Studying the structural dynamics of bipedal DNA motors with single-molecule fluorescence spectroscopy.
We present a test case example of a detailed single-molecule fluorescence study of one of the most sophisticated and complex DNA devices introduced to date, a recently published autonomous bipedal DNA motor. We used the diffusion-based single-molecule Förster resonance energy transfer technique, coupled to alternating laser excitation (sm-FRET-ALEX), to monitor the motor assembly and operation. The study included verification of the formation of the correct structures, and of the correct motor operation, determination of the formation and stepping reaction yields, and identification of side products. Finally, the mechanisms of the motor assembly and operation were elucidated by measuring the reaction kinetics profile of track-walker binding and of lifting of the walker's leg upon fuel addition. The profiles revealed a fast phase, in which about half of the reaction was completed, followed by a slow phase which adds somewhat to the yield, reflecting the incomplete motor assembly and operation identified in the equilibrium experiments. Although further study is needed to fully understand the reasons for the incomplete assembly and operation, this work demonstrates that single-molecule fluorescence, based on its ability to provide detailed in situ structural dynamics information, inaccessible for traditional methods, constitutes an excellent tool for chaperoning the development of DNA-based technology.


The High Effect of Chemomobilization with High-Dose Etopside + Granulocyte-Colony Stimulating Factor in Autologous Hematopoietic Peripheral Blood Stem Cell Transplantation: A Single Center Experience.
Autologous hematopoietic stem cell transplantation (auto-HSCT) provides hematopoietic support after high-dose chemotherapy and is the standard of care for patients with multiple myeloma (MM), chemo sensitive relapsed high or intermediate grade non-Hodgkin's lymphoma (NHL) and Hodgkin's lymphoma (HL). However, yields of hematopoietic stem cells vary greatly between patients, and the optimal strategy to mobilize hematopoietic stem cells into peripheral blood for collection has not been defined yet. We investigated the efficacy and safety of chemo mobilization with an intermediate dose etoposide (VP-16; 200 mg/m(2) on days 1-3) and granulocyte-colony stimulating factor (G-CSF)(5 µg/kg twice daily from day 4 through the final day of collection). We reviewed our institutional experience with 91 patients (71 MM, 12 HL, 8 NHL) mobilized with this regimen. VP-16 + G-CSF resulted in successful mobilization in 95.55% of the patients (on one patient stem cell collection with plerixafor was applied), including 76 patients (83.52%) whose stem cells were collected successfully in a single day. Collection was managed between min. D8 and max. D17. Patient age, gender, exposure to previous irradiation and chemotherapy, previous mobilization attempts, and disease characteristics were not considered during selection. Adverse effects of the regimen included supportive transfusions and fevers requiring hospitalization or intravenous antibiotics. VP-16 and G-CSF appears to be a safe and effective mobilization regimen for patients with multiple myeloma, non-Hodgkin's lymphoma and Hodgkin's lymphoma undergoing autologous stem cell transplantation, producing excellent stem cell yield with the majority of patients requiring 1 day of apheresis.


The role of longitudinal surveys among the elderly in predicting disability and longevity.
The burden of human suffering and the costs of money, manpower and material for the treatment and maintaining of disabled and/or chronically ill--particularly ageing and old--people are increasing immensely. Primary prevention--if possible--is therefore urgently needed in this field of health and social care. Prospective longitudinal epidemiological research may provide an important tool to learn more and better about the causes and development of many processes of malfunctioning and the incidence of disabling conditions at higher ages. For several reasons not many major extensive surveys of this kind have been undertaken so far, although a few are now underway. A very brief overview is presented of some main follow-up surveys, primarily where predictors of disability and longevity are involved. Comparability is difficult, results are sometimes conflicting. Good objective health, high scores on certain intelligence and memory tests seem to be good predictors for longevity, good subjective health more or less. In a Dutch survey disabilities with respect to activities of daily life were more strongly related to survival time in women than in men. Some variables indicating the use of health care services correlated all negatively with survival. The complexity of variables to predict better at high age the risks of disabilities, and survival time, requires a.o. sophisticated longitudinal studies, upon the results of which to base an adequate policy response.


Continuing to confront COPD International Surveys: comparison of patient and physician perceptions about COPD risk and management.
Using data from the Continuing to Confront COPD International Physician and Patient Surveys, this paper describes physicians' attitudes and beliefs regarding chronic obstructive pulmonary disease (COPD) prognosis, and compares physician and patient perceptions with respect to COPD. In 12 countries worldwide, 4,343 patients with COPD were identified through systematic screening of population samples, and 1,307 physicians who regularly saw patients with COPD were sampled from in-country professional databases. Both patients and physicians completed surveys about their COPD knowledge, beliefs, and perceptions; physicians answered further questions about diagnostic methods and treatment choices for COPD. Most physicians (79%) responded that the long-term health outlook for patients with COPD has improved over the past decade, largely attributed to the introduction of better medications. However, patient access to medication remains an issue in many countries, and some physicians (39%) and patients (46%) agreed/strongly agreed with the statement "there are no truly effective treatments for COPD". There was strong concordance between physicians and patients regarding COPD management practices, including the use of spirometry (86% of physicians and 76% of patients reporting they used/had undergone a spirometry test) and smoking cessation counseling (76% of physicians reported they counseled their smoking patients at every clinic visit, and 71% of smoking patients stated that they had received counseling in the past year). However, the groups differed in their perception about the role of smoking in COPD, with 78% of physicians versus 38% of patients strongly agreeing with the statement "smoking is the cause of most cases of COPD". The Continuing to Confront COPD International Surveys demonstrate that while physicians and patients largely agreed about COPD management practices and the need for more effective treatments for COPD, a gap exists about the causal role of smoking in COPD.


The comparison of intraocular pressure reductions after isometric and isokinetic exercises in normal individuals.
The lowering effect of physical exercise on intraocular pressure (IOP) has been reported both in healthy people and those with glaucoma, but a comparison of the lowering effect of isometric and isokinetic exercises on IOP has not been conducted in any study. Our aims were to investigate the relationship between intensity of exercise and IOP, and whether a significant difference in IOP lowering effect existed between isometric and isokinetic exercises. Sixty-seven patients with an age range of 23-40 who had no ocular disease were randomly divided into two groups. While 31 patients in the first group, group A, performed isokinetic exercise with the Cybex 6000 dynamometer, 32 patients in the second group, group B, had isometric exercises with the same machine. IOP was measured in the right eye of patients with Shiotz tonometer just before and 10 min following exercise. Exercise intensity and total energy consumption were determined by the machine for each patient. While IOP values measured before exercise, the degree of exercise applied, and total energy consumption did not differ significantly between groups, both isometric and isotonic exercises lowered IOP significantly. As a result, isometric and isokinetic exercises lowered IOP in ophthalmologically normal subjects with direct relationship to exercise intensity and total energy consumption. Since the pressure lowering effect of isokinetic exercise was more significant, it might prove useful to glaucomatous patients.


A Malaysian experience with animal disease.
The report summarizes a one year period of investigation of death losses in West Malaysian livestock. Lesions and etiological agents are mentioned for cattle, sheep, goats, swine, poultry and companion animals as well as some miscellaneous species. Special observations related to a common paramphistome induced hepatic biliary infestation in cattle, a serious malignant head catarrh outbreak in which possible cattle to cow aerosol transmission occurred. Trismus observed in some cattle with malignant head catarrh was associated with arteriolitis and ganglioneuritis of the V cranial nerve. Parasitic, bacterial, viral toxic and neoplastic diseases are recorded in the various species. The occurrence of fatal chronic fluorosis in laboratory guinea pigs and cerebral nematodiasis in a Thoroughbred racehorse are documented.


When is Higher Level Cognitive Control Needed for Locomotor Tasks Among Patients with Parkinson's Disease?
Turning has been implicated as a complex task that requires both motor and cognitive resources. Accumulating evidence shows that patients with Parkinson's disease (PD) require more steps and more time to complete a turn, however, the role of the prefrontal cortex during turning is not clear. Forty nine patients with PD without freezing of gait (mean age 71.7 ± 1.0 years; 67% men, disease duration 9.7 ± 1.3 years) performed motor and cognitive tests. Prefrontal activation, specifically in Brodmann area 10 (BA10), during turning and usual walking was measured using functional near infrared spectroscopy (fNIRS). The patients with PD were further divided into two subgroups with high and low functional status based on limitations in community ambulation. General Linear Model analysis adjusted for age, gender, disease duration and turn duration was used to assess differences between tasks and subgroups of patients with PD. In addition, Pearson's correlation was performed to assess association between BA10 activation and motor and cognitive scores. Activation in BA10 increased during walking (p < 0.001), while it decreased during turning (p = 0.006). A comparison between the two subgroups of patients with PD revealed that patients with relatively better ambulation decreased prefrontal activation during turning, as compared to patients with relatively worse ambulation (p < 0.001). These findings are the first to show that BA10 plays a different role during turning and walking and that ambulation status may alter BA10 activation during turning. Higher prefrontal activation during turning in the subgroup of patients with relatively worse ambulation may reflect a compensatory attempt at improving performance.


Immunoregulation in the rat: cellular and molecular requirements for B cell responses to types 1, 2, and T-dependent antigens.
The requirements for primary in vitro plaque-forming cell (PFC) development in cultures of purified rat splenic B cells have been examined. Rat B cells were directly responsive to the type 1 antigen trinitrophenyl-Brucella abortus (TNP-BA), but both T cells and adherent accessory cells were required for B cell responses to the type 2 antigen TNP-Ficoll and the T cell-dependent (TD) antigen sheep erythrocytes (SRBC). However, the cellfree supernatants from concanavalin A-induced spleen cells of rat or mouse origin replaced the requirement for T cells and macrophages, and resulted in PFC development in response to TNP-Ficoll and SRBC and augmented PFC numbers in response to TNP-BA. Culture supernatants from induced murine T cell and macrophage cell lines were used to partially deduce the molecular requirements for the support of PFC development by rat B cells to these three antigens. Supernatants from the EL-4 (EL-4 sup) and B151 K12 (B15 sup) T cell lines augmented TNP-BA responses, suggesting that B cell growth factor II (BCGF-II) mediated this effect. An admixture of purified interleukin 2 (IL 2) and B15 sup supported PFC development to SRBC; indicating that IL 2, BCGF-II, and the T cell-replacing factor in B15 sup (B15-TRF) were sufficient to support this response. In addition, the IL 2 plus B15 sup-supported anti-SRBC PFC response was increased by the addition of an interleukin 1-containing fraction from the supernatant of the macrophage line P388D1. PFC development in response to TNP-Ficoll had the most stringent requirements and only occurred in the presence of EL-4 sup and B15 sup (IL 2, BCGF-I, BCGF-II, EL-TRF, B15-TRF). These data indicate that different cellular and molecular requirements exist for PFC development in response to types 1, 2, and TD antigens by rat B cells.


Theory of density waves and organization of proteins in icosahedral virus capsids.
Understanding the physical principles underlying the structural organization of the proteinaceous viral shells is of major importance to advance antiviral strategies. Here, we develop a phenomenological thermodynamic theory, which considers structures of small and middle-size icosahedral viral shells as a result of condensation of a minimum number of protein density waves on a spherical surface. Each of these irreducible critical waves has icosahedral symmetry and can be expressed as a specific series of the spherical harmonics Ylm with the same wave number l. As we demonstrate, in small viral shells self-assembled from individual proteins, the maxima of one critical density wave determine the positions of proteins, while the spatial derivatives of the second one control the protein orientations on the shell surface. In contrast to the small shells, the middle-size ones are always formed from pentamers and hexamers (referred to as capsomers). Considering all such structures deposited in the Protein Data Bank, we unexpectedly found that the positions of capsomeres in these shells correspond to the maxima of interference patterns produced by no more than two critical waves with close wave numbers. This fact allows us to explain the observed limit size of the icosahedral shells assembled from pentamers and hexamers. We also construct nonequilibrium thermodynamic potentials describing the protein crystallization and discuss the reasons behind the specific handedness of the viral shells.


Soluble chitosan derivative treats wound infections and promotes wound healing in a novel MRSA-infected porcine partial-thickness burn wound model.
Burns are physically debilitating and potentially fatal injuries. The most common etiology of burn wound infections in the US is methicillin-resistant Staphylococcus aureus (MRSA), which is particularly recalcitrant when biofilms form. The current standard of care, silver sulfadiazine (SSD) is effective in reducing bacterial load, but less effective in improving burn wound healing. New treatments that can manage infection while simultaneously improving healing would provide a benefit in the treatment of burns. Porcine models are frequently used as a model for human wound healing but can be expensive due to the need to separate wounds to avoid cross contamination. The porcine model developed in this study offers the capability to study multiple partial thickness burn wound (PTBW) sites on a single animal with minimal crosstalk to study wound healing, infection, and inflammation. The current study evaluates a wound rinse and a wound gel formulated with a non-toxic, polycationic chitosan derivative that is hypothesized to manage infection while also promoting healing, providing a potential alternate to SSD. Studies in vitro and in this PTBW porcine model compare treatment with the chitosan derivative formulations to SSD. The wound rinse and wound gel are observed to disrupt mature MRSA biofilms in vitro and reduce the MRSA load in vivo when compared to that of the standard of care. In vivo data further show increased re-epithelialization and faster healing in burns treated with wound rinse/gel as compared to SSD. Taken together, the data demonstrate the potential of the wound rinse/gel to significantly enhance healing, promote re-epithelialization, and reduce bacterial burden in infected PTBW using an economical porcine model.


Studies on cell adhesion and recognition. II. The kinetics of cell adhesion and cell spreading on surfaces coated with carbohydrate-reactive proteins (glycosidases and lectins) and fibronectin.
The kinetics of cell attachment and cell spreading on the coated surfaces of two classes of carbohydrate-reactive proteins, enzymes and lectins, have been compared with those on fibronectin-coated surfaces with the following results: (a) A remarkable similarity between the kinetics of cell attachment to fibronectin-coated and glycosidase-coated surfaces was found. In contrast, cell attachment kinetics induced by lectin- and galactose oxidase-coated surfaces, in general, were strikingly different from those on fibronectin and glycosidase surfaces. The distinction between fibronectin- or glycosidase- and lectin- or galactose oxidase (an enzyme with lectin-type characteristics)-coated surfaces was further supported by the finding that cytochalasin B and EDTA inhibited cell attachment to fibronectin- and glycosidase-coated surfaces but not lectin-coated surfaces. (b) Fibronectin, if labeled and added to a cell suspension, showed only low or negligible interaction with the cell surface. However, fibronectin absorbed on plastic surfaces showed a high cell-attaching activity. It is assumed that fibronectin coated on plastic surfaces may form polyvalent attachment sites in contrast to its lower valency in aqueous solution. (c) Various inhibitors of cell attachment to both fibronectin-, galactose oxidase-, and lectin-coated surfaces were effective only during the first few minutes of the adhesion assay, after which time the attached cells became insensitive to the inhibitors. It is suggested that the initial specific recognition on either lectin-type or fibronectin-type surfaces is followed by an active cell-dependent attachment process. The primary role of the adhesion surface is to stimulate the cell-dependent attachment response. (d) Cells attached on tetravalent concanavalin A (Con A) spread very rapidly and quantitatively, whereas divalent succinyl Con A and monovalent Con A were effective stimulators of cell attachment but not cell spreading. Cross-linking of succinyl Con A restored the cell spreading activity. Tetravalent Con A surfaces specifically bind soluble glycoproteins, whereas succinyl Con A has a greatly reduced ability to bind the same glycoproteins. These results suggest that cross-linking of cell surface glycoproteins by the multivalent adhesive surface may trigger the cellular reaction leading to cell spreading.


Policies of screening for colorectal cancer in European countries.
The aim of this study was to analyze the current status of population screening for colon/rectum cancer in Europe to compare the different strategies, the coverage, the existence of pilot experiences, regional coverages, and the risk factors considered in each strategy. A comprehensive, systematic search was performed in the literature for documents addressing population screening for colon/rectum cancer in Europe. An ad hoc questionnaire was prepared including questions considered relevant. The questionnaire was reviewed by experts in the area. To identify key informants, colleague members of the International Network of Agencies for Health Technology Assessment (INAHTA), participants in the EUnetHTA project, or representatives of the ministries of health of the different European countries were contacted. The information provided by key informants was checked with information directly obtained from the ministries of health, gray literature, and research documents. An 88 percent response rate was obtained. In countries for which no questionnaire data were collected, information was directly retrieved from the Web sites of the corresponding ministries. Four countries were found to perform population screenings: Austria, France, Germany, and the United Kingdom. However, they used different strategies. Five countries had begun regional or local strategies: Denmark, Finland, Italy, Spain, and Switzerland, and two additional countries (the Netherlands and Norway) reported ongoing research studies intended to determine the best strategy to implement a population-based screening program. Differences were found in age range, procedure chosen, and follow-up period. Even though the European Council recommended a wider implementation of population screening for colon/rectum cancer, our results suggest that this recommendation continues to be valid. The differences found in screening strategies (in terms of age range, procedures, risk factors considered, and follow-up periods) are not warranted by the results obtained in research studies or regional-national cancer registries.


The effects of fitness on the aging process.
Decades of research support the fact that much age-related deterioration is the result of the effects of sedentary lifestyles and the development of medical conditions rather than of aging itself. Elite older athletes, who demonstrate enhanced performance compared with historic cohorts and even some younger peers, are models of this paradigm. Many non-elite middle-aged adults and older adults continue to remain increasingly active throughout middle age and beyond. A continually growing body of basic science and clinical evidence demonstrates how active persons modulate physical decline through training. An updated understanding of how active adults defy age helps orthopaedic surgeons not only manage their patients' performance but also improve their lives. A large segment of sedentary older adults will benefit from counseling that encourages the pursuit of more active and healthier lifestyles.


Chemotherapeutic evaluation of clotrimazole (Bay b 5097, 1 (o-chloro- - -diphenylbenzyl) imidazole).
Clotrimazole has a broad spectrum of activity against yeast and filamentous fungi in vitro and also in vivo when given orally or parenterally to experimentally infected mice and when administered orally or topically to infected guinea pigs. In vitro a distinct inoculum effect has been observed with a number of strains of Candida and Torulopsis; minimal inhibitory concentrations have tended to increase with increased incubation time. With prolonged incubation times, resistance can be developed to clotrimazole in vitro, but this resistance is readily reversible upon passage in drug-free broth. The degree of in vivo activity of clotrimazole against Candida depends on the severity of infection used. Orally it appears to be more effective when administered by gavage than when given mixed in the diet. Pretreatment with the agent may decrease its efficacy because of drug inactivation. Against dermatophytes, clotrimazole has a degree of activity similar to griseofulvin when given orally, but it is less active than tolnaftate topically in cutaneous infection of Trichophyton mentagrophytes in guinea pigs. In vitro, but not in vivo, some gram-positive and gram-negative bacteria are inhibited by low concentrations of clotrimazole.


Interpreting energy expenditure for anaerobic exercise and recovery: an anaerobic hypothesis.
Energy expenditure during and after exercise is composed of aerobic and anaerobic bioenergetics and the energy demands of aerobic recovery. Current attempts to measure energy expenditure include an exercise oxygen uptake + oxygen debt (EPOC) measurement or, an oxygen deficit + exercise oxygen uptake measurement. This investigation illustrates how oxygen debt and oxygen deficit interpretation can effect a total energy expenditure measurement. It was hypothesized that the total energy expenditure for several intermittent bouts of exercise and recovery would be greater than for one bout of continuous exercise and recovery when equivalent work was compared. Exercise was performed under low-intensity and high-intensity conditions. Both oxygen debt and oxygen deficit methodology resulted in similar energy expenditure measurements for both intermittent and continuous exercise. This implies little to no recovery energy demand or considerable methodology errors. Differences in total energy expenditure were found when the oxygen deficit and parts of the oxygen debt (EPOC) were considered separate and independent (p < 0.05). These differences can be accounted for when the data are interpreted utilizing thermodynamic (2nd law) and engineering (in-series efficiency) concepts rather than the heat equivalent of carbohydrate oxidation (20.9 kJ equals one liter of O2). It is suggested that while oxygen uptake provides an excellent representation of aerobic metabolism during exercise and recovery, oxygen uptake may be an inadequate measure of the energetics of lactate production (fermentation). In application, energy expenditure differences appear realistic only for high-intensity, intermittent exercise rather than lower intensity exercise.


[Retuning of segmental responses to peripheral stimulation during fictive locomotion in cats].
Segmental reflex responses of the lumbosacral spinal cord to peripheral afferent stimulation were investigated in immobilized decorticated cats before and during fictitious locomotion. Appearance of fictitious locomotion was accompanied by an increase of the N1 component of the dorsal cord potential and of the dorsal root potential. Modulation of these responses depending on the phase of fictitious locomotion was observed against a background of their tonic increase. The N1 component and dorsal root potential had larger amplitudes when they appear at the end of the "extensor" phase and at the beginning of the "flexor" phase and smaller amplitudes when they were evoked at the end of the "flexor" phase and at the beginning of the "extensor" phase. Poly- and monosynaptic reflex responses of motoneurons revealed the same phase dependence during fictitious locomotion. Mechanisms and physiological significance of the revealed retuning of segmental reflex responses are discussed on the basis of the obtained data.


Implementation of Supine Percutaneous Nephroscopic Surgery to Remove an Upward Migration of Ureteral Catheter in Infancy: A Case Report.
Double-J stents are favorably utilized after pyeloplasty. In rare situations, the stent may migrate upward. Here, we demonstrate the implementation and result of a supine percutaneous nephroscopic surgery (PNS) to retrieve a proximately migrated ureteral catheter in a pediatric patient. A 1-year-old boy was suffering from an upward migration of a ureteric catheter into the right ureter after an open Anderson-Hynes pyeloplasty. The child was placed in the Galdakao-modified supine Valdivia (GMSV) position and a PNS procedure was performed. The calyceal access was carefully punctured by ultrasonographic guidance. The nephrostomy tract was dilated with a metal dilator using a one-step technique. An exploratory nephroscopy of the renal pelvis was conducted with a 12Fr miniature nephroscope and the migrated ureteral catheter was removed. A hybrid guidewire was retrogradely inserted into the ureteric orifice using a rigid ureteroscope. An antegrade double J stent was inserted in the proper position and a percutaneous nephrostomy was performed. This is the first report of a successfully removed upwardly migrated ureteral catheter with concurrent insertion of an antegrade double J stent by supine PNS in the GMSV position in an infant. The patient recovered well after surgery with no adverse event, demonstrating that this operation can be carried out safely on pediatric patients.


Reducing diabetes risk in American Indian women.
American Indians experience high rates of type 2 diabetes. The impact of low-intensity interventions on diabetes risk among young American Indian women is unknown. Randomized controlled trial. Community-based; participants were 200 young urban American Indian women who were block-randomized on fasting blood glucose (FBG) into intervention and control groups. Inclusion criteria included self-reported identity, aged 18-40 years, not pregnant, willingness to stay in urban area for 2 years, and not having type 2 diabetes. Measures were taken at baseline, 6, 12, and 18 months. Data were gathered in 2002-2006 and analyzed in 2006-2007. Five discussion group sessions (one meeting per month for 5 months) were held focusing on healthful eating, physical activity, goal-setting, and social support. Primary outcomes included dietary fat and vegetable consumption and self-reported physical activity. Secondary outcomes included cardiorespiratory fitness, insulin sensitivity, blood pressure, lipid profiles, percent body fat, BMI, intake of fruit, total sugar and sweetened beverages, FBG, and television viewing. Mean vegetable and fruit intake increased significantly more in the intervention group than in the control group over time (group by visit interaction, p=0.02 and p=0.002, respectively). Both groups had significant increases in percent body fat and decreases in waist circumference, insulin sensitivity, blood cholesterol, LDL, television viewing, and total intakes of energy, saturated fat, sugar, and sweetened beverages. A culturally influenced, low-intensity lifestyle intervention can improve self-reported intakes of vegetables and fruit over 18 months in young, urban American Indian women.


Automated Peripheral Neuropathy Assessment Using Optical Imaging and Foot Anthropometry.
A large proportion of individuals who live with type-2 diabetes suffer from plantar sensory neuropathy. Regular testing and assessment for the condition is required to avoid ulceration or other damage to patient's feet. Currently accepted practice involves a trained clinician testing a patient's feet manually with a hand-held nylon monofilament probe. The procedure is time consuming, labor intensive, requires special training, is prone to error, and repeatability is difficult. With the vast increase in type-2 diabetes, the number of plantar sensory neuropathy sufferers has already grown to such an extent as to make a traditional manual test problematic. This paper presents the first investigation of a novel approach to automatically identify the pressure points on a given patient's foot for the examination of sensory neuropathy via optical image processing incorporating plantar anthropometry. The method automatically selects suitable test points on the plantar surface that correspond to those repeatedly chosen by a trained podiatrist. The proposed system automatically identifies the specific pressure points at different locations, namely the toe (hallux), metatarsal heads and heel (Calcaneum) areas. The approach is generic and has shown 100% reliability on the available database used. The database consists of Chinese, Asian, African, and Caucasian foot images.


Induction of N-nitrosodimethylamine metabolism in liver and lung by in vivo pyridine treatments of rabbits.
N-Nitrosodimethylamine is a procarcinogen that is activated by cytochrome P450 dependent N-nitrosodimethylamine N-demethylase to labile alpha-carbon hydroxylated products further resulting in active methylating agents. In vivo intraperitoneal administration of pyridine to rabbits significantly increased N-nitrosodimethylamine N-demethylase activity by 6.9- and 5.2-fold in liver and lung microsomes, respectively. Although, p-nitrophenol hydroxylase and aniline 4-hydroxylase activities were markedly enhanced by pyridine treatment in liver about 4.4- and 5.8-fold, respectively, no change was observed in the activities of these enzymes in lung microsomes. Pyridine treatment also elevated P450 contents of liver and lung by 2.04- and 1.4-fold, respectively. SDS-PAGE of pyridine-induced liver microsomes revealed a protein band of enhanced intensity having Mr of 51,000 migrating in the region of cytochrome P4502E1. The results obtained in this study demonstrated for the first time, a significant 5.2-fold induction of NDMA N-demethylase activity in the rabbit lung over the controls. Pyridine is readily absorbed by inhalation and is a constituent of tobacco and tobacco smoke. Thus induction of NDMA N-demethylase suggests that in the lung, as in the liver, pyridine may stimulate the metabolic activation of this nitrosamine significantly.


L-Aminoguanidine Induces Imbalance of ROS/RNS Homeostasis and Polyamine Catabolism of Tomato Roots after Short-Term Salt Exposure.
Polyamine (PA) catabolism mediated by amine oxidases is an important process involved in fine-tuning PA homeostasis and related mechanisms during salt stress. The significance of these amine oxidases in short-term responses to salt stress is, however, not well understood. In the present study, the effects of L-aminoguanidine (AG) on tomato roots treated with short-term salt stress induced by NaCl were studied. AG is usually used as a copper amine oxidase (CuAO or DAO) inhibitor. In our study, other alterations of PA catabolism, such as reduced polyamine oxidase (PAO), were also observed in AG-treated plants. Salt stress led to an increase in the reactive oxygen and nitrogen species in tomato root apices, evidenced by in situ fluorescent staining and an increase in free PA levels. Such alterations were alleviated by AG treatment, showing the possible antioxidant effect of AG in tomato roots exposed to salt stress. PA catabolic enzyme activities decreased, while the imbalance of hydrogen peroxide (H2O2), nitric oxide (NO), and hydrogen sulfide (H2S) concentrations displayed a dependence on stress intensity. These changes suggest that AG-mediated inhibition could dramatically rearrange PA catabolism and related reactive species backgrounds, especially the NO-related mechanisms. More studies are, however, needed to decipher the precise mode of action of AG in plants exposed to stress treatments.


[The efficacy of psychodynamic therapy: a controversy].
There is growing evidence from randomized controlled trials supporting the efficacy of psychodynamic psychotherapy (PDT) in specific mental disorders. Yet the evidence for the efficacy of psychodynamic psychotherapy has not gone unchallenged. Several responses have addressed these concerns, showing that most of the criticism was not justified. Nevertheless, the evidence for psychodynamic psychotherapy continues to be frequently ignored, criticized or presented in a distorted way. A recent controversy published in the Nervenarzt may serve as an illustrative example, which is discussed here more in detail. This example shows that some authors are not interested in a truly scientific discussion, but rather try to discredit a rival method of psychotherapy and its scientific representatives for political reasons.


Crimean-Congo hemorrhagic fever: CXCL10 correlates with the viral load.
Crimean-Congo hemorrhagic fever (CCHF) is a human disease with high fatality rate. Although its pathogenesis is not elucidated yet, it is considered that cytokines play a significant role in the progression and outcome of the disease. Serum CXCL10 levels were estimated in 35 patients with acute CCHF and were correlated with the viral load, and various demographic and clinical parameters. The mean CXCL10 concentration in the patients' group was higher compared to the respective value in the control group (4421.74 pg/ml vs. 28.47 pg/ml, P < 0.05). A strong positive correlation between CXCL10 and viral load was seen (rs = 0.57, P < 0.001), while the outcome of the disease was related with the viral load (rs = 0.47, P = 0.004) and the presence of hemorrhagic manifestations (P < 0.001). The study provides an insight into the strong correlation between CXCL10 and viral load in acute CCHF cases suggesting that it plays an important role in CCHF pathogenesis.


Lifestyle, body mass index and wellness in youth: Strengthens and weakness in Italian youth.
This study investigated the psychological wellbeing and body perception among young Italian people. Drinking, eating, and sexual behaviors have been examined in relation to body mass index (BMI) and psychological well-being by EPOCH framework. This was a cross-sectional observational study conducted on Italian adolescent and young adult population through an online survey. Qualitative and quantitative data on lifestyle, BMI classes, and psychological characteristics of wellness in youth were obtained from a sample of 1221 Italian participants using a self-report questionnaire on body perception and habits, a socio-demographics inventory, and the EPOCH measure. Findings suggest that being underweight or overweight is associated with various factors, including gender, self-control regarding food, perception of one's body, and the happiness domain. EPOCH framework revealed the psychological wellness of girls and young women did not seem strongly affected by BMI, though Perseverance and Happiness seemed reduced with increasing BMI. The Engagement, Optimism, and Connectedness domains were not significantly affected by the BMI variable. On the contrary, Perseverance and Happiness seemed reduced with increasing BMI and were related to physical shape. Our study offers a new perspective: promoting the development of positive psychological characteristics since adolescence to boost quality of life by improving wellness, by EPOCH approach could be functional reinforcing specific psychological aspects in young generations regarding future wellness, improving the positive perception and management of their own health.


Working mechanism for a redox switchable molecular machine based on cyclodextrin: a free energy profile approach.
This paper reports the working mechanism for a redox-responsive bistable [2]rotaxane incorporating an alpha-cyclodextrin (alpha-CD) ring (J. Am. Chem. Soc. 2008, 130, 11294-11296), based on free energy profiles obtained from all-atom molecular dynamics simulations. Employing an umbrella sampling technique, the free energy profiles (potential of mean force, PMF) were calculated for the shuttling motion of the alpha-CD ring between a tetrathiafulvalene (TTF) recognition site and a triazole (TZ) unit on the dumbbell of the rotaxane for three oxidation states (0, +1, +2) of the TTF unit. These calculated free energy profiles verified the experimentally observed binding preference for each state. Analysis of the free energy components reveals that, for these alpha-CD-based rotaxanes with charged TTF units, the real driving force for the shuttling in the oxidized states is actually the interactions between water and the rotaxane components, which overwhelms the attractive interactions between the alpha-CD ring and the charged dumbbell. In this work, we put forward a feasible approach to correctly describe the complexation behavior of CD with charged species, that is, free energy profiles obtained from all-atom molecular dynamics simulation.


Therapeutic potential and protective role of GRK6 overexpression in pulmonary arterial hypertension.
Abnormal proliferation of pulmonary arterial smooth muscle cells (PASMCs) is a key mechanism in the development of pulmonary arterial hypertension (PAH). Signal transducer and activator of transcription 3 (STAT3) signalling plays a critical role in modulating PASMC proliferation, and G-protein-coupled receptor kinase 6 (GRK6) regulates the STAT3 pathway. However, the mechanism underlying the relationship between GRK6 and PAH remains unclear. In this study, we aimed to investigate the role of GRK6 in PAH and determine its potential as a therapeutic target. We utilised hypoxia- and SU5416-induced PAH mouse models and a monocrotaline-induced PAH rat model to analyse the involvement of GRK6. We conducted gain- and loss-of-function experiments using mouse PASMCs. Modulation of GRK6 expression was achieved via a lentiviral vector in vitro and an adeno-associated virus serotype 1 encoding GRK6 in vivo. GRK6 was significantly downregulated in the lung tissues of PAH mice and rats, predominantly in PASMCs. Knockout of GRK6 exacerbated PAH, while both therapeutic and prophylactic overexpression of GRK6 alleviated PAH, as evidenced by a reduction in right ventricular systolic pressure, right ventricular wall to left ventricular wall plus ventricular septum ratio, pulmonary vascular media thickness, and pulmonary vascular muscularisation. Mechanistically, GRK6 overexpression attenuated hypoxia-induced PASMC proliferation and STAT3 phosphorylation. Conversely, knockdown of GRK6 promoted hypoxia-induced proliferation, which was mitigated by a STAT3 inhibitor. Our findings highlight the potential protective and beneficial roles of GRK6 in PAH; we propose a lung-targeted GRK6 gene therapy utilizing adeno-associated virus serotype 1 as a potential treatment approach for patients with PAH.


Modulation of CB1 cannabinoid receptor functions after a long-term exposure to agonist or inverse agonist in the Chinese hamster ovary cell expression system.
We have investigated the adaptive changes of the human central cannabinoid receptor (CB1) stably expressed in Chinese hamster ovary cells (CHO-CB1), after agonist (CP 55,940) or selective CB1 inverse agonist (SR 141716) treatment. CB1 receptor density and affinity constant as measured by binding assays with both tritiated ligands remained essentially unchanged after varying period exposure of CHO-CB1 cells (from 30 min to 72 hr) to saturating concentrations of CP 55,940 or SR 141716. However, using a C-myc-tagged version of the CB1 receptor, FACS analysis and confocal microscopy studies on CB1 expression indicated that the agonist promoted a disappearance of cell surface receptor although inverse agonist increased its cell surface density. Taken together these results suggest that 1) agonist induces internalization of the receptor into a cellular compartment that would be still accessible to both the hydrophobic ligands CP 55,940 or SR 141716; 2) inverse-agonist promotes externalization of the receptor from an intracellular preexisting pool to the cell surface. In parallel, we also investigated the associated effects of CP 55,940 and SR 141716 on CB1 receptor-coupled second messengers. We showed that preexposure of cells to CP 55,940 induced a rapid desensitization of the CB1 to the agonist response. The ability of CP 55,940 to inhibit the forskolin-stimulated adenylyl cyclase and to activate the mitogen-activated protein kinase activity was dramatically reduced. By striking contrast, SR 141716 pretreatment of CHO-CB1 cells not only had no significant effect on the potency of CP 55,940 to inhibit the forskolin-stimulated adenylyl cyclase but also induced a significant enhancement of the CP 55,940 ability to stimulate the mitogen-activated protein kinase activity. These results suggest that the modulation of the number of cell surface receptor could lead to functional desensitization or sensitization of the CB1 receptors.


Sludge as source of energy and revenue.
Sludge is a residue/product from wastewater treatment plants and contains most of the contaminants released during human activities. Some stringent environmental regulations on sludge treatment and disposal exist in many countries. This has resulted in increasing interest in sludge treatment methods that encourage sludge reduction and improvement in biogas production during anaerobic digestion processes. This work demonstrates the first exploitation of valuable energy from homogenised sludge at technical scale with mass reduction. The optimal combination of sludge homogenisation at relatively low pressures using a modified high-pressure homogeniser led to the success of this unique project. Results showed that about 30% more energy could be obtained from thickened and disrupted sludge than from untreated samples. The energy produced was higher than that invested during disruption and digestion processes. About 23% sludge reduction was also observed with no increase in chemical oxygen demand. This new process can produce extra energy for local electrification and heating the digester while the sludge reduction provides economic benefits. Concentration of sludge causes reduction in investment cost on digester as well as reduction in operational time for sludge dewatering.


Civil Society Organizations and medicines policy change: a case study of registration, procurement, distribution and use of misoprostol in Uganda.
Misoprostol use for postpartum haemorrhage (PPH) has been promoted by Civil Society Organizations (CSOs) since the early 2000s. Yet, CSOs' role in improving access to misoprostol and shaping health policy at global and national levels is not well understood. We document the introduction of misoprostol in Uganda in 2008 from its registration, addition to treatment guidelines and national Essential Medicines List (EML), to its distribution and use. We then analyse the contribution of CSOs to this health policy change and service provision. Policy documents, procurement data and 82 key informant interviews with government officials, healthcare providers, and CSOs in four Ugandan districts of Kampala, Mbarara, Apac, Bundibugyo were collected between 2010 and 2013. Five key CSOs promoted and accelerated the rollout of misoprostol in Uganda. They supported the registration of misoprostol with the National Drug Authority, the development of clinical guidelines, and the piloting and training of health care providers. CSOs and National Medical Stores were procuring and distributing misoprostol country-wide to health centres two years before it was added to the clinical guidelines and EML of Uganda and in the absence of good evidence. The evidence suggests an increasing trend of misoprostol procurement and availability over the medicine of choice, oxytocin. This shift in national priorities has serious ramifications for maternal health care that need urgent evaluation. The absence of clinical guidelines in health centres and the lack of training preclude rational use of misoprostol. CSOs shifted their focus from the public to the private sector, where some of them continue to promote its use for off-label indications including induction of labour and abortion. There is an urgent need to build capacity to improve the robustness of the national and local institutions in assessing the safety and effectiveness of all medicines and their indications in Uganda.


Generalized mean-field potential description for ferroelectric ordering in nematic liquid crystals.
Ferroelectric ordering in a nematic liquid crystal system is described using a generalized mean-field potential including effective potentials for both axial and polar interactions. From a self-consistent numerical analysis, a complete phase diagram is obtained as a function of the axial and polar interaction potential strengths. The obtained phase diagram exhibits not only the usual isotropic-nematic phase transition but also nematic-ferroelectric nematic and direct isotropic-ferroelectric nematic phase transitions with a tricritical point among the phases. The phase transition behaviors and the angular orientational distribution function of the molecules were investigated by studying the dependence of the polar and the axial order parameters on the reduced temperature. Moreover, the other polar order parameters responsible for second-harmonic generation (SHG) were also investigated in the generalized mean-field potential description. As a concrete example, we performed a quantitative analysis of the SHG signal reported previously in a lyotropic poly L-glutamate system, detailing the relationship between the angular distribution function and the order parameters based on our potential model. This clarifies the nature of the ferroelectric phase responsible for SHG in nematics.


Capture from the wild has long-term costs on reproductive success in Asian elephants.
Capturing wild animals is common for conservation, economic or research purposes. Understanding how capture itself affects lifetime fitness measures is often difficult because wild and captive populations live in very different environments and there is a need for long-term life-history data. Here, we show how wild capture influences reproduction in 2685 female Asian elephants (Elephas maximus) used in the timber industry in Myanmar. Wild-caught females demonstrated a consistent reduction in breeding success relative to captive-born females, with significantly lower lifetime reproduction probabilities, lower breeding probabilities at peak reproductive ages and a later age of first reproduction. Furthermore, these negative effects lasted for over a decade, and there was a significant influence on the next generation: wild-caught females had calves with reduced survival to age 5. Our results suggest that wild capture has long-term consequences for reproduction, which is important not only for elephants, but also for other species in captivity.


Uptake, Accumulation, and in Planta Distribution of Coexisting Cerium Oxide Nanoparticles and Cadmium in Glycine max (L.) Merr. .
Agricultural soils are likely to be polluted by both conventional and emerging contaminants at the same time. Understanding the interactions of coexisting engineered nanoparticles (ENPs) and trace elements (a common source of abiotic stress) is critical to gaining insights into the accumulation of these two groups of chemicals by plants. The objectives of this study were to determine the uptake and accumulation of coexisting ENPs and trace elements by soybeans and to gain insights into the physiological mechanisms resulting in different plant accumulation of these materials. The combinations of three cadmium levels (0 [control] and 0.25 and 1 milligrams per kilogram of dry soil) and two CeO2 NPs concentrations (0 [control] and 500 milligrams per kilogram of dry soil) were investigated. Measurements of the plant biomass and physiological parameters indicated that CeO2 NPs led to higher variable fluorescence to maximum fluorescence ratio, suggesting that CeO2 NPs enhanced the plant light energy use efficiency by photosystem II. In addition, the presence of CeO2 NPs did not affect Cd accumulation in soybean, but Cd significantly increased the accumulation of Ce in plant tissues, especially in roots and older leaves. The altered Ce in planta distribution was partially associated with the formation of root apoplastic barriers in the co-presence of Cd and CeO2 NPs.


Comparative clinical effectiveness of management strategies for sciatica: systematic review and network meta-analyses.
There are numerous treatment approaches for sciatica. Previous systematic reviews have not compared all these strategies together. To compare the clinical effectiveness of different treatment strategies for sciatica simultaneously. Systematic review and network meta-analysis. We searched 28 electronic databases and online trial registries, along with bibliographies of previous reviews for comparative studies evaluating any intervention to treat sciatica in adults, with outcome data on global effect or pain intensity. Network meta-analysis methods were used to simultaneously compare all treatment strategies and allow indirect comparisons of treatments between studies. The study was funded by the UK National Institute for Health Research Health Technology Assessment program; there are no potential conflict of interests. We identified 122 relevant studies; 90 were randomized controlled trials (RCTs) or quasi-RCTs. Interventions were grouped into 21 treatment strategies. Internal and external validity of included studies was very low. For overall recovery as the outcome, compared with inactive control or conventional care, there was a statistically significant improvement following disc surgery, epidural injections, nonopioid analgesia, manipulation, and acupuncture. Traction, percutaneous discectomy, and exercise therapy were significantly inferior to epidural injections or surgery. For pain as the outcome, epidural injections and biological agents were significantly better than inactive control, but similar findings for disc surgery were not statistically significant. Biological agents were significantly better for pain reduction than bed rest, nonopioids, and opioids. Opioids, education/advice alone, bed rest, and percutaneous discectomy were inferior to most other treatment strategies; although these findings represented large effects, they were statistically equivocal. For the first time, many different treatment strategies for sciatica have been compared in the same systematic review and meta-analysis. This approach has provided new data to assist shared decision-making. The findings support the effectiveness of nonopioid medication, epidural injections, and disc surgery. They also suggest that spinal manipulation, acupuncture, and experimental treatments, such as anti-inflammatory biological agents, may be considered. The findings do not provide support for the effectiveness of opioid analgesia, bed rest, exercise therapy, education/advice (when used alone), percutaneous discectomy, or traction. The issue of how best to estimate the effectiveness of treatment approaches according to their order within a sequential treatment pathway remains an important challenge.


Human herpesvirus 6 in cerebrospinal fluid of patients infected with HIV: frequency and clinical significance.
The objective was to evaluate the frequency of human herpesvirus 6 (HHV-6) DNA detection in the CSF of patients infected with HIV and its relation to brain disease and systemic HHV-6 infection. Nested polymerase chain reaction (PCR) was used to analyse CSF samples from 365 consecutive HIV infected patients with neurological symptoms. When available, plasma and brain tissues from patients whose CSF was HHV-6 positive were also studied. HHV-6 was found in the CSF of eight of the 365 patients (2.2%): two had type A and four type B; the HHV-6 variant could not be defined in the remaining two. All eight patients had neurological symptoms and signs related to concomitant opportunistic brain diseases, including cytomegalovirus (CMV) encephalitis in five patients whose CSF was also positive for CMV-DNA. Opportunistic infections but no other unexplained lesions were also found in the brain of all of the four patients who underwent neuropathological examination. Both HHV-6 and CMV were also detected in the plasma of respectively five and seven of seven patients whose CSF was HHV-6 positive. In conclusion, HHV-6 type A or B DNA was infrequently found in the CSF of HIV infected patients, in association with both CMV brain infection and systemic HHV-6 replication. However, no certain relation between HHV-6 and brain disease was found.


Pulmonary oxygen toxicity breath markers after heliox diving to 81 metres.
Pulmonary oxygen toxicity (POT), an adverse reaction to an elevated partial pressure of oxygen in the lungs, can develop as a result of prolonged hyperbaric hyperoxic conditions. Initially starting with tracheal discomfort, it results in pulmonary symptoms and ultimately lung fibrosis. Previous studies identified several volatile organic compounds (VOCs) in exhaled breath indicative of POT after various wet and dry hyperbaric hypoxic exposures, predominantly in laboratory settings. This study examined VOCs after exposures to 81 metres of seawater by three navy divers during operational heliox diving. Univariate testing did not yield significant results. However, targeted multivariate analysis of POT-associated VOCs identified significant (P = 0.004) changes of dodecane, tetradecane, octane, methylcyclohexane, and butyl acetate during the 4 h post-dive sampling period. No airway symptoms or discomfort were reported. This study demonstrates that breath sampling can be performed in the field, and VOCs indicative of oxygen toxicity are exhaled without clinical symptoms of POT, strengthening the belief that POT develops on a subclinical-to-symptomatic spectrum. However, this study was performed during an actual diving operation and therefore various confounders were introduced, which were excluded in previous laboratory studies. Future studies could focus on optimising sampling protocols for field use to ensure uniformity and reproducibility, and on establishing dose-response relationships.


Effects of continuous ketamine infusion on hemodynamics and mortality in critically ill children.
We investigated the hemodynamic and mortality effects of continuous ketamine infusion in critically ill pediatric patients. We conducted a retrospective cohort study in a tertiary pediatric intensive care unit (PICU). Patients who used continuous sedative from 2015 to 2017 for 24 hours or more were included. We compared blood pressure, heart and respiratory rates, vasogenic medications, and sedation and pain scores for 12 hours before and after initiation of continuous ketamine. The mortality rates for continuous ketamine and Non-ketamine groups were compared by multivariate logistic regression. A total of 240 patients used continuous sedation, and 82 used continuous ketamine. The median infusion rate of ketamine was 8.1 mcg/kg/min, and the median duration was 6 days. Heart rates (138 vs. 135 beat/minute, P = .033) and respiratory rates (31 vs. 25 respiration/minute, P = .001) decreased, but blood pressure (99.9 vs. 101.1 mm Hg, P = .124) and vasogenic medications did not change after ketamine infusion. Continuous ketamine was not a significant risk factor for mortality (hazard ratio 1.352, confidence interval 0.458-3.996). Continous ketamine could be used in PICU without hemodynamic instability. Further studies in randomized controlled design about the effects of continuous ketamine infusion on hemodynamic changes, sedation, and mortality are required.


Reporter Replicons for Antiviral Drug Discovery against Positive Single-Stranded RNA Viruses.
Single-stranded positive RNA ((+) ssRNA) viruses include several important human pathogens. Some members are responsible for large outbreaks, such as Zika virus, West Nile virus, SARS-CoV, and SARS-CoV-2, while others are endemic, causing an enormous global health burden. Since vaccines or specific treatments are not available for most viral infections, the discovery of direct-acting antivirals (DAA) is an urgent need. Still, the low-throughput nature of and biosafety concerns related to traditional antiviral assays hinders the discovery of new inhibitors. With the advances of reverse genetics, reporter replicon systems have become an alternative tool for the screening of DAAs. Herein, we review decades of the use of (+) ssRNA viruses replicon systems for the discovery of antiviral agents. We summarize different strategies used to develop those systems, as well as highlight some of the most promising inhibitors identified by the method. Despite the genetic alterations introduced, reporter replicons have been shown to be reliable systems for screening and identification of viral replication inhibitors and, therefore, an important tool for the discovery of new DAAs.


Project examining effectiveness in clinical ethics (PEECE): phase 1-- descriptive analysis of nine clinical ethics services.
The field of clinical ethics is relatively new and expanding. Best practices in clinical ethics against which one can benchmark performance have not been clearly articulated. The first step in developing benchmarks of clinical ethics services is to identify and understand current practices. Using a retrospective case study approach, the structure, activities, and resources of nine clinical ethics services in a large metropolitan centre are described, compared, and contrasted. The data yielded a unique and detailed account of the nature and scope of clinical ethics services across a spectrum of facilities. General themes emerged in four areas-variability, visibility, accountability, and complexity. There was a high degree of variability in the structures, activities, and resources across the clinical ethics services. Increasing visibility was identified as a significant challenge within organisations and externally. Although each service had a formal system for maintaining accountability and measuring performance, differences in the type, frequency, and content of reporting impacted service delivery. One of the most salient findings was the complexity inherent in the provision of clinical ethics services, which requires of clinical ethicists a broad and varied skill set and knowledge base. Benchmarks including the average number of consults/ethicist per year and the hospital beds/ethicist ratio are presented. The findings will be of interest to clinical ethicists locally, nationally, and internationally as they provide a preliminary framework from which further benchmarking measures and best practices in clinical ethics can be identified, developed, and evaluated.


Perioperative morbidity and mortality in dogs with invasive adrenal neoplasms treated by adrenalectomy and cavotomy.
To report the morbidity and mortality associated with adrenalectomy with cavotomy for resection of invasive adrenal neoplasms in dogs and evaluate risk factors for perioperative outcomes. Retrospective study. Forty-five client-owned dogs. Dogs that underwent open adrenalectomy with cavotomy for resection of adrenal masses with tumor thrombus extending into the vena cava were included. Clinicopathologic data were harvested from medical records. Selected clinical, imaging, and operative variables were statistically evaluated as risk factors for packed red blood cell transfusion, nephrectomy, perioperative death, and overall survival. Thirty-six of 45 masses were pheochromocytomas, 7 were adrenocortical carcinomas, and 2 were unknown type. Caval thrombus terminated prehepatically in 21 of 45 dogs and extended beyond the porta hepatis but terminated prediaphragmatically (intrahepatic prediaphragmatic location) in 15 dogs and thrombi extended postdiaphragmatically in 5 dogs. Thirty-four (76%) dogs were discharged from the hospital, and 11 (24%) dogs died or were euthanized prior to discharge. Median overall survival time for all 45 dogs was 547 days (95%CI 146-710). Bodyweight, tumor type, and size and extent of caval thrombus did not affect survival to discharge, but postdiaphragmatic (rather than prediaphragmatic) thrombus termination was associated with a greater risk of death. Long-term survival was common in dogs that survived the perioperative period. Postdiaphragmatic thrombus extension affected the prognosis for overall survival. Findings of this study help to stratify operative risk in dogs with adrenal neoplasia and caval invasion.


The endocrine function of adipose tissue: an update.
Adipose tissue secretes bioactive peptides, termed 'adipokines', which act locally and distally through autocrine, paracrine and endocrine effects. In obesity, increased production of most adipokines impacts on multiple functions such as appetite and energy balance, immunity, insulin sensitivity, angiogenesis, blood pressure, lipid metabolism and haemostasis, all of which are linked with cardiovascular disease. Enhanced activity of the tumour necrosis factor and interleukin 6 are involved in the development of obesity-related insulin resistance. Angiotensinogen has been implicated in hypertension and plasminogen activating inhibitor-1 (PAI-1) in impaired fibrinolysis. Other adipokines like adiponectin and leptin, at least in physiological concentrations, are insulin sparing as they stimulate beta oxidation of fatty acids in skeletal muscle. The role of resistin is less understood. It is implicated in insulin resistance in rats, but probably not in humans. Reducing adipose tissue mass, through weight loss in association with exercise, can lower TNF-alpha and IL-6 levels and increase adiponectin concentrations, whereas drugs such as thiazolinediones increase endogenous adiponectin production. In-depth understanding of the pathophysiology and molecular actions of adipokines may, in the coming years, lead to effective therapeutic strategies designed to protect against atherosclerosis in obese patients.


Clinical Audit of Minimally Invasive Nonsurgical Techniques in Active Periodontal Therapy.
Periodontitis is one of the most widespread diseases worldwide. Many efforts have been made to increase the efficacy of periodontitis therapy as much as possible. Recently, minimally invasive nonsurgical techniques (MINST) were introduced in the periodontal field as an alternative to minimally invasive surgical techniques (MIST). This clinical audit aims to evaluate the results of MINST in the initial phase of treatment for periodontitis. One hundred seven patients with periodontitis who were treated with MINST between 2013 and 2017 and reevaluated after 2 months were included in this clinical audit. The primary outcome analyzed was the proportion of pocket closure. The secondary outcomes were tooth extraction before active periodontal therapy, full-mouth plaque score (FMPS) change, full-mouth bleeding score (FMBS) change, average probing pocket depth (PPD) reduction, and average clinical attachment level (CAL) gain between the baseline and reevaluation values. A total of 2,407 teeth were included in the analysis. At the patient level, the treatment resulted in a mean pocket closure rate of 71.6 ± 15.7% for sites with an initial PPD ≥5 mm. The treatment was statistically significantly (p < 0.001) more effective with respect to the primary outcome compared with expected values reported in a recent meta-analysis (57%). The subgroup analysis revealed statistically significant differences between single and multirooted teeth and between shallow (5-6 mm) and deep pockets (≥7 mm) at the baseline. Nonsurgical periodontal therapy with MINST achieved satisfactory results that were better than expected based on the scientific literature. Single-rooted and shallow pockets showed the best proportion of pocket closure at the reevaluation after treatment. Minimally invasive nonsurgical techniques can be the treatment of choice when approaching periodontally diseased patients with nonsurgical periodontal therapy.


Cohesin organizes chromatin loops at DNA replication factories.
Genomic DNA is packed in chromatin fibers organized in higher-order structures within the interphase nucleus. One level of organization involves the formation of chromatin loops that may provide a favorable environment to processes such as DNA replication, transcription, and repair. However, little is known about the mechanistic basis of this structuration. Here we demonstrate that cohesin participates in the spatial organization of DNA replication factories in human cells. Cohesin is enriched at replication origins and interacts with prereplication complex proteins. Down-regulation of cohesin slows down S-phase progression by limiting the number of active origins and increasing the length of chromatin loops that correspond with replicon units. These results give a new dimension to the role of cohesin in the architectural organization of interphase chromatin, by showing its participation in DNA replication.


Highly Uniform Resistive Switching Properties of Solution-Processed Silver-Embedded Gelatin Thin Film.
The silver-embedded gelatin (AgG) thin film produced by the solution method of metal salts dissolved in gelatin is presented. Its simple fabrication method ensures the uniform distribution of Ag dots. Memory devices based on AgG exhibit good device performance, such as the ON/OFF ratio in excess of 105 and the coefficient of variation in less of 50%. To further investigate the position of filament formation and the role of each element, current sensing atomic force microscopy (CSAFM) analysis as well as elemental line profiles across the two different conditions in the LRS and HRS are analyzed. The conductive and nonconductive regions in the current map of the CSAFM image show that the conductive filaments occur in the AgG layer around Ag dots. The migration of oxygen ions and the redox reaction of carbon are demonstrated to be the driving mechanism for the resistive switching of AgG memory devices. The results show that dissolving metal salts in gelatin is an effective way to achieve high-performance organic-electronic applications.


Foster carer experience in Spain: Analysis of the vulnerabilities of a permanent model.
The voice of foster families is a valuable tool in the development and improvement of foster family services. Regularly evaluating the satisfaction of foster carers can facilitate the early identification of a range of problems that might pose a risk to the placement. This article reports the experience of 200 Spanish foster families (kinship and non-kinship) with foster services in relation to motivation for becoming foster carers, sources of stress and reward, satisfaction with the services and needs. Semi-structured interviews were performed. The aims of the research are principally of a descriptive character, so each group of variables was examined using frequency analysis. The foster carers interviewed demonstrated a high degree of satisfaction with the foster programs, although some areas seem more problematic, such as financial compensation, information provided about the fostered child, contact with the birth family and the sensitivity of professionals. This study reveals several differences with regard to international literature, that are related to particularities of the Spanish child care system. The results may be extremely useful for the implementation of policy changes which could contribute to raised levels of satisfaction for the foster carers, and increased effectiveness of the programs.


SEDIMENTARY GEOLOGY: Homegrown Quartz Muddies the Water.
Mudstones are an important source of hydrocarbons that migrate into petroleum deposits, and they can reveal much about Earth's history--if they are read correctly. Now a team of geologists has found that a telling feature of many mudstones may have been misinterpreted, throwing into question conclusions about everything from climate to ocean currents.


Rewriting the narrative of the epidemiology of HIV in sub-Saharan Africa.
The fight against HIV remains complicated with contracting donor resources and high burden of HIV among reproductive age adults still often limiting independent economic development. In the widespread HIV epidemics of sub-Saharan Africa (SSA), it is proposed that key populations with specific HIV acquisition and transmission risk factors, such as men who have sex with men (MSM), female sex workers (FSW), and people who use drugs (PUD), are less relevant because HIV transmission is sustained in the general population with average HIV acquisition and transmission risks. However, the understanding that key populations are less relevant in the epidemics of Africa is based on the surveillance system from which these populations are mostly excluded. Outside of SSA, the epidemics of HIV are generally concentrated in the same populations that are excluded from the primary HIV surveillance systems in SSA. The manuscripts included in this special issue present convincing data that FSW, MSM, and PUD carry disproportionate burdens of HIV wherever studied in SSA, are underrepresented in HIV programs and research, and require specific HIV prevention services. These manuscripts collectively suggest that the only effective path forward is one that transcends denial and stigma and focuses on systematically collecting data on all populations at risk for HIV. In addition, there is a need to move to a third generation of HIV surveillance as the current one inadvertently devalues HIV surveillance among key populations in the context of widespread HIV epidemics. Overall, the data reviewed here demonstrate that the dynamics of HIV in Africa are complex and achieving an AIDS-free generation necessitates acceptance of that complexity in all HIV surveillance, research, and prevention, treatment, and care programs.


Partition-Defective 3 (PARD3) Regulates Proliferation, Apoptosis, Migration, and Invasion in Esophageal Squamous Cell Carcinoma Cells.
BACKGROUND Altered expression of partition-defective 3 (PARD3), a polarity-related gene associated with oncogenesis, has been identified in some cancers, but the role of PARD3 in esophageal squamous cell carcinoma (ESCC) remains unclear. MATERIAL AND METHODS PARD3 expression in Eca109 cells was silenced using siRNA and overexpressed using an expression vector. We investigated the role of PARD3 in ESCC growth and motility to evaluate its potential role in ESCC. Transwell assay was used to evaluated cell migration and invasion. PARD3 protein expression was assessed by Western blot. RESULTS PARD3 overexpression promoted apoptosis, impaired proliferation, and inhibited cell migration and invasion in Eca109 cells, while PARD3 silencing promoted proliferation and increased migration and invasion. Overexpression of PARD3 exerted its antitumor activity in vitro by impairing cell proliferation, inducing apoptosis, and inhibiting migration and invasion of Eca109 cells, suggesting that PARD3 might play a tumor suppressor role in ESCC. CONCLUSIONS Overexpression of PARD3 could be a promising new therapeutic intervention against ESCC.


Recombinant hirudin in clinical practice: focus on lepirudin.
Clinical applications for recombinant hirudins have been investigated for the past 10 years. The first indication for which a hirudin-lepirudin-has been approved is treatment of heparin-induced thrombocytopenia (HIT). Also, the recently completed trials for use of lepirudin in unstable angina indicate a potentially new indication. This review describes pharmacology and clinical applications of lepirudin with an emphasis on HIT and unstable angina. An overview of usage of lepirudin in acute coronary syndromes is given, as well as a summary of rare indications for lepirudin, such as extracorporeal circulation, for which comprehensive data are lacking.


Minimum hyaluronic acid (HA) modified magnetic nanocrystals with less facilitated cancer migration and drug resistance for targeting CD44 abundant cancer cells by MR imaging.
We report minimal amount of hyaluronic acid (HA) conjugated magnetic nanocrystals (mHMs) for targeted imaging of CD44 abundant breast cancer cells via MRI. These mHMs lead to less induced cancer migration and drug resistance, which is distinct from conventional approaches using nanoplatforms (imaging or therapeutic systems) that are completely covered with HA. To synthesize mHMs, magnetic nanocrystals (MNCs), as MRI contrast agents, were encapsulated mostly with polysorbate 80 (P80, non-reactive to HA) and partially with aminated P80 (reactive to HA). This system enabled conjugation of an immensely diminished amount of HA onto MNCs. While these nanoparticles maintained good CD44 targeted imaging efficacy, they also showed no cytotoxicity and colloidal stability. We varied the HA ratios on an equal amount of MNCs and identified that when more HA was attached on nanoparticles, there was more facilitated cancer migration and drug resistant potentials. We chose the lowest amount of HA conjugated mHMs (mHM1) and demonstrated that mHM1 selectively diagnosed tumor regions in vivo. We believe that the technique described herein can be applied to various applications using HA to detect CD44 abundant cancer cell lines and offer a basis to understand the interaction between the cellular response and surface modification of nanoparticles.


Impact of educational intervention on knowledge, attitude and awareness of good clinical practice among health care providers.
Clinical trials play an important role in the generation of evidence-based data in health care practices. To ensure the credibility of data and the safety and well-being of the patients Good clinical practice (GCP) guidelines play an important role. At present, we have little knowledge about awareness of GCP guidelines among health care providers in India. To assess the level of awareness, and perception of the health care providers toward GCP and subsequent change in these after a dayer training session on GCP guidelines. A cross-sectional descriptive questionnaire-based study was conducted amongst health care providers, that is, doctors, dentists, nurses of a Tertiary Health Care and Teaching Institute. Participants were given descriptive questionnaire; they completed the questionnaire before and after undergoing a day training program in GCP guidelines. The impact of the effectiveness of educational intervention among healthcare professionals was evaluated by two-tailed Z-test. Out of 120 participants, 80 were medical doctors, 20 dental doctors, and 20 nurses. A dayse training program on GCP guidelines was found to increase positive attitudes toward various aspects of clinical trials. A day's training program on GCP guidelines may help to increase the knowledge as well as awareness about principles and techniques of clinical research, which will increase the credibility of clinical research in the country.


Personalized cardiorespiratory fitness and energy expenditure estimation using hierarchical Bayesian models.
Accurate estimation of energy expenditure (EE) and cardiorespiratory fitness (CRF) is a key element in determining the causal relation between aspects of human behavior related to physical activity and health. In this paper we estimate CRF without requiring laboratory protocols and personalize energy expenditure (EE) estimation models that rely on heart rate data, using CRF. CRF influences the relation between heart rate and EE. Thus, EE estimation based on heart rate typically requires individual calibration. Our modeling technique relies on a hierarchical approach using Bayesian modeling for both CRF and EE estimation models. By including CRF level in a hierarchical Bayesian model, we avoid the need for individual calibration or explicit heart rate normalization since CRF accounts for the different relation between heart rate and EE in different individuals. Our method first estimates CRF level from heart rate during low intensity activities of daily living, showing that CRF can be determined without specific protocols. Reference VO2max and EE were collected on a sample of 32 participants with varying CRF level. CRF estimation error could be reduced up to 27.0% compared to other models. Secondly, we show that including CRF as a group level predictor in a hierarchical model for EE estimation accounts for the relation between CRF, heart rate and EE. Thus, reducing EE estimation error by 18.2% on average. Our results provide evidence that hierarchical modeling is a promising technique for generalized CRF estimation from activities of daily living and personalized EE estimation.


Overgeneral autobiographical memory as a predictor of the course of depression: a meta-analysis.
Overgeneral autobiographical memory (OGM) is a robust phenomenon in depression, but the extent to which OGM predicts the course of depression is not well-established. This meta-analysis synthesized data from 15 studies to examine the degree to which OGM 1) correlates with depressive symptoms at follow-up, and 2) predicts depressive symptoms at follow-up over and above initial depressive symptoms. Although the effects are small, specific and categoric/overgeneral memories generated during the Autobiographical Memory Test significantly predicted the course of depression. Fewer specific memories and more categoric/overgeneral memories were associated with higher follow-up depressive symptoms, and predicted higher follow-up symptoms over and above initial symptoms. Potential moderators were also examined. The age and clinical depression status of participants, as well as the length of follow-up between the two depressive symptom assessments, significantly moderated the predictive relationship between OGM and the course of depression. The predictive relationship between specific memories and follow-up depressive symptoms became greater with increasing age and a shorter length of follow-up, and the predictive relationship was stronger for participants with clinical depression diagnoses than for nonclinical participants. These findings highlight OGM as a predictor of the course of depression, and future studies should investigate the mechanisms underlying this relationship.


Herpesvirus hominis infection in newborn mice: comparison of the therapeutic efficacy of 1-beta-D-arabinofuranosylcytosine and 9-beta-D-arabinofuranosyladenine.
Intranasal inoculation of newborn mice with Herpesvirus hominis type 2 provides an experimental infection that closely resembles disseminated herpesvirus infection of human newborn infants. After inoculation of mice, the virus multiplies in the respiratory tract and is disseminated through the blood to the liver and spleen and to the brain by both a viremia and nerve route transmission. Although therapy with 1-beta-d-arabinofuranosylcytosine (ara-C) did not reduce final mortality, it did increase the mean survival time by 1 day. This effect on the mean survival time was associated with a 1-day delay in the appearance of herpesvirus in the blood, liver, and spleen and a reduction of virus replication in lung and brain for 1 day as compared with untreated control animals. Treatment with 9-beta-d-arabinofuranosyladenine (ara-A) likewise had no effect on final mortality, but increased the mean survival time by 2 days. Therapy with ara-A delayed or suppressed virus replication in blood, lung, liver, spleen, and brain for 2 days. Although treatment with either ara-C or ara-A in this experimental H. hominis type 2 infection resulted in a temporary delay and/or suppression of viral replication in several target organs, neither compound was completely effective in inhibiting viral replication or in protecting animals from eventual death due to the infection.


Impacts of Cigarette Smoking Status on Metabolomic and Gut Microbiota Profile in Male Patients With Coronary Artery Disease: A Multi-Omics Study.
Background: Cigarette smoking has been considered a modifiable risk factor for coronary artery disease (CAD). Changes in gut microbiota and microbe-derived metabolites have been shown to influence atherosclerotic pathogenesis. However, the effect of cigarette smoking on the gut microbiome and serum metabolites in CAD remains unclear. Method: We profiled the gut microbiota and serum metabolites of 113 male participants with diagnosed CAD including 46 current smokers, 34 former smokers, and 33 never smokers by 16S ribosomal RNA (rRNA) gene sequencing and untargeted metabolomics study. A follow-up study was conducted. PICRUSt2 was used for metagenomic functional prediction of important bacterial taxa. Results: In the analysis of the microbial composition, the current smokers were characterized with depleted Bifidobacterium catenulatum, Akkermansia muciniphila, and enriched Enterococcus faecium, Haemophilus parainfluenzae compared with the former and never smokers. In the untargeted serum metabolomic study, we observed and annotated 304 discriminant metabolites, uniquely including ceramides, acyl carnitines, and glycerophospholipids. Pathway analysis revealed a significantly changed sphingolipids metabolism related to cigarette smoking. However, the change of the majority of the discriminant metabolites is possibly reversible after smoking cessation. While performing PICRUSt2 metagenomic prediction, several key enzymes (wbpA, nadM) were identified to possibly explain the cross talk between gut microbiota and metabolomic changes associated with smoking. Moreover, the multi-omics analysis revealed that specific changes in bacterial taxa were associated with disease severity or outcomes by mediating metabolites such as glycerophospholipids. Conclusions: Our results indicated that both the gut microbiota composition and metabolomic profile of current smokers are different from that of never smokers. The present study may provide new insights into understanding the heterogenic influences of cigarette smoking on atherosclerotic pathogenesis by modulating gut microbiota as well as circulating metabolites.


Cytophagic histiocytic panniculitis and subcutaneous panniculitis-like T-cell lymphoma: report of 7 cases.
Cytophagic histiocytic panniculitis (CHP) is a rare subtype of panniculitis that usually follows a fatal course, with a terminal hemophagocytic syndrome. Recent reports on a subset of peripheral T-cell lymphoma named subcutaneous panniculitis-like T-cell lymphoma (SPTL) raised the question about the relationship between these entities. We describe 7 patients in the study: 1 with fatal CHP, 4 with SPTL, and 2 with long-term CHP. The 5 patients with fatal CHP and SPTL died of complications of hemophagocytic syndrome, with a disease duration ranging from 8 to 74 months. The other 2 patients were still alive 6 and 41 years after disease onset. Immunohistochemical results proved that 2 of the SPTL cases were type alpha/beta and expressed the cytotoxic/suppressor antigen CD8, while the other 2 were type gamma/delta and were positive for the natural killer-associated antigen CD56. In these 4 cases, molecular biology studies by polymerase chain reaction detected T-cell receptor gamma gene rearrangement, indicating a clonal process. In contrast, in the 2 patients who had long-term CHP, the polymerase chain reaction results failed to disclose clonality. In the subject with fatal CHP, genotypic analysis was not performed. Our observations suggest that CHP and SPTL may span a clinicopathologic spectrum in which there is a natural disease progression from CHP to SPTL.


Modulation of the Primary Astrocyte-Enriched Cultures' Oxylipin Profiles Reduces Neurotoxicity.
Recently, manipulations with reactive astrocytes have been viewed as a new therapeutic approach that will enable the development of treatments for acute brain injuries and neurodegenerative diseases. Astrocytes can release several substances, which may exert neurotoxic or neuroprotective effects, but the nature of these substances is still largely unknown. In the present work, we tested the hypothesis that these effects may be attributed to oxylipins, which are synthesized from n-3 or n-6 polyunsaturated fatty acids (PUFAs). We used astrocyte-enriched cultures and found that: (1) lipid fractions secreted by lipopolysaccharide (LPS)-stimulated rat primary astrocyte-enriched cultures-possessed neurotoxic activity in rat primary neuronal cultures; (2) both of the tested oxylipin synthesis inhibitors, ML355 and Zileuton, reduce the LPS-stimulated release of interleukin 6 (IL-6) by astrocyte cultures, but only ML355 can change lipid fractions from neurotoxic to non-toxic; and (3) oxylipin profiles, measured by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) from neurotoxic and non-toxic lipid fractions, reveal a group of n-3 docosahexaenoic acid derivatives, hydroxydocosahexaenoic acids (HdoHEs)-4-HdoHE, 8-HdoHE, and 17-HdoHE, which may reflect the neuroprotective features of lipid fractions. Regulating the composition of astrocyte oxylipin profiles may be suggested as an approach for regulation of neurotoxicity in inflammatory processes.


Parenteral anticoagulation may prolong the survival of patients with limited small cell lung cancer: a Cochrane systematic review.
To determine the efficacy and safety of heparin (unfractionated heparin (UFH) or low-molecular-weight-heparin (LMWH)) and fondaparinux in improving the survival of patients with cancer. We conducted in January 2007 a comprehensive search for relevant randomized clinical trials (RCTs). We used a standardized form to extract in duplicate data on methodological quality, participants, interventions and outcomes of interest including all cause mortality, thromboembolic events, and bleeding events. We assessed the methodological quality for each outcome by grading the quality of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology Of 3986 identified citations, we included 5 RCTs, none of which evaluated fondaparinux. The quality of evidence was moderate for survival, low for major and minor bleeding, and very low for DVT. Heparin therapy was associated with a statistically and clinically significant survival benefit (hazard ratio (HR) = 0.77; 95%CI = 0.65-0.91). In subgroup analyses, patients with limited small cell lung cancer experienced a clear survival benefit (HR = 0.56; 95%CI = 0.38-0.83). The survival benefit was not statistically significant for either patients with extensive small cell lung cancer (HR = 0.80; 95%CI = 0.60-1.06) or patients with advanced cancer (HR = 0.84; 95%CI = 0.68-1.03). The increased risk of bleeding with heparin was not statistically significant (relative risk (RR) = 1.78; 95%CI = 0.73-4.38). This review suggests a survival benefit of heparin in cancer patients in general, and in patients with limited small cell lung cancer in particular.


Saliva as a source of feline leukemia virus antigen for diagnosis of disease.
An enzyme-linked immunosorbent assay (ELISA) for detection of feline leukemia virus (FeLV) p27 in saliva was tested for its accuracy and sensitivity in diagnosing FeLV infections. Saliva and serum samples from 564 clinical cases were tested with a 99.2% specificity. The overall accuracy of the saliva ELISA reactive to the serum ELISA was 97.9%. Experimentally, the ELISA saliva was the least sensitive in diagnosing early FeLV infections. However, the overall accuracy, ease of use, and simplicity of the test support its use as a screening procedure in clinical practice.


Quality of end-of-life care for patients with advanced cancer in an academic medical center.
We assessed key aspects of the quality of end-of-life care using validated explicit process quality measures in an academic medical center (hospital and cancer center) before expanding to a broader palliative care initiative. We evaluated 21 indicators most relevant to end-of-life care from the Cancer Quality-ASSIST supportive oncology indicator set for 238 patients with advanced/metastatic solid tumors who died between 2-15 months after diagnosis. These included outpatient and hospital indicators for cancer symptoms and information and care planning that met criteria for feasibility, reliability, and validity. We abstracted detailed information from medical records to specify the necessary data elements. Overall adherence was 53% (95% confidence interval [CI], 50%-56%); this varied widely among indicators. Adherence was highest for pain indicators; in particular, 97% of eligible subjects' hospitalizations had documented screening for pain, and, after an outpatient pain medication was changed, 97% of patients had a pain assessment at the subsequent visit. For other symptoms, adherence ranged from 0% for documentation of life expectancy for patients starting parenteral or enteral nutrition to 87% for assessment of nausea or vomiting on hospital admission. For information and care planning, results ranged from 6% for documentation of ventilation preferences prior to intubation to 68% for documented communication of risks and benefits or prognosis prior to starting chemotherapy. In conclusion, Cancer Quality-ASSIST indicators are useful for practical quality assessment of cancer end-of-life care in an academic medical center. These results will serve as useful data for targeting areas for quality improvement and measuring progress.


Suppression of hepatoma tumor growth by systemic administration of the phytotoxin gelonin driven by the survivin promoter.
Hepatocellular carcinoma (HCC) is one of the most common types of cancer worldwide. However, there is currently no effective therapy strategy in the clinical practice. Recombinant phytotoxin gelonin fused to other factors have been used to treat different cancers. But there have been no reports of gelonin gene therapy. In this study, we have constructed a recombinant plasmid which contained a tumor-specific survivin promoter to drive phytotoxin gelonin (pSur-Gel). And the cytotoxicity effects of pSur-Gel in HCC were also validated both in vitro and in vivo. The expression level of survivin was detected in different liver cancer cell lines and normal liver cell lines by western blot analysis, and a survivin promoter-driven green fluorescent protein (GFP) expression vectors (pSur-GFP) was also tested in liver cancer cell line HepG2 and normal liver cell line LO2. Moreover, phytotoxin gelonin expression experiment and cytotoxicity experiment of pSur-Gel was performed in HepG2 cells and LO2 cells in vitro. Furthermore, anti-tumor effect of pSur-Gel against HepG2 xenografts and toxicity of this gene were evaluated in the mice model. Finally, LDH release assay, apoptosis assay and immunoblot analyse LC3 conversion (LC3-I to LC3-II) were tested. We found that the expression of survivin protein was higher in liver cancer cell lines compared with the normal liver cells. Further study showed that the pSur-GFP and pSur-Gel was expressed specially in liver cancer cell other than in normal liver cells. pSur-Gel plasmid could effectively inhibit the proliferation of liver cancer cells (*P<0.05), and significantly repress the growth of HepG2 xenografts via intravenous in vivo (*P<0.05). Otherwise, compared to cytomegalovirus promoter-driven gelonin expression vectors (pCMV-Gel), no significantly systemic toxicity or organ injuries had been observed in pSur-Gel treated mice. Further studies revealed that the phytotoxin gelonin induced cell death might be mediated by apoptosis and the damage of cell membrane. Taken together, treating hepatocellular carcinoma with the pSur-Gel may be a novel and interesting cancer gene therapy protocol and is worthy of further development for future clinical trials. liver cancer, gelonin, survivin promoter, gene therapy.


The Alberta Ambassador Program: delivering Health Technology Assessment results to rural practitioners.
The purpose of Health Technology Assessment (HTA) is to make the best possible summary of the evidence regarding specific health interventions in order to influence health care and policy decisions. The need for decision makers to find relevant HTA data when it is needed is a barrier to its usefulness. These barriers are highest in rural areas and amongst isolated practitioners. A multidisciplinary team developed an interactive case-based instructional strategy on the topic of chronic non-cancer pain (CNCP) management using clinical evidence derived by HTA. The evidence for each of 18 CNCP interventions was distilled into single-sheet summaries. Clinicians and HTA specialists ('Ambassadors') conducted 11 two-hour interactive sessions on CNCP in eight of Alberta's nine health regions. Pre- and post-session evaluations were conducted. The sessions were attended by 130 individuals representing 14 health and administrative disciplines. The ambassador model was well received. The use of content experts as ambassadors was highly rated. The educational strategy was judged to be effective. Awareness of the best evidence in CNCP management was increased. Although some participants reported practice changes as a result of the workshops, the program was not designed to measure changes in patient outcome. The ambassador program was successful in increasing awareness of the best evidence in CNCP management, and positively influenced treatment decisions. Its teaching methods were felt to be unique and innovative by participants. Its methods could be applied to other clinical content areas in order to increase the uptake of the results of HTA.


Supersensitivity in rat caudate nucleus: effects of 6-hydroxydopamine on the time course of dopamine receptor and cyclic AMP changes.
The intranigral administration of 6-hydroxydopamine resulted in the destruction of dopaminergic nerve terminals in the rat caudate nucleus and a 98% decrease in dopamine content. The time courses of the effects of this treatment on dopamine stimulated cyclic 3',5'-AMP accumulation in slices of caudate nucleus and on dopamine receptors in two behaviorally distinct denervation syndromes were determined in an investigation of the mechanisms underlying supersensitivity in this system. The density of dopamine receptors was determined by measuring the high affinity binding of the dopamine receptor antagonist [3H]haloperidol. The density of dopamine receptors was decreased 4 days after the lesion surgery and this effect was probably due to the loss of presynaptic receptors. The density of dopamine receptors and the acumulation of cyclic AMP then increased, with a slower time course, reaching peak levels 10 days after lesioning. The maximal increase in density of dopamine receptors was 70% in both denervation syndromes, while the maximal increase in dopamine-stimulating cyclic 3',5'-AMP levels was 300% at maximally stimulating concentration. The equilibrium dissociation constant (Kd) for haloperidol remained unchanged for 3 weeks following denervation, but there was a slight increase in Kd 40 days post-surgery. The turning behaviour in both syndromes was correlated with a decrease in doapmine levels. The present results are consistent with the notion that the supersensitivity to dopamine that occurs in caudate nucleus following 6-hydroxydopamine lesions has both pre- and post-synaptic components in both syndromes.


Physico-chemical characterization of indoor/outdoor particulate matter in two residential houses in Oslo, Norway: measurements overview and physical properties--URBAN-AEROSOL Project.
Indoor/outdoor measurements have been performed in the Oslo metropolitan area during summer and winter periods (2002-2003) at two different residential houses. The objective of the measurement study was to characterize, physically and chemically, the particulate matter (PM) and gaseous pollutants associated with actual human exposure in the selected places, and their indoor/outdoor relationship. In this paper, we focus on the PM measurements and examine the relationship between the indoor and outdoor PM concentrations taking into account the ventilation rate, indoor sources and meteorological conditions. The indoor/outdoor measurements indicate the important contribution of the outdoor air to the indoor air quality and the influence of specific indoor sources such as smoking and cooking to the concentration of PM inside houses. However, no specific correlation was found between the indoor/outdoor concentration ratio and the meteorological parameters. This study provides information on the physical characteristics and the relationship of indoor to outdoor concentration of particulate matter in residential houses. Moreover, the parameters that influence this relationship are discussed. The results presented here are specific to the sampled houses and conditions used and provide data on the actual human exposure characteristics which occur in the spatial and temporal scales of the present study.