it revealed dynamic fluctuations in transcriptional programs that associate with HSC behavior and may compromise HSC function, such as dysregulation of PBX1 regulated genetic networks. This culture system serves now as a platform for modeling human multilineage hematopoietic stem/progenitor cell hierarchy and studying the complex regulation of HSC identity and function required for successful ex vivo expansion of transplantable HSC.


Binding of the GABA(A) receptor-associated protein (GABARAP) to microtubules and microfilaments suggests involvement of the cytoskeleton in GABARAPGABA(A) receptor interaction.
GABA(A) receptor-associated protein (GABARAP) was isolated on the basis of its interaction with the gamma2 subunit of GABA(A) receptors. It has sequence similarity to light chain 3 (LC3) of microtubule-associated proteins 1A and 1B. This suggests that GABARAP may link GABA(A) receptors to the cytoskeleton. GABARAP associates with tubulin in vitro. However, little is known about the mechanism for the interaction, and it is not clear whether the interaction occurs in vivo. Here, we report that GABARAP interacts directly with both tubulin and microtubules in a salt-sensitive manner, indicating the association is mediated by ionic interactions. GABARAP coimmunoprecipitates with tubulin and associates with both microtubules and microfilaments in intact cells. The cellular distribution is altered by treatment with taxol, nocodazole, and cytochalasin D. The tubulin binding domain was located at the N terminus of GABARAP by using synthetic peptides and deletion constructs and is marked by a specific arrangement of basic amino acids. The interaction between GABARAP and actin might be mediated by other proteins. These results demonstrate the GABARAP interacts with the cytoskeleton both in vitro and in cells and suggest a role of GABARAP in the interaction between GABA(A) receptors and the cytoskeleton. Such interactions are presumably needed for receptor trafficking, anchoring, and/or synaptic clustering. The structural arrangement of the basic amino acids present in the tubulin binding domain of GABARAP may aid in recognition of the potential of tubulin binding activity in other known proteins.


Foreign body granulomas induced by intramuscular leuprorelin acetate injection for prostate cancer: clinical mimics of soft tissue sarcoma.
We describe two cases of florid, foreign body granulomatous reaction occurring in the upper arms of males in their eighth decade, who were undergoing treatment with depot injection of leuprorelin acetate for prostatic carcinoma. These patients presented with rapidly enlarging extremity soft tissue masses and were referred to a tertiary sarcoma center with clinical suspicion of a primary soft tissue neoplasm. The occurrence of injection site granulomas secondary to leuprorelin acetate administration is rarely known outside the urological and dermatological communities, and their recognition is important due to the spectrum of clinical differential diagnoses and potential for diagnostic confusion with metastatic prostatic cancer and primary sarcoma and in order to avoid unnecessary stress and clinical intervention for patients.


Anabolic Androgenic Steroid Abuse and their Health Impacts: A Cross-sectional Study among Body Builders in a City of Eastern India.
Anabolic-androgenic steroids (AASs), when taken in supraphysiologic doses, increase muscle strength and athletic performance. Evidence suggests that long-term use of AAS in supraphysiologic doses have adverse effects on health. Therefore, the study was conducted to find crude estimate of the prevalence of AAS use among attendees of the gymnasium, the factors that could have influenced them for AAS abuse and to assess the short- and long-term side effects as perceived by them. A cross-sectional study was conducted in selected gymnasiums of a smart city of India using a predesigned and pretested questionnaire. Snowball sampling method was undertaken. The study was from July 2015 to June 2016. Informed written consent was taken. The analysis was done using SPSS v. 20.0. Of 84 bodybuilders approached, 74 participants used AAS. All users were male with mean age of 26.5 + 0.55 years. The mean age of initiation of AAS abuse was 23 years, and 66.2% (49) were unmarried. Eighty-five percent (63) preferred injectable. Seventy percent (52) abusers were influenced by trainers for abuse. Most commonly abused was Nandrolone decanoate (55.4%). Seventy-three percent were not aware of any legal ban on steroids. Reported benefits include increased strength, muscle size, and power, while harms were increased acne, deepening of voice, swelling of feet, increased irritability, depressive thoughts, impaired judgment, panic disorder, and withdrawal effect. Frequency of ASS use was substantial among young bodybuilders. Awareness about side effects was not a deterrent factor. Abusers were highly influenced by coaches. Efforts should be made for preventing easy access to AAS.


Intraoperative anaphylaxis caused by a hepatic hydatid cyst.
Anaphylactic and anaphylactoid reactions during anaesthesia are a major cause of concern for anaesthesiologists. During the perioperative period, any symptomatology relating to sudden-onset haemodynamic collapse or increased airway pressures during certain surgical procedures should raise suspicion of anaphylaxis. We report a case of anaphylaxis during pericystectomy for hydatid cyst of the liver intraoperatively in a 29-year-old Indian woman. Although a rare occurrence, reporting of such perioperative events is crucial for future references. Anaphylactic reactions should be seriously considered whenever a hydatid cystectomy is performed, especially in the event of a sudden haemodynamic collapse. Early diagnosis and correct treatment are essential to ensure a favourable patient outcome.


Irradiation of myxoid/round cell liposarcoma induces volume reduction and lipoma-like morphology.
The aim of the study was to investigate the clinical and morphological effects of radiotherapy in the treatment of myxoid/round cell liposarcoma (MLS/RCLS). Thirty-three primary and metastatic MLS/RCLS tumours in 15 patients were treated with radiation therapy. Twenty-seven of the 33 tumours were surgically removed after preoperative radiation (34-46 Gy) while six tumours were treated with radiotherapy alone (44-60 Gy). The pretreatment diagnosis was established in all 15 patients based on fine needle aspirates or histological findings. Tumour size was measured by CT or MRI before and after radiotherapy in 30 tumours. Thirteen tumours from 11 patients were genetically characterised before and/or after radiation therapy. Twenty-three of 30 irradiated tumours showed a median reduction in tumour volume of 52% and seven lesions a median progression of 36%. All 27 surgically removed tumours revealed histological features of radiation response. The most striking morphological changes were lipoma-like appearance, paucicellularity and hyalinisation. Twelve of 13 tumours analysed before and/or after radiation therapy showed the FUS-DDIT3 translocation. Radiation therapy of MLS/RCLS induces histopathologic accumulation of mature lipoma-like areas and tumour volume reduction that may facilitate resectability.


Retrospective evaluation of 155 adult equids and 21 foals with tetanus in Western, Northern, and Central Europe (2000-2014). Part 1: Description of history and clinical evolution.
To describe clinical data of hospitalized adult equids and foals with tetanus. Multicenter retrospective study (2000-2014). Twenty Western, Northern, and Central European university teaching hospitals and private referral centers. One hundred fifty-five adult equids (>6 months) and 21 foals (<6 months) with tetanus. None. Information on geographic, annual and seasonal data, demographic- and management-related data, clinical history, clinical examination and blood analysis on admission, complications, treatments, and outcomes were described and statistically compared between adults and foals. The described cases were often young horses. In 4 adult horses, tetanus developed despite appropriate vaccination and in 2 foals despite preventive tetanus antitoxin administration at birth. Castration, hoof abscesses, and wounds were the most common entry sites for adults; umbilical cord infections and wounds for foals. Stiffness was the commonest observed initial clinical sign. Blood analyses frequently revealed an inflammatory response, hemoconcentration, muscle damage, azotemia, negative energy balance, liver damage, and electrolyte and acid base disturbances. Common complications or clinical signs developing during hospitalization included dysphagia, dyspnea, recumbency, hyperthermia, seizures, hyperlipemia, gastrointestinal impactions, dysuria, and laryngeal spasms. Cases were supported with wound debridement, antimicrobial treatment, tetanus antitoxin, muscle spasm and seizure control, analgesia, anti-inflammatory drugs, fluid therapy, and nutritional support. Mortality rates were 68.4% in adult horses and 66.7% in foals. Foals differed from adult horses with respect to months of occurrence, signalment, management-related data, potential causative events, clinical signs on admission, blood analysis, complications, and severity grades. This is the first study that rigorously describes a large population of equids affected by tetanus. The information provided is potentially useful to clinicians for early recognition and case management of tetanus in adult horses and foals. Tetanus affects multiple organ systems, requiring broad supportive and intensive care. Neonatal and adult tetanus in the horse should be considered as distinct syndromes, as in human medicine.


Plant community tolerant to trace elements growing on the degraded soils of São Domingos mine in the south east of Portugal: environmental implications.
The selection of trace element tolerant species is a key factor to the success of remediation of degraded mine soils. Mining activities generate a large amount of waste rocks and tailings, which get deposited at the surface. The degraded soils, the waste rocks and tailings are often very unstable and will become sources of pollution. The direct effects will be the loss of cultivated land, forest or grazing land, and the overall loss of production. The indirect effects will include air and water pollution and siltation of rivers. These will eventually lead to the loss of biodiversity, amenity and economic wealth. Restoration of a vegetation cover can fulfil the objectives of stabilization, pollution control, visual improvement and removal of threats to human beings. Thus, remediation of mine spoils/tailings and biogeochemical prospecting would rely on the appropriate selection of plant species. Plant community responds differently on their ability to uptake or exclude a variety of metals. In this work, plant species were sampled from all populations established in an abandoned copper mine of São Domingos, SE Portugal. Plants belonging to 24 species, 16 genera and 13 families were collected from the degraded copper mine of São Domingos. Plant samples were analysed for total Ag, As, Cu, Ni, Pb, and Zn. The highest concentrations of metals in soils dry matter were 11217.5 mg Pb kg(-1), 1829 mg Cu kg(-1), 1291 mg As kg(-1), 713.7 mg Zn kg(-1), 84.6 mg Cr kg(-1), 54.3 mg Co kg(-1), 52.9 mg Ni kg(-1) and 16.6 mg Ag kg(-1). With respect to plants, the higher concentrations of Pb and As were recorded in the semi-aquatic species Juncus conglomeratus with 84.8 and 23.5 mg kg(-1) dry weight (DW), Juncus efusus with 22.4 and 8.5 mg kg(-1) DW, and Scirpus holoschoenus with 51.7 and 8.0 mg kg(-1) DW, respectively. Thymus mastichina also showed high content of As in the aboveground parts, 13.6 mg kg(-1) DW. Overall, the results indicate accumulation of various metals by different plant species, with some of these metals being partitioned to the shoots. Environmental implications of these observations are discussed.


Transforming growth factor-beta1, interleukin-10 and interferon-gamma cytokine polymorphisms in patients with hereditary, familial and sporadic chronic pancreatitis.
The genetic influence is undefined in about 40% of patients with hereditary and familial pancreatitis and in the majority of patients with sporadic chronic pancreatitis. The pathophysiological mechanisms underlying the progression from acute to chronic pancreatitis have not been clarified. Cytokines participate in the immunological progression of pancreatic inflammation and may play an important role in the development of pancreatic fibrosis. We determined whether functional polymorphisms in the transforming growth factor-beta1 gene at positions -509, +869 (codon 10) and +915 (codon 25), in the interleukin-10 gene at position -1082, and in the intron 1 of the interferon-gamma gene at position +874 are associated with hereditary, familial or sporadic pancreatitis. We investigated 78 patients with hereditary and familial pancreatitis and 62 patients with sporadic pancreatitis that were tested negative for cationic trypsinogen gene mutations, and 73 controls. Mutational analysis was performed by direct DNA sequencing or by amplification refractory mutational system polymerase chain reaction. We used the age at onset as marker of disease severity. The genotype frequencies were similar between patients and controls for all investigated cytokine polymorphisms (p > 0.05). We did not find an association between the different genotypes and the age at onset of the disease, and we did not detect different genotype distributions in patients with morphological alterations on pancreatic imaging after a disease duration of up to 5 years. These genetic variants do not play a dominant role in hereditary, familial or sporadic chronic pancreatitis.


Reducing nitrogen excretion and soybean meal use by feeding a lower rumen degradable protein balance and protected soybean meal to dairy cattle.
To reduce N pollution by dairy cows, two levels of rumen degradable protein balance (RDPB) and the use of protected protein sources were studied in two feeding trials. Trial 1 investigated if the effect of lowering the RDPB, at a constant DPI (digestible protein in the intestine) supply, could be compensated by using protected protein sources (formaldehyde treated (= formolated) soybean meal (FSBM) or a combination of FSBM and formolated rapeseed meal at a ratio of 60:40). Trial 2 studied if FSBM is as effective as soybean meal (SBM) at a low RDPB level. Each trial was set up as a Latin square design, with three treatments and three periods, involving 18 lactating Holstein cows. Reducing RDPB from about 150 g/d to below -40 g/d resulted in small negative effects on the milk production, independent of the protein source (protected or not). However, N excretion per kg fat and protein corrected milk (FPCM) and N efficiency were both improved. At a low RDPB level, the performance of FSBM (35.0 kg FPCM) was no better than after feeding a combination of FSBM and formolated rapeseed meal (34.7 kg FPCM). The use of FSBM (32.8 kg FPCM and 34.2% N efficiency) was as effective as SBM (32.5 kg FPCM and 34.2% N efficiency). As such, SBM use can approximately be halved by using FSBM, possibly in combination with locally produced rapeseed meal.


Strong diabetes.
The case of a 36-year-old male professional bodybuilder is reported. He presented to the accident and emergency department with right upper quadrant pain. This was on the background of a 15-year history of anabolic steroid and growth hormone misuse. Examination revealed mild hepatomegaly and a random blood sugar of 30.2 mmol/l. There was no evidence of ketonuria or acidosis. Biochemical evidence of hepatitis was found, and the patient was in acute renal failure. He was given a sliding scale of insulin and an intravenous infusion of crystalloid. The hepatitis and hyperglycaemia settled with conservative treatment. It is believed that this is the first reported case of frank diabetes precipitated by supraphysiological recreational growth hormone misuse.


Appropriate outcome measures in trials evaluating treatment of atrial fibrillation.
Atrial fibrillation (AF) is a widespread disease that has only recently received the focused attention of arrhythmia specialists despite being the most frequently occurring significant cardiac arrhythmia. The wide variety of trial designs used to evaluate AF treatment is a reflection of the diverse outcomes associated with this condition. The best trials assess the impact of treatment on a clearly measured outcome that is of clinical relevance to patients. This review discusses the different designs of AF treatment trials and analyzes the utility of the various outcomes that can be assessed. A sensible goal of AF treatment is to reduce the frequency of recurrences and to prolong the time between them. The most appropriate trials focus on AF recurrences that are symptomatic and therefore relevant to the patient. We still do not know if there is value in AF prevention, beyond preventing symptoms. However, ongoing and future studies will show whether AF suppression reduces the longer-term risks of stroke or death and improves patient quality of life. Cost of care will increasingly be studied in future trials of AF management.


Patient-safety and quality initiatives in the intensive-care unit.
Patient safety has become the primary focus of health-care improvement in the last few years as an increasing body of evidence emphasizes the magnitude of harm posed to patients by medical errors. The intensive-care unit, by virtue of the high technology aggressive level of care the unit provides, has been identified as a significant source of patient harm. Consequently, the intensive-care unit also represents a tremendous opportunity to study and implement patient-safety initiatives, as significant improvements can be realized in this environment. Several broad areas of successful patient-safety initiatives have been reported over the recent past including implementation of Comprehensive Unit-based Safety Programs, introduction of communication tools (for example daily goal sheets), application of care bundles (that is mechanical ventilation or sepsis), as well as team approaches that can eradicate catheter-related bloodstream infections. Specific interventions are gaining supportive evidence and widespread acceptance for their ability to reduce harm including tight glucose control and ultrasonography for reducing central-line placement complications. Recent data also demonstrate the value of an intensivist as the team leader for the critically ill within the intensive-care unit and potentially with rapid-response teams. Many patient safety and quality-of-care initiatives that have broad application to all areas of medical care have been successfully developed in the intensive-care unit. The intensive-care unit appears to be a fertile ground for the development of safety initiatives.


Monoclonal Gammopathy of Undetermined Significance (MGUS)Monoclonal Gammopathy of Undetermined Significance (MGUS).
Monoclonal gammopathy of undetermined significance (MGUS) is one of the most prevalent premalignant conditions associated with a risk of malignant transformation to multiple myeloma (MM) or other forms of lymphoproliferative disorders with risk of progression of approximately 1% per year. IgG and IgA MGUS are precursor conditions of multiple myeloma (MM), whereas light-chain MGUS is a precursor condition of light chain MM. IgM MGUS is a precursor condition of Waldenström macroglobulinemia (MW) or other lymphoproliferative diseases. Assessment of the risk of progression of patients with asymptomatic monoclonal gammopathies (MG) is based on various factors, including the serum paraprotein (M protein) concentration, isotype of M protein, serum free light chain ratio, infiltration of bone marrow plasmocytes, reduction of one or two noninvolved immunoglobulin subtype levels (immunoparesis), evolving and non-evolving subtype of MGUS, ratio of normal/abnormal plasma cells in bone marrow identified by multiparametric flow cytometry techniques and number of circulating plasma cells in peripheral blood. Three risk stratification models have been constructed that are useful in daily practice for predicting risk of progression of MGUS into malignant forms of monoclonal gammopathy - MAYO, PETHEMA and CMG model. The goal of all three models is to identify correctly prognostic markers that can divide patients into low-risk MGUS and high-risk MGUS groups. This review provides a look at the definition, pathogenesis, diagnostic algorithm, clinical significance and stratification of MGUS patients, followed by recommendations for patient risk dispensarisation intervals.


Engineering the Performance and Stability of Molybdenum Disulfide for Heavy Metal Removal.
Molybdenum disulfide (MoS2) has recently emerged as one of the most promising water nano-based adsorbent materials for heavy metal removal with the potential to provide an alternative to conventional water decontamination technologies. In this study, we demonstrate the trade-off between mercuric removal capacity and overall MoS2 adsorbent stability, both driven by MoS2 synthesis parameters. A bottom-up hydrothermal synthesis setup at various growth temperatures was employed to grow flower-like MoS2 films onto planar alumina supports. A thorough material characterization suggests that an increase in growth temperature from 150 to 210 °C results in higher MoS2 crystallinity. Interestingly, elevated growth temperatures resulted in poor mercuric removal (525 mg g-1, K = 2.2 × 10-3 h-1), yet showed enhanced chemical stability (i.e., minimal molybdenum leaching during exposure to mercury). On the other hand, low growth temperatures produce amorphous supported MoS2, exhibiting superb mercuric removal capabilities (5158 mg g-1, K = 36.1 × 10-3 h-1) but displaying poor stability, resulting in substantial byproduct molybdate leaching. Mercuric removal by crystalline MoS2 was accomplished by adsorption and electrostatic attraction-based removal mechanisms, whereas redox reactions and HgS crystallization-based removal mechanisms were more dominant when using amorphous MoS2 for mercury removal. Overall, our study provides essential insights into the delicate balance between MoS2 mercuric removal capabilities and MoS2 degradation, both related to material synthesis growth conditions. Employment of nano-enabled water treatments in general, and MoS2 for heavy metal removal in particular, requires us to better understand these important fundamental trade-off behaviors to achieve sustainable, effective, and responsible implementation of nanotechnologies in large scale systems.


Perioperative Management of Patients Receiving Sodium-Glucose Cotransporter 2 Inhibitors: Development of a Clinical Guideline at a Large Academic Medical Center.
The use of sodium-glucose cotransporter 2 inhibitors (SGLT2i) is increasing rapidly for patients with diabetes, heart failure, and chronic kidney disease. These medications can cause euglycemic diabetic ketoacidosis in the perioperative period, and the Food and Drug Administration recently updated their recommendations that they be held for at least 3-to-4 days preoperatively. There is a paucity of guidelines for the perioperative management of patients taking SGLT2i who present for emergent surgery or elective surgery having not held the medications per Food and Drug Administration guidelines. At the University of Pennsylvania, a multidisciplinary team from the Departments of Anesthesiology, Endocrinology, and Pharmacy has developed comprehensive guidelines detailing preoperative, intraoperative, and postoperative management for patients using these medications. In this article, the authors present these guidelines and discuss challenges encountered while implementing them at a large academic medical center with satellite hospitals and surgery centers with varying resources and patient populations.


Individual neuropeptides regulate gut-associated lymphoid tissue integrity, intestinal immunoglobulin A levels, and respiratory antibacterial immunity.
Total parenteral nutrition (TPN) leads to atrophy of the gut-associated lymphoid tissue (GALT) and a significant decrease in intestinal immunoglobulin A (IgA) levels, a major constituent of mucosal immunity. Bombesin (BBS) prevents TPN-induced GALT atrophy and maintains intestinal IgA levels. BBS, a neuropeptide analogous to gastrin-releasing peptide in humans, stimulates the release of other gut neuropeptides including cholecystokinin (CCK), gastrin, and neurotensin (NT). This study investigates the ability of CCK, gastrin, or NT to individually prevent TPN-induced GALT atrophy and preserve respiratory immunity. Experiment 1: Male mice were randomly assigned to receive chow, TPN, TPN plus CCK, TPN plus gastrin, or TPN plus NT. After 5 days of feeding, Peyer's patches (PP) from the proximal and distal small bowel were harvested and analyzed for cell yields. PP cells were also analyzed for GALT cell type. Small bowel IgA levels were measured by enzyme-linked immunosorbent assay (ELISA). Experiment 2: Mice were randomly assigned to receive either liposomes containing Pseudomonas antigen or liposomes without antigen. After 10 days, mice were randomly assigned to the same five treatment groups, fed for 5 days, and then given intratracheal Pseudomonas. Mortality was assessed after 48 hours. Experiment 1: GALT cell reductions due to IV-TPN were greater in the distal than proximal small bowel. All three neuropeptides prevented most TPN-induced GALT atrophy due mainly to the maintenance of the B-cell and T-cell populations in the PP of the distal bowel. Intestinal IgA levels were significantly higher in the animals treated with neuropeptides than animals treated with TPN only; however, these IgA levels were not maintained at levels observed in chow-fed animals. Experiment 2: Immunization resulted in significantly lower mortality in animals fed chow, TPN plus CCK, and TPN plus gastrin. TPN alone and TPN plus NT resulted in loss of immunity and mortality rate at comparable levels to unimmunized animals. Supplementation of IV-TPN with CCK, gastrin, and NT prevents GALT atrophy, primarily in the distal bowel. Intestinal IgA levels improve but not to normal levels. CCK and gastrin reversed IV-TPN-induced effects on antibacterial pneumonia in immunized animals while NT did not.


Gonorrhoea in London: usefulness of first line therapies.
To determine the true prevalence and patterns of resistance of Neisseria gonorrhoeae to antimicrobial agents used for therapy in London. A longitudinal study of a representative sample of isolates of N gonorrhoeae linked to demographic data of infected patients was undertaken. Isolates were collected from consecutive patients attending genitourinary medicine clinics in the North and South Thames regions of London during 3 months of each of 4 years, 1997-2000. Prevalence of plasmid mediated resistance to penicillin and chromosomally mediated resistance to penicillin and ciprofloxacin was determined by susceptibility testing. The association of antimicrobial resistance among gonococci with sexual orientation of the patient and country of acquisition of infection was determined. Numbers of gonococcal isolates collected over the same time period between 1997-2000 have increased by 74%. Plasmid mediated resistance to penicillin was low but has risen above 5% in 2000. Chromosomal resistance to penicillin has fallen below the 5% level but total resistance to penicillin, plasmid and chromosomally mediated, was above 5% in all 4 years. The incidence of resistance and reduced susceptibility to the alternative therapeutic choice, ciprofloxacin, is low but numbers are increasing in each year. High level resistance, to both penicillin and ciprofloxacin, has generally been found among heterosexual men and is often acquired abroad. However, there is some evidence of a change to endemic spread in 2000. This surveillance programme shows that the epidemiology of gonorrhoea in London is changing with increasing numbers and changing patterns of resistance. If gonorrhoea is to be controlled and targets set by the sexual health strategy are to be met, intervention with effective and appropriate antimicrobial agents is essential.


Transmen in San Francisco: what do we know from HIV test site data?
The HIV epidemic has disproportionately affected marginalized populations. Societal marginalization contributes to the lack of appropriate prevention programs focusing on these populations, which in turn may contribute to ongoing HIV transmission. Transmen (female-to-male transgender persons) may also be a marginalized population at risk for HIV infection. Unfortunately, few studies that focus on transmen have been conducted. We considered the available existing data sources that may include members of the transmen population in San Francisco to describe what is known and what remains to be understood with respect to their risk for HIV. Data used for this descriptive analysis were collected at HIV test sites in 2009. In 2009, 59 unduplicated test seekers identified as transmen. While behavioral risk factors present in this study point to the high potential for HIV risk, there may still be low HIV prevalence and time to intervene. Lest we be caught off guard as another marginalized sexual minority experiences the tragedy of a rapid HIV epidemic, more detailed, specifically designed studies are needed to complete what we do not know about this population.


Antimycobacterial screening of selected medicinal plants against Mycobacterium tuberculosis H37Rv using agar dilution method and the microplate resazurin assay.
Tuberculosis (TB), has been serious disease to the global human population causing millions of deaths worldwide. The recent increase in the number of multi-drug resistant clinical isolates of Mycobacterium tuberculosis has created an urgent need for the discovery and development of new anti-TB drugs. Medicinal plants have had a great influence on the daily lives of people living in developing countries, particularly in India. Medicinal plants were selected, and they were evaluated for its anti-TB activity against the pathogenic strain of M. tuberculosis H37Rv. Eleven medicinal plants were selected on the basis of its literature survey, and three different extracts were prepared. Antimycobacterial activities were screened using two in vitro assays, namely agar dilution assay and microplate resazurin assay against M. tuberculosis H37Rv at different concentrations of prepared extracts. We analyzed minimal inhibition concentrations and percentage of inhibition of the used strain of Mycobacteria. Isoniazid was used as a standard anti-TB drug. The results of this study showed that aqueous extracts four selected medicinal plants Ocimum sanctum, Adhatoda vasica, Leptadenia reticulata, and Cocculus hirsutus having minimum inhibitory concentration at 500 μg/ml, 500 μg/ml, 250 μg/ml, and 250 μg/ml, respectively, and O. sanctum (60.24%), A. vasica (62.89%), L. reticulata (74.26%), and C. hirsutus (81.67%) showed significant anti-TB activity against M. tuberculosis. This study helps society to found new anti-TB agents having better anti-TB activity with lesser or no side effects.


Cardiac diagnostic testing: what bedside nurses need to know.
Coronary artery disease affects more than 385000 persons annually and continues to be a leading cause of death in the United States. Recently, the number of available noninvasive cardiac diagnostic tests has increased substantially. Nurses should be knowledgeable about available noninvasive cardiac diagnostic testing. The common noninvasive cardiac diagnostic testing procedures used to diagnose coronary heart disease are transthoracic echocardiography, stress testing (exercise, pharmacological, and nuclear), multidetector computed tomography, coronary artery calcium scoring (with electron beam computed tomography or computed tomographic angiography), and cardiac magnetic resonance imaging. Objectives include (1) describing available methods for noninvasive assessment of coronary artery disease, (2) identifying which populations each test is most appropriate for, (3) discussing advantages and limitations of each method of testing, (4) identifying nursing considerations when caring for patients undergoing various methods of testing, and (5) describing outcome findings of various methods.


Representation and disconnection in imaginal neglect.
Patients with neglect failure to detect, orient, or respond to stimuli from a spatially confined region, usually on their left side. Often, the presence of perceptual input increases left omissions, while sensory deprivation decreases them, possibly by removing attention-catching right-sided stimuli (Bartolomeo, 2007). However, such an influence of visual deprivation on representational neglect was not observed in patients while they were imagining a map of France (Rode et al., 2007). Therefore, these patients with imaginal neglect either failed to generate the left side of mental images (Bisiach & Luzzatti, 1978), or suffered from a co-occurrence of deficits in automatic (bottom-up) and voluntary (top-down) orienting of attention. However, in Rode et al.'s experiment visual input was not directly relevant to the task; moreover, distraction from visual input might primarily manifest itself when representation guides somatomotor actions, beyond those involved in the generation and mental exploration of an internal map (Thomas, 1999). To explore these possibilities, we asked a patient with right hemisphere damage, R.D., to explore visual and imagined versions of a map of France in three conditions: (1) 'imagine the map in your mind' (imaginal); (2) 'describe a real map' (visual); and (3) 'list the names of French towns' (propositional). For the imaginal and visual conditions, verbal and manual pointing responses were collected; the task was also given before and after mental rotation of the map by 180 degrees . R.D. mentioned more towns on the right side of the map in the imaginal and visual conditions, but showed no representational deficit in the propositional condition. The rightward inner exploration bias in the imaginal and visual conditions was similar in magnitude and was not influenced by mental rotation or response type (verbal responses or manual pointing to locations on a map), thus suggesting that the representational deficit was robust and independent of perceptual input in R.D. Structural and diffusion MRI demonstrated damage to several white matter tracts in the right hemisphere and to the splenium of corpus callosum. A second right-brain damaged patient (P.P.), who showed signs of visual but not imaginal neglect, had damage to the same intra-hemispheric tracts, but the callosal connections were spared. Imaginal neglect in R.D. may result from fronto-parietal dysfunction impairing orientation towards left-sided items and posterior callosal disconnection preventing the symmetrical processing of spatial information from long-term memory.


Identification of a novel loss-of-function PHEX mutation, Ala720Ser, in a sporadic case of adult-onset hypophosphatemic osteomalacia.
Adults presenting with sporadic hypophosphatemia and elevations in circulating fibroblast growth factor-23 (FGF23) concentrations are usually investigated for an acquired disorder of FGF23 excess such as tumor induced osteomalacia (TIO). However, in some cases the underlying tumor is not detected, and such patients may harbor other causes of FGF23 excess. Indeed, coding-region and 3'UTR mutations of phosphate-regulating neutral endopeptidase (PHEX), which encodes a cell-surface protein that regulates circulating FGF23 concentrations, can lead to alterations in phosphate homeostasis, which are not detected until adulthood. Here, we report an adult female who presented with hypophosphatemic osteomalacia and raised serum FGF23 concentrations. The patient and her parents, who were her only first-degree relatives, had no history of rickets. The patient was thus suspected of having TIO. However, no tumor had been identified following extensive localization studies. Mutational analysis of the PHEX coding-region and 3'UTR was undertaken, and this revealed the patient to be heterozygous for a novel germline PHEX mutation (c.2158G>T; p.Ala720Ser). In vitro studies involving the expression of WT and mutant PHEX proteins in HEK293 cells demonstrated the Ala720Ser mutation to impair trafficking of PHEX, with ~20% of the mutant protein being expressed at the cell surface, compared to ~80% cell surface expression for WT PHEX (p<0.05). Thus, our studies have identified a pathogenic PHEX mutation in a sporadic case of adult-onset hypophosphatemic osteomalacia, and these findings highlight a role for PHEX gene analysis in some cases of suspected TIO, particularly when no tumor has been identified.


Perceptions of tilt angles of an agricultural tractor.
A tractor stability simulator has been developed to help study tractor operators' perceptions of angles when the simulator is tilted to the side. The simulator is a trailer-mounted tractor cab equipped with hydraulic lift that can tilt the tractor cabin up to 30 degrees. This paper summarizes data from 82 participants who sat in the simulator while it was tilted. Demographic variables, estimates of tilt angles, and measured tilt angles were collected. The effects of age, gender, tractor driving experience, and frequency of operation on the estimated and measured tilt angles were analyzed. The results showed that about 50% of the participants reported estimations of side tilt angles within ±5 degrees of the actual angles, and nearly the same percentage overestimated the actual side tilt angles. Only a small percentage underestimated the angles. Older, more experienced, and male participants set higher limits on the actual angle at which they felt uncomfortable and would not drive.


Effects of tibolone or continuous combined oestradiol/norethisterone acetate on glucose and insulin metabolism.
To determine the effects of tibolone or oestradiol (E(2) )/norethisterone acetate (NETA) hormone replacement therapy on glucose and insulin metabolism in postmenopausal women. Single-centre double-blind placebo-controlled randomized clinical trial. We randomized 105 healthy postmenopausal women to tibolone 2·5 mg daily, continuous combined oral E(2) 2 mg/NETA 1 mg daily or placebo over a 2-year study. We performed intravenous glucose tolerance tests (IVGTT) with measurements of plasma glucose, insulin and C-peptide concentrations and the IVGTT glucose elimination rate, k. Mathematical modelling was performed to determine measures of insulin sensitivity, S(i) , pancreatic insulin secretion and hepatic and plasma insulin elimination. Tibolone decreased S(i) to 53-63% and k to 72-79% of baseline values but increased IVGTT phase 2 C-peptide concentrations 1·6-1·8-fold and pancreatic insulin secretion 2·2-2·4-fold, so overall IVGTT glucose concentrations were unaffected. Similar, but for k, significantly smaller changes in insulin and C-peptide secretion were seen with E(2) /NETA, also with no effect on overall IVGTT glucose concentrations. Tibolone reduces insulin sensitivity. Healthy postmenopausal women seem able to compensate for this and maintain normal postload glucose concentrations, but it may not be advisable to prescribe tibolone to women with, or at increased risk for, diabetes.


Solution structure and interaction of cupiennin 1a, a spider venom peptide, with phospholipid bilayers.
The solution structure of cupiennin 1a, a 35 residue, basic antibacterial peptide isolated from the venom of the spider Cupiennius salei, has been determined by nuclear magnetic resonance (NMR) spectroscopy. The peptide was found to adopt a helix-hinge-helix structure in a membrane mimicking solvent. The hinge may play a role in allowing the amphipathic N-terminal helix and polar C-terminal helix to orient independently upon membrane binding, in order to achieve maximal antibacterial efficacy. Solid-state 31P and 2H NMR was used to further study the effects of cupiennin 1a on the dynamic properties of lipid membranes, using zwitterionic chain deuterated dimyristoylphosphatidylcholine (d54-DMPC) and anionic dimyristoylphosphatidylglycerol (DMPG) multilamellar vesicles. In d54-DMPC alone, cupiennin 1a caused a decrease in the 31P chemical shift anisotropy, indicating some interaction with the lipid head groups, and a decrease in order over the entire acyl chain. In contrast, for the mixed (d54-DMPC/DMPG) lipid system cupiennin 1a appeared to induce lateral separation of the two lipids as evidenced by the 31P spectra, in which the peptide preferentially interacted with DMPG. Little effect was observed on the deuterated acyl chain order parameters in the d54-DMPC/DMPG model membranes. Furthermore, 31P NMR relaxation measurements confirmed a differential effect on the lipid motions depending upon the membrane composition. Therefore, subtle differences are likely in the mechanism by which cupiennin 1a causes membrane lysis in either prokaryotic or eukaryotic cells, and may explain the specific spectrum of activity.


[An adverse effect of arterial hypertension on the outcomes of endovascular grafting of aortic aneurysms].
Today distant transluminal aortic grafting as a method for the treatment of aneurysms of varying sites and etiology holds a steady position in all the developed countries of the world. Powerful industrial support makes it possible to widely introduce into clinical practice an ever more perfect and reliable appliances. Over the recent years the direct outcomes of operations have significantly improved, the indications for surgery have been broadened. Universal approaches to the assessment of surgical outcomes and complications have been formed. Experimental studies pertaining to the method development have become more goal-oriented. The quality of the in vitro experimental studies allows the conclusions to be drawn, which are afterwards are supported and can be used in clinical practice. An experience gained over the recent years has shown that today the long-term results of the use of the above-indicated method remain most problematic. Complications that occur in the late postoperative period and are determined by the surgical procedure of distant transluminal aortic grafting may present a real threat to the patient's health and life and require repeat surgical intervention. Analysis of the potential causes of the late complications evidences that undesirable complications cannot be always prevented only by refinement of the design and properties of vascular endografts employed. The study of additional circumstances which are likely to influence the surgical outcomes is carried out on an ever broader scale. The present paper analyzes the scientific literature and provides the data of the author's own experimental study in order to describe an adverse role which is played in all probability by arterial hypertension with respect to the outcomes of distant transluminal aortic grafting.


Analytical Performance of Quantitative DiaSorin Liaison SARS-COV-2 Antigen Test for the Asymptomatic Population.
Background: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) antigen (Ag) tests have been widely employed to identify patients for a rapid diagnosis and pandemic control. Rapid lateral-flow techniques are currently the most used, but automated technologies have emerged as another viable alternative to molecular methods. We aimed to evaluate the analytical performance of the DiaSorin Liaison SARS-CoV-2 Ag test in asymptomatic population and close contacts, for its use as a tool in pandemic control efforts. Material and Methods: A retrospective study was conducted. A total of 861 samples were included, 291 (34%) were positive for SARS-CoV-2 with cycle threshold (Ct) <40, and 570 (66%) were negative. Results: A strong correlation was observed between reverse transcriptase-PCR (RT-PCR) Ct and Ag 50% Tissue Culture Infectious Dose per milliliter (TCID50/ml; r = 0.6486; p < 0.0001) and all RT-PCR negative samples tested negative for the 200 TCID50/ml SARS-Cov-2 Ag cutoff, i.e., a specificity of 100% was reached (95% CI: 99.4-100.0%). Samples with <25 Ct and/or >106 extrapolated copies/ml were reached a sensitivity of 100% (95% IC 97.0-100.0%). For intermediate viral loads (>105 extrapolated copies/ml or <30 Ct), the sensitivity value still exceeded 80%. As with other Ag methods, samples between 30 and 40 Ct could not be detected with a reliable sensitivity. Conclusions: The LIAISON® SARS-CoV-2 Ag assay displays an acceptable sensitivity and a very high specificity that is useful for detecting the presence of SARS-CoV-2 in nasal swabs (NPS) of asymptomatic population or to regular monitoring of risk groups in controlled settings. Additionally, the flexibility in processing different samples and in the sampling preparation process makes this test an option for its use in high throughput laboratories. Automated tests may facilitate result reporting and yield consistent data, while avoiding some of the pitfalls of rapid lateral-flow techniques, such as observer variability.


Maize ZmVPP5 is a truncated Vacuole H(+) -PPase that confers hypersensitivity to salt stress.
In plants, Vacuole H(+) -PPases (VPPs) are important proton pumps and encoded by multiple genes. In addition to full-length VPPs, several truncated forms are expressed, but their biological functions are unknown. In this study, we functionally characterized maize vacuole H(+) -PPase 5 (ZmVPP5), a truncated VPP in the maize genome. Although ZmVPP5 shares high sequence similarity with ZmVPP1, ZmVPP5 lacks the complete structure of the conserved proton transport and the inorganic pyrophosphatase-related domain. Phylogenetic analysis suggests that ZmVPP5 might be derived from an incomplete gene duplication event. ZmVPP5 is expressed in multiple tissues, and ZmVPP5 was detected in the plasma membrane, vacuole membrane and nuclei of maize cells. The overexpression of ZmVPP5 in yeast cells caused a hypersensitivity to salt stress. Transgenic maize lines with overexpressed ZmVPP5 also exhibited the salt hypersensitivity phenotype. A yeast two-hybrid analysis identified the ZmBag6-like protein as a putative ZmVPP5-interacting protein. The results of bimolecular luminescence complementation (BiLC) assay suggest an interaction between ZmBag6-like protein and ZmVPP5 in vivo. Overall, this study suggests that ZmVPP5 might act as a VPP antagonist and participate in the cellular response to salt stress. Our study of ZmVPP5 has expanded the understanding of the origin and functions of truncated forms of plant VPPs.


Necrotic Cell Sensor Clec4e Promotes a Proatherogenic Macrophage Phenotype Through Activation of the Unfolded Protein Response.
Atherosclerotic lesion expansion is characterized by the development of a lipid-rich necrotic core known to be associated with the occurrence of complications. Abnormal lipid handling, inflammation, and alteration of cell survival or proliferation contribute to necrotic core formation, but the molecular mechanisms involved in this process are not properly understood. C-type lectin receptor 4e (Clec4e) recognizes the cord factor of Mycobacterium tuberculosis but also senses molecular patterns released by necrotic cells and drives inflammation. We hypothesized that activation of Clec4e signaling by necrosis is causally involved in atherogenesis. We addressed the impact of Clec4e activation on macrophage functions in vitro and on the development of atherosclerosis using low-density lipoprotein receptor-deficient (Ldlr-/-) mice in vivo. We show that Clec4e is expressed within human and mouse atherosclerotic lesions and is activated by necrotic lesion extracts. Clec4e signaling in macrophages inhibits cholesterol efflux and induces a Syk-mediated endoplasmic reticulum stress response, leading to the induction of proinflammatory mediators and growth factors. Chop and Ire1a deficiencies significantly limit Clec4e-dependent effects, whereas Atf3 deficiency aggravates Clec4e-mediated inflammation and alteration of cholesterol efflux. Repopulation of Ldlr-/- mice with Clec4e-/- bone marrow reduces lipid accumulation, endoplasmic reticulum stress, and macrophage inflammation and proliferation within the developing arterial lesions and significantly limits atherosclerosis. Our results identify a nonredundant role for Clec4e in coordinating major biological pathways involved in atherosclerosis and suggest that it may play similar roles in other chronic inflammatory diseases.


Mechanical Properties of Solution-Processed Small-Molecule Semiconductor Films.
Advantages of semiconducting small molecules-as opposed to semiconducting polymers-include synthetic simplicity, monodispersity, low cost, and ease of purification. One purported disadvantage of small-molecule films is reduced mechanical robustness. This paper measures the tensile modulus and crack-onset strain for pure films of the high-performance solution-processable small-molecule donors 7,7'-[4,4-bis(2-ethylhexyl)-4H-silolo[3,2-b:4,5-b']dithiophene-2,6-diyl]bis[6-fluoro-4-(5'-hexyl-[2,2'-bithiophen]-5-yl)benzo[c][1,2,5]thiadiazole] (DTS(FBTTh2)2), 2,5-di(2-ethylhexyl)-3,6-bis(5″-n-hexyl-[2,2',5',2″]terthiophen-5-yl)-pyrrolo[3,4-c]pyrrole-1,4-dione (SMDPPEH), and 6,13-bis(triisopropylsilylethynyl)pentacene (TIPS-pentacene), the acceptor 5,5'-(2,1,3-benzothiadiazole-4,7-diyldi-2,1-ethenediyl)bis[2-hexyl-1H-isoindole-1,3(2H)-dione] (HPI-BT), blends of DTS(FBTTh2)2 and SMDPPEH with [6,6]-phenyl C71 butyric acid methyl ester (PC71BM) and with HPI-BT, and bulk heterojunction films processed with the additives 1,8-diiodooctane (DIO) and polystyrene (PS). The most deformable films of solution-processed organic semiconductors are found to exhibit tensile moduli and crack-onset strains comparable to those measured for conjugated polymers. For example, the tensile modulus of as-cast DTS(FBTTh2)2 is 0.68 GPa (i.e., comparable to poly(3-hexylthiophene) (P3HT), the common polymer), while it exhibits no cracks when stretched on an elastomeric substrate to strains of 14%. While this high degree of stretchability is lost upon the addition of PC71BM (4.2 GPa, 1.42%), it can be partially recovered using processing additives. Tensile modulus and crack-onset strain are highly correlated, which is typical of van der Waals solids. Increased surface roughness was correlated to increased modulus and brittleness within films of similar composition. Decreased stiffness for soluble molecular semiconductors can be rationalized by the presence of alkyl side chains, which decrease the van der Waals attraction between molecules in the crystalline grains. These measurements and observations could have important consequences for the stability of devices based on molecular semiconductors, especially those destined for stretchable or ultraflexible applications, or those demanding mechanical robustness during roll-to-roll fabrication or use in the outdoor environment.


Intranasal oxytocin and a polymorphism in the oxytocin receptor gene are associated with human-directed social behavior in golden retriever dogs.
The oxytocin system may play an important role in dog domestication from the wolf. Dogs have evolved unique human analogue social skills enabling them to communicate and cooperate efficiently with people. Genomic differences in the region surrounding the oxytocin receptor (OXTR) gene have previously been associated with variation in dogs' communicative skills. Here we have utilized the unsolvable problem paradigm to investigate the effects of oxytocin and OXTR polymorphisms on human-directed contact seeking behavior in 60 golden retriever dogs. Human-oriented behavior was quantified employing a previously defined unsolvable problem paradigm. Behaviors were tested twice in a repeated, counterbalanced design, where dogs received a nasal dose of either oxytocin or saline 45min before each test occasion. Buccal DNA was analysed for genotype on three previously identified SNP-markers associated with OXTR. The same polymorphisms were also genotyped in 21 wolf blood samples to explore potential genomic differences between the species. Results showed that oxytocin treatment decreased physical contact seeking with the experimenter and one of the three polymorphisms was associated with degree of physical contact seeking with the owner. Dogs with the AA-genotype at this locus increased owner physical contact seeking in response to oxytocin while the opposite effect was found in GG-genotype individuals. Hence, intranasal oxytocin treatment, an OXTR polymorphism and their interaction are associated with dogs' human-directed social skills, which can explain previously described breed differences in oxytocin response. Genotypic variation at the studied locus was also found in wolves indicating that it was present even at the start of dog domestication.


In situ decorated Pd NPs on chitosan-encapsulated Fe3O4/SiO2-NH2 as magnetic catalyst in Suzuki-Miyaura coupling and 4-nitrophenol reduction.
Chitosan is a linear polysaccharide and non-toxic bioactive polymer with a wide variety of applications due to its functional properties such as ease of modification, and biodegradability. In this study, a green protocol for in situ fabrication of ultrafine Pd nanoparticles on chitosan-encapsulated Fe3O4/SiO2-NH2 nanoparticles, without the use of any toxic reducing agents, is described. The catalytic activity of Fe3O4/SiO2-NH2@CS/Pd nanocomposite was investigated through Suzuki-Miyaura coupling to synthesize biaryl derivatives, and reduction of 4-nitrophenol to 4-aminophenol. The core-shell nanoparticle modified with chitosan highly stabilizes the exterior Pd NPs. Leaching test was performed to assure heterogeneity of the catalyst. The magnetically retrievable catalyst was recycled up to eight times in both reactions without significant loss in its activity.


Spinal poly-GA inclusions in a C9orf72 mouse model trigger motor deficits and inflammation without neuron loss.
Translation of the expanded (ggggcc)n repeat in C9orf72 patients with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) causes abundant poly-GA inclusions. To elucidate their role in pathogenesis, we generated transgenic mice expressing codon-modified (GA)149 conjugated with cyan fluorescent protein (CFP). Transgenic mice progressively developed poly-GA inclusions predominantly in motoneurons and interneurons of the spinal cord and brain stem and in deep cerebellar nuclei. Poly-GA co-aggregated with p62, Rad23b and the newly identified Mlf2, in both mouse and patient samples. Consistent with the expression pattern, 4-month-old transgenic mice showed abnormal gait and progressive balance impairment, but showed normal hippocampus-dependent learning and memory. Apart from microglia activation we detected phosphorylated TDP-43 but no neuronal loss. Thus, poly-GA triggers behavioral deficits through inflammation and protein sequestration that likely contribute to the prodromal symptoms and disease progression of C9orf72 patients.


Burn depth estimation by use of indocyanine green fluorescence: initial human trial.
Indocyanine green dye (ICG) fluoresces when illuminated by infrared light. After successful trials in a porcine model and with approval of the Massachusetts General Hospital's human studies committee, 10 adult patients with burn injuries were given 0.2 mg/kg ICG intravenously, and 825 nm fluorescence images were obtained with 780 nm excitation at 5 minutes after injection in the initial five patients and at 1, 2, 3, 4, 5, and 10 minutes in the subsequent five patients. Fluorescence intensities at burned and unburned sites were determined and images were correlated with burn depth as determined by healing or intraoperative assessment. In the latter five patients, seven sites were imaged (six that were of partial thickness and one that was of full thickness). The burn/normal skin fluorescence ratio was greater than 1 for superficial burns and less than 1 for deep burns. Imaging within 5 minutes of injection resulted in optimal contrast between injured and uninjured tissue. In this initial pilot trial it is apparent that ICG fluorescence has potential value as an aid in the early estimation of burn depth. In subsequent trials we will attempt to refine our ability to correlate ICG fluorescence images with burn depth.