Infections after living-donor liver transplantation.
Despite greater awareness of organ donation among the general public, the supply of cadaveric organs has fallen short of identified needs. Living-donor liver transplantation (LDLT) is an effective means of overcoming the shortage of adult organs, as outcomes are now comparable to those of cadaveric donor liver transplantation. From January, 2002 through January, 2006, 40 LDLTs were performed at our center. With two exceptions, the donor was a first-degree relative of the recipient; all donors were in excellent health with good hepatic function and morphology. All but two donors contributed the right lobe. Infections in the donors and recipients were analyzed. Clinically relevant infections occurred in three donors. In the recipients, the infections did not differ significantly from those experienced by recipients of cadaveric organs in terms of risk factors (e.g., poor graft function, re-transplantation, surgical complications such as bile duct stenosis, or vascular anastomotic stenosis) or type of infection. Cholangitis was the most frequent infection, leading to septic shock in five of the 14 patients with infections; intra-abdominal infections related to surgical complications led to septic shock in three additional patients. The other most commonly observed infections were urinary tract infections (n=10) and pneumonia (n=3). Living-donor liver transplantation offers hope to patients with end-stage liver disease in geographic areas where the waiting time mortality is high and available organs from deceased donors fall short of the population's need.


Effects of pistachios on cardiovascular disease risk factors and potential mechanisms of action: a dose-response study.
Nut consumption lowers cardiovascular disease (CVD) risk. Studies are lacking about the effects of pistachios, a nutrient-dense nut, on CVD risk factors, dose-response relations, and lipid-lowering mechanisms. We evaluated the effects of 2 doses of pistachios, added to a lower-fat diet, on lipids and lipoproteins, apolipoprotein (apo)-defined lipoprotein subclasses, and plasma fatty acids. To investigate the mechanisms of action, we measured cholesteryl ester transfer protein and indexes of plasma stearoyl-CoA desaturase activity (SCD). In a randomized crossover controlled-feeding study, 28 individuals with LDL cholesterol > or = 2.86 mmol/L consumed 3 isoenergetic diets for 4 wk each. Baseline measures were assessed after 2 wk of a typical Western diet. The experimental diets included a lower-fat control diet with no pistachios [25% total fat; 8% saturated fatty acids (SFAs), 9% monounsaturated fatty acids (MUFAs), and 5% polyunsaturated fatty acids (PUFAs)], 1 serving/d of a pistachio diet (1 PD; 10% of energy from pistachios; 30% total fat; 8% SFAs, 12% MUFAs, and 6% PUFAs), and 2 servings/d of a pistachio diet (2 PD; 20% of energy from pistachios; 34% total fat; 8% SFAs, 15% MUFAs, and 8% PUFAs). The 2 PD decreased (P < 0.05 compared with the control diet) total cholesterol (-8%), LDL cholesterol (-11.6%), non-HDL cholesterol (-11%), apo B (-4%), apo B/apo A-I (-4%), and plasma SCD activity (-1%). The 1 PD and 2 PD, respectively, elicited a dose-dependent lowering (P < 0.05) of total cholesterol/HDL cholesterol (-1% and -8%), LDL cholesterol/HDL cholesterol (-3% and -11%), and non-HDL cholesterol/HDL cholesterol (-2% and -10%). Inclusion of pistachios in a healthy diet beneficially affects CVD risk factors in a dose-dependent manner, which may reflect effects on SCD.


Patterns of hyaluronan staining are modified by fixation techniques.
The apparent intensity of hyaluronan (HA) staining in tissue sections can vary as a function of fixation techniques. We examined the histochemical distribution of HA in normal human skin using an HA-specific binding peptide derived from bovine nasal cartilage. The HA, particularly in the dermis, was best preserved in sections fixed in 10% acid-formalin with 70% ethanol. In contrast, sections fixed in the routine 10% neutral-buffered formalin had a much weaker intensity of HA staining. Furthermore, acid-formalin/ethanol-fixed sections retained much of their apparent HA after incubation with saline, in contrast to the neutral formalin-fixed sections, in which most of the stainable HA was lost. Such marked differences in staining intensity were not observed in slides stained with Alcian blue, a procedure presumed to stain HA as well as other glycosaminoglycans. Staining using the HA binding peptide was entirely absent when sections were first preincubated in hyaluronidase, whereas similar Alcian blue-stained sections retained most of their staining intensity. Caution should be exercised in evaluating the distribution of HA in tissues using the HA binding peptide, particularly when different fixation techniques among several laboratories are being compared. In addition, the ability to evaluate the HA content of tissues using Alcian blue staining should be reconsidered. The sulfated glycosaminolglycans of the "ground substance" appear to be the predominant substrates for Alcian blue.


Maternal and pregnancy predictive risk factors for having a compensated maternal injury claim: a Swedish nationwide cohort study.
To describe trends and identify maternal and pregnancy predictive risk factors for having a compensated claim for a maternal injury during delivery, as a proxy for having received suboptimal care. This nationwide retrospective cohort study included 1 754 869 births in Sweden between 2000 and 2016, including 4488 maternal injury claims filed with The National Swedish Patient Insurance Company (Löf), of which 1637 were compensated. Descriptive statistics on maternal and pregnancy characteristics, trends in filed/compensated claims over time, and distribution of compensated claims by clinical classification are presented. Characteristics associated with suboptimal care were identified using multivariable logistic regression, with mutual adjustment in the final model. Compensated claims were sorted into 14 clinical classifications (ICD-10 codes for main condition, injury, and causality). Overall, there was a two-fold increase in filed claims from 2000 to 2016, peaking in 2014. The rate of compensated claims only increased marginally, and 36.5% of filed claims were deemed avoidable. Perineal and pelvic floor injuries, as well as medical and diagnostic errors, were responsible for the majority of compensated claims. Women with a previous caesarean section, post term delivery, chronic or gestational disease, > 13 antenatal visits, or a multiple pregnancy had increased risk of having a compensated claim for a maternal injury during delivery. Understanding the risk factors for having a compensated maternal injury claim may guide health workers and maternity wards in improving the quality and organisation of care to reduce the risk of childbirth related injuries.


Anaerobic treatment of natural tannin extracts in UASB reactors.
Tannin extracts are substances commonly used in leather production processes. Since most of the steps of tannery manufacturing processes are carried out in aqueous environments, the presence of these compounds in the wastewaters is important. The aim of this work is to study the feasibility of the anaerobic degradation of three natural tannin extracts in three Upflow Anaerobic Sludge Blanket (UASB) reactors, which were fed with increasing concentrations of two condensed (quebracho and wattle) and one hydrolysable tannin extract (chestnut). Concentrations of applied extracts were 100, 200, 400, 800 and 1,000 mg/l, and 5 g/l of glucose was used as cosubstrate. Reactors were operated during 210 days and their performance was evaluated from the values of total and soluble COD, total and intermediate alkalinity, volatile fatty acids, pH and UV absorption at 280 nm. COD removal efficiencies higher than 85% were achieved in all cases. However, tannin extract removal efficiencies (based on UV-280 nm absorption measurements) were significantly lower, around 20% for condensed extracts and 60% for the hydrolysable one, when the reactors operated with the highest tannin extract concentration. The operation of the reactors was stable, commonly with alkalinity ratios below 0.30. Mass balances carried out indicate that most of the COD removal efficiencies are due to the removal of the readily biodegradable organic matter (glucose), whereas the tannin extracts are hardly anaerobically biodegradable, especially condensed extracts (wattle and quebracho).


Poly(triazolyl methacrylate) glycopolymers as potential targeted unimolecular nanocarriers.
Synthetic glycopolymers are increasingly investigated as multivalent ligands for a range of biological and biomedical applications. This study indicates that glycopolymers with a fine-tuned balance between hydrophilic sugar pendant units and relatively hydrophobic polymer backbones can act as single-chain targeted nanocarriers for low molecular weight hydrophobic molecules. Non-covalent complexes formed from poly(triazolyl methacrylate) glycopolymers and low molecular weight hydrophobic guest molecules were characterised through a range of analytical techniques - DLS, SLS, TDA, fluorescence spectroscopy, surface tension analysis - and molecular dynamics (MD) modelling simulations provided further information on the macromolecular characteristics of these single chain complexes. Finally, we show that these nanocarriers can be utilised to deliver a hydrophobic guest molecule, Nile red, to both soluble and surface-immobilised concanavalin A (Con A) and peanut agglutinin (PNA) model lectins with high specificity, showing the potential of non-covalent complexation with specific glycopolymers in targeted guest-molecule delivery.


Repetitive DNA elements as mediators of genomic change in response to environmental cues.
There is no logical or theoretical barrier to the proposition that organismal and cell signaling could transduce environmental signals into specific, beneficial changes in primary structure of noncoding DNA via repetitive element movement or mutation. Repetitive DNA elements, including transposons and microsatellites, are known to influence the structure and expression of protein-coding genes, and to be responsive to environmental signals in some cases. These effects may create fodder for adaptive evolution, at rates exceeding those observed for point mutations. In many cases, the changes are no doubt random, and fitness is increased through simple natural selection. However, some transposons insert at specific sites, and certain regions of the genome exhibit selectively and beneficially high mutation rates in a range of organisms. In multicellular organisms, this could benefit individuals in situations with significant potential for clonal expansion: early life stages or regenerative tissues in animals, and most plant tissues. Transmission of the change to the next generation could occur in plants and, under some circumstances, in animals.


Prediction of chemical carcinogenicity in rodents from in vitro genetic toxicity assays.
Four widely used in vitro assays for genetic toxicity were evaluated for their ability to predict the carcinogenicity of selected chemicals in rodents. These assays were mutagenesis in Salmonella and mouse lymphoma cells and chromosome aberrations and sister chromatid exchanges in Chinese hamster ovary cells. Seventy-three chemicals recently tested in 2-year carcinogenicity studies conducted by the National Cancer Institute and the National Toxicology Program were used in this evaluation. Test results from the four in vitro assays did not show significant differences in individual concordance with the rodent carcinogenicity results; the concordance of each assay was approximately 60 percent. Within the limits of this study there was no evidence of complementarity among the four assays, and no battery of tests constructed from these assays improved substantially on the overall performance of the Salmonella assay. The in vitro assays which represented a range of three cell types and four end points did show substantial agreement among themselves, indicating that chemicals positive in one in vitro assay tended to be positive in the other in vitro assays.


Aptamer-Engineered Natural Killer Cells for Cell-Specific Adaptive Immunotherapy.
Natural killer (NK) cells are a key component of the innate immune system as they can attack cancer cells without prior sensitization. However, due to lack of cell-specific receptors, NK cells are not innately able to perform targeted cancer immunotherapy. Aptamers are short single-stranded oligonucleotides that specifically recognize their targets with high affinity in a similar manner to antibodies. To render NK cells with target-specificity, synthetic CD30-specific aptamers are anchored on cell surfaces to produce aptamer-engineered NK cells (ApEn-NK) without genetic alteration or cell damage. Under surface-anchored aptamer guidance, ApEn-NK specifically bind to CD30-expressing lymphoma cells but do not react to off-target cells. The resulting specific cell binding of ApEn-NK triggers higher apoptosis/death rates of lymphoma cells compared to parental NK cells. Additionally, experiments with primary human NK cells demonstrate the potential of ApEn-NK to specifically target and kill lymphoma cells, thus presenting a potential new approach for targeted immunotherapy by NK cells.


Desmoplastic small round cell tumor: a clinical, pathological, and immunohistochemical study of 18 Chinese cases.
Desmoplastic small round cell tumor (DSRCT) was first reported in 1989. Generally, DSRCT is considered to be an aggressive malignant neoplasm that mainly occurs in the abdominal cavity and has been often seen in adolescents and young male adults. In the present study, a total of 18 cases of DSRCT reported in China between October 1998 and June 2006, including one case treated by the authors, were reviewed and analyzed. Among them, 14 had tumors in the abdominal cavity; the other four cases had tumors in the left fossa orbitalis, the root of the tongue, the soft tissue behind the left eyeball, and the abdominal wall (umbilicus). Overall, the 1-year, 3-year, and 5-year survival rates were 52.36%, 27.92%, and 27.92%, respectively. The survival rate of DSRCT patients is disappointing; however, the survival of patients who had resection of the tumor or received comprehensive clinical treatment is satisfactory.


Allergic rhinitis and impairment issues in schoolchildren: a consensus report.
Allergic rhinitis (AR) can have substantial negative impact on children. Most notably, it can impede learning during the school-age years. Other consequences include adverse behavioral and psychosocial effects, poor quality of life, and potential impact on serious comorbidities, such as asthma. In February 2004, in a conference sponsored by Aventis Pharmaceuticals, a multidisciplinary group convened to review relevant clinical data for the purposes of developing consensus recommendations for the management of AR in children. The consensus panel consisted of academic, school health, and medical providers, who were identified based on previous work and publications. The focus of discussions was to assess the degree of impact of AR in schoolchildren and, based on this information, to determine how to improve screening, diagnosis, prevention, and treatment, to help ensure quality of life and maximal school performance in this population. The group considered the most critical factor in successful management ot be communication and collaboration among parents, educators, and healthcare professionals. Knowledge of the common signs and symptoms of AR in children can help to ensure early diagnosis, appropriate intervention, and clinically favorable outcomes. Importantly, both uncontrolled symptoms of AR, as well as adverse effects from medications, can diminish cognitive function and learning. When choosing treatment for children with AR, consideration must be given to the side effects of medications. All first-generation and some second-generation antihistamines can be associated with adverse effects on cognitive function and learning, as a result of their sedative properties. Treatment with non-sedating second-generation antihistamine has been shown to improve learning potential and is an ideal choice for treatment in this population. Existing data indicate that further studies using objective measures of impairment in children taking antihistamine medications should be conducted to evaluate the impact of disease and treatment.


CHACO outreach project: the development of a primary health care-based medical genetic service in an Argentinean province.
Dissemination of knowledge in genetics to be applied in medicine has created a growing need for capacity building in health care workers. The CAPABILITY ARGENTINA outreach project protocol was designed as a model to introduce genetics in areas without genetic services. Our aim was for genetic health care to become part of primary care in an Argentine province lacking genetic services. The program was innovative as professionals from the referral center (Garrahan Hospital S.A.M.I.C.) traveled to remote areas to train professionals through problem-based education. A logical framework was designed for a local needs assessment. Teaching materials (Powerpoint presentations, printed syllabus, and CD) and a web page were developed. A demonstration project was carried out in the Province of Chaco, Argentina. A total of 485 health workers were trained. The number of consultations increased significantly in participating areas comparing before and after the training period. To support this increase, a complementary project was set up from a public hospital sponsored from within Argentina to build a cytogenetic laboratory in the capital of the Province of Chaco. The model was improved for reproduction in other areas in Argentina. CAPABILITY ARGENTINA is a capacity building model for training of primary care professionals in genetics that may be applied to other medical specialties. The outcomes of the programme have a direct impact on clinical practice.


[The immunomodulating and antioxidant action of beta-carotene and essentiale in a lipid metabolic disorder].
Excessive supply of lipids to the organism of rats causes increase in lipid peroxidation, reduction of red cell energy status, the appearance in them of immunosuppressive properties, and inhibition of immunological reactivity. Administration of beta-carotene and essential corrects the biochemical status and immunological reactivity of the organism in alimentary lipid loading. beta-Carotene cancels the immunosuppressive properties of light red blood cells, whereas essential induces the appearance of immunostimulating properties in the heavy cells.


Shock wave and modelling study of the dissociation pathways of (C2F5)3N.
The thermal decomposition of perfluorotriethylamine, (C2F5)3N, was investigated in shock waves by monitoring the formation of CF2. Experiments were performed over the temperature range of 1120-1450 K with reactant concentrations between 100 and 1000 ppm of (C2F5)3N in the bath gas Ar and with [Ar] in the range of (0.7-5.5) × 10-5 mol cm-3. The experiments were accompanied by quantum-chemical calculations of the energies of various dissociation paths and by rate calculations, in particular for the dissociation of C2F5via C2F5 → CF3 + CF2. The overall reaction can proceed in different ways, either by a sequence of successive C-N bond ruptures followed by fast C2F5 decompositions, or by a sequence of alternating C-C and C-N bond ruptures. A cross-over between the two pathways can also take place. At temperatures below about 1300 K, yields of less than one CF2 per (C2F5)3N decomposed were observed. On the other hand, at temperatures around 2000 K, when besides the parent molecule, CF3 also dissociates, yields of six CF2 per (C2F5)3N decomposed were measured. The rate-delaying steps of the dissociation mechanism at intermediate temperatures were suggested to be the processes (C2F5)NCF2 → (C2F5)N + CF2 and (CF2)N → N + CF2. The reduction of the CF2 yields at low temperatures was tentatively attributed to a branching of the mechanism at the level of (C2F5)2NCF2, from where the cyclic final product perfluoro-N-methylpyrrolidine, (C4F8)NCF3, is formed which was identified in earlier work from the literature.


Coupled temporal memories in Parkinson's disease: a dopamine-related dysfunction.
Dysfunction of the basal ganglia and the brain nuclei interconnected with them leads to disturbances of movement and cognition, including disordered timing of movement and perceptual timing deficits. Patients with Parkinson's disease (PD) were studied in temporal reproduction tasks. We examined PD patients when brain dopamine (DA) transmission was impaired (OFF state) and when DA transmission was reestablished, at the time of maximal clinical benefit following administration of levodopa + apomorphine (ON state). Patients reproduced target times of 8 and 21 sec trained in blocked trials with the peak interval procedure, which were veridical in the ON state, comparable to normative performance by healthy young and aged controls (Experiment 1). In the OFF state, temporal reproduction was impaired in both accuracy and precision (variance). The 8-sec signal was reproduced as longer and the 21-sec signal was reproduced as shorter than they actually were (Experiment 1). This "migration" effect was dependent upon training of two different durations. When PD patients were trained on 21 sec only (Experiment 2), they showed a reproduction error in the long direction, opposite to the error produced under the dual training condition of Experiment 1. The results are discussed as a mutual attraction between temporal processing systems, in memory and clock stages, when dopaminergic regulation in the striatum is dysfunctional.


Clinical management of severe infections caused by carbapenem-resistant gram-negative bacteria: a worldwide cross-sectional survey addressing the use of antibiotic combinations.
Optimal treatment of carbapenem-resistant Gram-negative bacteria (CR-GNB) infections is uncertain because of the lack of good-quality evidence and the limited effectiveness of available antibiotics. The aim of this survey was to investigate clinicians' prescribing strategies for treating CR-GNB infections worldwide. A 36-item questionnaire was developed addressing the following aspects of antibiotic prescribing: respondent's background, diagnostic and therapeutic availability, preferred antibiotic strategies and rationale for selecting combination therapy. Prescribers were recruited following the snowball sampling approach, and a post-stratification correction with inverse proportional weights was used to adjust the sample's representativeness. A total of 1012 respondents from 95 countries participated in the survey. Overall, 298 (30%) of the respondents had local guidelines for treating CR-GNB at their facility and 702 (71%) had access to Infectious Diseases consultation, with significant discrepancies according to country economic status: 85% (390/502) in high-income countries versus 59% (194/283) in upper-medium-income countries and 30% (118/196) in lower-middle-income countries/lower-income-countries). Targeted regimens varied widely, ranging from 40 regimens for CR-Acinetobacter spp. to more than 100 regimens for CR-Enterobacteriaceae. Although the majority of respondents acknowledged the lack of evidence behind this choice, dual combination was the preferred treatment scheme and carbapenem-polymyxin was the most prescribed regimen, irrespective of pathogen and infection source. Respondents noticeably disagreed around the meaning of 'combination therapy' with 20% (150/783) indicating the simple addition of multiple compounds, 42% (321/783) requiring the presence of in vitro activity and 38% (290/783) requiring in vitro synergism. Management of CR-GNB infections is far from being standardized. Strategic public health focused randomized controlled trials are urgently required to inform evidence-based treatment guidelines.


[Expulsive hemorrhage in cataract extraction].
This article reports on six cases of massive expulsive hemorrhage during intracapsular cataract extraction (incidence = 0.17%). Some of the known risk factors are old age, hypertony, glaucoma, and an insufficient decrease in intraocular pressure following oculopression prior to surgery. Drainage of the suprachoroidal hemorrhage, closure of the wound and reformation of the anterior chamber are necessary surgical interventions. In one case the treated eye was saved and a visual acuity of 0.1 achieved.


The availability of abortion at state hospitals in Turkey: A national study.
Abortion in Turkey has been legal since 1983 and remains so today. Despite this, in 2012 the Prime Minister declared that, in his opinion, abortion was murder. Since then, there has been growing evidence that abortion access particularly in state hospitals is being restricted, although no new legislation has been offered. The study aimed to determine the number of state hospitals in Turkey that provide abortions. The study employed a telephone survey in 2015-2016 where 431 state hospitals were contacted and asked a set of questions by a mystery patient. If possible, information was obtained directly from the obstetrics/gynecology department. I removed specialist hospitals from the data set and the remaining data were analyzed for frequency and cross-tabulations were performed. Only 7.8% of state hospitals provide abortion services without regard to reason which is provided for by the current law, while 78% provide abortions when there is a medical necessity. Of the 58 teaching and research hospitals in Turkey, 9 (15.5%) provide abortion care without restriction to reason, 38 (65.5%) will do the procedure if there is a medical necessity and 11 (11.4%) of these hospitals refuse to provide abortion services under any circumstances. There are two regions, encompassing 1.5 million women of childbearing age, where no state hospital provides for abortion without restriction as to reason. The vast majority of state hospitals only provide abortions in the narrow context of a medical necessity, and thus are not implementing the law to its full extent. It is clear that although no new legislation restricting abortion has been enacted, state hospitals are reducing the provision of abortion services without restriction as to reason. This is the only nationwide study to focus on abortion provision at state hospitals.


Vaginitis.
Bacterial vaginosis, trichomoniasis, and vulvovaginal candidiasis are the most common infectious causes of vaginitis. Bacterial vaginosis occurs when the normal lactobacilli of the vagina are replaced by mostly anaerobic bacteria. Diagnosis is commonly made using the Amsel criteria, which include vaginal pH greater than 4.5, positive whiff test, milky discharge, and the presence of clue cells on microscopic examination of vaginal fluid. Oral and topical clindamycin and metronidazole are equally effective at eradicating bacterial vaginosis. Symptoms and signs of trichomoniasis are not specific; diagnosis by microscopy is more reliable. Features of trichomoniasis are trichomonads seen microscopically in saline, more leukocytes than epithelial cells, positive whiff test, and vaginal pH greater than 5.4. Any nitroimidazole drug (e.g., metronidazole) given orally as a single dose or over a longer period resolves 90 percent of trichomoniasis cases. Sex partners should be treated simultaneously. Most patients with vulvovaginal candidiasis are diagnosed by the presence of vulvar inflammation plus vaginal discharge or with microscopic examination of vaginal secretions in 10 percent potassium hydroxide solution. Vaginal pH is usually normal (4.0 to 4.5). Vulvovaginal candidiasis should be treated with one of many topical or oral antifungals, which appear to be equally effective. Rapid point-of-care tests are available to aid in accurate diagnosis of infectious vaginitis. Atrophic vaginitis, a form of vaginitis caused by estrogen deficiency, produces symptoms of vaginal dryness, itching, irritation, discharge, and dyspareunia. Both systemic and topical estrogen treatments are effective. Allergic and irritant contact forms of vaginitis can also occur.


Conformationally restricted calpain inhibitors.
The cysteine protease calpain-I is linked to several diseases and is therefore a valuable target for inhibition. Selective inhibition of calpain-I has proved difficult as most compounds target the active site and inhibit a broad spectrum of cysteine proteases as well as other calpain isoforms. Selective inhibitors might not only be potential drugs but should act as tools to explore the physiological and pathophysiological roles of calpain-I. α-Mercaptoacrylic acid based calpain inhibitors are potent, cell permeable and selective inhibitors of calpain-I and calpain-II. These inhibitors target the calcium binding domain PEF(S) of calpain-I and -II. Here X-ray diffraction analysis of co-crystals of PEF(S) revealed that the disulfide form of an α-mercaptoacrylic acid bound within a hydrophobic groove that is also targeted by a calpastatin inhibitory region and made a greater number of favourable interactions with the protein than the reduced sulfhydryl form. Measurement of the inhibitory potency of the α-mercaptoacrylic acids and X-ray crystallography revealed that the IC50 values decreased significantly on oxidation as a consequence of the stereo-electronic properties of disulfide bonds that restrict rotation around the S-S bond. Consequently, thioether analogues inhibited calpain-I with potencies similar to those of the free sulfhydryl forms of α-mercaptoacrylic acids.


Exposure to pups influences the strength of maternal motivation in virgin female rats.
Following repeated exposure to foster pups, virgin female rats acquire and eventually express a full spectrum of maternal caretaking behaviors directed toward pups. Though these behaviors are vigorous, these females are reportedly less motivated to seek out and interact with pups (i.e. maternally motivated) than parturient females during early postpartum. The present study systematically assesses how the length of pup-exposure and nature of interactions between the female-pup dyad affect maternal motivation in the virgin female rat. Virgin females were exposed to young pups consistently (24 h/day) across a prolonged period (21 days), briefly (1 h/day) across a relatively brief period (7 days), or distally (pups inaccessible in mesh bag). During final pup-exposure days, females were conditioned and tested for their preference for a pup-associated chamber (e.g. maternal motivation) using conditioned place preference. Early postpartum females provided a comparison group. Fully maternal behavior only emerged in females given prolonged pup-exposure; this behavior improved significantly over time and was maximally expressed for a duration equivalent to early postpartum. Females given brief pup-exposure expressed only emergent maternal behaviors initiated by pups; distal pup-exposure evoked pup-avoidance. Virgin females given prolonged or brief pup-exposure expressed substantial pup-associated chamber preference, with more females preferring the pup-associated chamber following longer pup-exposures in a subtle stepwise relationship. Maternal motivation was strikingly similar in prolonged pup-exposure virgin and early postpartum females. Females given distal pup-exposure completely lacked maternal motivation. Maternal behavior did not predict chamber preference. Results suggest that pup-exposure, regardless of length, is sufficient to support strong maternal motivation, whereas parity is not required.


Thyroid function disturbance and type 3 iodothyronine deiodinase induction after myocardial infarction in rats a time course study.
In humans, there is a significant decrease in serum T(3) and increase in rT(3) at different time points after myocardial infarction, whereas serum TSH and T(4) remain unaltered. We report here a time course study of pituitary-thyroid function and thyroid hormone metabolism in rats subjected to myocardial infarction by left coronary ligation (INF). INF- and sham-operated animals were followed by serial deiodination assays and thyroid function tests, just before, and 1, 4, 8, and 12 wk after surgery. At 4 and 12 wk after INF, liver type 1 deiodinase activity was significantly lower, confirming tissue hypothyroidism. Type 3 deiodinase (D3) activity was robustly induced 1 wk after INF only in the infarcted myocardium. Reminiscent of the consumptive hypothyroidism observed in patients with large D3-expressing tumors, this induction of cardiac D3 activity was associated with a decrease in both serum T(4) ( approximately 50% decrease) and T(3) (37% decrease), despite compensatory stimulation of the thyroid. Thyroid stimulation was documented by both hyperthyrotropinemia and radioiodine uptake. Serum TSH increased by 4.3-fold in the first and 3.1-fold in the fourth weeks (P < 0.01), returning to the basal levels thereafter. Thyroid sodium/iodide-symporter function increased 1 wk after INF, accompanying the increased serum TSH. We conclude that the acute decrease in serum T(4) and T(3) after INF is due to increased thyroid hormone catabolism from ectopic D3 expression in the heart.


Inhibition of protein phosphatase activity induces p53-dependent apoptosis in the absence of p53 transactivation.
Inhibitors of type 1 and type 2A protein phosphatases were used to examine the involvement of protein phosphorylation in regulating the functions of endogenous p53. Exposure of Balb/c 3T3 cells to okadaic acid, an inhibitor of protein phosphatases 1 and 2A, increased the phosphorylation of p53 without changing p53 levels. Okadaic acid treatment enhanced the binding of p53 to a consensus DNA target sequence and caused a 5-8-fold increase in p53 transcriptional activity. Transient expression of SV40 small tumor antigen, a specific inhibitor of protein phosphatase 2A, caused a 4-fold increase in p53 transcriptional activity. Incubation of Balb/c 3T3 cells with okadaic acid also induced programmed cell death in a dose- and time-dependent manner. Decreases in viability, morphological changes, and the appearance of DNA fragmentation were dependent on p53 since cells lacking functional p53 were resistant to okadaic acid-induced apoptosis. The p53-dependent apoptosis induced by okadaic acid was rapid and did not require p53 transcriptional activity. The fact that SV40 small tumor antigen did not induce apoptosis provides additional evidence that p53 transcriptional activity is not sufficient for p53-mediated apoptosis. These results indicate that signaling pathways involving protein phosphorylation play critical roles in controlling the apoptotic activity of p53. Furthermore, a basal level of protein phosphatase 1 or 2A activity is necessary to prevent p53-dependent apoptosis.


Inhibition of CXCR4 in Spinal Cord and DRG with AMD3100 Attenuates Colon-Bladder Cross-Organ Sensitization.
Cross-sensitization of pelvic organs is one theory for why symptoms of gut sickness and interstitial cystitis/bladder pain syndrome overlap. Experimental colitis has been shown to trigger bladder hyperactivity and hyperalgesia in rats. The chemokine receptor CXCR4 plays a key role in bladder function and central sensitization. We aim to study the role of CXCR4 and its inhibitor AMD3100 in colon-bladder cross-organ sensitization. The colitis model was established by rectal infusion of trinitrobenzene sulfonic acid. Western blot and immunofluorescence were used to assess the expression and distribution of CXCR4. Intrathecal injection of AMD3100 (a CXCR4 inhibitor) and PD98059 (an ERK inhibitor) were used to inhibit CXCR4 and downstream extracellular signal-regulated kinase (ERK) in the spinal cord and dorsal root ganglion (DRG). Intravesical perfusion of resiniferatoxin was performed to measure the pain behavior counts of rats, and continuous cystometry was performed to evaluate bladder voiding function. Compared to the control group, CXCR4 was expressed more in bladder mucosa and colon mucosa, L6-S1 dorsal root ganglion (DRG), and the corresponding segment of the spinal dorsal horn (SDH) in rats with colitis. Moreover, intrathecal injection of the AMD3100 suppressed bladder overactivity, bladder hyperalgesia, and mastocytosis symptoms caused by colitis. Furthermore, AMD3100 effectively inhibited ERK activation in the spinal cord induced by experimental colitis. Finally, treatment with PD98059 alleviated bladder overactivity and hyperalgesia caused by colitis. Increased CXCR4 in the DRG and SDH contributes to colon inflammation-induced bladder overactivity and hyperalgesia partly via the phosphorylation of spinal ERK. Treatment targeting the CXCR4/ERK pathway might provide a potential new approach for the comorbidity between the digestive system and the urinary system.


Cannabinoids inhibit excitatory inputs to neurons in the shell of the nucleus accumbens: an in vivo electrophysiological study.
The nucleus accumbens (NAc) represents a critical site for the rewarding properties of diverse classes of drugs of abuse. Glutamatergic afferents to the NAc are involved in the actions of psychostimulants and opioids, while the potentiation of dopaminergic neurotransmission in the NAc is a common feature of abused drugs, including cannabinoids. Cannabinoid receptors (CB1) are densely expressed in regions that provide excitatory innervation to the NAc, such as the amygdala, the cortex and the hippocampus. Recent in vitro evidence suggests that indeed cannabinoids modulate glutamatergic synapses in the NAc. In this study we recorded extracellularly from neurons in the shell of the NAc which responded to the stimulation of the baso-lateral amygdala (BLA) or the medial prefrontal cortex (PFC) in urethane anaesthetized rats. BLA or PFC stimulation induced generation of action potentials in NAc neurons. This excitatory effect was strongly inhibited by the synthetic cannabinoid agonists WIN 55212,2 (0.062-0.25 mg/kg, i.v.) and HU-210 (0.125-0.25 mg/kg, i.v.) or the psychoactive principle of Cannabis delta(9)-tetrahydrocannabinol (1.0 mg/kg, i.v.). Neither the D1 or D2 dopamine receptor antagonists (SCH23390 0.5-1.0 mg/kg, sulpiride 5-10 mg/kg, i.v.) or the opioid antagonist naloxone (1.0 mg/kg, i.v.) were able to reverse the action of cannabinoids, while the selective CB1 receptor antagonist/reverse agonist SR141716A (0.5 mg/kg, i.v.) fully suppressed the action of cannabinoid agonists, whereas per se had no significant effect. These results provide evidence that cannabinoids, in common with other drugs of abuse, in vivo strongly inhibit the excitability of neurons in the shell of the NAc.


The non-specific effects of vaccines and other childhood interventions: the contribution of INDEPTH Health and Demographic Surveillance Systems.
Most childhood interventions (vaccines, micronutrients) in low-income countries are justified by their assumed effect on child survival. However, usually the interventions have only been studied with respect to their disease/deficiency-specific effects and not for their overall effects on morbidity and mortality. In many situations, the population-based effects have been very different from the anticipated effects; for example, the measles-preventive high-titre measles vaccine was associated with 2-fold increased female mortality; BCG reduces neonatal mortality although children do not die of tuberculosis in the neonatal period; vitamin A may be associated with increased or reduced child mortality in different situations; effects of interventions may differ for boys and girls. The reasons for these and other contrasts between expectations and observations are likely to be that the immune system learns more than specific prevention from an intervention; such training may enhance or reduce susceptibility to unrelated infections. INDEPTH member centres have been in an ideal position to document such additional non-specific effects of interventions because they follow the total population long term. It is proposed that more INDEPTH member centres extend their routine data collection platform to better measure the use and effects of childhood interventions. In a longer perspective, INDEPTH may come to play a stronger role in defining health research issues of relevance to low-income countries.


Increased oxidative stress and toxicity in ADH and CYP2E1 overexpressing human hepatoma VL-17A cells exposed to high glucose.
High glucose mediated oxidative stress and cell death is a well documented phenomenon. Using VL-17A cells which are HepG2 cells over-expressing alcohol dehydrogenase (ADH) and cytochrome P450 2E1 (CYP2E1) and control HepG2 cells, the association of ADH and CYP2E1 with high glucose mediated oxidative stress and toxicity in liver cells was investigated. Cell viability was measured and apoptosis or necrosis was determined through caspase-3 activity, Annexin V-propidium iodide staining and detecting decreases in mitochondrial membrane potential. Reactive oxygen species, lipid peroxidation and the formation of advanced glycated-end products were assessed. The levels of several antioxidants which included glutathione, glutathione peroxidase, catalase and superoxide dismutase were altered in high glucose treated VL-17A cells. Greater toxicity was observed in VL-17A cells exposed to high glucose when compared to HepG2 cells. Oxidative stress parameters were greatly increased in high glucose exposed VL-17A cells and apoptotic cell death was observed. Inhibition of CYP2E1 or caspase 3 or addition of the antioxidant trolox led to significant decreases in high glucose mediated oxidative stress and toxicity. Thus, the over-expression of ADH and CYP2E1 in liver cells is associated with increased high glucose mediated oxidative stress and toxicity.


Pain-related beliefs are associated with arm function in persons with frozen shoulder.
Frozen shoulder is a painful glenohumeral joint condition. Pain-related beliefs are recognized drivers of function in musculoskeletal conditions. This cross-sectional study investigates associations between pain-related beliefs and arm function in frozen shoulder. Pain intensity, arm function (Disabilities of the Arm, Shoulder and Hand Questionnaire (DASH)), pain catastrophizing (Pain Catastrophizing Scale (PCS)), pain-related fear (Tampa Scale for Kinesiophobia (TSK-11)) and pain self-efficacy (Pain Self-Efficacy Questionnaire (PSEQ)) were administered in 85 persons with frozen shoulder. Correlation analyses assessed associations between pain-related beliefs and arm function. Regression analysis calculated the explained variance in arm function by pain-related beliefs. Pain-related fear, pain catastrophizing and pain self-efficacy were significantly associated with arm function (r = 0.51; r = 0.45 and r = -0.69, all p < .0001, respectively). Thirty-one percent of variance in arm function was explained by control variables, with pain intensity being the only significant one. After adding TSK-11, PCS and PSEQ scores to the model, 26% extra variance in arm function was explained, with significant contributions of pain intensity, pain-related fear and pain self-efficacy (R2 = 0.57). Attention should be paid towards the negative effect of pain-related fear on outcomes in frozen shoulder and towards building one's pain self-efficacy given its protective value in pain management.


Preference heterogeneity and selection in private health insurance: the case of Australia.
A basic prediction of theoretical models of insurance is that if consumers have private information about their risk of suffering a loss there will be a positive correlation between risk and the level of insurance coverage. We test this prediction in the context of the market for private health insurance in Australia. Despite a universal public system that provides comprehensive coverage for inpatient and outpatient care, roughly half of the adult population also carries private health insurance, the main benefit of which is more timely access to elective hospital treatment. Like several studies on different types of insurance in other countries, we find no support for the positive correlation hypothesis. Because strict underwriting regulations create strong information asymmetries, this result suggests the importance of multi-dimensional private information. Additional analyses suggest that the advantageous selection observed in this market is driven by the effect of risk aversion, the ability to make complex financial decisions and income.


Synaptic plasticity and connectivity requirements to produce stimulus-pair specific responses in recurrent networks of spiking neurons.
Animals must respond selectively to specific combinations of salient environmental stimuli in order to survive in complex environments. A task with these features, biconditional discrimination, requires responses to select pairs of stimuli that are opposite to responses to those stimuli in another combination. We investigate the characteristics of synaptic plasticity and network connectivity needed to produce stimulus-pair neural responses within randomly connected model networks of spiking neurons trained in biconditional discrimination. Using reward-based plasticity for synapses from the random associative network onto a winner-takes-all decision-making network representing perceptual decision-making, we find that reliably correct decision making requires upstream neurons with strong stimulus-pair selectivity. By chance, selective neurons were present in initial networks; appropriate plasticity mechanisms improved task performance by enhancing the initial diversity of responses. We find long-term potentiation of inhibition to be the most beneficial plasticity rule by suppressing weak responses to produce reliably correct decisions across an extensive range of networks.


Increasing Cervical Cancer Screening Coverage: A Randomised, Community-Based Clinical Trial.
Opportunistic cervical cancer screening can lead to suboptimal screening coverage. Coverage could be increased after a personalised invitation to the target population. We present a community randomized intervention study with three strategies aiming to increase screening coverage. The CRICERVA study is a community-based clinical trial to improve coverage of population-based screening in the Cerdanyola SAP area in Barcelona.A total of 32,858 women residing in the study area, aged 30 to 70 years were evaluated. A total of 15,965 women were identified as having no registration of a cervical cytology in the last 3.5 years within the Public Health data base system. Eligible women were assigned to one of four community randomized intervention groups (IGs): (1) (IG1 N = 4197) personalised invitation letter, (2) (IG2 N = 3601) personalised invitation letter + informative leaflet, (3) (IG3 N = 6088) personalised invitation letter + informative leaflet + personalised phone call and (4) (Control N = 2079) based on spontaneous demand of cervical cancer screening as officially recommended. To evaluate screening coverage, we used heterogeneity tests to compare impact of the interventions and mixed logistic regression models to assess the age effect. We refer a "rescue" visit as the screening visit resulting from the study invitation. Among the 13,886 women in the IGs, 2,862 were evaluated as having an adequate screening history after the initial contact; 4,263 were lost to follow-up and 5,341 were identified as having insufficient screening and thus being eligible for a rescue visit. All intervention strategies significantly increased participation to screening compared to the control group. Coverage after the intervention reached 84.1% while the control group reached 64.8%. The final impact of our study was an increase of 20% in the three IGs and of 9% in the control group (p<0.001). Within the intervention arms, age was an important determinant of rescue visits showing a statistical interaction with the coverage attained in the IGs. Within the intervention groups, final screening coverage was significantly higher in IG3 (84.4%) (p<0.001). However, the differences were more substantial in the age groups 50-59 and those 60+. The highest impact of the IG3 intervention was observed among women 60+ y.o with 32.0% of them being rescued for screening. The lowest impact of the interventions was in younger women. The study confirms that using individual contact methods and assigning a fixed screening date notably increases participation in screening. The response to the invitation is strongly dependent on age. ClinicalTrials.gov NCT01373723.


Assessing anti-SARS-CoV-2 cellular immunity in 571 vaccines by using an IFN-γ release assay.
Memory T cell responses have been analyzed only in small cohorts of COVID-19 vaccines. Herein, we aimed to assess anti-SARS-CoV-2 cellular immunity in a large cohort using QuantiFERON assays, which are IFN-γ release assays (IGRAs) based on short-term whole blood culture. The study included 571 individuals receiving the viral spike (S) protein-expressing BNT162b2 mRNA vaccine. QuantiFERON assays revealed antigen-specific IFN-γ production in most individuals 8 weeks after the second dose. Simultaneous flow cytometric assays to detect T cells expressing activation-induced markers (AIMs) performed for 28 randomly selected individuals provided data correlating with the QuantiFERON data. Simultaneous IFN-γ enzyme-linked immunospot and AIM assays for another subset of 31 individuals, based on short-term peripheral blood mononuclear cell culture, also indicated a correlation between IFN-γ production and AIM positivity. These observations indicated the acquisition of T cell memory responses and supported the usability of IGRAs to assess cellular immunity. The QuantiFERON results were weakly correlated with serum IgG titers against the receptor-binding domain of the S protein and were associated with pre-vaccination infection and adverse reactions after the second dose. The present study revealed cellular immunity after COVID-19 vaccination, providing insights into the effects and adverse reactions of vaccination.


Molecular mechanism of photoactivation of a light-regulated adenylate cyclase.
The photoactivated adenylate cyclase (PAC) from the photosynthetic cyanobacterium Oscillatoria acuminata (OaPAC) detects light through a flavin chromophore within the N-terminal BLUF domain. BLUF domains have been found in a number of different light-activated proteins, but with different relative orientations. The two BLUF domains of OaPAC are found in close contact with each other, forming a coiled coil at their interface. Crystallization does not impede the activity switching of the enzyme, but flash cooling the crystals to cryogenic temperatures prevents the signature spectral changes that occur on photoactivation/deactivation. High-resolution crystallographic analysis of OaPAC in the fully activated state has been achieved by cryocooling the crystals immediately after light exposure. Comparison of the isomorphous light- and dark-state structures shows that the active site undergoes minimal changes, yet enzyme activity may increase up to 50-fold, depending on conditions. The OaPAC models will assist the development of simple, direct means to raise the cyclic AMP levels of living cells by light, and other tools for optogenetics.


Exploring the Relevance of Senotherapeutics for the Current SARS-CoV-2 Emergency and Similar Future Global Health Threats.
The higher death rate caused by COVID-19 in older people, especially those with comorbidities, is a challenge for biomedical aging research. Here we explore the idea that an exacerbated inflammatory response, in particular that mediated by IL-6, may drive the deleterious consequences of the infection. Data shows that other RNA viruses, such as influenza virus, can display enhanced replication efficiency in senescent cells, suggesting that the accumulation of senescent cells with aging and age-related diseases may play a role in this phenomenon. However, at present, we are completely unaware of the response to SARS-CoV and SARS-COV-2 occurring in senescent cells. We deem that this is a priority area of research because it could lead to the development of several therapeutic strategies based on senotherapeutics or prevent unsuccessful attempts. Two of these senotherapeutics, azithromycin and ruxolitinib, are currently undergoing testing for their efficacy in treating COVID-19. The potential of these strategies is not only for ameliorating the consequences of the current emergence of SARS-CoV-2, but also for the future emergence of new viruses or mutated ones for which we are completely unprepared and for which no vaccines are available.


The ambient pollen distribution in Beijing urban area and its relationship with consumption of outpatient anti-allergic prescriptions.
The impact of pollen exposure on allergy medication is poorly characterized. We aim to study the main kind of ambient pollen in Beijing urban area and the correlation with outpatient anti-allergic prescriptions throughout one year in a tertiary hospital. With a modified volumetric trap, ambient pollens were sampled from January to December 2015. Meanwhile, information on 15 anti-allergic medication prescriptions in outpatient pharmacy was obtained and analyzed by generalized linear model. The total quantity of pollens amounted to 76164 grains in 2015. Two peaks of pollen concentration were observed, which happened from March to April 2015, and from August to September 2015. Consumption of antihistamines, LATRA, nasal sprays, and SABA showed two peaks trend in accordance with pollen distribution (p<0.01). ICS+LABA showed no seasonal peak without a significant correlation with pollen counts (p>0.05). Medication peak was higher in autumn than spring (p<0.01). The ambient pollen distribution was in accordance with the anti-allergic prescription amount with the two-peak season. The autumn medication peak was higher than spring peak, which clarified that outpatients were more sensitive to autumn pollen compared with spring pollen.


Comparison of loop-mediated isothermal amplification (LAMP) and PCR for the diagnosis of infection with Trypanosoma brucei ssp. in equids in The Gambia.
Infection of equids with Trypanosoma brucei (T. brucei) ssp. is of socioeconomic importance across sub-Saharan Africa as the disease often progresses to cause fatal meningoencephalitis. Loop-mediated isothermal amplification (LAMP) has been developed as a cost-effective molecular diagnostic test and is potentially applicable for use in field-based laboratories. Threshold levels for T. brucei ssp. detection by LAMP were determined using whole equine blood specimens spiked with known concentrations of parasites. Results were compared to OIE antemortem gold standard of T. brucei-PCR (TBR-PCR). Threshold for detection of T. brucei ssp. on extracted DNA from whole blood was 1 parasite/ml blood for LAMP and TBR-PCR, and there was excellent agreement (14/15) between tests at high (1 x 103/ml) concentrations of parasites. Detection threshold was 100 parasites/ml using LAMP on whole blood (LWB). Threshold for LWB improved to 10 parasites/ml with detergent included. Performance was excellent for LAMP at high (1 x 103/ml) concentrations of parasites (15/15, 100%) but was variable at lower concentrations. Agreement between tests was weak to moderate, with the highest for TBR-PCR and LAMP on DNA extracted from whole blood (Cohen's kappa 0.95, 95% CI 0.64-1.00). A prospective cross-sectional study of working equids meeting clinical criteria for trypanosomiasis was undertaken in The Gambia. LAMP was evaluated against subsequent TBR-PCR. Whole blood samples from 321 equids in The Gambia were processed under field conditions. There was weak agreement between LWB and TBR-PCR (Cohen's kappa 0.34, 95% CI 0.19-0.49) but excellent agreement when testing CSF (100% agreement on 6 samples). Findings support that LAMP is comparable to PCR when used on CSF samples in the field, an important tool for clinical decision making. Results suggest repeatability is low in animals with low parasitaemia. Negative samples should be interpreted in the context of clinical presentation.


Ga3+ as a mechanistic probe in Fe3+ transport: characterization of Ga3+ interaction with FbpA.
The obligate human pathogens Haemophilus influenzae, Neisseria gonorrhoeae, and N. meningitidis utilize a highly conserved, three-protein ATP-binding cassette transporter (FbpABC) to shuttle free Fe(3+) from the periplasm and across the cytoplasmic membrane. The periplasmic binding protein, ferric binding protein (FbpA), is capable of transporting other trivalent cations, including Ga(3+), which, unlike Fe(3+), is not redox-active. Because of a similar size and charge as Fe(3+), Ga(3+) is widely used as a non-redox-active Fe(3+) substitute for studying metal complexation in proteins and bacterial populations. The investigations reported here elucidate the similarities and differences in FbpA sequestration of Ga(3+) and Fe(3+), focusing on metal selectivity and the resulting transport function. The thermodynamic binding constant for Ga(3+) complexed with FbpA at pH 6.5, in 50 mM 4-morpholineethanesulfonic acid, 200 mM KCl, 5 mM KH(2)PO(4) was determined by UV-difference spectroscopy as log K'eff=13.7+/-0.6. This represents a 10(5)-fold weaker binding relative to Fe(3+) at identical conditions. The unfolding/refolding behavior of Ga(3+) and Fe(3+) holo-FbpA were also studied using a matrix-assisted laser desorption/ionization time-of-flight mass spectroscopy technique, stability of unpurified proteins from rates of H/D exchange (SUPREX). This analysis indicates significant differences between Fe(3+) and Ga(3+) sequestration with regard to protein folding behavior. A series of kinetic experiments established the lability of the Ga(3+)FbpA-PO(4) assembly, and the similarities/differences of stepwise loading of Fe(3+) into apo- or Ga(3+)-loaded FbpA. These biophysical characterization data are used to interpret FbpA-mediated Ga(3+) transport and toxicity in cell culture studies.


Treatment considerations for persons with metastatic prostate cancer: survival versus out-of-pocket costs.
Treatment decisions for metastatic prostate cancer require the consideration of factors such as survival, quality of life, costs of care, and toxicities. In this study, we queried physicians who had extensive experience with prostate cancer about features of metastatic prostate cancer, patients' quality of life, and factors influencing their decision to prescribe flutamide. Data were gathered through physician surveys and focus group discussions. Demographic information on the physicians and their patients was collected. Physicians made assessments of five health states related to metastatic prostate cancer, based on the time trade-off technique, and on the desirability of flutamide, based on average expected improvement in survival free of progressive disease, side effects, and drug cost. Physicians were internally consistent in their judgments of the factors most important to quality of life for individuals with metastatic prostate cancer. Physicians considered bone pain and weight loss/anorexia the most important factors. Physicians who cared for a higher proportion of older persons or Medicare recipients rated each scenario as less undesirable than did physicians with a lower proportion of these patients. Out-of-pocket cost was the major factor predicting whether a physician would prescribe flutamide. Physicians working for health maintenance organizations were more likely to prescribe flutamide but were more sensitive to out-of-pocket costs than were other physicians. Physicians-varied in their perceptions of quality of life for persons with metastatic prostate cancer and in their willingness to prescribe flutamide. These perceptions and prescribing preferences are strongly influenced by factors other than health status or specific health benefits. In deciding to prescribe flutamide, concerns over out-of-pocket expenditures loom large for most clinicians. It would be important to know the degree to which these concerns are shared by patients and whether prescribing preferences differ for Medicare managed-care patients who have pharmaceutical benefits.


Human autophagy gene ATG16L1 is post-transcriptionally regulated by MIR142-3p.
Multiple genetic studies have implicated the autophagy-related gene, ATG16L1, in the pathogenesis of Crohn disease (CD). While CD-related research on ATG16L1 has focused on the functional significance of ATG16L1 genetic variations, the mechanisms underlying the regulation of ATG16L1 expression are unclear. Our laboratory has described that microRNAs (miRNAs), key regulators of gene expression, are dysregulated in CD. Here, we report miRNA-mediated regulation of ATG16L1 in colonic epithelial cells as well as Jurkat T cells. Dual luciferase reporter assays following the transfection of vectors containing the ATG16L1 3'-untranslated region (3'UTR) or truncated 3'UTR fragments suggest that the first half of ATG16L1 3'UTR in the 5' end is more functional for miRNA targeting. Of 5 tested miRNAs with putative binding sites within the region, MIR142-3p, upon transient overexpression in the cells, resulted in decreased ATG16L1 mRNA and protein levels. Further observation demonstrated that the luciferase reporter vector with a mutant MIR142-3p binding sequence in the 3'UTR was unresponsive to the inhibitory effect of MIR142-3p, suggesting ATG16L1 is a gene target of MIR142-3p. Moreover, the regulation of ATG16L1 expression by a MIR142-3p mimic blunted starvation- and L18-MDP-induced autophagic activity in HCT116 cells. Additionally, we found that a MIR142-3p inhibitor enhanced starvation-induced autophagy in Jurkat T cells. Our study reveals MIR142-3p as a new autophagy-regulating small molecule by targeting ATG16L1, implying a role of this miRNA in intestinal inflammation and CD.


Consumption of herbal infusions/decoctions and tea in Greece: a Planeterranean perspective on the results of Hydria survey.
The consumption of various herbal infusions was and is common in the traditional Mediterranean diet, and apparently are used in many other regions of the world outside of the Mediterranean region. The present study aimed to investigate the consumption of herbal infusions/decoctions and tea in a nationally representative sample of Greece, considering also their Planetary use. 3951 adult participants of the HYDRIA Survey (2013-2014) were included from the 13 regions of Greece. The diet of participants was assessed by two 24-h dietary recalls (24-HDR) and the Food Propensity Questionnaire (FPQ). All food items were analyzed through the HYDRIA Food Composition Tables. Information on socio-demographics, lifestyle, and health characteristics during the baseline was also provided. 26.9% of herbal infusions and decoctions consumers are ≥ 75 years old, pensioners with a low level of education, and residents of urban areas. However, 22.2% of tea consumers belong to the 18-34-year age group, being employed with an intermediate level of education and living in an urban area. Elderly men and women use more herbal infusions/decoctions (55.4%; 40.6%) compared to tea (41.8%; 25.2%). According to FPQ, 7.1% of men and 9.7% of women use herbal infusions and decoctions four times or more per week, while 7.1 and 10.9% of men and women, respectively, consume tea at the same frequency. Green tea, mountain tea (Sideritis spp.), and black tea are reported most frequently. In addition, mountain tea (61.2%), black tea (60.3%), mixed herbal infusions/decoctions (58.4%), and sage (59.4%) are consumed mostly at breakfast, while chamomile was reported mainly at dinner or during the night (42.4%). Based on the FPQ results, the moderate and high consumption of herbal infusions/decoctions and tea is low in Greece, especially among adults (18-64 years). Thus, our results indicate the existence of a generation gap to the attachment to the traditional Med Diet and the consumption of herbal infusions. The present study could encourage future research to focus on herbal infusions and decoctions consumption by other populations for cross-cultural comparison, as well as on emphasizing the value of consuming locally available herbs in a Planeterranean perspective.


Hamartoma affecting ampullary electroreceptors and epitheliotropic lymphoma in a captive electric eel Electrophorus varii.
Few reports are available describing lesions in captive electric eels Electrophorus spp. This report describes 2 types of cutaneous proliferative lesions (i.e. hamartoma and neoplasm) in a captive electric eel. Ampullary electroreceptor hamartomas appeared grossly as 2 discrete, smooth, pink, spherical, cutaneous masses measuring 6 and 18 mm in diameter. Histologically, hamartomas were composed of predominately spindle cells that were separated into lobules by a peripheral rim of polygonal cells. Spindle cells were arranged in vague streams and occasionally whorls within a myxomatous matrix. Polygonal cells arranged in variably sized trabeculae and cords within a pre-existing fibrovascular stroma surrounded the streams of spindle cells. Admixed with the polygonal cell population were multiple mucous glands and alarm cells, similar to those seen in normal regions of epidermis. Histochemical stains confirmed similar components in the normal ampullary electroreceptor as in the hamartomas. Lymphoma was also present, appearing grossly as patchy pitting, erythematous, and thickened areas of the skin affecting the entire animal. Lymphoma was diffusely infiltrating and expanding the epidermis, oral mucosa, and branchial mucosa up to 1.5 mm in thickness. It was composed of an unencapsulated, well-demarcated, moderately cellular neoplasm composed of lymphocytes arranged in small dense sheets and clusters that separated and effaced epidermal cells. This is the first report of lymphoma in an electric eel, and the first report of ampullary electroreceptor hamartoma in any animal species.


Porphyrin metabolism and haem biosynthesis in Gilbert's syndrome.
Studies in 14 patients with unconjugated hyperbilirubinaemia caused by Gilbert's syndrome have revealed abnormalities of the enzymes of haem biosynthesis measured in peripheral blood cells. The activity of the penultimate enzyme of haem biosynthesis protoporphyrinogen (PROTO) oxidase was reduced at 3.1 +/- 2.6 nmol PROTO/g protein/h (mean +/- ISD) compared with 8.2 +/- 5.1 in controls (p less than 0.005). This was associated with a compensatory increase in the activity of the initial and rate controlling enzyme of the pathway delta-aminolaevulinic acid (ALA) synthase at 866 +/- 636 nmol ALA/g/protein/h compared with 156 +/- 63 in controls (p less than 0.001). Unlike variegate porphyria in which there is a genetic deficiency of PROTO oxidase there was no increased excretion of porphyrins or their precursors in Gilbert's syndrome. Accentuation and subsequent correction of the unconjugated hyperbilirubinaemia with rifampicin produced reciprocal changes in PROTO oxidase activity indicating that bilirubin may be inhibiting the activity of this enzyme.


Recent advances in the syntheses and properties of polynitrogen pentazolate anion cyclo-N5- and its derivatives.
The pentazolate anion, or cyclo-N5-, which is a five-membered ring composed solely of nitrogen atoms, has a unique structure among polynitrogen compounds. Cyclo-N5- is receiving ever-increasing levels of attention because of its potential ability to store large amounts of energy compared to the azide ion, its environmentally friendly decomposition products, and its carbon- and hydrogen-free composition, which are promising characteristics for advancing the field of high-energy-density materials (HEDMs), that include explosives, oxidisers, and propellants in closed environments. In this review, we provide a detailed introduction to cyclo-N5- and cover the following topics: (1) substituted pentazoles as precursors of cyclo-N5-, with a focus on the syntheses and stabilities of substituted pentazole derivatives; (2) routes to cyclo-N5- through cleavage of C-N bonds in substituted pentazoles, during which competitive reactions between pentazole decomposition and C-N bond cleavage need to be considered to ensure a successful outcome; (3) complexes of cyclo-N5-, summarising recent progress toward producing cyclo-N5--based complexes through the assembly of isolated cyclo-N5- with both metallic and nonmetallic components; and (4) interactions between cyclo-N5- and metal cations and non-metal species, as well as factors that influence the stability of these complexes; in particular, the thermal stabilities of prepared cyclo-N5- salts are discussed. This review summarises recent studies and is intended to improve the understanding of polynitrogen chemistry while supporting further research into its potential application as an efficient, safe, and environmentally friendly HEDM.


ADOPS--Automatic Detection Of Positively Selected Sites.
Maximum-likelihood methods based on models of codon substitution have been widely used to infer positively selected amino acid sites that are responsible for adaptive changes. Nevertheless, in order to use such an approach, software applications are required to align protein and DNA sequences, infer a phylogenetic tree and run the maximum-likelihood models. Therefore, a significant effort is made in order to prepare input files for the different software applications and in the analysis of the output of every analysis. In this paper we present the ADOPS (Automatic Detection Of Positively Selected Sites) software. It was developed with the goal of providing an automatic and flexible tool for detecting positively selected sites given a set of unaligned nucleotide sequence data. An example of the usefulness of such a pipeline is given by showing, under different conditions, positively selected amino acid sites in a set of 54 Coffea putative S-RNase sequences. ADOPS software is freely available and can be downloaded from http://sing.ei.uvigo.es/ADOPS.


Sodium hyaluronate increases the fibrinolytic response of human peritoneal mesothelial cells exposed to tumor necrosis factor alpha.
Sodium hyaluronate interferes with the fibrin degrading capacity of human peritoneal mesothelial cells exposed to tumor necrosis factor (TNF) alpha. Controlled laboratory experiment. Human peritoneal mesothelial cells were harvested from 5 patients undergoing laparotomy and cultured in vitro. Cells were treated with TNF-alpha, a cytokine typically involved in peritoneal inflammation, and sodium hyaluronate was added in a final concentration of 0.1%, 0.2%, or 0.4%. Controls received medium only. After 24 hours' incubation, tissue-type plasminogen activator (tPA), urokinase-type plasminogen activator (uPA), and plasminogen activator inhibitor type 1 (PAI-1) were measured in the medium and cell lysates using enzyme-linked immunosorbent assay techniques. Specific gene transcripts in cells treated with 0.4% sodium hyaluronate and controls were determined using a quantitative reverse transcription polymerase chain reaction. Concentrations of tPA, uPA, and PAI-1, and their specific gene transcripts. Sodium hyaluronate significantly increased tPA concentration in cell lysates without affecting its gene expression as determined after 24 hours (P =.02). The uPA concentration was significantly decreased by sodium hyaluronate in the medium but not in cell lysates (P<.0001). The uPA messenger RNA expression was 1000-fold increased compared with control. Sodium hyaluronate significantly decreased PAI-1 concentration in the medium and reduced its gene expression 500-fold (P =.04), while PAI-1 concentration in cell lysates did not change. Sodium hyaluronate affected the fibrinolytic response of TNF-alpha-stimulated human peritoneal mesothelial cells, most notably by decreasing PAI-1 transcription and release. This observation indicates that sodium hyaluronate counteracts the fibrinolytic decline induced by TNF-alpha and suggests a biological mechanism of action for sodium hyaluronate intra-abdominally.


Inadequate PAX-1 gene expression as a cause of agenesis of the thoracolumbar spine with failure of segmentation. Case report.
An unusual case with absence and "fusion" of several thoracic and lumbar vertebral bodies leading to a severe thoracolumbar kyphos is presented. Late-onset neurological deterioration occurred due to spinal cord compression, which was treated with anterior decompression. Although several mechanisms for the development of these extensive and rare abnormalities have been proposed, the cause in humans remains unknown. An embryological basis is presented in the light of recent advances in molecular genetics, which show that abnormal notochordal signals and Pax-1 gene expression can produce an experimental phenotype very similar to the one in the patient described here. Thus it is suggested that faults in these early developmental processes may be, at least in part, responsible for the development of such extensive anomalies.


Pharmacologic approaches to chronic pain in the older adult.
A key aspect of chronic pain management in the older adult is pharmacologic. Although not every elderly person has a chronic condition that leads to pain, these illnesses are more frequent in the later years as a consequence of the aging process. An understanding of physiologic changes and suggested pharmacologic interventions for dealing with issues related to chronic pain is essential. The psychosocial, cultural, and cost variables surrounding pain management of the older adult are also important to consider. A brief review of pain types and terminology precedes discussion of the key principles of pain management for the older adult. These principles are based on the guidelines published and distributed by the Agency for Health Care Policy and Research and the American Pain Society and are presented with a clinical focus aimed at improving clinician practice patterns related to pain management in the older adult. Concise, user-friendly medication information is presented to supplement the current knowledge base of practicing clinicians who prescribe analgesics and adjuvant medications for their patients with pain.


Cellular dissection of psoriasis for transcriptome analyses and the post-GWAS era.
Genome-scale studies of psoriasis have been used to identify genes of potential relevance to disease mechanisms. For many identified genes, however, the cell type mediating disease activity is uncertain, which has limited our ability to design gene functional studies based on genomic findings. We identified differentially expressed genes (DEGs) with altered expression in psoriasis lesions (n = 216 patients), as well as candidate genes near susceptibility loci from psoriasis GWAS studies. These gene sets were characterized based upon their expression across 10 cell types present in psoriasis lesions. Susceptibility-associated variation at intergenic (non-coding) loci was evaluated to identify sites of allele-specific transcription factor binding. Half of DEGs showed highest expression in skin cells, although the dominant cell type differed between psoriasis-increased DEGs (keratinocytes, 35%) and psoriasis-decreased DEGs (fibroblasts, 33%). In contrast, psoriasis GWAS candidates tended to have highest expression in immune cells (71%), with a significant fraction showing maximal expression in neutrophils (24%, P < 0.001). By identifying candidate cell types for genes near susceptibility loci, we could identify and prioritize SNPs at which susceptibility variants are predicted to influence transcription factor binding. This led to the identification of potentially causal (non-coding) SNPs for which susceptibility variants influence binding of AP-1, NF-κB, IRF1, STAT3 and STAT4. These findings underscore the role of innate immunity in psoriasis and highlight neutrophils as a cell type linked with pathogenetic mechanisms. Assignment of candidate cell types to genes emerging from GWAS studies provides a first step towards functional analysis, and we have proposed an approach for generating hypotheses to explain GWAS hits at intergenic loci.


Burden of Neurological Diseases in the Philippines as Revealed by Web Searches: An Infodemiological Study.
Due to the real-time acquisition of big data from the Internet, analysis of Google queries is now recognized as a valuable tool to explore and predict human behavior and interests. It was suggested that online data can be correlated with actual health data. Although the data are not structured nor systematic, the huge data from search engines can easily identify trends concerning diseases and other health concepts from a population perspective. Moreover, Internet data with the use of web search advertising nowadays may not only reveal the interest of the general population but also of the healthcare industry as reflected by the bid prices in search terms for medications. We aimed to compare the interests of the general population using monthly search volumes from Google and the healthcare industry using bid prices in web searches. Data used in this study were obtained from the Google Ads Application Programming Interface (API). This study evaluated the population's interest in neurological disorders by using search volumes related to neurology, either disease diagnosis or medications. Bid values generated in API were used as a proxy for the interests of the healthcare industry. Spearman's rank-order correlation was performed between search volumes and bid prices to determine significance. Among the neurologic diseases listed, the most searched were attention deficit hyperactivity disorder, migraine, and Alzheimer's disease. The most commonly searched drugs were oral antihypertensives (amlodipine, losartan, carvedilol), lipid-lowering agents (atorvastatin, simvastatin, rosuvastatin), and antiplatelets (acetylsalicylic acid, clopidogrel). The other most searched drugs were analgesics such as acetaminophen, tramadol, diclofenac, and morphine. The correlational analysis did not reveal a statistically significant correlation between search volume and bid price for both neurologic diseases and medications. Web searches may reflect the interest of the general population and the healthcare industry. However, there was disagreement in the search interests of the general population and the scientific community, including the pharmaceutical industry. Further studies are necessary in order to align these interests for the common benefit of all stakeholders.


Evidence synthesis to inform model-based cost-effectiveness evaluations of diagnostic tests: a methodological review of health technology assessments.
Evaluations of diagnostic tests are challenging because of the indirect nature of their impact on patient outcomes. Model-based health economic evaluations of tests allow different types of evidence from various sources to be incorporated and enable cost-effectiveness estimates to be made beyond the duration of available study data. To parameterize a health-economic model fully, all the ways a test impacts on patient health must be quantified, including but not limited to diagnostic test accuracy. We assessed all UK NIHR HTA reports published May 2009-July 2015. Reports were included if they evaluated a diagnostic test, included a model-based health economic evaluation and included a systematic review and meta-analysis of test accuracy. From each eligible report we extracted information on the following topics: 1) what evidence aside from test accuracy was searched for and synthesised, 2) which methods were used to synthesise test accuracy evidence and how did the results inform the economic model, 3) how/whether threshold effects were explored, 4) how the potential dependency between multiple tests in a pathway was accounted for, and 5) for evaluations of tests targeted at the primary care setting, how evidence from differing healthcare settings was incorporated. The bivariate or HSROC model was implemented in 20/22 reports that met all inclusion criteria. Test accuracy data for health economic modelling was obtained from meta-analyses completely in four reports, partially in fourteen reports and not at all in four reports. Only 2/7 reports that used a quantitative test gave clear threshold recommendations. All 22 reports explored the effect of uncertainty in accuracy parameters but most of those that used multiple tests did not allow for dependence between test results. 7/22 tests were potentially suitable for primary care but the majority found limited evidence on test accuracy in primary care settings. The uptake of appropriate meta-analysis methods for synthesising evidence on diagnostic test accuracy in UK NIHR HTAs has improved in recent years. Future research should focus on other evidence requirements for cost-effectiveness assessment, threshold effects for quantitative tests and the impact of multiple diagnostic tests.


Assessing spatial accessibility to maternity units in Shenzhen, China.
With the rapid development of urbanization, pregnant population is growing rapidly in Shenzhen, and it has been a difficulty to serve more and more pregnant women and reduce spatial access disparities to maternity units (MUs). Understanding of the current status of accessibility to MUs is valuable for supporting the rational allocation of MUs in the future. Based on pregnant population data and MUs data, this study uses a two-step floating catchment area (2SFCA) method based on Geographic Information System (GIS) to analyze the current spatial accessibility to MUs, and then make a comparison between that to public MUs and private MUs. Our analysis of the accessibility to all MUs within a distance of 20 km shows that the accessibilities of the areas alongside the traditional border management line are acceptable, meanwhile highlights some critical areas, such as the west part of Nanshan district and the vast east part of Longgang district. The comparison between spatial accessibility to public MUs and private MUs shows statistically significant difference. Results of this study suggest a great effort should be made to improve the equity of spatial accessibility to MUs in Shenzhen. For policy-making, strategy for the siting and allocation of future MUs, no matter public or private, should guarantee the greatest spatial accessibility for every pregnant woman.


Isolation of Daudi cells with reduced sensitivity to interferon. II. On the mechanisms of resistance.
The mechanism of interferon resistance was studied in two clones of Daudi cells, DIF2 and DIF3, which exhibit respectively moderate and pronounced resistance to both the antiviral and antiproliferative actions of human interferons-alpha and -beta. Clones DIF2 and DIF3 were found to possess specific high affinity interferon receptors similar to those of parental Daudi cells. However, DIF2 cells, which have a tetraploid karyotype, had approximately twice as many interferon-binding sites as either DIF3 or parental Daudi cells. One of the first detectable changes in Daudi cells following interferon treatment is a rapid increase in the intracellular concentration of cyclic GMP. No increase in cyclic GMP was observed in DIF2 or DIF3 cells treated with interferon-alpha. However, neither DIF2 nor DIF3 cells respond to sodium azide, a nonphysiological inducer of cyclic GMP. Interferon treatment was found to induce the production of 2'-5'-oligo-isoadenylate synthetase in DIF2 and DIF3 cells in a manner similar to parental Daudi cells, indicating that these cells possess functional interferon receptors. The levels of 2'-5'-oligo-isoadenylate synthetase and 2'-5' A phosphodiesterase activity were similar in all three cell lines, suggesting that the interferon resistance of clones DIF2 and DIF3 was not due to a deficiency of pp(A2' p)nA.


Integrity of mGluR-LTD in the associative/commissural inputs to CA3 correlates with successful aging in rats.
The impact of aging on cognitive capabilities varies among individuals ranging from significant impairment to preservation of function on par with younger adults. Research on the neural basis for age-related memory decline has focused primarily on the CA1 region of the hippocampus. However, recent studies in elderly human and rodents indicate that individual differences in cognitive aging are more strongly tied to functional alterations in CA3 circuits. To examine synaptic plasticity in the CA3 region, we used aged rats behaviorally characterized in a hippocampal-dependent task to evaluate the status of long-term potentiation and long-term depression (LTP and LTD) in the associative/commissural pathway (A/C → CA3), which provides the majority of excitatory input to CA3 pyramidal neurons. We found that, unlike in CA1 synapses, in A/C → CA3 LTP is minimally affected by age. However, two forms of LTD, involving NMDA and metabotropic glutamate receptors (mGluR), are both greatly reduced in age-impaired rats. Age-unimpaired rats, in contrast, had intact mGluR LTD. These findings indicate that the integrity of mGluR-LTD at A/C → CA3 inputs may play a crucial role in maintaining the performance of CA3 circuitry in aging.


Transporters for Bile Formation in Physiology and Pathophysiology.
The liver fulfills many vital functions for the body, among them bile formation and detoxification. Bile salts are organic anions, are the major constituents of bile and are at high concentrations cytotoxic. Detoxification exposes the liver to many harmful compounds. This function is therefore potentially damaging to the liver. Impaired bile formation may lead to hepatic accumulation of bile salts and subsequently to liver disease. Diagnosis of liver diseases involves the measurement of so-called liver function parameters. This overview aims to characterize and summarize the role of organic anion transporters in bile formation at the protein level under normal physiologic conditions and in liver function tests used for diagnosing liver diseases in pathophysiologic situations.


Cell cycle re-entry in Alzheimer's disease: a major neuropathological characteristic?
Alzheimer's disease (AD) is an irreversible, progressive brain disease that slowly destroys memory and thinking skills. With over 26 million patients in 2006, AD is the most prevalent neurodegenerative disease worldwide. Different hypotheses have been suggested to explain the pathogenesis of AD, like those involving inflammation, mitochondrial dysfunction or oxidative stress. Many of these studies have addressed amyloid plaque formation, tau hyperphosphorylation and apoptotic neuronal loss, the three main histopathological hallmarks of this disease. Increasing evidences, however, suggest another feature that can also be considered a neuropathological marker for AD: ectopic cell cycle re-entry. Cell cycle events have been frequently registered in the brains of AD patients. Although the exact starting point of cell cycle re-entry remains unclear, a number of subsequent cascades, which include events such as kinase upregulation, DNA replication and cytoskeletal alterations, have already been described. There are also increasing reports suggesting that cell cycle reactivation in mature neurons occurs as part of the apoptotic process. Upon a brief overview of the different theories and models addressing cell cycle reactivation in AD, we will describe possible mechanisms that trigger cell cycle re-entry, with special attention to links between this feature and the main neuropathological markers of AD. Finally, we will also analyze possible similarities between cell cycle dysregulation in AD and in other pathologies, such as Prion-Related Encephalopathies.


A comparison of perceived health, attitudes to work, leisure time, and social welfare systems among people in a rural area in the north of Sweden and among people in the city of Stockholm.
A problem attracting considerable attention in Sweden today is the substantial regional differences in sickness absence. The aim of the study was to investigate and compare how people, from a random sample of the population in both a rural area in the north of Sweden and the Swedish capital Stockholm, perceive their health, and what their attitudes are to work, leisure time and social welfare systems. Results showed that a larger proportion of those answering in Stockholm considered their health status to be "very good", compared with those in the rural area (p<0.0001). A majority in the rural area compared to the city of Stockholm reported a high or very high level of aches/pain (p<0.0001) and that work causes them physical problems p<0.0001). The population in both Stockholm and the rural area is of the opinion that the increase in sickness absence is mainly due to deterioration in the work environment. Almost half of the individuals in both the rural area and in Stockholm are of the opinion that many of those sick-listed are not actually ill. It may be that in the rural area in north Sweden people are more inclined to put their opinions to practice than those in Stockholm are.


Surface Passivation of Niobium Superconducting Quantum Circuits Using Self-Assembled Monolayers.
Superconducting coplanar waveguide (CPW) microwave resonators in quantum circuits are the best components for reading and changing the state of artificial atoms because of their excellent coupling to quantum systems. This coupling forms the basis of the developing circuit quantum electrodynamic architecture. In quantum processors, oscillators are used to store and transmit quantum information using microwave-frequency wave packets. However, the presence of amorphous thin-film defects is deleterious and can result in an irrevocable loss of coherent information with uncontrolled degrees of freedom. Although there has been extensive research into techniques to reduce the coherent loss of such devices, the precise structure of amorphous dielectric layers on surfaces and interfaces and their associated loss mechanism are being actively studied. In particular, planar superconducting resonators are very sensitive to defects on their surfaces, such as two-level systems in oxidized metals and nonequilibrium quasiparticles, making these devices suitable probes for the different loss mechanisms. In this work, we present the design, fabrication, and characterization of Nb CPW resonators with different surface treatments with self-assembled monolayers (SAMs), which mitigate the growth of oxides in superconducting circuits. We demonstrate SAM-passivated resonators having internal quality factors of greater than 106 at a single-photon excitation power (measured at 100 mK), which were probed using scanning electron microscopy, X-ray photoelectron spectroscopy, and transmission electron microscopy to demonstrate the efficiency of our surface treatment. Finally, we compared the improvements in the experimental quality factors to those obtained by numerical simulation.


Increased 1-year healthcare use in survivors of severe sepsis.
Hospitalizations for severe sepsis are common, and a growing number of patients survive to hospital discharge. Nonetheless, little is known about survivors' post-discharge healthcare use. To measure inpatient healthcare use of severe sepsis survivors compared with patients' own presepsis resource use and the resource use of survivors of otherwise similar nonsepsis hospitalizations. This is an observational cohort study of survivors of severe sepsis and nonsepsis hospitalizations identified from participants in the Health and Retirement Study with linked Medicare claims, 1998-2005. We matched severe sepsis and nonsepsis hospitalizations by demographics, comorbidity burden, premorbid disability, hospitalization length, and intensive care use. Using Medicare claims, we measured patients' use of inpatient facilities (hospitals, long-term acute care hospitals, and skilled nursing facilities) in the 2 years surrounding hospitalization. Severe sepsis survivors spent more days (median, 16 [interquartile range, 3-45] vs. 7 [0-29]; P < 0.001) and a higher proportion of days alive (median, 9.6% [interquartile range, 1.4-33.8%] vs. 1.9% [0.0-7.9%]; P < 0.001) admitted to facilities in the year after hospitalization, compared with the year prior. The increase in facility-days was similar for nonsepsis hospitalizations. However, the severe sepsis cohort experienced greater post-discharge mortality (44.2% [95% confidence interval, 41.3-47.2%] vs. 31.4% [95% confidence interval, 28.6-34.2%] at 1 year), a steeper decline in days spent at home (difference-in-differences, -38.6 d [95% confidence interval, -50.9 to 26.3]; P < 0.001), and a greater increase in the proportion of days alive spent in a facility (difference-in-differences, 5.4% [95% confidence interval, 2.8-8.1%]; P < 0.001). Healthcare use is markedly elevated after severe sepsis, and post-discharge management may be an opportunity to reduce resource use.


Imaging Intranuclear Actin Rods in Live Heat Stressed Drosophila Embryos.
The purpose of this protocol is to visualize intranuclear actin rods that assemble in live Drosophila melanogaster embryos following heat stress. Actin rods are a hallmark of a conserved, inducible Actin Stress Response (ASR) that accompanies human pathologies, including neurodegenerative disease. Previously, we showed that the ASR contributes to morphogenesis failures and reduced viability of developing embryos. This protocol allows the continued study of mechanisms underlying actin rod assembly and the ASR in a model system that is highly amenable to imaging, genetics and biochemistry. Embryos are collected and mounted on a coverslip to prepare them for injection. Rhodamine-conjugated globular actin (G-actinRed) is diluted and loaded into a microneedle. A single injection is made into the center of each embryo. After injection, embryos are incubated at elevated temperature and intranuclear actin rods are then visualized by confocal microscopy. Fluorescence recovery after photobleaching (FRAP) experiments may be performed on the actin rods; and other actin-rich structures in the cytoplasm can also be imaged. We find that G-actinRed polymerizes like endogenous G-actin and does not, on its own, interfere with normal embryo development. One limitation of this protocol is that care must be taken during injection to avoid serious injury to the embryo. However, with practice, injecting G-actinRed into Drosophila embryos is a fast and reliable way to visualize actin rods and can easily be used with flies of any genotype or with the introduction of other cellular stresses, including hypoxia and oxidative stress.


Alabama laws on drug testing in the work place.
Alabama law related to employee work place drug testing consists of the newly enacted drug free work place program, the workers' compensation law and the unemployment compensation law. These laws contain specific requirements relating to the performance of employee drug testing. Physicians will play a key role in the management, supervision and implementation of employer drug testing programs and should become familiar with state and federal laws and regulations pertaining to the operation of those programs.


Evolutionary path control strategy for solving many-objective optimization problem.
The number of objectives in many-objective optimization problems (MaOPs) is typically high and evolutionary algorithms face severe difficulties in solving such problems. In this paper, we propose a new scalable evolutionary algorithm, called evolutionary path control strategy (EPCS), for solving MaOPs. The central component of our algorithm is the use of a reference vector that helps simultaneously minimizing all the objectives of an MaOP. In doing so, EPCS employs a new fitness assignment strategy for survival selection. This strategy consists of two procedures and our algorithm applies them sequentially. It encourages a population of solutions to follow a certain path reaching toward the Pareto optimal front. The essence of our strategy is that it reduces the number of nondominated solutions to increase selection pressure in evolution. Furthermore, unlike previous work, EPCS is able to apply the classical Pareto-dominance relation with the new fitness assignment strategy. Our algorithm has been tested extensively on several scalable test problems, namely five DTLZ problems with 5 to 40 objectives and six WFG problems with 2 to 13 objectives. Furthermore, the algorithm has been tested on six CEC09 problems having 2 or 3 objectives. The experimental results show that EPCS is capable of finding better solutions compared to other existing algorithms for problems with an increasing number of objectives.


Fabrication of nanoelectrode ensembles by electrodepositon of Au nanoparticles on single-layer graphene oxide sheets.
Nanoelectrode ensembles (NEEs) have been fabricated by the electrodeposition of Au nanoparticles (AuNPs) on single-layer graphene oxide (GO) sheets coated on a glassy carbon electrode (GCE). The fabricated NEEs show a typical sigmoidal shaped voltammetric profile, arising from the low coverage density of AuNPs on GCE and large distance among them, which can be easily controlled by varying the electrodeposition time. As a proof of concept, after the probe HS-DNA is immobilized on the NEEs through the Au-S bonding, the target DNA is detected with the methylene blue intercalator. Our results show that the target DNA can be detected as low as 100 fM, i.e. 0.5 amol DNA in 5 μL solution.


Synthesized nano particles of glimepiride via spray freezing into cryogenic liquid: characterization, antidiabetic activity, and bioavailability.
The aim of this work was to formulate glimepiride (class II drug) which is characterized by low solubility and high permeability as nanostructured particles using a cryogenic technique with an aid of water-soluble polymer to improve its aqueous solubility and hence its bioavailability. 27 formula of glimepiride nano size particles were prepared by a spray freezing into cryogenic liquid (SCFL) using poly vinyl pyrrolidone K-30 (PVP K-30); that three drug polymer ratio (1:1, 1:2, and 1:3), with three different volumes of feeding solution (50, 100, 150 mL), at three flow rates (10, 20, and 30 mL/min). The prepared formulations were evaluated for production yield, particle size, zeta potential, drug content, release rate, in vivo hypoglycemic activity, and bioavailability. All prepared formulations showed high production yield and drug content ranged between 91.1 ± 3.4% and 94.3 ± 1.8% and 95.1 ± 2.8% and 97.1 ± 2.5%, respectively. The mean particles size was ranged between 280 ± 62 nm and 520 ± 30 nm. The results of in vitro release study revealed significant enhancement in the solubility of prepared formulations compared with the pure drug. It was found that optimal formula showed a significant reduction in blood glucose levels in diabetic rats, and 1.79-fold enhancements in oral bioavailability compared with market tablets. Nanoparticle prepared by SCFL method is an encouraging formula for improving the solubility and the bioavailability of glimepiride.