Effect of preexisting anti-herpes immunity on the efficacy of herpes simplex viral therapy in a murine intraperitoneal tumor model.
HSV-1716, a replicating nonneurovirulent herpes simplex virus type 1, has shown efficacy in treating multiple types of human tumors in immunodeficient mice. Since the majority of the human population has been previously exposed to herpes simplex virus, the efficacy of HSV-based oncolytic therapy was investigated in an immunocompetent animal tumor model. EJ-6-2-Bam-6a, a tumor cell line derived from h-ras-transformed murine fibroblast, exhibit a diffuse growth pattern in the peritoneal cavity of BALB/c mice and replicate HSV-1716 to titers observed in human tumors. An established intraperitoneal (ip) tumor model of EJ-6-2-Bam-6a in naive and HSV-immunized mice was used to evaluate the efficacy of single or multiple ip administrations of HSV-1716 (4 x 10(6) pfu/treatment) or of carrier cells, which are irradiated, ex vivo virally infected EJ-6-2-Bam-6a cells that can amplify the viral load in situ. All treated groups significantly prolonged survival versus media control with an approximately 40% long-term survival rate (cure) in the multiply treated, HSV-naive animals. Prior immunization of the mice with HSV did not significantly decrease the median survival of the single or multiply treated HSV-1716 or the carrier cell-treated groups. These studies support the development of replication-selective herpes virus mutants for use in localized intraperitoneal malignancies.


European Paediatric Surgeons' Association Survey on the Management of Pediatric Appendicitis.
To define patterns in the management of pediatric appendicitis. A total of 169 delegates from 42 (24 European) countries completed a validated survey administered at the EUPSA 2017 annual congress. In the work-up of children with suspected acute appendicitis, most surgeons rely on full blood count (92%), C-reactive protein (82%), and abdominal ultrasonography (76%), but rarely on computed tomography scans or magnetic resonance imaging. In suspected simple appendicitis, most surgeons (76%) do not perform appendectomy at night in clinically stable patients and start antibiotic preoperatively (64%), but only 15% offer antibiotic therapy alone (no appendectomy). In suspected perforated appendicitis, 96% start antibiotic preoperatively, and 92% perform an appendectomy. Presence of phlegmon/abscess is the main contraindication to immediate surgery. In case of appendix mass, most responders (75%) favor a conservative approach and perform interval appendectomy always (56%) or in selected cases (38%) between 2 and 6 months from the first episode (81%). Children with large intraperitoneal abscesses are managed by percutaneous drainage (59% responders) and by surgery (37% responders). Laparoscopy is the preferred surgical approach for both simple (89%) and perforated appendicitis (81%). Most surgeons send the appendix for histology (96%) and pus for microbiology, if present (78%). At the end of the operation, 58% irrigate the abdominal cavity only if contaminated using saline solution (93%). In selected cases, 52% leave a drain in situ. Some aspects of appendicitis management lack consensus, particularly appendix mass and intraperitoneal abscess. Evidence-based guidelines should be developed, which may help standardize care and improve clinical outcomes.


Acquisition and retention of long-term habituation in Aplysia: correlation of behavioral and cellular processes.
To examine the cellular mechanisms responsible for transition from a short-term to a long-term behavioral modification, a rapid training procedure was developed for producing long-term habituation of the defensive withdrawal of gill and siphon in Aplysia. Four ten-trial training sessions, with 1(1/2)-hour intersession intervals, produced habituation that was retained for more than 1 week. This 5-hour procedure could be applied to a test system in the isolated abdominal ganglion where the cellular changes accompanying the acquisition of long-term habituation can be examined. During acquisition, intracellular recordings were obtained from L7, a major gill and siphon motor neuron, and the pattern of stimulation used in the behavioral experiments was applied to an afferent nerve. Acquisition was associated with a progressive decrease in the complex excitatory synaptic potential produced in L7 by afferent nerve stimulation. When retention was tested 24 hours later, the synaptic decrement was still evident. Thus, a behaviorally meaningful stimulus sequence, consisting of only 40 patterned stimuli, leads to changes in synaptic effectiveness lasting one or more days in a neural pathway involved in short-term habituation of this reflex.


Circular grating coupler for creating focused azimuthally and radially polarized beams.
We show a planar optical circuit design that takes light from an input waveguide and creates a focused azimuthally or radially polarized beam emanating from the surface of the substrate. It is implemented in silicon-on-insulator waveguides and does not require any external components to focus the beam. The focal spot size can be subwavelength and is potentially useful for lithography, imaging, optical data storage, optical trapping, optical excitation of molecules, or coupling to optical fibers.


Implementation issues of neuro-fuzzy hardware: going toward HW/SW codesign.
This paper presents an annotated overview of existing hardware implementations of artificial neural and fuzzy systems and points out limitations, advantages, and drawbacks of analog, digital, pulse stream (spiking), and other implementation techniques. We analyze hardware performance parameters and tradeoffs, and the bottlenecks which are intrinsic in several implementation methodologies. The constraints posed by hardware technologies onto algorithms and performance are also described. The results of the analyses proposed lead to the use of hardware/software codesign, as a means of exploiting the best from both hardware and software techniques. Hardware/software codesign appears, at present, the most promising research area concerning the implementation of neuro-fuzzy systems (not including bioinspired systems, which are out of the scope of this work), as it allows the fast design of complex systems with the highest performance/cost ratio.


Hybrid Au@alendronate nanoparticles as dual chemo-photothermal agent for combined cancer treatment.
A gold therapeutic nanoplatform with the same molecule used as reductant, coating and therapeutic agent has been developed in a one-pot, one-phase process using alendronate, a drug from the bisphosphonate family known for its antitumor effects. In addition, the core made of gold nanoparticles (NPs) brings thermal functionalities under irradiation within the first biological window (650-900 nm). The Au@alendronate nanoplatform thus provided a combined antitumor activity through drug delivery and photothermal therapy. Au@alendronate NPs inhibited in vitro the proliferation of prostate cancer cells (PC3) in a dose-dependent manner, with an IC50 value of 100 µM. Under NIR irradiation a temperature increase was observed leading to a reduction of the IC50 value to 1 µM, with total tumor cell death at 100 µM.


Pharmacological assessment of adrenergic receptors in human varicose veins.
Experiments were to characterize pharmacologically adrenergic receptors in human varicose veins to the natural transmitter norepinephrine and to an extract of Ruscus. Greater saphenous veins and varicose tributaries from patients undergoing elective surgery for primary varicose disease and portions of greater saphenous veins from patients undergoing peripheral arterial reconstruction (control) were suspended for the measurement of isometric force in organ chambers. Concentration response curves were obtained to norepinephrine or the extract of Ruscus aculeatus in the absence and presence of selective antagonists of alpha, and alpha2 adrenergic receptors. Norepinephrine and Ruscus extract caused concentration-dependent contractions in all veins. Contractions to norepinephrine were greater in control veins than in varicose tributaries. Contractions to the extract were greater in varicose tributaries than in greater saphenous veins from varicose patients. Contractions to norepinephrine were reduced similarly by alpha and alpha2-adrenergic agonists in control and varicose veins but to a greater extent by alpha2-blockade in greater saphenous veins from varicose patients. Contractions to Ruscus extract were not reduced by alpha-adrenergic blockade in control veins but were reduced by alpha2-adrenergic blockade in varicose veins. These results suggest a differential distribution of alpha adrenergic receptors on greater saphenous veins from non-varicose patients compared to those with primary varicose disease. Venotropic agents from plant extract probably exert effects by way of multiple receptor and non-receptor mediated events.


[Morphology of thrombolysis as affected by a plasmakinase preparation].
The effect of a new thrombolytic preparation, plasmakinase, on experimental coagulates and thrombi was studied morphologically. Histological and electron microscopic studies revealed changes in the structure of fibrin fibers in the form of separation of fibers into individual protofibrils and subsequent degradation into globular particles. There were disorders in the fibrin association with blood cells, washing out of partially hemolyzed red blood cells into the bloodstream, decrease in the size of thrombi and restoration of the vessel lumen.


Flavonolignans from Elymus natans L. and Phytotoxic Activities.
Elymus natans, a perennial gramineous grass, plays an important role in animal husbandry and environmental sustenance in the Qinghai-Tibet plateau as a result of its high forage quality and good adaptability to the local environment. A bioassay showed that the extracts of green grasses of E. natans (GG) exhibited stronger phytotoxic activities than withered grasses (WG) against crops and grasses. In view of the secondary metabolites, which may be responsible for the resistance of the plant, the chemical components of GG were investigated. The flavone tricin, E1, and 10 flavonolignans, E2-E11, including three new flavonolignans, E2, E10, and E11, were isolated and identified. As far as we know, this is the first report on the chemical constitutions of the plant until now. The contents of compounds E1 and E4-E7 in GG were significantly higher than those in WG in high-performance liquid chromatography analysis, and they also showed observably phytotoxic activities against lettuce and Festuca arundinacea.


'Labouring' on the frontlines of global health research: mapping challenges experienced by frontline workers in Africa and Asia.
Drawing on the reflections and discussions from a special session at the 2021 Global Health Bioethics Network summer school, this paper has summarised the key challenges faced by Frontline Workers (FWs) across research sites in Africa and Asia in performing the everyday 'body work' entailed in operationalising global health research. Using a 'body work' lens, we specifically explore and map key challenges that FWs face in Africa and Asia and the physical, social, ethical, emotional, and political labour involved in operationalising global health in these settings. The research encounter links with wider social and economic structures, and spatial dimensions and impacts on the FWs' performance and well-being. Yet, FWs' 'body-work' and the embedded emotions during the research encounter remain hidden and undervalued.


Dispersion of coils after parent-artery occlusion of radiation-induced internal carotid artery pseudoaneurysm.
We report a rare complication following parent-artery occlusion in a patient with radiation-induced carotid pseudoaneurysms. Both the right internal carotid artery pseudoaneurysm and the recurrent external carotid artery pseudoaneurysm were treated by parent-artery occlusion with coils. Although rebleeding was not observed after the second embolization, angiography and endoscopy at the 12-month follow-up showed dispersion and migration of coils into the pharynx and the external auditory canal due to progressive radiation necrosis.


Anastomotic Outcomes in Military Exploratory Laparotomies in the Modern Combat Era.
Intestinal anastomoses in military settings are performed in severely injured patients who often undergo damage control laparotomy in austere environments. We describe anastomotic outcomes of patients from recent wars. Military personnel with combat-related intra-abdominal injuries (June 2009-December 2014) requiring laparotomy with resection and anastomosis were analyzed. Patients were evacuated from Iraq or Afghanistan to Landstuhl Regional Medical Center (Germany) before being transferred to participating U.S. military hospitals. Among 341 patients who underwent 1053 laparotomies, 87 (25.5%) required ≥1 anastomosis. Stapled anastomosis only was performed in 57.5% of patients, while hand-sewn only was performed in 14.9%, and 9.2% had both stapled and hand-sewn techniques (type unknown for 18.4%). Anastomotic failure occurred in 15% of patients. Those with anastomotic failure required more anastomoses (median 2 anastomoses, interquartile range [IQR] 1-3 vs. 1 anastomosis, IQR 1-2, P = .03) and more total laparotomies (median 5 laparotomies, IQR 3-12 vs. 3, IQR 2-4, P = .01). There were no leaks in patients that had only hand-sewn anastomoses, though a significant difference was not seen with those who had stapled anastomoses. While there was an increasing trend regarding surgical site infections (SSIs) with anastomotic failure after excluding superficial SSIs, it was not significant. There was no difference in mortality. Military trauma patients have a similar anastomotic failure rate to civilian trauma patients. Patients with anastomotic failure were more likely to have had more anastomoses and more total laparotomies. No definitive conclusions can be drawn about anastomotic outcome differences between hand-sewn and stapled techniques.


Transmission scanning system for a gamma camera coincidence scanner.
The goal of this research was to develop and evaluate a practical transmission scanning system for attenuation correction on a 2-head gamma camera coincidence scanner. The transmission system operates in singles mode and uses point sources of 137Cs that emit 662-keV gamma-radiation. Each point source is inserted between existing septa that are normally used to provide an approximately 2-dimensional emission acquisition geometry. The sources are placed along a line parallel to the axis of rotation near the edge of 1 camera. Data are acquired with the opposing camera. The septa provide axial collimation for the sources so that the transmission system operates in a 2-dimensional offset fanbeam geometry. Camera energy and spatial resolution were measured at 511 and 662 keV. Sensitivity was measured at 662 keV. The effects on axial resolution of adding supplemental collimation to the septa were shown. The system was calibrated and tested using a resolution (rod) phantom and a uniformity phantom. Torso phantom data were acquired. Patient transmission and emission scans were obtained. Postinjection transmission data were used to correct patient emission data. The camera resolution at postinjection counting rates was 11.7% full width at half maximum (FWHM) for 662-keV gamma-rays. Intrinsic spatial resolution was 2.7 mm (FWHM) at 662 keV. The sensitivity of the system was 280 Hz/MBq using five 74-MBq sources of 137Cs in the transmission geometry, with supplemental collimation added to the septa to improve axial resolution. The transaxial resolution of the system was such that the smallest rods (6-mm diameter and 12-mm spacing) were well resolved in a reconstructed resolution-phantom image. The corrected patient emission scans were free of attenuation-induced artifacts. An easily implemented transmission system for a 2-head gamma camera coincidence scanner that can be used for postinjection transmission scanning has been developed.


Focus on Feeding! Evaluation of a framework for maximizing mealtime in aged care facilities.
Unintentional weight loss is a health risk for residents of aged care facilities, a concern for families and places demands on nursing staff. An existing weight loss framework to assess and manage residents' weight developed by a multidisciplinary team was implemented and evaluated with nurses and residents in aged care facilities within an area health service of Sydney, Australia. Thematic analysis generated seven binary concepts relating to relational, procedural, behavioural, physical, psychological, environmental and temporal aspects of feeding assistance provided by nurses to residents. Theoretical sampling was applied to the literature confirming those concepts which were organized as a model of feeding assistance labelled the Focus on Feeding! Decision Model. Nurses can play a pivotal role in the assessment of feeding difficulty and implementation of innovative mealtime programs. The Model aims to promote nurses' critical thinking and decision-making to improve nutritional intake of residents and avoid preventable weight loss.


Disseminated Nonleukemic Myeloid Sarcoma of the Spleen With Involvement of the Liver in an Infant.
Nonleukemic myeloid sarcoma (MS) is a rare tumor that can occur in several locations without myeloid leukemia. We reported a first case of nonleukemic MS of the spleen involving the liver in a 5-month-old boy presenting with hematochezia, petechial hemorrhage, fever, and hepatosplenomegaly. Bone marrow trephine biopsy and immunophenotypic flow cytometry revealed no evidence of myeloid leukemia. The patient underwent liver biopsy and splenectomy. Clinicopathology and immunohistochemistry suggested a disseminated nonleukemic MS. The patient died of respiratory failure on the seventh postoperative day. Early diagnosis of a disseminated nonleukemic MS may be quite important for patient survival and it should be considered one of the differential diagnoses of hepatosplenomegaly with atypical clinical features.


[Formulating the question of "primary plot" in the paranoidal delusional syndrome and "delusional behavior"].
The paper is concerned with studies of a delusional "primary plot". During the process of a systematization of the "primary plot" and a formation of the paranoial syndrome, the total information is formed according to the "predetermined" programme, kept in the "code" of the "primary plot" and is read of it in the logical prerequisite and motivation of all delusional constructions. The hypotheses of "delusional behaviour", as a behavioural actualization of delusions and implementing tendencies of a "struggle for the idea" are discussed. It is formed in connection with the actuality of delusional experiences, is subjected to regularities of psychopathological symptomatology and should be studied as joint symptoms. Certain forms of "delusional behaviour" in delusional paranoial delusions of jealousy, hypochondria, inventive- and litigious-querulousness are described on the basis of a study of 401 patients.


Spermine enhances the activity of anti-tuberculosis drugs.
This is the first study that attempted to demonstrate the mechanisms of reactive oxygen species (ROS) generation by spermine (Spm) in Mycobacterium tuberculosis (M.tb). Furthermore, this is the first study to demonstrate that it is able to enhance the activity of currently available and World Health Organization (WHO)-approved tuberculosis (TB) drugs. Spermine can easily be obtained since it is already found in our diet. Moreover, as opposed to conventional antibiotics, it is less toxic to humans since it is found in millimolar concentrations in the body. Finally, with the difficulty of curing TB with conventional antibiotics, this study suggests that less toxic molecules, such as Spm, could in a long-term perspective be incorporated in a TB regimen to boost the treatment.


Cellular immune responses persist and humoral responses decrease two decades after recovery from a single-source outbreak of hepatitis C.
As acute hepatitis C virus (HCV) infection is clinically inapparent in most cases, the immunologic correlates of recovery are not well defined. The cellular immune response is thought to contribute to the elimination of HCV-infected cells and a strong HCV-specific T-helper-cell (Th) response is associated with recovery from acute hepatitis C (ref. 2). However, diagnosis of resolved hepatitis C is based at present on the detection of HCV-specific antibodies and the absence of detectable HCV RNA, and detailed comparison of the humoral and cellular immune response has been hampered by the fact that patient cohorts as well as HCV strains are usually heterogeneous and that clinical data from acute-phase and long-term follow-up after infection generally are not available. We studied a cohort of women accidentally exposed to the same HCV strain of known sequence and found that circulating HCV-specific antibodies were undetectable in many patients 18-20 years after recovery, whereas HCV-specific helper and cytotoxic T-cell responses with an interferon (IFN)-gamma-producing (Tc1) phenotype persisted. The data indicate these HCV-specific CD4 + and CD8+ T cells are biomarkers for a prior HCV exposure and recovery. Because of undetectable antibodies against HCV, the incidence of self-limited HCV infections and recovery may be underestimated in the general population.


Enterovirus 71 infection of monocytes with antibody-dependent enhancement.
Enterovirus (EV) is an RNA virus that has circulated with different serotypes and genotypes worldwide. Enterovirus 71 (EV71) is a major neurotropic virus that causes severe brain stem encephalitis (BE) in infants and young children. The most vulnerable age for fatal infection is 6 to 11 months. This is associated with the coincident decline in maternal antibodies. The current report describes our finding that EV71 can infect human peripheral blood monocytes. We were able to show that EV71 infection is enhanced in the monocytic cell line THP-1 by the presence of subneutralizing concentrations of anti-EV71 antibodies. We also found that antibody-dependent enhancement (ADE) is mediated in part by Fcγ receptors. These observations support the concept that ADE augments the infectivity of EV71 for human monocytes and contributes to the age-dependent pathogenesis of EV71-induced disease. The ADE phenomenon must be considered during the development of an EV71 vaccine.


COL1A2 Barcoding: Bone Species Identification via Shotgun Proteomics.
Species identification of fragmentary bones remains a challenging task in archeology and forensics. A species identification method for such fragmentary bones that has recently attracted interest is the use of bone collagen proteins. Here, we describe a method similar to DNA barcoding that reads collagen protein sequences in bone and automatically determines the species by performing sequence database searches. The method is almost identical to conventional shotgun proteomics analysis of bone samples, except that the database used by the SEQUEST search engine consisted only of entries for collagen type 1 alpha 2 (COL1A2) proteins from various vertebrates. Accordingly, the COL1A2 peptides that differ in sequence among species act as species marker peptides. In SEQUEST-based shotgun proteomics, the protein entries that contain more marker peptide sequences are assigned higher scores; therefore, the highest-scoring protein entry will be the COL1A2 entry for the species from which the analyzed bone was derived. We tested our method using bone samples from 30 vertebrate species and found that all species were correctly identified. In conclusion, COL1A2 can be used as a bone protein barcode and can be read through shotgun proteomics, allowing for automatic bone species identification. Data are available via ProteomeXchange with the identifier PXD045402.


Consensus guidelines for management of hyperammonaemia in paediatric patients receiving continuous kidney replacement therapy.
Hyperammonaemia in children can lead to grave consequences in the form of cerebral oedema, severe neurological impairment and even death. In infants and children, common causes of hyperammonaemia include urea cycle disorders or organic acidaemias. Few studies have assessed the role of extracorporeal therapies in the management of hyperammonaemia in neonates and children. Moreover, consensus guidelines are lacking for the use of non-kidney replacement therapy (NKRT) and kidney replacement therapies (KRTs, including peritoneal dialysis, continuous KRT, haemodialysis and hybrid therapy) to manage hyperammonaemia in neonates and children. Prompt treatment with KRT and/or NKRT, the choice of which depends on the ammonia concentrations and presenting symptoms of the patient, is crucial. This expert Consensus Statement presents recommendations for the management of hyperammonaemia requiring KRT in paediatric populations. Additional studies are required to strengthen these recommendations.


"We move kids"-the consensus report from the roundtable to examine strategies for promoting walking in the school environment.
In conjunction with the Walking for Health Conference, a Roundtable with 12 physical education teachers and 11 pedagogy researchers and public health professionals was organized to initiate a dialog between practicing school teachers and a group of researchers to identify practical and effective strategies for increasing physical activity, particularly walking, in the school setting. Discussions were organized on the following major themes: (1) promoting physical activity, (2) barriers for physical activity promotion in children, and (3) integrating physical activity with other health behaviors in the curriculum. There was a focus that came through on strategies to overcome barriers to allow opportunities for students to increase their physical activity levels. These strategies require the commitment not only of physical education teachers but also of their fellow teachers, school administrators, parents, local community members, and of course the students themselves. The issue of limited resources continually came up, thus realistically limiting strategies to those that could be implemented without additional cost. Any progress to be made with respect to the implementation of these strategies depends on the infrastructure of support that can be built on the excellent recommendations provided by the Roundtable focus groups.


Regulation of hydrogenase in Rhizobium japonicum: analysis of mutants altered in regulation by carbon substrates and oxygen.
The synthesis of the H2 uptake system in free-living Rhizobium japonicum SR is repressed both by oxygen and by carbon substrates. Mutants selected for the ability to express hydrogenase in 10.0% partial pressure O2 were also less sensitive than the wild type to repression by carbon substrates such as arabinose, glycerol, gluconate, and succinate. The H2 uptake system in another class of mutants, previously shown to be hypersensitive to repression by O2, is also more sensitive to repression by carbon substrates. The oxygen- and carbon-insensitive mutants express the hydrogen uptake system during heterotrophic growth in the absence of hydrogen and thus can be considered constitutive (Hupc). The amount of cytochromes in the Hupc mutants is similar to that in the wild-type strain; however, the Hupc mutants contain greater methylene blue-dependent and O2-dependent hydrogenase activity, both as free-living cells and as bacteroids. Two-dimensional polyacrylamide gel electrophoresis revealed that during heterotrophic growth the Hupc mutant strain SR470 synthesized at least six peptides not found in the wild-type strain. The concentrations of cyclic AMP and guanosine tetraphosphate were similar in strain SR and the Hupc mutants during heterotrophic growth.


Synthetic human chorionic gonadotropin-related oligopeptides impair early innate immune responses to Listeria monocytogenes in Mice.
Background. Synthetic human chorionic gonadotropin (hCG)-related oligopeptides are potent inhibitors of pathogenic inflammatory responses induced by in vivo lipopolysaccharide exposure or hemorrhagic shock-induced injury. In this study, we tested whether hCG-related oligopeptide treatment similarly altered inflammatory responses and innate host defenses in mice during experimental Listeria monocytogenes infection. Methods. Mice were infected with L. monocytogenes and treated with hCG-related oligopeptides (LQGV, VLPALP, or AQGV) or phosphate-buffered saline. Subsequently, mice were analyzed for bacterial loads, cytokine and chemokine responses, and inflammatory cell infiltrates in target organs. Results. Oligopeptide administration increased bacterial numbers in the spleen and liver at 6 h after infection. Simultaneously, CXCL1/KC and CCL2/MCP-1 plasma levels as well as neutrophil numbers in the spleen, blood, and peritoneal cavity decreased. In contrast, at 18 h after infection, systemic tumor necrosis factor alpha, interleukin 12 p70, interleukin 6, and interferon gamma levels increased statistically significantly in oligopeptide-treated mice compared with controls, which correlated with increased bacterial numbers. Conclusion. These data show that treatment with hCG-related oligopeptides (LQGV, VLPALP, and AQGV) inhibits early innate immune activation by reducing initial chemokine secretion following infection. This leads to bacterial overgrowth with subsequent enhanced systemic inflammation. Our data underscore the importance of early innate immune activation and suggest a role for hCG-derived oligopeptides at the placenta that increases the risk of L. monocytogenes infections.


Combination therapy with various combinations of aliskiren, valsartan, and hydrochlorothiazide in hypertensive patients not adequately responsive to hydrochlorothiazide alone.
This study investigated the efficacy and safety of several different multi-drug regimens including aliskiren, valsartan, and hydrochlorothiazide (HCTZ) in patients not adequately responsive to HCTZ as monotherapy. After 4 weeks of HCTZ treatment, patients (N=641) whose diastolic blood pressure (DBP) was > or =95 mm Hg were treated for 8 weeks with either aliskiren/valsartan/HCTZ, aliskiren/HCTZ, valsartan/HCTZ, or HCTZ alone. The primary efficacy variable was change in DBP from baseline to week 8 end point. The aliskiren/valsartan/HCTZ combination produced statistically significant additional reductions in systolic blood pressure (SBP)/DBP when compared with other groups. At week 8 end point, reductions in SBP/DBP in the respective treatment groups were 22/16, 15/11, 18/14, or 6/6 mm Hg. Aliskiren/valsartan/HCTZ produced significantly better blood pressure control (SBP/DBP <140/90 mm Hg; 66.7%) compared with other treatment groups (20.5%-48.7%). The safety profile of aliskiren/valsartan/HCTZ was similar to the 2-drug combinations, with a greater blood pressure-lowering effect in patients who had not responded to HCTZ monotherapy.


A neural network-based algorithm for high-throughput characterisation of viscoelastic properties of flowing microcapsules.
Microcapsules, consisting of a liquid droplet enclosed by a viscoelastic membrane, have a wide range of biomedical and pharmaceutical applications and also serve as a popular mechanical model for biological cells. In this study, we develop a novel high throughput approach, by combining a machine learning method with a high-fidelity mechanistic capsule model, to accurately predict the membrane elasticity and viscosity of microcapsules from their dynamic deformation when flowing in a branched microchannel. The machine learning method consists of a deep convolutional neural network (DCNN) connected by a long short-term memory (LSTM) network. We demonstrate that with a superior prediction accuracy the present hybrid DCNN-LSTM network can still be faster than a conventional inverse method by five orders of magnitude, and can process thousands of capsules per second. We also show that the hybrid network has fewer restrictions compared with a simple DCNN.


The personal response: A novel writing assignment to engage first year students in large human biology classes.
The teaching of highly valued scientific writing skills in the first year of university is challenging. This report describes the design, implementation, and evaluation of a novel written assignment, The Personal Response and accompanying Peer Review, in the course, Human Biology (BIOL1015) at The University of Queensland. These assignments were the first assessment tasks of the course and were set early in the first semester of university. BIOL1015 had a diverse cohort of 319 first year students from five bachelor degree programs, primarily from Pharmacy and Human Movement Studies. Audio files in the form of interviews with eminent biomedical scientists were obtained from a leading public radio program. Students used these files as triggers to submit a short but highly structured assignment written from a personal perspective and in an expressive style. Evaluations revealed that overall, students found the task interesting and challenging. Students performed well, regardless of their background knowledge, disciplinary interest, or preference for topics within human biology. This study demonstrated that The Personal Response was an appropriate task for these first year students of human biology. It represents an alternative to traditional essay writing.


Psychological impact of electrocardiogram screening in National Collegiate Athletic Association athletes.
Determine the psychological impact of false-positive ECG screening in National Collegiate Athletic Association (NCAA) athletes. Athletes representing seven NCAA institutions received a standardised history, physical examination and ECG interpreted using the 2013 Seattle Criteria. Assessments of health attitudes, anxiety and impact of screening on sport were conducted using validated prescreen and postscreen measurements. 1192 student-athletes participated (55.4% male, median age 19 years, 80.4% Caucasian). 96.8% of athletes had a normal cardiovascular screen, 2.9% had a false-positive ECG and 0.3% were diagnosed with a serious cardiac condition. Prior to screening, 4.5% worried about potentially harbouring cardiac disease and 70.1% preferred knowing about an underlying condition, rather than play sports without this knowledge. There was no difference in anxiety described by athletes with a normal versus false-positive screen (p=0.369). Reported anxiety levels during screening also did not differ when analysed by different gender, race, division of play or sport. Athletes with normal and false-positive screens had similar levels of satisfaction (p=0.714) and would recommend ECG screening to other athletes at similar rates (p=0.322). Compared with athletes with a normal screen, athletes with false-positive results also reported feeling safer during competition (p>0.01). In contrast, athletes with false-positive screens were more concerned about the possibility of sports disqualification (p<0.001) and the potential for developing a future cardiac condition (p<0.001). Athletes with a false-positive ECG do not experience more anxiety than athletes with a normal screen but do express increased concern regarding sports disqualification and the development of a cardiac disorder. These findings do not justify avoiding advanced cardiovascular screening protocols. Further understanding of athlete experiences could better prepare the practising physician to counsel athletes with an abnormal ECG.


Role of central nervous system and ovarian insulin receptor substrate 2 signaling in female reproductive function in the mouse.
Insulin receptor signaling regulates female reproductive function acting in the central nervous system and ovary. Female mice that globally lack insulin receptor substrate (IRS) 2, which is a key mediator of insulin receptor action, are infertile with defects in hypothalamic and ovarian functions. To unravel the tissue-specific roles of IRS2, we examined reproductive function in female mice that lack Irs2 only in the neurons. Surprisingly, these animals had minimal defects in pituitary and ovarian hormone levels, ovarian anatomy and function, and breeding performance, which indicates that the central nervous system IRS2 is not an obligatory signaling component for the regulation of reproductive function. Therefore, we undertook a detailed analysis of ovarian function in a novel Irs2 global null mouse line. Comparative morphometric analysis showed reduced follicle size, increased numbers of atretic follicles, as well as impaired oocyte growth and antral cavity development in Irs2 null ovaries. Granulosa cell proliferation was also defective in the Irs2 null ovaries. Furthermore, the insulin- and eCG-stimulated phosphoinositide-3-OH kinase signaling events, which included phosphorylation of Akt/protein kinase B and glycogen synthase kinase 3-beta, were impaired, whereas mitogen-activated protein kinase signaling was preserved in Irs2 null ovaries. These abnormalities were associated with reduced expression of cyclin D2 and increased CDKN1B levels, which indicates dysregulation of key components of the cell cycle apparatus implicated in ovarian function. Our data suggest that ovarian rather than central nervous system IRS2 signaling is important in the regulation of female reproductive function.


EGFR-Mutant NSCLC: Spotlight on Amivantamab.
Data from three phase III trials-PAPILLON, MARIPOSA, and MARIPOSA-2-highlight amivantamab, an EGFR-MET bispecific antibody, as a potential contender as a standard treatment for EGFR-mutant non-small cell lung cancer. Amivantamab paired with chemotherapy is a superior first-line option for patients with exon 20-mutated disease. Beyond this subset, compared with standard osimertinib, the combination with or without lazertinib also boosted progression-free survival, albeit at the cost of added toxicity.


Use of perfusion fixation for improved neuropathologic examination.
To assess the efficacy of 10% formalin perfusion fixation as a method of rapid fixation to examine the human brain immediately following autopsy. Compare the histology and immunohistochemistry from human brains in which one hemisphere undergoes perfusion fixation using 10% buffered formalin, and the contralateral nonperfused hemisphere undergoes standard 14-day immersion fixation in 8 L of 10% buffered formalin. Autopsy material in a general medical-surgical university hospital. Pathologists, neuropathologists, resident pathologists, and pathology assistants. Immediately following brain removal, a single hemisphere was perfused with 1 L 10% buffered formalin over a 15- to 20-minute period. The contralateral nonperfused hemisphere served as a control, undergoing standard immersion fixation for 2 weeks in 10% formalin. The perfusion-fixation hemisphere was immediately available for neuropathologic examination, and histologic sections of the brain were processed immediately with the other necropsy tissue sections. This allows completion of a final autopsy neuropathology report within 3 to 5 days in concert with the systemic section of the report. Perfusion-fixation brain sections were compared with immersion-fixation brain sections from the same brain. The effects on hematoxylin-eosin, Bielschowsky's silver, and immunohistochemical staining were evaluated by an experienced neuropathologist and a general pathologist with no prior knowledge of the fixation technique. Perfusion fixation revealed equal and occasionally superior histologic sections compared with traditional immersion fixation in terms of (1) technical preparation of section, (2) quality and intensity of staining with both hematoxylin-eosin and silver, and (3) immunoreactivity localization with a variety of immunohistochemical reactions. Immediate perfusion of the brain is an easily performed fixation technique that yields comparable or superior fixation to prolonged immersion fixation and allows an immediate complete neuropathologic examination and report within 3 to 5 days of performance of the autopsy.


H. pylori induces the expression of Hath1 in gastric epithelial cells via interleukin-8/STAT3 phosphorylation while suppressing Hes1.
Chronic gastritis associated with Helicobacter pylori is a leading cause of gastric intestinal metaplasia (IM), which arises from abnormal cell differentiation of the epithelium in the gastric mucosa. However, the mechanisms involved in H. pylori-mediated IM remain elusive. The aim of our study was to explore the effects and the underlying mechanisms of H. pylori on the abnormal expression of Hath1 and Sox2 and to reveal its relationship to the development of gastric IM. We found that Hath1 and Sox2 were overexpressed in gastric IM tissue. Hath1 expression was up-regulated, whereas Sox2 expression, which was independent of the CagA virulence factor, was down-regulated in gastric epithelial cells and coincided with increased IL-6 and IL-8 levels in the culture media. Stimulation with H. pylori-related cytokine IL-8, but not IL-6 or IL-1β, was induced by Hath1 expression in the gastric epithelial cells. Although IL-8 and IL-6 levels correlated with STAT3 (signal transducer and activator of transcription) phosphorylation before and after H. pylori eradication in the gastric mucosa, only the blocking of IL-8-induced STAT3 activation using AG490 or STAT3-targeting RNA interference altered Hath1 expression. Additionally, we found that H. pylori down-regulated Hes1, which is a direct downstream target gene of Notch signaling and a repressor of Hath1 expression. These findings suggest that H. pylori induced inflammation up-regulate Hath1 expression via interleukin-8/STAT3 (IL-8) phosphorylation while suppressing Hes1, which provides a novel molecular connection between a H. pylori infection and intestinal metaplasia.


Dynamical entropy production in spiking neuron networks in the balanced state.
We demonstrate deterministic extensive chaos in the dynamics of large sparse networks of theta neurons in the balanced state. The analysis is based on numerically exact calculations of the full spectrum of Lyapunov exponents, the entropy production rate, and the attractor dimension. Extensive chaos is found in inhibitory networks and becomes more intense when an excitatory population is included. We find a strikingly high rate of entropy production that would limit information representation in cortical spike patterns to the immediate stimulus response.


Sestrin 2 and AMPK connect hyperglycemia to Nox4-dependent endothelial nitric oxide synthase uncoupling and matrix protein expression.
Mesangial matrix accumulation is an early feature of glomerular pathology in diabetes. Oxidative stress plays a critical role in hyperglycemia-induced glomerular injury. Here, we demonstrate that, in glomerular mesangial cells (MCs), endothelial nitric oxide synthase (eNOS) is uncoupled upon exposure to high glucose (HG), with enhanced generation of reactive oxygen species (ROS) and decreased production of nitric oxide. Peroxynitrite mediates the effects of HG on eNOS dysfunction. HG upregulates Nox4 protein, and inhibition of Nox4 abrogates the increase in ROS and peroxynitrite generation, as well as the eNOS uncoupling triggered by HG, demonstrating that Nox4 functions upstream from eNOS. Importantly, this pathway contributes to HG-induced MC fibronectin accumulation. Nox4-mediated eNOS dysfunction was confirmed in glomeruli of a rat model of type 1 diabetes. Sestrin 2-dependent AMP-activated protein kinase (AMPK) activation attenuates HG-induced MC fibronectin synthesis through blockade of Nox4-dependent ROS and peroxynitrite generation, with subsequent eNOS uncoupling. We also find that HG negatively regulates sestrin 2 and AMPK, thereby promoting Nox4-mediated eNOS dysfunction and increased fibronectin. These data identify a protective function for sestrin 2/AMPK and potential targets for intervention to prevent fibrotic injury in diabetes.


Transcriptional changes and developmental abnormalities in a zebrafish model of myotonic dystrophy type 1.
Myotonic dystrophy type I (DM1) is a multi-system, autosomal dominant disorder caused by expansion of a CTG repeat sequence in the 3'UTR of the DMPK gene. The size of the repeat sequence correlates with age at onset and disease severity, with large repeats leading to congenital forms of DM1 associated with hypotonia and intellectual disability. In models of adult DM1, expanded CUG repeats lead to an RNA toxic gain of function, mediated at least in part by sequestering specific RNA splicing proteins, most notably muscleblind-related (MBNL) proteins. However, the impact of CUG RNA repeat expression on early developmental processes is not well understood. To better understand early developmental processes in DM1, we utilized the zebrafish, Danio rerio, as a model system. Direct injection of (CUG)91 repeat-containing mRNA into single-cell embryos induces toxicity in the nervous system and muscle during early development. These effects manifest as abnormal morphology, behavioral abnormalities and broad transcriptional changes, as shown by cDNA microarray analysis. Co-injection of zebrafish mbnl2 RNA suppresses (CUG)91 RNA toxicity and reverses the associated behavioral and transcriptional abnormalities. Taken together, these findings suggest that early expression of exogenously transcribed CUG repeat RNA can disrupt normal muscle and nervous system development and provides a new model for DM1 research that is amenable to small-molecule therapeutic development.


Antigenic features and structural correlates of basement membranes. Relationship to epidermolysis bullosa.
Numerous antigenic epitopes are present within the dermoepidermal junction of human skin. Using monoclonal antibodies, the distribution of these epitopes in ontogeny, wound healing, and epidermolysis bullosa are being defined. These studies provide insight into the pathogenic mechanisms involved and offer opportunities for prenatal and postnatal diagnosis.


Allyloxyporphyrin-functionalized multiwalled carbon nanotubes: synthesis by radical polymerization and enhanced optical-limiting properties.
Allyloxyporphyrin-functionalized multiwalled carbon nanotubes (MWCNT-TPP) were synthesized by radical polymerization and characterized by FTIR, UV/Vis absorption, and X-ray photoelectron spectroscopy; elemental analysis; TEM; and thermogravimetric analysis. Z-scan studies revealed that this nanohybrid exhibits enhanced nonlinear optical (NLO) properties compared to a control sample consisting of a covalently unattached physical blend of MWCNTs and porphyrin, as well as to the separate MWCNTs and porphyrin. At the wavelengths used, the mechanism of enhanced optical limiting likely involves reverse saturable absorption, nonlinear scattering, and photoinduced electron/energy transfer between the MWCNTs and the porphyrin. The role of electron/energy transfer in the NLO performance of MWCNT-TPP was investigated by Raman and fluorescence spectroscopy.


Imaging and targeted therapy of pancreatic ductal adenocarcinoma using the theranostic sodium iodide symporter (NIS) gene.
The theranostic sodium iodide symporter (NIS) gene allows detailed molecular imaging of transgene expression and application of therapeutic radionuclides. As a crucial step towards clinical application, we investigated tumor specificity and transfection efficiency of epidermal growth factor receptor (EGFR)-targeted polyplexes as systemic NIS gene delivery vehicles in an advanced genetically engineered mouse model of pancreatic ductal adenocarcinoma (PDAC) that closely reflects human disease. PDAC was induced in mice by pancreas-specific activation of constitutively active KrasG12D and deletion of Trp53. We used tumor-targeted polyplexes (LPEI-PEG-GE11/NIS) based on linear polyethylenimine, shielded by polyethylene glycol and coupled with the EGFR-specific peptide ligand GE11, to target a NIS-expressing plasmid to high EGFR-expressing PDAC. In vitro iodide uptake studies in cell explants from murine EGFR-positive and EGFR-ablated PDAC lesions demonstrated high transfection efficiency and EGFR-specificity of LPEI-PEG-GE11/NIS. In vivo 123I gamma camera imaging and three-dimensional high-resolution 124I PET showed significant tumor-specific accumulation of radioiodide after systemic LPEI-PEG-GE11/NIS injection. Administration of 131I in LPEI-PEG-GE11/NIS-treated mice resulted in significantly reduced tumor growth compared to controls as determined by magnetic resonance imaging, though survival was not significantly prolonged. This study opens the exciting prospect of NIS-mediated radionuclide imaging and therapy of PDAC after systemic non-viral NIS gene delivery.


Optimised production of multifunctional microfibres by microfluidic chip technology for tissue engineering applications.
This paper describes a method for the production of alginate microfibres using glass-based microfluidic chips fabricated by a photolithography-wet etching procedure. The main focus of the work is the fabrication of a cell containing multifunctional microfibres which have great potential for applications in drug release formulations and tissue engineering scaffolds (to guide the regeneration of tissues in predefined sizes and shapes) providing cell structural support and immunoisolation. The key parameters, which critically influence the formation of microfibres and their geometries, were identified by a classical intuitive approach COST (Changing One Separate factor a Time). In particular, their effects on the microfibre diameter were investigated, which are directly associated with their functionalities relating to the implantation site, the nutrient availability and diffusion/transport of oxygen, essential nutrients, growth factors, metabolic waste and secretory products. The interplay between the alginate solution concentration, pumping rate and gelling bath concentration in controlling the diameter of the produced microfibres was investigated with a statistical approach by means of a "design of the experiments" (DoEs) optimization and screening. Finally, the processing impacts on cell viability, the cellular effect of wall thickness consistency and the spatial distribution of cells within the alginate microfibre were examined. We provide an approach for the production of alginate microfibres with controlled shape and content, which could be further developed for scaling up and working towards FDA approval.


The effects of alcoholic extract of saffron (Crocus satious L.) on mild to moderate comorbid depression-anxiety, sleep quality, and life satisfaction in type 2 diabetes mellitus: A double-blind, randomized and placebo-controlled clinical trial.
Depression and anxiety are major health problems throughout the world. Metabolic changes in type 2 diabetes mellitus induces and aggravates mental disorders, such as depression and anxiety. Saffron as a therapeutic herb may attenuate Comorbid Depression- Anxiety (CDA). So, this trial is designed to investigate the effect of saffron alcoholic extract on symptoms of CDA in type 2 diabetic patients. Fifty-four outpatients suffered from mild to moderate CDA diagnosed by using Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV), were assessed by Hamilton Depression and anxiety measurements, the Pittsburgh Sleep Quality Index (PSQI), and the Satisfaction with Life Scale (SWLS). The participants of this double-blind, placebo-controlled, single center and randomized trial were randomly assigned to intake 30 mg/day saffron or placebo capsules for 8 weeks. After the intervention, mild to moderate CDA, anxiety and sleep disturbance, but not depression alone, were relieved significantly in the saffron group (P < 0.05), whereas, the changes were not significant in the placebo group. Anthropometric measures and blood pressure parameters of the patients in either groups did not change significantly (P > 0.05) during the intervention. Moreover, dietary intake and physical activity did not differ during the study in the two groups. Changes in the life satisfaction were not significant. The results indicate the beneficial effect of saffron on the mild to moderate CDA in type 2 diabetic patients.


Clinical outcome measures in dementia with Lewy bodies trials: critique and recommendations.
The selection of appropriate outcome measures is fundamental to the design of any successful clinical trial. Although dementia with Lewy bodies (DLB) is one of the most common neurodegenerative conditions, assessment of therapeutic benefit in clinical trials often relies on tools developed for other conditions, such as Alzheimer's or Parkinson's disease. These may not be sufficiently valid or sensitive to treatment changes in DLB, decreasing their utility. In this review, we discuss the limitations and strengths of selected available tools used to measure DLB-associated outcomes in clinical trials and highlight the potential roles for more specific objective measures. We emphasize that the existing outcome measures require validation in the DLB population and that DLB-specific outcomes need to be developed. Finally, we highlight how the selection of outcome measures may vary between symptomatic and disease-modifying therapy trials.


Sphingosine kinase mediates resistance to the synthetic retinoid N-(4-hydroxyphenyl)retinamide in human ovarian cancer cells.
A2780 human ovarian carcinoma cells respond to treatment with the synthetic retinoid N-(4-hydroxyphenyl)retinamide (HPR) with the production of dihydroceramide and with a concomitant reduction of cell proliferation and induction of apoptosis. The derived HPR-resistant clonal cell line, A2780/HPR, is less responsive to HPR in terms of dihydroceramide generation. In this report, we show that the production of sphingosine 1-phosphate (S1P) is significantly higher in A2780/HPR versus A2780 cells due to an increased sphingosine kinase (SK) activity and SK-1 mRNA and protein levels. Treatment of A2780 and A2780/HPR cells with a potent and highly selective pharmacological SK inhibitor effectively reduced S1P production and resulted in a marked reduction of cell proliferation. Moreover, A2780/HPR cells treated with a SK inhibitor were sensitized to the cytotoxic effect of HPR, due to an increased dihydroceramide production. On the other hand, the ectopic expression of SK-1 in A2780 cells was sufficient to induce HPR resistance in these cells. Challenge of A2780 and A2780/HPR cells with agonists and antagonists of S1P receptors had no effects on their sensitivity to the drug, suggesting that the role of SK in HPR resistance in these cells is not mediated by the S1P receptors. These data clearly demonstrate a role for SK in determining resistance to HPR in ovarian carcinoma cells, due to its effect in the regulation of intracellular ceramide/S1P ratio, which is critical in the control of cell death and proliferation.


Epidemiological study of an outbreak of infection with Staphylococcus aureus resistant to lincosamides and streptogramin A in a French hospital.
A significant increase in the incidence of isolates of methicillin-resistant Staphylococcus aureus (MRSA), that were also resistant to lincosamides and streptogramin A (LSA-MRSA), was observed in a French university hospital. Twenty-seven isolates from the outbreak were characterised, including 17 isolates from a plastic surgery ward and six control strains of MRSA. The strains were examined by antibiotyping and biotyping, and by three molecular methods: plasmid analysis, ribotyping and insertion sequence (IS) typing with IS256 sequence as a probe. Antibiotyping (five antibiotypes) was discriminatory because of the uncommon resistance phenotype of the epidemic strain. Biotyping (three biotypes), DNA plasmid analysis (four profiles) and ribotyping (two profiles) were poorly sensitive, in contrast to IS-typing (12 profiles). By the latter method, a coefficient of similarity (percentage similarity) compared to the predominant IS profile was calculated. Strains with a coefficient of similarity > or = to 82% were considered as highly related to the epidemic strain, while those with a coefficient of similarity < or = to 40% were regarded as distant. Results obtained with the five markers confirmed that an outbreak of hospital infection had occurred in the plastic surgery ward, with spread of the epidemic strain throughout the hospital.


Symmetry for Flavor-Kinematics Duality from an Action.
We propose a new representation of the nonlinear sigma model that exhibits a manifest duality between flavor and kinematics. The fields couple exclusively through cubic Feynman vertices which define the structure constants of an underlying kinematic algebra. The action is invariant under a combination of internal and spacetime symmetries whose conservation equations imply flavor-kinematics duality, ensuring that all Feynman diagrams satisfy kinematic Jacobi identities. Substituting flavor for kinematics, we derive a new cubic action for the special Galileon theory. In this picture, the vanishing soft behavior of amplitudes is a by-product of the Weinberg soft theorem.


The determinants of saccade targeting strategy in neurodevelopmental disorders: The influence of suboptimal reading experience.
Whether eye-movements deficits are causal in reading disorders (RD) or rather a consequence of linguistic processing difficulty experienced by disabled readers has been extensively debated.Since RD are frequently comorbid with the Neurofibromatosis type1 (NF1), children with NF1 were used as a comparison group for children with dyslexia in this study.Eye movements were recorded while 21 dyslexic, 20 NF1, and 20 typically developing children performed an oculomotor lateralized bisection task. In this experiment, we manipulated the type of stimulus - discrete (words and strings of hashes) versus continuous (solid lines) - and the visual field where the stimulus was displayed (left vs right). The results showed that (1) only proficient readers (TD and NF1 without RD) showed fully developed oculomotor mechanisms for efficient reading, with a clear preferred viewing location located to the left of the word's centre in both visual fields, and fine-tuned saccade targeting guided by the between-character space information and (2) NF1 poor readers mirrored the dyslexic eye movement behaviour, with less accuracy and more variability in saccadic programming, no sensitivity to the discreteness of the stimuli, particularly in the left visual field. We concluded that disruption to oculomotor behaviour reflectsthe fact that many of the processes involved in reading are not yet automatized for children with RD, independently of NF1. This suggests that the differences in saccade targeting strategy between children with and without RD would be secondary consequences of their reduced reading experience.


Activation of protein kinase C{eta} by type I interferons.
Type I interferons (IFNs) are cytokines with diverse biological properties, including antiviral, growth inhibitory, and immunomodulatory effects. Although several signaling pathways are activated during engagement of the type I IFN receptor and participate in the induction of IFN responses, the mechanisms of generation of specific signals for distinct biological effects remain to be elucidated. We provide evidence that a novel member of the protein kinase C (PKC) family of proteins is rapidly phosphorylated and activated during engagement of the type I IFN receptor. In contrast to other members of the PKC family that are also regulated by IFN receptors, PKCeta does not regulate IFN-inducible transcription of interferon-stimulated genes or generation of antiviral responses. However, its function promotes cell cycle arrest and is essential for the generation of the suppressive effects of IFNalpha on normal and leukemic human myeloid (colony-forming unit-granulocyte macrophage) bone marrow progenitors. Altogether, our studies establish PKCeta as a unique element in IFN signaling that plays a key and essential role in the generation of the regulatory effects of type I IFNs on normal and leukemic hematopoiesis.


Periferal cystic hyperplasia of the prostate gland.
Cystic transformation of the periferal prostate affecting at least 10 cm3 of tissue was found in 19 out of 300 consecutive prostatic glands at autopsy. The etiology is probably multifactorial and no correlation is found with nodular hyperplasia or carcinoma. Periferal cystic hyperplasia may be a cause of palpatoric enlargement of the prostate and thus may be a differential diagnostic possibility to nodular hyperplasia or cancer.


Educational and experiential effects on radiographers' radiation safety behavior.
Forty-four radiographers from 11 hospitals in Northern California were observed for radiation safety behaviors in six categories. A multiple regression analysis was performed to determine if there was a significant relationship between the six radiation safety behaviors and the radiographer's age, sex, type of professional training, years since completion of professional training, years of professional practice, time of day, and exposure frequency. The multiple regression analysis showed that there was a significant relationship between use of gonadal shielding and years since completion of professional training, years of professional practice, type of training, and age. The multiple regression analysis also showed that the number of repeated films due to technical error was significantly related to the type of professional training a radiographer received.


Bioevaluation of superparamagnetic iron oxide nanoparticles (SPIONs) functionalized with dihexadecyl phosphate (DHP).
Superparamagnetic iron oxide nanoparticles (SPIONs) have been investigated for wide variety of applications. Their unique properties render them highly applicable as MRI contrast agents, in magnetic hyperthermia or targeted drug delivery. SPIONs surface properties affect a whole array of parameters such as: solubility, toxicity, stability, biodistribution etc. Therefore, progress in the field of SPIONs surface functionalization is crucial for further development of therapeutic or diagnostic agents. In this study, SPIONs were synthesized by thermal decomposition of iron (III) acetylacetonate Fe(acac)3 and functionalized with dihexadecyl phosphate (DHP) via phase transfer. Bioactivity of the SPION-DHP was assessed on SW1353 and TCam-2 cancer derived cell lines. The following test were conducted: cytotoxicity and proliferation assay, reactive oxygen species (ROS) assay, SPIONs uptake (via Iron Staining and ICP-MS), expression analysis of the following genes: alkaline phosphatase (ALPL); ferritin light chain (FTL); serine/threonine protein phosphatase 2A (PP2A); protein tyrosine phosphatase non-receptor type 11 (PTPN11); transferrin receptor 1 (TFRC) via RT-qPCR. SPION-DHP nanoparticles were successfully obtained and did not reveal significant cytotoxicity in the range of tested concentrations. ROS generation was elevated, however not correlated with the concentrations. Gene expression profile was slightly altered only in SW1353 cells.


Human fibrillarin forms a sub-complex with splicing factor 2-associated p32, protein arginine methyltransferases, and tubulins alpha 3 and beta 1 that is independent of its association with preribosomal ribonucleoprotein complexes.
Fibrillarin (FIB, Nop1p in yeast) is an RNA methyltransferase found not only in the fibrillar region of the nucleolus but also in Cajal bodies. FIB is essential for efficient processing of preribosomal RNA during ribosome biogenesis, although its precise function in this process and its role in Cajal bodies remain uncertain. Here, we demonstrate that the human FIB N-terminal glycine- and arginine-rich domain (residues 1-77) and its spacer region 1 (78-132) interact with splicing factor 2-associated p32 (SF2A-p32) and that the FIB methyltransferase-like domain (133-321) interacts with protein-arginine methyltransferase 5 (PRMT5, Janus kinase-binding protein 1). We also show that these proteins associate with several additional proteins, including PRMT1, tubulin alpha 3, and tubulin beta 1 to form a sub-complex that is principally independent of the association of FIB with preribosomal ribonucleoprotein complexes that co-immunoprecipitate with the sub-complex in human cells expressing FLAG-tagged FIB. Based on the physical association of FIB with SF2A-p32 and PRMTs, as well as the other reported results, we propose that FIB may coordinate both RNA and protein methylation during the processes of ribosome biogenesis in the nucleolus and RNA editing such as small nuclear (nucleolar) ribonucleoprotein biogenesis in Cajal bodies.


[About an autochtonous case of neurocysticercosis in Mali].
Cysticercosis has been reported in Muslim countries in workers coming from endemic regions for Taenia solium. For the first time in Mali, the authors report a case of autochtonous neurocysticercosis where Muslim religion is predominent. The patient was a woman student with fever, arthralgia, headaches, consciousness troubles followed by partial motor epilepsy. Diagnosis was confirmed by clinic, serology ELISA and Western blotting and cephalic tomodensitometry analysis. The medical treatment was successfully based on combination of albendazole and praziquantel. The origin of contamination remains unknown and further investigations are needed, particularly with veterinary research team and the National League against epilepsy recently founded in Mali.


Basement membrane stiffness determines metastases formation.
The basement membrane (BM) is a special type of extracellular matrix and presents the major barrier cancer cells have to overcome multiple times to form metastases. Here we show that BM stiffness is a major determinant of metastases formation in several tissues and identify netrin-4 (Net4) as a key regulator of BM stiffness. Mechanistically, our biophysical and functional analyses in combination with mathematical simulations show that Net4 softens the mechanical properties of native BMs by opening laminin node complexes, decreasing cancer cell potential to transmigrate this barrier despite creating bigger pores. Our results therefore reveal that BM stiffness is dominant over pore size, and that the mechanical properties of 'normal' BMs determine metastases formation and patient survival independent of cancer-mediated alterations. Thus, identifying individual Net4 protein levels within native BMs in major metastatic organs may have the potential to define patient survival even before tumour formation. The ratio of Net4 to laminin molecules determines BM stiffness, such that the more Net4, the softer the BM, thereby decreasing cancer cell invasion activity.


Body fat distribution and risk of premenopausal breast cancer in the Nurses' Health Study II.
Body mass index is inversely associated with risk of premenopausal breast cancer, but the underlying mechanisms for this association are poorly understood. Abdominal adiposity is associated with metabolic and hormonal changes, many of which have been associated with the risk of premenopausal breast cancer. We investigated the association between body fat distribution, assessed in 1993 by self-reported waist circumference, hip circumference, and waist to hip ratio, and the incidence of premenopausal breast cancer in the Nurses' Health Study II. Cox proportional hazards regression models were used to calculate hazard ratios and 95% confidence intervals (CIs). Statistical tests were two-sided. During 426,164 person-years of follow-up from 1993 to 2005, 620 cases of breast cancer were diagnosed among 45,799 women. Hormone receptor status information was available for 84% of the breast cancers. The age-standardized incidence rates of breast cancer were 131 per 100,000 person-years among those in the lowest quintile of waist circumference and 136 per 100,000 person-years among those in the highest quintile. No statistically significant associations were found between waist circumference, hip circumference, or the waist to hip ratio and risk of breast cancer. However, each of the three body fat distribution measures was statistically significantly associated with greater incidence of estrogen receptor (ER)-negative breast cancer. The multivariable-adjusted hazard ratios of ER-negative breast cancer for the highest vs the lowest quintile of each body fat distribution measure were 2.75 (95% CI = 1.15 to 6.54; P(trend) = .05) for waist circumference, 2.40 (95% CI = 0.95 to 6.08; P(trend) = .26) for hip circumference, and 1.95 (95% CI = 1.10 to 3.46; P(trend) = .01) for waist to hip ratio. Our findings suggest that body fat distribution does not play an important role in the overall incidence of premenopausal breast cancer but is associated with an increased risk for ER-negative breast cancer.


Pregnancy in an Abnormal Location.
Cesarean scar pregnancy and cervical pregnancy are 2 relatively rare types of abnormally implanted pregnancies. Both if unrecognized can result in significant morbidity to the patient. The most important issue regarding cesarean scar pregnancy and cervical pregnancy is to establish the diagnosis early in order for the patient to be adequately counseled and appropriate management carried out. For both of these conditions early detection and treatment can result in preservation of fertility.


The Function of G-Protein-Coupled Receptor-Regulatory Cascade in Southern House Mosquitoes (Diptera: Culicidae).
G-protein-coupled receptors (GPCRs) are a large family of seven-transmembrane domain proteins that exist in plants and animals, playing critical physiological functions through intracellular cascades. Previous studies revealed an important regulation pathway of GPCR/Guanine nucleotide-binding protein (G-protein)/Adenylyl Cyclase (AC)/cAMP-dependent protein kinase A (PKA) in the insecticide resistance and regulation of resistance-related P450 gene expression in highly resistant southern house mosquitoes, Culex quinquefasciatus Say (Diptera: Culicidae). However, the function of this regulation pathway in field-collected and laboratory-susceptible mosquitoes is still unknown. In the current study, we characterized the function of each effector (GPCR, G-protein, AC, and PKA) in this GPCR intracellular pathway in both field-collected and laboratory Cx. quinquefasciatus strains, showing that knockdown of the expression of each effector gene can cause 1) decreased expression of their downstream respective genes and 2) increased sensitivity of the mosquitoes to permethrin insecticide. These results, together with our previous findings, strongly suggest the universal function of the GPCR-regulation cascade in the mosquito's sensitivity to insecticides and its regulation of resistance development through P450-mediated detoxification.


LncRNA ANRIL knockdown ameliorates retinopathy in diabetic rats by inhibiting the NF-κB pathway.
To evaluate the impacts of long non-coding ribonucleic acid (lncRNA) antisense non-coding RNA in the INK4 locus (ANRIL) on diabetic retinopathy (DR) in rats and the underlying mechanism. A total of 60 adult male Sprague Dawley (SD) rats were randomly divided into 3 groups: the Sham group (n=20), DR group (n=20) and DR + lncRNA ANRIL knockdown group [DR + lncRNA ANRIL small interfering RNA (siRNA) group, n=20]. DR model in rats was established by intraperitoneal injection of streptozocin (STZ; 60 mg/kg). Meanwhile, a certain dose of lncRNA ANRIL siRNA was added dropwise into rat eyes of DR + lncRNA ANRIL siRNA group during model induction to downregulate lncRNA ANRIL expression in the retina. 16 weeks later, rat retinal tissues were taken to extract total RNA and protein. Reverse Transcription-Polymerase Chain Reaction (RT-PCR) was applied to detect the expression levels of lncRNA ANRIL, interleukin-1 (IL-1), IL-6 and monocyte chemotactic protein-1 (MCP-1) in each group of the rat retina. Pathological structure of rat retinal tissues in each group was observed via hematoxylin and eosin (H&E) staining. Immunohistochemistry was adopted to measure the expression levels of B-cell lymphoma-2 (Bcl-2), Bcl-2-associated X protein (Bax) and P65 in each group of retinal tissues. In addition, the retinal vascular permeability in each group of rats was detected by fluorescent staining. Finally, Western blotting was utilized to determine the expressions of genes in the P65 signaling pathway. Compared with rats in the Sham group, lncRNA ANRIL was upregulated in rat retinal tissues harvested from the DR + lncRNA ANRIL siRNA group (p<0.05). After knockdown of lncRNA ANRIL in the retinal tissues of DR rats, pathologic damage was alleviated notably, and the levels of inflammatory markers (IL-1, IL-10 and MCP-1) were lowered markedly (p<0.05). The protein expressions of Bax and P65 decreased evidently, while the protein level of Bcl-2 increased markedly (p<0.05) in DR rats with ANRIL knockdown. Furthermore, Western blotting results revealed that inhibition of lncRNA ANRIL could prominently repress the phosphorylation level of P65 in the retinal tissues of DR rats (p<0.05). LncRNA ANRIL knockdown can significantly ameliorate the retinopathy in diabetic rats by blocking the nuclear factor-kappa B (NF-κB) signaling pathway.


Segmental variations in the elastic fiber content of the lateral costotransverse ligaments in the vervet monkey (Cercopithecus pygerythrus aethiops).
The segmental and zonal variations in the quantitative relationships between elastic and collagen fibers within the lateral costotransverse ligaments have been investigated in the vervet monkey. The lateral costotransverse ligaments of the caudal segments have a largely elastic structure in contrast to those of the cranial segments, which are characteristically collagenous. In the transitional zone extending from the 4th through to the 6th costotransverse joints, the lateral costotransverse ligaments show a zonal differentiation into a superficial collagenous portion and a deep elastic portion. It is noted that the craniocaudal structural differentiation in the lateral costotransverse ligaments corresponds with similar changes in the vertebral ligaments in that the ligamenta flava gradually extend into the interspinous spaces from the 1st thoracic vertebra (T1) so that at T5 the ligaments occupy 50% of the interspinous space and at T7 the elastic fibers almost completely replace the interspinous ligament. Functionally, however, the regional differences in the elastic fiber content of the lateral costotransverse ligament may have no collateral relationship with the morphology of the ligamenta flava, but are conditioned by movements of the ribs. Whereas movements of the upper six joints are limited by virtue of the configuration of their articular surfaces, which are reciprocally curved, on the 7th to 10th joints the articular facets are almost flat and, therefore, allow considerable movements between the ribs and the corresponding transverse processes.


Fabrication of Dual pH/Reduction-Responsive P(CL-co-ACL)-Based Cross-Linked Polymeric Micelles for PTX Delivery.
To enhance the stability of the polymeric micelles and optimize their drug-controlled release ability, three disulfide-linked polyethylene glycol methyl ether methacrylate-disulfide-poly(ε-caprolactone-co-γ-amine-ε-caprolactone) (PPEGMA-SS-P(CL-co-ACL)) polymers were synthesized and characterized by 1H NMR, GPC, and FT-IR successfully, and their dual pH/reduction-responsive cross-linked polymeric micelles were prepared for paclitaxel (PTX) delivery by using 2,3-dimethylmaleic anhydride (DMMA) as the cross-linking agent. The PTX loading capacity (LC) and encapsulation efficiency (EE) values of the cross-linked micelles formed by PPEGMA8-SS-P(CL47-co-ACL15) achieved were 23.96% and 71.58%, slightly higher than those of un-cross-linked micelles. Both particle sizes of blank micelles and in vitro drug release of PTX-loaded micelles confirmed that compared with those un-cross-linked micelles, the cross-linked micelles were more stable at pH 7.4 + 0 mM DTT, with a PTX cumulative release of 13% at 120 h, while the PTX cumulative release of the cross-linked micelles at pH 5.0 + 10 mM DTT were close to that of un-cross-linked micelles after 60 h, indicating the successful reversible cross-linking and smooth drug release of the cross-linked micelles. The cytotoxicity assay showed that PPEGMA8-SS-P(CL47-co-ACL15) and its cross-linked micelles had low cell cytotoxicity, and both PTX-loaded micelles revealed a certain inhibitory effect on HepG2 cells. These results revealed that the dual pH/reduction-responsive cross-linked polymeric micelles prepared from PPEGMA8-SS-P(CL47-co-DCL15) were a promising candidate for PTX delivery.


Varicella-zoster virus IE63, a virion component expressed during latency and acute infection, elicits humoral and cellular immunity.
Varicella-zoster virus (VZV) latency in human dorsal root ganglia is characterized by the transcription of large regions of its genome and by the expression of large amounts of some polypeptides, which are also expressed during lytic cycles. The immediate early 63 protein (IE63) is a virion component expressed very early in cutaneous lesions and the first viral protein detected during latency. Immune response against IE63 has been evaluated among naturally immune adults with a history of chickenpox: Specific antibodies were detected in serum, and most subjects who had a T cell proliferation with unfractionated VZV antigens had T cell recognition of purified IE63. The cytotoxic T cell (CTL) response to IE63 was equivalent to CTL recognition of IE62, the major tegument component of VZV, whose immunogenicity has been previously described. T cell recognition of IE63 and other VZV proteins is one of the likely mechanisms involved in controlling VZV reactivation from latency.


Total and regional brain volumes in a population-based normative sample from 4 to 18 years: the NIH MRI Study of Normal Brain Development.
Using a population-based sampling strategy, the National Institutes of Health (NIH) Magnetic Resonance Imaging Study of Normal Brain Development compiled a longitudinal normative reference database of neuroimaging and correlated clinical/behavioral data from a demographically representative sample of healthy children and adolescents aged newborn through early adulthood. The present paper reports brain volume data for 325 children, ages 4.5-18 years, from the first cross-sectional time point. Measures included volumes of whole-brain gray matter (GM) and white matter (WM), left and right lateral ventricles, frontal, temporal, parietal and occipital lobe GM and WM, subcortical GM (thalamus, caudate, putamen, and globus pallidus), cerebellum, and brainstem. Associations with cross-sectional age, sex, family income, parental education, and body mass index (BMI) were evaluated. Key observations are: 1) age-related decreases in lobar GM most prominent in parietal and occipital cortex; 2) age-related increases in lobar WM, greatest in occipital, followed by the temporal lobe; 3) age-related trajectories predominantly curvilinear in females, but linear in males; and 4) small systematic associations of brain tissue volumes with BMI but not with IQ, family income, or parental education. These findings constitute a normative reference on regional brain volumes in children and adolescents.


Ethnic and gender differences in ideal body size and related attitudes among Asians, Native Hawaiians, and Whites.
Often overlooked explanations for the varied obesity rates across ethno-cultural groups include differences in attitudes toward excess weight, with certain populations assumed to have larger ideal body sizes (IBS). Past studies found ethnic and gender difference in IBS across and within different groups. This study examined the effects of ethnicity and gender, and their interaction, in accounting for differences in IBS and attitudes toward those ideals. Multiple regression analyses were used to better understand the effects of ethnicity and gender in accounting for differences in perceived IBS according to ethnic-specific and Western ideals and attitudes in 1,124 people of Native Hawaiian, Filipino, Japanese, and White ancestry. The analyses controlled for socio-demographics, body mass index, health-related behaviors, and psychosocial variables. The results indicated that Native Hawaiians selected larger ethnic IBS, Filipinos selected smaller ethnic IBS, and Native Hawaiians selected slightly smaller Western IBS than other ethnic groups. Overall, males selected larger IBS compared to females. Interaction analyses indicated that the relationship between ethnic IBS and attitude toward that IBS varied as a function of ethnicity, such that Native Hawaiians who selected a larger ethnic IBS held less favorable attitudes toward that IBS. The discrepancy between Native Hawaiians' selection of larger ethnic IBS as ideal and their less positive attitude toward that selection warrants more investigation. However, it does suggest that Native Hawaiians, on a personal level, do not prefer larger body sizes, which contradicts their perceptions of social norms. These findings have important implications for obesity interventions among Native Hawaiians.


IL28B polymorphism, blood interferon-alpha concentration, and disease stage of HCV mono-infected and HCV-HIV co-infected patients.
Interferon (IFN) preactivation, interleukin-28B (IL28B) alleles, and liver fibrosis act as predictors of response to antiviral therapy against hepatitis C. We aimed to verify if blood IFN concentration, a putative biomarker of interferon preactivation, might depend on carriage of a given IL28B genotype and/or advanced hepatic fibrosis. The study population included 187 hepatitis C patients (75 of whom were HIV coinfected), who were genotyped for the rs12979860 polymorphism and staged non-invasively by transient elastography. Blood IFN, measured by an enzyme immunoassay, was detectable in 68/187 patients (36%). Seventy-three patients (39%) were C/C homozygotes, 25 (13%) were T/T homozygotes, and 89 (48%) were heterozygotes. The fibrosis stage was F0-F1 in 70 patients (37%), F2-F3 in 54 patients (29%), and F4 in 63 patients (34%). IFN levels were higher among patients with HIV coinfection (p=0.044) and patients with better renal function (p=0.041), without association with the IL28B genotype or the hepatitis C stage. From the multivariate analysis, the only independent predictor of higher level of IFN was the age of patients (p=0.019), whereas independent predictors of a fibrosis stage ≥ F2 were age (p=0.007), belonging to the HIV/HCV group (p=0.048) and current alcohol consumption (p=0.008). In conclusion, a sizable proportion of HCV carriers have detectable IFN levels that do not indicate a greater severity of disease or display any relationships to specific rs12979860 variants.


A Scoping Review of Suicide Prevention Training Programs for Pharmacists and Student Pharmacists.
Objective. This scoping review updates a 2018 review of suicide prevention training programs for community and student pharmacists. Five scholarly databases were searched for articles published between January 2018 and December 2020. Articles were excluded if they did not describe an educational or training program for pharmacists or student pharmacists, did not explicitly include suicide, focused solely on attitudes, or did not provide sufficient detail to evaluate program content. The quality of each study was examined using a quality assessment tool.Findings. Seven studies met inclusion criteria. Most trainings (86%) were delivered live with interactive or role play scenarios to promote verbal and behavioral skill practice. About half (57%) assessed changes in knowledge, and fewer programs (29%) assessed changes in communication. All assessed participants' ability to identify suicide warning signs and included referral resources. Six studies were assessed for quality, of which 67% had a rating of good and 33% were rated as fair.Summary. Given the increase in suicide rates nationally, it is likely that pharmacists will encounter a patient in need of suicide prevention services. Since 2018, seven new suicide prevention training programs for community and student pharmacists have been reported, which demonstrates growing interest in suicide prevention training in the pharmacy profession. When integrated in Doctor of Pharmacy (PharmD) curricula, trainings may help prepare the pharmacy workforce for encounters with patients in crisis. The impact of training on self-efficacy and communication skills warrants additional attention. Variation between programs should be evaluated to understand which instructional methods best prepare pharmacy professionals to engage in suicide prevention.


Predicting nearest neighbor free energies of modified RNA with LIE: results for pseudouridine and N1-methylpseudouridine within RNA duplexes.
Pseudouridine (Ψ) and N1-methylpseudouridine (m1Ψ) are among the key modifications in the field of mRNA therapeutics and vaccine research. The accuracy of the design and development of therapeutic RNAs containing such modifications depends on the accuracy of the secondary structure prediction, which in turn depends on the nearest neighbor (NN) thermodynamic parameters for the standard and modified residues. Here, we propose a simple approach based on molecular dynamics simulations and linear interaction energy (LIE) approximation that is able to predict the NN free energy parameters for U-A, Ψ-A and m1Ψ-A pairs in reasonable agreement with the recent experimental reports. We report the NN thermodynamic parameters for different U, Ψ and m1Ψ base pairs, which might be helpful for a deeper understanding of the effect of these modifications in RNA. The predicted NN free energy parameters in this study are able to closely reproduce the folding free energies of duplexes containing internal Ψ for which the thermodynamic data were available. Additionally, we report the predicted folding free energies for the duplexes containing internal m1Ψ.


Investigation into the physicochemical stability and rheological properties of beta-carotene emulsion stabilized by soybean soluble polysaccharides and chitosan.
In this study, the possibility of producing stable O/W emulsions incorporating beta-carotene in oil droplets surrounded by multiple-layer interfacial membranes has been demonstrated. Emulsions were prepared using a two-stage process by homogenization, which relied on the adsorption of chitosan to anionic droplets coated with soybean soluble polysaccharides (SSPS). Results showed that the zeta-potential, particle size, and rheological properties of emulsions were greatly dependent on the chitosan concentration. The electrical charge on the droplets increased from -34 to 58.2 mV as the chitosan concentration was increased from 0 to 2 wt %, which indicated that chitosan adsorbed to the droplet surfaces. The mean particle diameter of the emulsions increased dramatically with the rise of chitosan concentration from 0 to 0.33 wt %, indicating the formation of large aggregated structures. At chitosan concentrations above 0.33 wt %, the mean particle diameter of emulsions decreased and reached a minimum value of 0.79 mum at a chitosan concentration of 0.5 wt %. Dynamic oscillatory shear tests indicated that the viscoelastic behavior could be enhanced by the adsorption of chitosan onto the SSPS-coated droplet surfaces. Chitosan concentration had a significant (p < 0.05) impact on the stability of beta-carotene. The least degradation occurred in the emulsion with chitosan concentration of 0.5%. These results implied that the physicochemical stability of beta-carotene emulsions has been improved by the adsorption of chitosan.


Vitamin C alleviates acute enterocolitis in Campylobacter jejuni infected mice.
Human foodborne infections with the zoonotic pathogen Campylobacter jejuni are on the rise and constitute a significant socioeconomic burden worldwide. The health-beneficial, particularly anti-inflammatory effects of vitamin C (ascorbate) are well known. In our preclinical intervention study, we assessed potential anti-pathogenic and immunomodulatory effects of ascorbate in C. jejuni-infected secondary abiotic IL-10-/- mice developing acute campylobacteriosis similar to humans. Starting 4 days prior peroral C. jejuni-infection, mice received synthetic ascorbate via the drinking water until the end of the experiment. At day 6 post-infection, ascorbate-treated mice harbored slightly lower colonic pathogen loads and suffered from less severe C. jejuni-induced enterocolitis as compared to placebo control animals. Ascorbate treatment did not only alleviate macroscopic sequelae of infection, but also dampened apoptotic and inflammatory immune cell responses in the intestines that were accompanied by less pronounced pro-inflammatory cytokine secretion. Remarkably, the anti-inflammatory effects of ascorbate pretreatment in C. jejuni-infected mice were not restricted to the intestinal tract but could also be observed in extra-intestinal compartments including liver, kidneys and lungs. In conclusion, due to the potent anti-inflammatory effects observed in the clinical murine C. jejuni-infection model, ascorbate constitutes a promising novel option for prophylaxis and treatment of acute campylobacteriosis.


[Development and evaluation of a transitional care program for patients discharged from military hospitals].
The purpose of this study was to develop and evaluate a transitional care program for patients discharged from military hospitals. The study consists of two phases: developing the program and evaluating its effectiveness. The conceptual framework used to guide the development of the program was Meleis's transition theory. A quasi-experimental design was employed for this study. Participants were recruited from patients discharged from one military hospital, 72 in the control group and 56 in the experiment group. Data were analyzed using SPSS WIN 12.0 program with chi-square, Fisher's exact test, independent t-test, and mixed model. Participants in the transitional care program reported promoting a positive personal condition, and more healthy patterns of response in the first week after being discharged and a smoother discharge transition. The transitional care program developed for discharge patients from military hospital promoted discharge readiness and promoted smooth discharge transition.


Rigid Plate Fixation for Closure of Emergent Sternotomies for Trauma.
No studies to date have evaluated the use of rigid plate fixation for emergent sternotomy in trauma patients. We evaluated our use of rigid plate fixation vs wire cerclage in patients requiring emergent sternotomy. We hypothesized there would be no difference in complications related to sternal closure between the two groups. We performed a retrospective cohort study to include all patients who underwent emergent sternotomy from 1/1/2018 to 1/31/2021 and survived to have their sternum closed. Outcomes in patients closed with wire cerclage group (WC) were compared to patients who underwent rigid plate fixation (RPF). Twenty-two patients underwent emergent sternotomy. There were 11 patients in each group. There was no significant difference in admission demographics, ISS, or admission characteristics between the two groups. Complication rates related to closure (wound infection and hardware removal) were not significantly different (WC 27% vs RPF 9%, P = .58). Neither hospital length of stay (WC: 29 days vs RPF: 13 days, P = .13), ICU length of stay (WC: 6 days vs RPF: 7 days, P = .62), nor the number of ventilator days (WC: 3 days vs RPF: 1 day, P .11) were statistically different. All patients survived to discharge. This is the first study comparing RPF and WC for sternotomy closure in the setting of trauma. We found no difference in the rate of wound related complications. This study demonstrates the feasibility of rigid plate fixation for trauma sternotomy closure and lays the foundation for future prospective studies.


Endothelin-activated calcium signaling in enteric glia derived from neonatal guinea pig.
The ability of guinea pig enteric glia to respond to endothelins was examined using fura 2-based digital microscopy in glial cells derived from guinea pig taenia coli. Each isoform of endothelin (ET-1, ET-2, ET-3) evoked dose-dependent and equipotent increases in intracellular Ca2+ concentration ([Ca2+]i) and in percentage of cells responding, 4alaEt-1, an ETB receptor agonist, elicited similar [Ca2+]i increments. BQ-788, an ETB antagonist, inhibited [Ca2+]i responses to endothelin. Preincubation of glia with U-73122 a phospholipase C inhibitor, abolished the [Ca2+]i response to ET-3 exposure. Thapsigargin also eliminated ET-3-evoked Ca2+ signaling. The inositol 1,4,5-trisphosphate (IP3) receptor antagonist heparin, introduced into glial cells by radio frequency electroporation, blocked [Ca2+]i responses to ET-3 (100 nM) in 63% of glia. Sustained elevation in [Ca2+]i was abolished by removal of Ca2+ from the buffer and inhibited 85. -3% by Ni2+ (1 mM). Preincubation of glia with 100 nM phorbol 12-myristate 13-acetate (24 h) also inhibited sustained increments in [Ca2+]i by 87%. The presence of IP3 receptors in enteric glia was confirmed by immunofluorescent confocal microscopy.


The effects of hypercapnia on force and rate of contraction and intracellular pH of perfused ventricles from the land snail Helix lucorum (L.).
The effects of hypercapnia, together with low and high levels of extracellular Ca(2+), on heart activity and intracellular pH were examined in isolated perfused hearts from the land snail Helix lucorum. In addition, the intracellular level of Ca(2+) was determined in slices of ventricles superfused with both normal and hypercapnic salines, containing low and high concentrations of Ca(2+), to investigate whether low extracellular pH affects the entry of Ca(2+) into the heart cells. We also examined the effect of a saline that simulated the composition of the haemolymph of snails after estivating for 3 months on the heart activity and intracellular pH. The results showed that hypercapnia causes decreases in the rate and force of heart contraction, and these are more pronounced in the presence of low levels of extracellular Ca(2+). Moreover, the present results indicate that Ca(2+) maintains the contractility of the heart muscle under acidic conditions and seems to act by competing with protons for the Ca(2+ )binding sites on sarcolemma. The negative effect of hypercapnia on heart activity appears to be due to a reduction in extracellular pH rather than to changes in intracellular pH.


Long-term optical imaging of the spinal cord in awake, behaving animals.
Advances in optical imaging approaches and fluorescent biosensors have enabled an understanding of the spatiotemporal and long-term neural dynamics in the brain of awake animals. However, methodological difficulties and the persistence of post-laminectomy fibrosis have greatly limited similar advances in the spinal cord. To overcome these technical obstacles, we combined in vivo application of fluoropolymer membranes that inhibit fibrosis; a redesigned, cost-effective implantable spinal imaging chamber; and improved motion correction methods that together permit imaging of the spinal cord in awake, behaving mice, for months to over a year. We also demonstrate a robust ability to monitor axons, identify a spinal cord somatotopic map, conduct Ca2+ imaging of neural dynamics in behaving animals responding to pain-provoking stimuli, and observe persistent microglial changes after nerve injury. The ability to couple neural activity and behavior at the spinal cord level will drive insights not previously possible at a key location for somatosensory transmission to the brain.


Differentiation of South American crack and domestic (US) crack cocaine via headspace-gas chromatography/mass spectrometry.
South American 'crack' cocaine, produced directly from coca leaf, can be distinguished from US domestically produced crack on the basis of occluded solvent profiles. In addition, analysis of domestically produced crack indicates the solvents that were used for cocaine hydrochloride (HCl) processing in South America. Samples of cocaine base (N=3) from South America and cocaine from the USA (N=157 base, N=88 HCl) were analyzed by headspace-gas chromatography-mass spectrometry (HS-GC-MS) to determine their solvent profiles. Each cocaine HCl sample was then converted to crack cocaine using the traditional crack production method and re-examined by HS-GC-MS. The resulting occluded solvent profiles were then compared to their original HCl solvent profiles. Analysis of the corresponding crack samples confirmed the same primary processing solvents found in the original HCl samples, but at reduced levels. Domestically seized crack samples also contained reduced levels of base-to-HCl conversion solvents. In contrast, analysis of South American crack samples confirmed the presence of low to high boiling hydrocarbons and no base-to-HCl conversion solvents. The presented study showed analysis of crack cocaine samples provides data on which processing solvents were originally utilized in the production of cocaine HCl in South America, prior to conversion to crack cocaine. Determination of processing solvents provides valuable information to the counter-drug intelligence community and assists the law enforcement community in determining cocaine distribution and trafficking routes throughout the world.


Maternal Social Information Processing and the Frequency and Severity of Mother-Perpetrated Physical Abuse.
The frequency and severity of physical abuse influences children's outcomes, yet little theory-based research has explored what predicts its course. This study examined the potential role of social information processing (SIP) factors in the course of abuse. Mothers with histories of perpetrating physical abuse ( N = 62) completed measures of SIP, and the frequency and severity of mother-perpetrated physical abuse were collected from Child Protection Services records. Poorer problem-solving capacities were significantly related to greater frequency of physical abuse. Hostile attributions toward children were positively associated with abuse severity. Controlling for demographics and co-occurrence of neglect, SIP factors together accounted for a significant proportion of variance in the frequency of physical abuse, but not severity. With the exception of unrealistic expectations, preliminary evidence supported a link between maternal SIP and the course of abuse perpetration. Future research directions and implications for intervention are discussed.