Symptom experiences of children and adolescents with cancer.
This paper examines nursing research focused on the symptom experiences of children and adolescents with cancer, and the extent to which the perspective and methods of developmental science have been used in this research. CINALH, MEDLINE, and PSYCHLIT were searched for publications between 1990 and 2002. The researcher or research team had to include a nurse or developmentally oriented researchers from other disciplines. Studies focused exclusively on pain were excluded because of recent published reviews. While nurse researchers have contributed influential knowledge related to symptom experiences and symptom distress in children and adolescents with cancer, this research is still in a formative but exciting stage. Two nurse researchers and their teams laid the foundation for this research through their individual studies and collaborative multisite studies. In general, children and adolescents from 10 through 18 years of age were primarily studied; few studies focused on preschool children. Given the fact that these are rare populations, sample sizes were generally small, limiting power and generalizability. Gender, ethnicity, and socioeconomic status were rarely considered in analyses. Most studies used cross-sectional designs, although several included short-term longitudinal or repeated measure designs. To date, longitudinal designs focused on long-term outcomes have not been conducted. There were only a few qualitative studies. There was limited use of conceptual models or theories, and inadequate attention was paid to broader ecological perspectives in the children's lives. Studies included a focus on global symptoms and on individual symptoms, particularly pain and fatigue. Few focused on nausea and vomiting. Operationalization of symptom distress generally involved adapting instruments designed for adults. A more explicit employment of a developmental science perspective in future studies would call for more longitudinal designs that conceptualize the symptom experience from the perspective of the child and that view their responses as complex and multidimensional in nature. This would necessitate measuring clusters of symptoms at multiple levels (e.g., emotional, behavioral, and biophysiological) using developmental data collection methods. Furthermore, attention needs to be paid in conceptualizing studies to ecological factors related to families, social networks, communities, and ethnicity, as well as to the ecology of the health care system, which likely influences the symptom experience of children.


PupaSuite: finding functional single nucleotide polymorphisms for large-scale genotyping purposes.
We have developed a web tool, PupaSuite, for the selection of single nucleotide polymorphisms (SNPs) with potential phenotypic effect, specifically oriented to help in the design of large-scale genotyping projects. PupaSuite uses a collection of data on SNPs from heterogeneous sources and a large number of pre-calculated predictions to offer a flexible and intuitive interface for selecting an optimal set of SNPs. It improves the functionality of PupaSNP and PupasView programs and implements new facilities such as the analysis of user's data to derive haplotypes with functional information. A new estimator of putative effect of polymorphisms has been included that uses evolutionary information. Also SNPeffect database predictions have been included. The PupaSuite web interface is accessible through http://pupasuite.bioinfo.cipf.es and through http://www.pupasnp.org.


Cloning, sequencing, and expression of Bacillus subtilis genes involved in ATP-dependent nuclease synthesis.
The genes encoding the subunits of the Bacillus subtilis ATP-dependent nuclease (add genes) have been cloned. The genes were located on an 8.8-kb SalI-SmaI chromosomal DNA fragment. Transformants of a recBCD deletion mutant of Escherichia coli with plasmid pGV1 carrying this DNA fragment showed ATP-dependent nuclease activity. Three open reading frames were identified on the 8.8-kb SalI-SmaI fragment, which could encode three proteins with molecular masses of 135 (AddB protein), 141 (AddA protein), and 28 kDa. Only the AddB and AddA proteins are required for ATP-dependent exonuclease activity. Both the AddB and AddA proteins contained a conserved amino acid sequence for ATP binding. In the AddA protein, a number of small regions were present showing a high degree of sequence similarity with regions in the E. coli RecB protein. The AddA protein contained six conserved motifs which were also present in the E. coli helicase II (UvrD protein) and the Rep helicase, suggesting that these motifs are involved in the DNA unwinding activity of the enzyme. When linked to the T7 promoter, a high level of expression was obtained in E. coli.


Directory of education.
One of the most important tools to career building and personal satisfaction is education! And there are a wide variety of ways for you to get it. Some are available through your professional associations (see the "Directory of National Associations" for more information on those), others are available through correspondence courses, on-site courses at local colleges and universities, seminar programs of associations, vendors and seminar groups, and still others are available in audiovisual formats. We've assembled a list of educational offerings that should be of interest to you and your colleagues. There may be others offered in your area, so contact your local institutions of higher learning to take advantage of what they have--or to develop a course with them!


Composite edible films based on hydroxypropyl methylcellulose reinforced with microcrystalline cellulose nanoparticles.
It has been stated that hydroxypropyl methyl cellulose (HPMC) based films have promising applications in the food industry because of their environmental appeal, low cost, flexibility and transparency. Nevertheless, their mechanical and moisture barrier properties should be improved. The aim of this work was to enhance these properties by reinforcing the films with microcrystalline cellulose (MCC) at the nano scale level. Three sizes of MCC nanoparticles were incorporated into HPMC edible films at different concentrations. Identical MCC nanoparticles were lipid coated (LC) prior to casting into HPMC/LC-MCC composite films. The films were examined for mechanical and moisture barrier properties verifying how the addition of cellulose nanoparticles affected the water affinities (water adsorption/desorption isotherms) and the diffusion coefficients. The expected reinforcing effect of the MCC was observed: HPMC/MCC and HPMC/LC-MCC films showed up to 53% and 48% increase, respectively, in tensile strength values in comparison with unfilled HPMC films. Furthermore, addition of unmodified MCC nanoparticles reduced the moisture permeability up to 40% and use of LC-MCC reduced this value up to 50%. Water vapor permeability was mainly influenced by the differences in water solubility of different composite films since, in spite of the increase in water diffusivity values with the incorporation of MCC to HPMC films, better moisture barrier properties were achieved for HPMC/MCC and HPMC/LC-MCC composite films than for HPMC films.


Limits to sustained energy intake. XX. Body temperatures and physical activity of female mice during lactation.
Lactating animals consume greater amounts of food than non-reproductive animals, but energy intake appears to be limited in late lactation. The heat dissipation limit theory suggests that the food intake of lactating mice is limited by the capacity of the mother to dissipate heat. Lactating mice should therefore have high body temperatures (Tb), and changes in energy intake during lactation should be reflected by variation in Tb. To investigate these predictions, 26 mice (Mus musculus) were monitored daily throughout lactation for food intake, body mass, litter size and litter mass. After weaning, 21 days postpartum, maternal food intake and body mass were monitored for another 10 days. Maternal activity and Tb were recorded every minute for 23 h a day using implanted transmitters (vital view). Energy intake increased to a plateau in late lactation (days 13-17). Daily gain in pup mass declined during this same period, suggesting a limit on maternal energy intake. Litter size and litter mass were positively related to maternal energy intake and body mass. Activity levels were constantly low, and mice with the largest increase in energy intake at peak lactation had the lowest activity. Tb rose sharply after parturition and the circadian rhythm became compressed within a small range. Tb during the light period increased considerably (1.1 ° C higher than in baseline), and lactating mice faced chronic hyperthermia, despite their activity levels in lactation being approximately halved. Average Tb increased in relation to energy intake as lactation progressed, but there was no relationship between litter size or litter mass and the mean Tb at peak lactation. These data are consistent with the heat dissipation limit theory, which suggests performance in late lactation is constrained by the ability to dissipate body heat.


Pharmacological treatment and prevention of cerebral small vessel disease: a review of potential interventions.
Small vessel disease encompasses lacunar stroke, white matter hyperintensities, lacunes and microbleeds. It causes a quarter of all ischemic strokes, is the commonest cause of vascular dementia, and the cause is incompletely understood. Vascular prophylaxis, as appropriate for large artery disease and cardioembolism, includes antithrombotics, and blood pressure and lipid lowering; however, these strategies may not be effective for small vessel disease, or are already used routinely so precluding further detailed study. Further, intensive antiplatelet therapy is known to be hazardous in small vessel disease through enhanced bleeding. Whether acetylcholinesterase inhibitors, which delay the progression of Alzheimer's dementia, are relevant in small vessel disease remains unclear. Potential prophylactic and treatment strategies might be those that target brain microvascular endothelium and the blood brain barrier, microvascular function and neuroinflammation. Potential interventions include endothelin antagonists, neurotrophins, nitric oxide donors and phosphodiesterase 5 inhibitors, peroxisome proliferator-activated receptor-gamma agonists, and prostacyclin mimics and phosphodiesterase 3 inhibitors. Several drugs that have relevant properties are licensed for other disorders, offering the possibility of drug repurposing. Others are in development. Since influencing multiple targets may be most effective, using multiple agents and/or those that have multiple effects may be preferable. We focus on potential small vessel disease mechanistic targets, summarize drugs that have relevant actions, and review data available from randomized trials on their actions and on the available evidence for their use in lacunar stroke.


Planned home versus hospital care for preterm prelabour rupture of the membranes (PPROM) prior to 37 weeks' gestation.
Preterm prelabour rupture of membranes (PPROM) is associated with increased risk of maternal and neonatal morbidity and mortality. Women with PPROM have been predominantly managed in hospital. It is possible that selected women could be managed at home after a period of observation. The safety, cost and women's views about home management have not been established. To assess the safety, cost and women's views about planned home versus hospital care for women with PPROM. We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (January 2010) and the reference lists of all the identified articles. Randomised and quasi-randomised trials comparing planned home versus hospital management for women with PPROM before 37 weeks' gestation. Two review authors independently assessed clinical trials for eligibility for inclusion, risk of bias, and carried out data extraction. We included two trials (116 women) comparing planned home versus hospital management for PPROM. Overall, the number of included women in each trial was too small to allow adequate assessment of pre-specified outcomes. Investigators used strict inclusion criteria and in both studies relatively few of the women presenting with PPROM were eligible for inclusion. Women were monitored for 48 to 72 hours before randomisation. Perinatal mortality was reported in one trial and there was insufficient evidence to determine whether it differed between the two groups (risk ratio (RR) 1.93, 95% confidence interval (CI) 0.19 to 20.05). There was no evidence of differences between groups for serious neonatal morbidity, chorioamnionitis, gestational age at delivery, birthweight and admission to neonatal intensive care.There was no information on serious maternal morbidity or mortality. There was some evidence that women managed in hospital were more likely to be delivered by caesarean section (RR (random-effects) 0.28, 95% CI 0.07 to 1.15). However, results should be interpreted cautiously as there is a moderate heterogeneity for this outcome (I(2) = 35%). Mothers randomised to care at home spent approximately 10 fewer days as inpatients (mean difference -9.60, 95% CI -14.59 to -4.61) and were more satisfied with their care. Furthermore, home care was associated with reduced costs. The review included two relatively small studies that did not have sufficient statistical power to detect meaningful differences between groups. Future large and adequately powered randomised controlled trials are required to measure differences between groups for relevant pre-specified outcomes. Special attention should be given to the assessment of maternal satisfaction with care and cost analysis as they will have social and economic implications in both developed and developing countries.


The peculiar autoimmunity of primary biliary cirrhosis.
Autoantibodies to mitochondria (AMA, anti-M2) are a serologic hallmark of primary biliary cirrhosis (PBC). These react with three structurally and functionally related multienzymic complexes, the 2-oxoacid dehydrogenase complexes, but chiefly with the E2 subunit of pyruvate dehydrogenase complex (PDC-E2). Their very dose (95%) and specific association with PBC underpins the autoimmune concept of pathogenesis of that disease, notwithstanding several non-congruent features. Detailed studies, including structural analysis of epitopes, do not disclose how these autoantibodies originate. Their ubiquity in PBC has overshadowed the existence of a second set of relatively PBC-specific autoantibodies to nuclear antigens for which reactants have been cloned and characterized. These include centromeric proteins; proteins of the nuclear pore complex; nuclear dot proteins, which include Sp-100 and the promyelocytic leukemia antigen; and a recently identified autoantigen, SOX13. Certain of these reactants are DNA-binding proteins with transcriptional regulatory activity. Thus serum from individuals with the same clinical syndrome can have autoimmune reactivity to disparate mitochondrial and nuclear constituents in different cellular compartments. Antibody probing of phage displayed random peptide libraries, together with epitope scanning using overlapping sequential octameric peptides from the PDC-E2 sequence, showed that the discontinuous motifs MH, FV(E) and SYP contributed to a predicted conformational antibody epitope in the inner lipoyl domain of PDC-E2.


Effect of Ta Additions on the Microstructure, Damping, and Shape Memory Behaviour of Prealloyed Cu-Al-Ni Shape Memory Alloys.
The influence of Ta additions on the microstructure and properties of Cu-Al-Ni shape memory alloys was investigated in this paper. The addition of Ta significantly affects the green and porosity densities; the minimum percentage of porosity was observed with the modified prealloyed Cu-Al-Ni-2.0 wt.% Ta. The phase transformation temperatures were shifted towards the highest values after Ta was added. Based on the damping capacity results, the alloy of Cu-Al-Ni-3.0 wt.% Ta has very high internal friction with the maximum equivalent internal friction value twice as high as that of the prealloyed Cu-Al-Ni SMA. Moreover, the prealloyed Cu-Al-Ni SMAs with the addition of 2.0 wt.% Ta exhibited the highest shape recovery ratio in the first cycle (i.e., 100% recovery), and when the number of cycles is increased, this ratio tends to decrease. On the other hand, the modified alloys with 1.0 and 3.0 wt.% Ta implied a linear increment in the shape recovery ratio with increasing number of cycles. Polarization tests in NaCl solution showed that the corrosion resistance of Cu-Al-Ni-Ta SMA improved with escalating Ta concentration as shown by lower corrosion current densities, higher corrosion potential, and formation of stable passive film.


Atomic structures of a liquid-phase bonded metal/nitride heterointerface.
Liquid-phase bonding is a technologically important method to fabricate high-performance metal/ceramic heterostructures used for power electronic devices. However, the atomic-scale mechanisms of how these two dissimilar crystals specifically bond at the interfaces are still not well understood. Here we analyse the atomically-resolved structure of a liquid-phase bonded heterointerface between Al alloy and AlN single crystal using aberration corrected scanning transmission electron microscopy (STEM). In addition, energy-dispersive X-ray microanalysis, using dual silicon drift X-ray detectors in STEM, was performed to analyze the local chemistry of the interface. We find that a monolayer of MgO is spontaneously formed on the AlN substrate surface and that a polarity-inverted monolayer of AlN is grown on top of it. Thus, the Al alloy is bonded with the polarity-inverted AlN monolayer, creating a complex atomic-scale layered structure, facilitating the bonding between the two dissimilar crystals during liquid-phase bonding processes. Density-functional-theory calculations confirm that the bonding stability is strongly dependent on the polarity and stacking of AlN and MgO monolayers. Understanding the spontaneous formation of layered transition structures at the heterointerface will be key in fabricating very stable Al alloy/AlN heterointerface required for high reliability power electronic devices.


Phase II randomized trial of carboplatin, paclitaxel, bevacizumab with or without cixutumumab (IMC-A12) in patients with advanced non-squamous, non-small-cell lung cancer: a trial of the ECOG-ACRIN Cancer Research Group (E3508).
Cixutumumab is a fully human IgG1 monoclonal antibody to the insulin-like growth factor type I receptor that can potentially reverse resistance and enhance the efficacy of chemotherapy. Bevacizumab-eligible patients with stage IV or recurrent non-squamous, non-small-cell lung cancer and good performance status were randomized to receive standard doses of paclitaxel, carboplatin, and bevacizumab to a maximum of six cycles followed by bevacizumab maintenance (CPB) until progression (arm A) or CPB plus cixutumumab 6 mg/kg i.v. weekly (arm B). Of 175 patients randomized, 153 were eligible and treated (78 in arm A; 75 in arm B). The median progression-free survival was 5.8 months (95% CI 5.4-7.1) in arm A versus 7 months (95% CI 5.7-7.6) in arm B (P = 0.33); hazard ratio 0.92 (95% CI 0.65-1.31). Objective response was 46.2% versus 58.7% in arm A versus arm B (P = 0.15). The median overall survival was 16.2 months in arm A versus 16.1 months in arm B (P = 0.95). Grade 3/4 neutropenia and febrile neutropenia, thrombocytopenia, fatigue, and hyperglycemia were increased with cixutumumab. The addition of cixutumumab to CPB increased toxicity without improving efficacy and is not recommended for further development in non-small-cell lung cancer. Both treatment groups had longer OS than historical controls which may be attributed to several factors, and emphasizes the value of a comparator arm in phase II trials. NCT00955305.


Thymoma: a clinicopathological comparative study of 25 cases.
We reviewed 25 patients with thymoma for clinical symptoms at presentation, X-ray findings and outcome. The tumours of all patients were classified using 3 different pathologic classification systems and each system was evaluated for its predictive power with respect to survival. The recent classification system by Müller-Hermelink allowed to distinguish thymomas with associated systemic syndromes from those without. However, no good prediction with respect to outcome could be made by any of the 3 systems.


Direct interaction and functional coupling between metabotropic glutamate receptor subtype 1 and voltage-sensitive Cav2.1 Ca2+ channel.
Intracellular Ca2+ concentrations ([Ca2+]i) are regulated in a spatiotemporal manner via both entry of extracellular Ca2+ and mobilization of Ca2+ from intracellular stores. Metabotropic glutamate receptor subtype 1 (mGluR1) is a G protein-coupled receptor that stimulates the inositol 1,4,5-trisphosphate-Ca2+ signaling cascade, whereas Cav2.1 is a pore-forming channel protein of P/Q-type voltage-sensitive Ca2+ channels. In this investigation, we showed that mGluR1 and Cav2.1 are colocalized at dendrites of cerebellar Purkinje neurons and form the heteromeric assembly in both the brain and heterologously expressing COS-7 cells. This assembly occurs through the direct interaction between their carboxyl-terminal intracellular domains. Calcium imaging and whole-cell recording showed that mGluR1 inhibits Cav2.1-mediated [Ca2+]i increases and Ba2+ currents in HEK 293 cells expressing Cav2.1 with auxiliary alpha2/delta and beta1 subunits, respectively. This inhibition occurred in a ligand-independent manner and was enhanced by pre-activation of mGluR1 in a ligand-dependent manner. In contrast, simultaneous stimulation of mGluR1 and Cav2.1 induced large [Ca2+]i increases. Furthermore, the temporally regulated inhibition and stimulation of [Ca2+]i increases by mGluR1 and Cav2.1 were observed at dendrites but not soma of cultured Purkinje neurons. These data suggest that the assembly of mGluR1 and Cav2.1 provides the mechanism that ensures spatiotemporal regulation of [Ca2+]i in glutamatergic neurotransmission.


Caerulein and carbamoylcholine stimulate pancreatic amylase release at resting cytosolic free Ca2+.
Cytosolic free calcium concentrations ([Ca2+]i) and amylase secretion were measured in isolated rat pancreatic acini loaded with the intracellularly trapped fluorescent indicator quin2. Both caerulein and carbamoylcholine caused a rapid increase in [Ca2+]i, with a maximal 3-fold increase at 10(-9) M-caerulein and 10(-4) M-carbamoylcholine. However, caerulein (10(-12) M and 10(-11) M) as well as carbamoylcholine (10(-7) M) caused a significant stimulation of amylase release, while not inducing any detectable rise in [Ca2+]i. Changes in [Ca2+]i after addition of either secretagogue were transient and did not last more than 2-3 min. By contrast, when amylase secretion was monitored as a function of time, two distinct secretory phases could be observed upon addition of either carbamoylcholine (10(-5) M) or caerulein (10(-10) M). An initial, rapid phase (0-5 min) which caused a 6-7-fold increase above basal, followed by a sustained (5-30 min), but less marked, secretory rate (2-3-fold above basal). Addition of atropine (10(-4) M) 5 min after carbamoylcholine (10(-5) M) (i.e. after termination of the rise in [Ca2+]i and of the first secretory phase) did not cause any significant change in [Ca2+]i, while significantly inhibiting amylase secretion from 5 to 30 min to the same rate observed in the absence of the secretagogue. These results show that caerulein and carbamoylcholine, two agents thought to activate secretion mainly through mobilization of Ca2+ from intracellular stores, are capable of eliciting amylase secretion independently of a concomitant rise in [Ca2+]i. Furthermore, with both secretagogues the rise in [Ca2+]i, when observed, was only transient, while the stimulation of amylase release was sustained.


The duck enteritis virus early protein, UL13, found in both nucleus and cytoplasm, influences viral replication in cell culture.
The UL13 protein of the duck enteritis virus (DEV), predicted to encode a Ser/Thr protein kinase, belongs to the family of conserved herpesvirus protein kinases (CHPK), which plays an important role in herpesvirus proliferation. In this study, truncated UL13 was expressed as a fusion protein of approximately 44 kDa using a prokaryotic expression system, and this protein was used to generate a specific anti-UL13 antibody. This antibody detected UL13 starting at 4 h post infection in duck embryonic fibroblast cells and identified UL13 to be present in both the cytoplasm and the nucleus. UL13 RNA was found to be transcribed starting at 2 h post infection, and the synthesis of the UL13 mRNA was found to be sensitive to the protein synthesis inhibitor cycloheximide (CHX) and tolerant of the DNA polymerase inhibitor ganciclovir (GCV). Its nuclear location and status as an early gene suggested that DEV UL13 might play important roles in DEV replication, which was confirmed by comparing the proliferation of a UL13-knockout mutant virus, a revertant virus, and the parent virus in cell culture. The specific mechanisms of UL13 in viral replication need to be further studied.


Targeting cancers in the gastrointestinal tract: role of capecitabine.
Capecitabine is currently the only novel, orally home-administered fluorouracil prodrug. It offers patients more freedom from hospital visits and less inconvenience and complications associated with infusion devices. The drug has been extensively studied in large clinical trials in many solid tumors, including breast cancer, colorectal cancer, gastric cancer, and many others. Furthermore, the drug compares favorably with fluorouracil in patients with such cancers, with a safe toxicity profile, consisting mainly of gastrointestinal and dermatologic adverse effects. Whereas gastrointestinal events and hand-foot syndrome occur often with capecitabine, the tolerability profile is comparatively favorable. Prompt recognition of severe adverse effects is the key to successful management of capecitabine. Ongoing and future clinical trials will continue to examine, and likely expand, the role of capecitabine as a single agent and/or in combination with other anticancer agents for the treatment of gastrointestinal as well as other solid tumors, both in the advanced palliative and adjuvant settings. The author summarizes the current data on the role of capecitabine in the management of gastrointestinal cancers.


[Effect of infrared low power laser irradiation on blood acid-base balance and respiratory gases tension].
Small volume (0.5 ml) of arterial or venous rat's blood was subjected to impulse LPILR (lambda = 0.89 microns) in the light transparent cuvette. In arterial blood, a decrease of the pO2 (by 15.5 +/- 2.6%) and an increase of the pCO2 (by 22.0 +/- 4.8%) in respect to initial values, were determined. The acid-base shift from 7.39 +/- 0.02 to 7.34 +/- 0.02 was recorded. Only in few experiments, there were changes of pO2, pCO2 and pH in venous blood. Probable mechanism(s) of the mentioned parameters changes are discussed.


Nitric oxide regulation of maspin expression in normal mammary epithelial and breast cancer cells.
In this study, we examined the unique relationship of maspin, a serine protease inhibitor (serpin), that plays a critical role in mammary gland development and is silenced during breast cancer progression, and nitric oxide (NO), a multifaceted water and lipid soluble free radical. The hypothesis tested was that there is a correlation between endothelial nitric oxide synthase and maspin in MCF-7 cells and that NO is capable of regulating maspin expression. An experimental system was developed in which cellular levels of NO in normal human mammary epithelial cells and the breast cancer cell line MCF-7 could be altered using NO modulators. The effect(s) of NO modulators on maspin was measured using reverse transcriptase-polymerase chain reaction and Western blot analysis of subcellular fractions of both cell types. The data revealed that NO induced maspin expression in MCF-7 cells, and the induced maspin resulted in diminished cell motility and invasion, concomitant with an increase in the apoptotic index. This novel finding provides new information regarding the molecular role of maspin in regulating mammary epithelial growth, remodeling, tumor progression, and the metastatic process. More significantly, these findings could have a potential impact on future therapeutic intervention strategies for breast cancer. Targeted delivery of NO within the tumor microenvironment could provide a feasible noninvasive approach for effective treatment.


Anti-recurrence/metastasis and chemosensitization therapy with thioredoxin reductase-interfering drug delivery system.
Thioredoxin reductase (TrxR) is an essential mammalian enzyme that possesses a selenocysteine active site. TrxR is overexpressed in many malignant tumors and has a close relationship with apoptosis, drug resistance, recurrence and metastasis of tumors. Recently, TrxR has emerged as a promising target for anticancer therapy. Herein, we developed a TrxR-interfering drug delivery system (DDS) based on RGD-PEG-PUSeSe-PEG-RGD self-assembling micelles for imaging-guided gemcitabine (GEM) chemosensitization and anti-recurrence/metastasis therapy. The diselenide-containing micelles were degraded in response to TrxR stimuli for GEM releasing. In the meantime, the dissociated polymers' chain segments targeted the active site of TrxR via Se-Se/Se-S dynamic reactions for activity inhibition. This inhibition by the micelles not only provided chemosensitization, but reduced tumor recurrence/metastasis risk via the induction of residual tumor cell apoptosis by triggering ROS production post-chemotherapy. In this work, we took the transformation between Se-containing dynamic covalent bonds developed by our group from in vitro to in vivo, which furthered the knowledge on the biochemistry of selenium and provided aspects to develop new TrxR inhibitors. Overall, the TrxR-interfering DDS combined excellent antitumor effects for primary solid tumors with the inhibition of tumor recurrence/metastasis during post-treatment care, providing new perspectives for efficient cancer therapy.


Treatment of intestinal helminths does not reduce plasma concentrations of HIV-1 RNA in coinfected Zambian adults.
Infection with intestinal helminths may stimulate dysfunctional immune responses in human immunodeficiency virus (HIV)-infected persons. Studies have yielded conflicting results regarding the impact of antihelminthic treatment on plasma concentrations of HIV-1 RNA.Methods. We conducted a prospective study of 54 HIV-1- and helminth-coinfected and 57 HIV-1-infected, helminth-uninfected asymptomatic adults living in Lusaka, Zambia, to assess the impact of antihelminthic treatment on plasma concentrations of HIV-1 RNA. Median baseline viral load was 0.33 log(10) copies/mL lower in the helminth-infected group than in the uninfected group. Mean viral load between pretreatment and posttreatment visits increased in the helminth-infected (mean, 4.23 vs. 4.29 log(10) copies/mL; P=.6) and helminth-uninfected (mean, 4.39 vs. 4.52 log(10) copies/mL; P=.2) groups. Helminth-infected participants with high pretreatment viral loads had a mean 0.25-log(10) copies/mL decrease after treatment (P=.3), and helminth-uninfected participants had a mean 0.02-log(10) copies/mL decrease (P=.8). We did not find an overall association between treatment of intestinal helminth infections and reduction in viral load in coinfected adults. Future studies may need to focus on adults with intense helminth infections who live in rural areas or on adults or children who harbor higher helminth burdens and plasma concentrations of HIV-1 RNA.


The use of vein grafts in the repair of the inferior alveolar nerve following surgery.
Damage to the branches of the trigeminal nerve can occur as a result of a variety of causes. The most common damage to all divisions of this nerve occurs as a result of facial trauma. Unfortunately, iatrogenic damage to the inferior alveolar branch of the mandibular division of the trigeminal nerve is common because of its anatomical position within the mandible and its closeness to the teeth, particularly the third molar. It has been reported there is an incidence of approximately 0.5% of permanent damage to the inferior alveolar nerve following third molar removal. Extraction of other teeth within the mandible carries a lower incidence of permanent damage. However, damage can still occur in the premolar area, where the nerve exits the mandible via the mental foramen. Dental implants are a relatively new but increasing cause of damage to this nerve, particularly if the preoperative planning is inadequate. CT scanning is important for planning the placement of implants if this damage is to be reduced. Primary repair of the damaged nerve will offer the best chance of recovery. However, if there is a gap, and the nerve ends cannot be approximated without tension, a graft is required. Traditionally, nerve grafts have been used for this purpose but other conduits have also been used, including vein grafts. This article demonstrates the use of vein grafts in the reconstruction of the inferior dental branch of the mandibular division of the trigeminal nerve following injury, in this case due to difficulty in third molar removal, following sagittal split osteotomy and during the removal of a benign tumour from the mandible. In the five cases presented, this technique has demonstrated good success, with an acceptable return of function occurring in most patients.


The molecular genetics of type-4 fimbriae in Pseudomonas aeruginosa--a review.
Type-4 fimbriae (or pili) are filaments found at the poles of a wide range of bacterial pathogens, including Neisseria gonorrhoeae, Moraxella bovis, Dichelobacter nodosus and Pseudomonas aeruginosa. They are composed of a small subunit which is highly conserved among different species and appear to mediate adhesion and translocation across epithelial surfaces via a phenomenon termed "twitching motility'. These fimbriae are key host colonisation factors and important protective antigens. We have analysed the genetics and biosynthesis of type-4 fimbriae in P. aeruginosa, which is an opportunistic pathogen of compromised individuals, including those suffering cystic fibrosis, AIDS or burns. A library of P. aeruginosa transposon mutants was constructed which exhibited loss of twitching motility, as determined by altered colony morphology. Analysis of these mutants, and of similar collections by other groups, have revealed that there are at least 22 genes involved in type-4 fimbrial assembly and function. A large number (pilA, B, C, D, E, M, N, O, P, Q, T, U, V and Z) appear to be involved in the biogenesis of the fimbriae and to represent a subset of a supersystem involved in the assembly of surface-associated protein complexes. Homologs of at least some of these genes have subsequently been identified in other type-4 fimbriate bacteria. In P. aeruginosa, the system is also regulated via two signal transduction pathways-a classic sensor-regulator system (encoded by pilS, pilR and rpoN) which controls transcription of the fimbrial subunit, presumably in response to host cues, and a chemotactic system (encoded by pilG, H, I, J, K and L) which may be involved in the directional or rate control of twitching motility in response to local environmental variables.


Tilapia Piscidin 4 (TP4) Reprograms M1 Macrophages to M2 Phenotypes in Cell Models of Gardnerella vaginalis-Induced Vaginosis.
Gardnerella vaginalis is associated with bacterial vaginosis (BV). The virulence factors produced by G. vaginalis are known to stimulate vaginal mucosal immune response, which is largely driven by activated macrophages. While Tilapia piscidin 4 (TP4), an antimicrobial peptide isolated from Nile tilapia, is known to display a broad range of antibacterial functions, it is unclear whether TP4 can affect macrophage polarization in the context of BV. In this study, we used the culture supernatants from G. vaginalis to stimulate differentiation of THP-1 and RAW264.7 cells to an M1 phenotype. The treatment activated the NF-κB/STAT1 signaling pathway, induced reactive nitrogen and oxygen species, and upregulated inflammatory mediators. We then treated the induced M1 macrophages directly with a non-toxic dose of TP4 or co-cultured the M1 macrophages with TP4-treated vaginal epithelial VK2 cells. The results showed that TP4 could not only decrease pro-inflammatory mediators in the M1 macrophages, but it also enriched markers of M2 macrophages. Further, we found that direct treatment with TP4 switched M1 macrophages toward a resolving M2c phenotype via the MAPK/ERK pathway and IL-10-STAT3 signaling. Conversely, tissue repair M2a macrophages were induced by TP4-treated VK2 cells; TP4 upregulated TSG-6 in VK2 cells, which subsequently activated STAT6 and M2a-related gene expression in the macrophages. In conclusion, our results imply that TP4 may be able to attenuate the virulence of G. vaginalis by inducing resolving M2c and tissue repair M2a macrophage polarizations, suggesting a novel strategy for BV therapy.


Computer modeling of the spatial resolution properties of a dedicated breast CT system.
Computer simulation methods were used to evaluate the spatial resolution properties of a dedicated cone-beam breast CT system. X-ray projection data of a 70 microm nickel-chromium wire were simulated. The modulation transfer function (MTF) was calculated from the reconstructed axial images at different radial positions from the isocenter to study the spatial dependency of the spatial resolution of the breast CT scanner. The MTF was also calculated in both the radial and azimuthal directions. Subcomponents of the cone beam CT system that affect the MTF were modeled in the computer simulation in a serial manner, including the x-ray focal spot distribution, gantry rotation under the condition of continuous fluoroscopy, detector lag, and detector spatial resolution. Comparison between the computer simulated and physically measured MTF values demonstrates reasonable accuracy in the simulation process, with a small systematic difference (approximately 9.5 +/- 6.4% difference, due to unavoidable uncertainties from physical measurement and system calibration). The intrinsic resolution in the radial direction determined by simulation was about 2.0 mm(-1) uniformly through the field of view. The intrinsic resolution in the azimuthal direction degrades from 2.0 mm(-1) at the isocenter to 1.0 mm(-1) at the periphery with 76.9 mm from the isocenter. The results elucidate the intrinsic spatial resolution properties of the prototype breast CT system, and suggest ways in which spatial resolution can be improved with system modification.


Canoe functions at the CNS midline glia in a complex with Shotgun and Wrapper-Nrx-IV during neuron-glia interactions.
Vertebrates and insects alike use glial cells as intermediate targets to guide growing axons. Similar to vertebrate oligodendrocytes, Drosophila midline glia ensheath and separate axonal commissures. Neuron-glia interactions are crucial during these events, although the proteins involved remain largely unknown. Here, we show that Canoe (Cno), the Drosophila ortholog of AF-6, and the DE-cadherin Shotgun (Shg) are highly restricted to the interface between midline glia and commissural axons. cno mutant analysis, genetic interactions and co-immunoprecipitation assays unveil Cno function as a novel regulator of neuron-glia interactions, forming a complex with Shg, Wrapper and Neurexin IV, the homolog of vertebrate Caspr/paranodin. Our results also support additional functions of Cno, independent of adherens junctions, as a regulator of adhesion and signaling events in non-epithelial tissues.


Neutrophil migration through preexisting holes in the basal laminae of alveolar capillaries and epithelium during streptococcal pneumonia.
The purpose of this study was to determine whether or not there are preexisting holes in the endothelial and epithelial basal laminae of alveolar walls and to determine the path taken by neutrophils as they migrate from the capillaries to the airspace of the alveoli during inflammation. Using transmission electron microscopy and serial thin sections of normal rabbit and mouse lung, we have demonstrated the presence of slit-like holes in the capillary basal laminae and round holes in the basal laminae of type 2 pneumocytes. The slits in the capillary basal laminae were observed at the intersection of the thick and thin walls where endothelium, pericytes, and fibroblasts make close contact. The round holes in the type 2 cell basal laminae were observed at sites of close contact with fibroblasts. Neutrophils were observed to migrate through these slits and holes during streptococcal pneumonia in rabbit lungs. We conclude that during inflammation in the lung, migrating neutrophils displace pericytes and fibroblasts from the slits in the capillary basal lamina and then crawl through these slits into the alveolar interstitium. We postulate that neutrophils find their way to type 2 pneumocytes by following interstitial fibroblasts. We believe that neutrophils displace fibroblasts from their close contacts with the type 2 cells and then crawl through the holes in the basal lamina into the basal lateral space of the type 2 cells. From there, neutrophils migrate into the alveolar airspace.


In vivo micro computed tomography detection and decrease in amyloid load by using multifunctionalized gold nanorods: a neurotheranostic platform for Alzheimer's disease.
The development and use of nanosystems is an emerging strategy for the diagnosis and treatment of a broad number of diseases, such as Alzheimer's disease (AD). Here, we developed a neurotheranostic nanosystem based on gold nanorods (GNRs) that works as a therapeutic peptide delivery system and can be detected in vivo for microcomputed tomography (micro-CT), being a diagnostic tool. GNRs functionalized with the peptides Ang2 (a shuttle to the Central Nervous System) and D1 (that binds to the Aβ peptide, also inhibiting its aggregation) allowed detecting differences in vivo between wild type and AD mice (APPswe/PSEN1dE9) 15 minutes after a single dose by micro-CT. Moreover, after a recurrent treatment for one month with GNRs-D1/Ang2, we observed a diminution of amyloid load and inflammatory markers in the brain. Thus, this new designed nanosystem exhibits promising properties for neurotheranostics of AD.


Phosphorylation of ARC is a critical element in the antiapoptotic effect of anesthetic preconditioning.
Transient exposure to volatile anesthetics before cardiac ischemia/reperfusion (I/R), termed anesthetic preconditioning, limits myocardial injury and inhibits apoptosis. Apoptosis repressor with caspase recruitment domain (ARC) is a novel protein that has been demonstrated to protect cardiomyocytes from apoptosis induced by I/R and is regulated by phosphorylation. We therefore hypothesized that the antiapoptotic effect of anesthetic preconditioning is, in part, mediated by phosphorylation of ARC. In the experiments we used a perfused rat heart model of sevoflurane anesthetic preconditioning and I/R. In addition to measures of left ventricular function, phosphorylation of ARC was measured with and without anesthetic preconditioning. Because the phosphorylation status of ARC is determined by calcineurin and protein kinase CK2, the role of ARC was defined by measuring calcineurin activity and using the calcineurin inhibitor FK506 and the ARC phosphorylation inhibitor 4,5,6,7-tetrabromobenzotrizole (TBB). I/R without anesthetic preconditioning increased calcineurin and reduced ARC phosphorylation levels, whereas anesthetic preconditioning significantly improved functional recovery, decreased ischemic injury, limited the increase in calcineurin activity, increased the phosphorylation level of ARC, reduced cytochrome c release, and blocked the increase in caspase-8 after I/R. The effects of anesthetic preconditioning were mirrored by FK506 and abolished by TBB. This study has identified a novel cardiac pathway in which anesthetic preconditioning prevents the increase in calcineurin after I/R, resulting in increased phosphorylated ARC and decreased markers of apoptosis.


Early Childhood Nutrition Is Positively Associated with Adolescent Educational Outcomes: Evidence from the Andhra Pradesh Child and Parents Study (APCAPS).
India's Integrated Child Development Scheme, which provides supplementary nutrition and other public health services to >91 million women and children aged <6 y, is the largest program of its kind in the world. We estimated the long-term associations of maternal and early childhood nutrition provided under the Integrated Child Development Scheme with educational outcomes when the children became adolescents. We used longitudinal data from a controlled nutrition trial conducted near the city of Hyderabad, India. From 1987 to 1990, a balanced protein-energy supplement (corn-soya meal, called upma) was offered to pregnant women and children aged <6 y in 15 intervention villages, whereas no supplementation was offered in 14 control villages. Both groups had equal access to other public programs such as immunization and anemia control in pregnancy. Children born during the original trial period were resurveyed (654 intervention and 511 control group children) in 2003-2005. We used propensity score matching methods to correct for estimation bias in our regression models to assess the associations of supplementary nutrition with school enrollment, schooling grades completed, and academic test performance of these adolescents. Children born in intervention villages were 7.8% (95% CI: 0.1%, 15.4%; P < 0.05) more likely to be enrolled in school and completed 0.84 (95% CI: 0.28, 1.39; P < 0.005) more schooling grades than children born in control villages. We found no association between supplementary nutrition and academic performance, as measured by school test scores. Offering a nutritional supplement to pregnant women and children <6 y of age during the Hyderabad Nutrition Trial was associated with improved school enrollment and completion of more schooling grades when the children became adolescents.


Clinical problems in neurodevelopmental diagnosis: a 7-year neurological and psychological follow-up study of low risk preterm infants.
24 selected urban middle class low risk preterm infants and 10 full term infants have been followed up to the age of 7 years in a prospective neurodevelopmental study. The aim was to find out whether the neurological and behavioral peculiarities of the preterm infant fall within the range of variability of sign and function development or whether they are the clinical features of minor neurological dysfunction. The infants were assessed neurologically according to Amiel-Tison at 3, 6, 9 and 12 months of corrected age and by Touwen's examination for minor neurological dysfunction at 3, 5 and 7 years. They were assessed psychologically at 6, 9, 12 and 36 months on Griffiths' Developmental Scale and at 7 years on the Wechsler Bellevue Scale. 33% of the sample was lost to follow-up. The outcome of neurological assessment was as follows: no major sequelae such as cerebral palsy or mental deficiency; 50% had transient neurological anomalies (TNA) during the first year of life, lasting more than 6 months in 16.7%; no minor neurological dysfunctions were detected at 5 and 7 years but the non optimal signs scores were higher in infants of low gestational age. The scores on the Griffiths scale were poorer in the preterm infants between 6 months and 5 years of corrected age, especially in the performance and hearing-speech areas. Performance failures seemed to be related to the duration and type of TNA in the first year of life. General, verbal and performance quotients on the WISC at 7 years were normal and there were no learning or behavior problems. The mild TNA found in low risk preterm infants in the first year of life appear to be of no predictive value for school age problems.


Using in situ rheology to characterize the microstructure in photopolymerized polyacrylamide gels for DNA electrophoresis.
Photopolymerized cross-linked polyacrylamide hydrogels are attractive sieving matrix formulations for DNA electrophoresis owing to their rapid polymerization times and the potential to locally tailor the gel pore structure through spatial variation of illumination intensity. This capability is especially important in microfluidic systems, where photopolymerization allows gel matrices to be precisely positioned within complex microchannel networks. Separation performance is also directly related to the nanoscale gel pore structure, which is in turn strongly influenced by polymerization kinetics. Unfortunately, detailed studies of the interplay among polymerization kinetics, mechanical properties, and structural morphology are lacking in photopolymerized hydrogel systems. In this paper, we address this issue by performing a series of in situ dynamic small-amplitude oscillatory shear measurements during photopolymerization of cross-linked polyacrylamide electrophoresis gels to investigate the relationship between rheology and parameters associated with the gelation environment including UV intensity, monomer and cross-linker composition, and reaction temperature. In general, we find that the storage modulus G' increases with increasing initial monomer concentration, cross-linker concentration, and polymerization temperature. The steady-state value of G', however, exhibits a more complex dependence on UV intensity that varies with gel concentration. A simple model based on rubber elasticity theory is used to obtain estimates of the average gel pore size that are in surprisingly good agreement with corresponding data obtained from analysis of DNA electrophoretic mobility in gels cast under identical polymerization conditions.


IL-17A produced by gammadelta T cells plays a critical role in innate immunity against listeria monocytogenes infection in the liver.
IL-17A is originally identified as a proinflammatory cytokine that induces neutrophils. Although IL-17A production by CD4(+) Th17 T cells is well documented, it is not clear whether IL-17A is produced and participates in the innate immune response against infections. In the present report, we demonstrate that IL-17A is expressed in the liver of mice infected with Listeria monocytogenes from an early stage of infection. IL-17A is important in protective immunity at an early stage of listerial infection in the liver because IL-17A-deficient mice showed aggravation of the protective response. The major IL-17A-producing cells at the early stage were TCR gammadelta T cells expressing TCR Vgamma4 or Vgamma6. Interestingly, TCR gammadelta T cells expressing both IFN-gamma and IL-17A were hardly detected, indicating that the IL-17A-producing TCR gammadelta T cells are distinct from IFN-gamma-producing gammadelta T cells, similar to the distinction between Th17 and Th1 in CD4(+) T cells. All the results suggest that IL-17A is a newly discovered effector molecule produced by TCR gammadelta T cells, which is important in innate immunity in the liver.


Orteronel plus prednisone in patients with chemotherapy-naive metastatic castration-resistant prostate cancer (ELM-PC 4): a double-blind, multicentre, phase 3, randomised, placebo-controlled trial.
Orteronel is an investigational, partially selective inhibitor of CYP 17,20-lyase in the androgen signalling pathway, a validated therapeutic target for metastatic castration-resistant prostate cancer. We assessed orteronel in chemotherapy-naive patients with metastatic castration-resistant prostate cancer. In this phase 3, double-blind, placebo-controlled trial, we recruited patients with progressive metastatic castration-resistant prostate cancer and no previous chemotherapy from 324 study centres (ie, hospitals or large urologic or group outpatient offices) in 43 countries. Eligible patients were randomly assigned in a 1:1 ratio to receive either 400 mg orteronel plus 5 mg prednisone twice daily or placebo plus 5 mg prednisone twice daily. Randomisation was done centrally with an interactive voice response system and patients were stratified by region (Europe, North America, and not Europe or North America) and the presence or absence of radiographic disease progression at baseline. The two primary endpoints were radiographic progression-free survival and overall survival, determined in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01193244. From Oct 31, 2010, to June 29, 2012, 2353 patients were assessed for eligibility. Of those, 1560 were randomly assigned to receive either orteronel plus prednisone (n=781) or placebo plus prednisone (n=779). The clinical cutoff date for the final analysis was Jan 15, 2014 (with 611 deaths). Median follow-up for radiographic progression-free survival was 8·4 months (IQR 3·7-16·6). Median radiographic progression-free survival was 13·8 months (95% CI 13·1-14·9) with orteronel plus prednisone and 8·7 months (8·3-10·9) with placebo plus prednisone (hazard ratio [HR] 0·71, 95% CI 0·63-0·80; p<0·0001). After a median follow-up of 20·7 months (IQR 14·2-25·4), median overall survival was 31·4 months (95% CI 28·6-not estimable) with orteronel plus prednisone and 29·5 months (27·0-not estimable) with placebo plus prednisone (HR 0·92, 95% CI 0·79-1·08; p=0·31). The most common grade 3 or worse adverse events were increased lipase (137 [17%] of 784 patients in the orteronel plus prednisone group vs 14 [2%] of 770 patients in the placebo plus prednisone group), increased amylase (77 [10%] vs nine [1%]), fatigue (50 [6%] vs 14 [2%]), and pulmonary embolism (40 [5%] vs 27 [4%]). Serious adverse events were reported in 358 [46%] patients receiving orteronel plus prednisone and in 292 [38%] patients receiving placebo plus prednisone. In chemotherapy-naive patients with metastatic castration-resistant prostate cancer, radiographic progression-free survival was prolonged with orteronel plus prednisone versus placebo plus prednisone. However, no improvement was noted in the other primary endpoint, overall survival. Orteronel plus prednisone was associated with increased toxic effects compared with placebo plus prednisone. On the basis of these and other data, orteronel is not undergoing further development in metastatic castration-resistant prostate cancer. Millennium Pharmaceuticals, Inc, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited.


Adhesive Interactions between Mononuclear Phagocytes and Intestinal Epithelium Perturb Normal Epithelial Differentiation and Serve as a Therapeutic Target in Inflammatory Bowel Disease.
Disturbance of intestinal homeostasis is associated with the development of inflammatory bowel disease [IBD], and TGF-β signalling impairment in mononuclear phagocytes [MPs] causes murine colitis with goblet cell depletion. Here, we examined an organoid-MP co-culture system to study the role of MPs in intestinal epithelial differentiation and homeostasis. Intestinal organoids were co-cultured with lamina propria leukocytes and bone marrow-derived dendritic cells [BMDCs] from CD11c-cre Tgfbr2fl/fl mice. Organoid-MP adhesive interactions were evaluated by microscopy, RT-PCR, and flow cytometry. Murine colitis models (dextran sodium sulphate [DSS], CD11c-cre Tgfbr2fl/fl, T-cell-transfer) were used for histological and immunohistochemical analysis. Anti-E-cadherin antibody treatment or CD11c+-cell-specific CDH1 gene deletion were performed for E-cadherin neutralization or knockout. Colonic biopsies from patients with ulcerative colitis were analysed by flow cytometry. Intestinal organoids co-cultured with CD11c+ lamina propria leukocytes or BMDCs from CD11c-cre Tgfbr2fl/fl mice showed morphological changes and goblet cell depletion with Notch signal activation, analogous to CD11c-cre Tgfbr2fl/fl colitis. E-cadherin was upregulated in CD11c+ MPs, especially CX3CR1+CCR2+ monocytes, of CD11c-cre Tgfbr2fl/fl mice. E-cadherin-mediated BMDC adhesion promoted Notch activation and cystic changes in organoids. Anti-E-cadherin antibody treatment attenuated colitis in CD11c-cre Tgfbr2fl/fl and T-cell-transferred mice. In addition, E-cadherin deletion in CD11c+ cells attenuated colitis in both CD11c-cre Tgfbr2fl/fl and DSS-treated mice. In patients with ulcerative colitis, E-cadherin expressed by intestinal CD11c+ leukocytes was enhanced compared with that in healthy controls. E-cadherin-mediated MP-epithelium adhesion is associated with the development of colitis, and blocking these adhesions may have therapeutic potential for IBD.


Structural changes of yellow Cameleon domains observed by quantitative FRET analysis and polarized fluorescence correlation spectroscopy.
Förster resonance energy transfer (FRET) is a widely used method for monitoring interactions between or within biological macromolecules conjugated with suitable donor-acceptor pairs. Donor fluorescence lifetimes in absence and presence of acceptor molecules are often measured for the observation of FRET. However, these lifetimes may originate from interacting and noninteracting molecules, which hampers quantitative interpretation of FRET data. We describe a methodology for the detection of FRET that monitors the rise time of acceptor fluorescence on donor excitation thereby detecting only those molecules undergoing FRET. The large advantage of this method, as compared to donor fluorescence quenching method used more commonly, is that the transfer rate of FRET can be determined accurately even in cases where the FRET efficiencies approach 100% yielding highly quenched donor fluorescence. Subsequently, the relative orientation between donor and acceptor chromophores is obtained from time-dependent fluorescence anisotropy measurements carried out under identical conditions of donor excitation and acceptor detection. The FRET based calcium sensor Yellow Cameleon 3.60 (YC3.60) was used because it changes its conformation on calcium binding, thereby increasing the FRET efficiency. After mapping distances and orientation angles between the FRET moieties in YC3.60, cartoon models of this FRET sensor with and without calcium could be created. Independent support for these representations came from experiments where the hydrodynamic properties of YC3.60 under ensemble and single-molecule conditions on selective excitation of the acceptor were determined. From rotational diffusion times as found by fluorescence correlation spectroscopy and consistently by fluorescence anisotropy decay analysis it could be concluded that the open structure (without calcium) is flexible as opposed to the rather rigid closed conformation. The combination of two independent methods gives consistent results and presents a rapid and specific methodology to analyze structural and dynamical changes in a protein on ligand binding.


The Effect of Single-Dose Intraperitoneal Bevacizumab on Peritoneal Adhesion Formation.
Intra-abdominal adhesions and their complications following abdominal surgery are serious problems, with an incidence of 67-93%. Prevention of peritoneal adhesion formation may eliminate the need for surgical intervention, decreasing complications, morbidity, and cost. Bevacizumab is a recombinant monoclonal antibody which specifically binds vascular endothelial growth factor, an important cytokine in adhesion formation, and neutralizes its biological activity. We developed an experimental model in rats to determine the effect of bevacizumab in preventing adhesion formation and analyzed its effect both micro- and macroscopically. We used 32. Wistar rats randomly divided into two groups: Group A (control) and Group B (bevacizumab), with 16 rats each. A modified cecum abrasion model was developed; 0.9% NaCl solution was administered intraperitoneally to Group A and bevacizumab to Group B. On day 15, adhesion formation was evaluated both macro- and microscopically. Both micro- and macroscopic adhesion grades in Group B were significantly lower than those of control Group A; macroscopic grades were 2.69 ± 0.95 and 0.69 ± 0.8, and microscopic grades were 2.25 ± 1.06 and 0.5 ± 0.52 for Groups A and B, respectively. Bevacizumab was effective in preventing intraperitoneal adhesion formation in our study; however, its inhibitory effects on embryogenesis and the hematopoietic, endocrine, and immune systems may limit its clinical use.


Forgoing life support in western European intensive care units: the results of an ethical questionnaire.
To determine current views of European intensive care physicians regarding end-of-life decisions. A questionnaire was sent to all physician members of the European Society of Intensive Care Medicine. All questionnaires were anonymous. A total of 504 completed questionnaires from 16 western European countries were analyzed. Eighty-seven percent of the respondents were male. Forty-six percent of respondents said that intensive care unit admissions were generally or commonly affected by bed shortages, particularly in the south. Nevertheless, 73% of units frequently admit patients with no hope of survival, although only 33% of respondents felt that such patients should be admitted. Eighty percent of respondents felt that written do-not-resuscitate orders should be applied, but only 58% did so, with a wide variation according to country (from 8% in Italy to 91% in The Netherlands). Ninety-three percent of physicians sometimes withhold treatment from patients with no hope of a meaningful life, but withdrawal of treatment is less common. Forty percent of respondents said that they would deliberately administer large doses of drugs to such patients until death ensued. Forty-nine percent of respondents involved staff, patients, and family in end-of-life decisions. Forty-five percent of respondents felt that an ethics consultation was useful in such situations. Physicians in the countries of southern Europe were less likely than those in the north to apply do-not-resuscitate orders, withhold treatment, and discuss such issues with the patients. However, they were more likely to value the opinion of an ethics consultant. Intensive care unit admissions are frequently limited by the availability of beds across Europe, particularly in the south and in the United Kingdom, yet 73% of intensivists still admit patients with no hope of survival. When treating patients with no hope of survival, 40% of intensivists will deliberately administer large doses of drugs until death ensues. There are interesting differences between what a physician actually does and what he or she believes should be done with regard to various ethical questions. Important differences in attitudes also exist between European countries.


Cervical intraepithelial neoplasia diagnosis: emotional impact and nursing implications.
Cervical intraepithelial neoplasia (CIN) is a progressive disease process that starts with abnormal cellular development in the cervical epithelium and can be identified as low- or high-grade squamous intraepithelial lesions (LGSIL or HGSIL) by the Papanicolaou (Pap) smear test. Persistent abnormal results require follow-up colposcopy, an anxiety-producing procedure. Anxiety and fear can interfere with adequate treatment and follow-up. Early education efforts may reduce anxiety and enhance adherence to treatment and are invaluable in halting the progression of CIN. Diagnosis and treatment, the emotional impact on women, and implications for client education are discussed.


Nasobronchial interaction.
Upper and lower airways can be considered as a unified morphofunctional unit. In this paper, nasobronchial interactions are evaluated based on literature.To discuss nasobronchial interactions, literature review from PubMed since 1982 is evaluated. Data base was including the terms "nasobronchial interaction, nasal and bronchial". Asthma and rhinosinusitis may be associated with environmental factors and immunological predisposition. Treatment of rhinosinusitis may decrease asthma exacerbations. It was concluded that "one airway, one disease"-concept may be accepted when considering naso-bronchial interaction. Asthma treatment should also mean treating the nose as good as treating patients with nasal symptoms. To reach the succesful results ıt should be associated with evaluation of lung functions.


[Effects of gender on severity and pulmonary artery vascular reactivity in chronic hypoxic pulmonary hypertension in mice].
To explore the effects of gender on pathology and pulmonary vascular reactivity in chronic hypoxic pulmonary hypertension (HPH) in mice. HPH was induced by a 4-week exposure of male and female mice (8 weeks old C57BL/6, n = 15 each) to chronic hypoxia (10%O2). Normoxic controls were established both in male and female groups (n = 15 each). Right ventricular systolic pressure (RVSP) and Fulton index were detected.Isolated pulmonary artery ring contraction induced by high potassium (K(+)) and U-46619 was recorded and compared between two groups. Chronic hypoxia induced pulmonary hypertension after 4 weeks.RVSP significantly increased both in hypoxic female and male groups (normoxic vs hypoxic: (23.40 ± 0.16) vs (31.46 ± 2.33) and (24.71 ± 0.44) vs (33.66 ± 1.38) mmHg (1 mmHg = 0.133 kPa), P = 0.029 and P < 0.001).However, there were no inter-group differences (P = 0.447). The Fulton index of hypoxic female and male mice was higher than normoxic counterparts (P = 0.001, P < 0.001). But there were no gender differences (P = 0.471). Contraction of high K(+) and U-46619 was calcium ion (Ca(2+))-dependent and decreased markedly without calcium (P < 0.001, P = 0.007). High K(+) and U-46619-induced contraction of pulmonary artery was concentration dependent and greater in chronic hypoxic female (P = 0.002, P < 0.001) and male mice (both P < 0.001). But no differences existed between male and female mice in high K(+) (P = 0.657) or U-46619 (P = 0.751)-induced contraction. No significant correlation exists between gender and occurrence and severity of pulmonary hypertension or pulmonary artery vascular reactivity in HPH mice.


Postoperative healing complications associated with Gore-Tex Periodontal Material. Part I. Incidence and characterization.
Guided tissue regeneration procedures with Gore-Tex Periodontal Material are associated with a unique set of postoperative healing characteristics. Five healing complications are described in this study examining 102 sites. The occurrence of pain and purulence were the most common. In purulent sites, the majority of bacteria cultured were Actinomyces and Streptococcus spp. Resistance to antibiotics was common. Prevention and treatment of the healing complications are discussed.


Identification of individual thiophene-, indane-, tetralin-, cyclohexane-, and adamantane-type carboxylic acids in composite tailings pore water from Alberta oil sands.
Naphthenic acids (NAs) accumulate in oil sands process-affected water (OSPW) as a result of the water-based extraction processes, and represent one of the toxic fractions in OSPW. They exist as a complex mixture and so the development of an analytical method to characterize and quantify individual acids has been an on-going challenge. The multidimensional separation technique of two-dimensional gas chromatography (GC × GC) has the potential to provide a fingerprint of the sources of NAs and can potentially resolve individual analytes for target analysis. However, the identity and toxicity of a large proportion of the acids present in tailing waters are still unknown. Comprehensive two-dimensional gas chromatography/time-of-flight mass spectrometry (GC × GC/TOFMS) was used to characterize NAs in a pore water sample from a Syncrude composite tailings (CT) deposit in Fort McMurray, Alberta, Canada. The extractable organic acid fraction was derivatized with diazomethane and the structures of selected resolved esters were elucidated through interpretation of their electron ionization (EI) mass spectra and, if available, confirmed by comparison with the spectra of reference standards. The high resolving power of the GC × GC/TOFMS technique allowed for the structural elucidation of numerous as yet unidentified acids in the CT pore water sample such as carboxylic acids containing a thiophene, indane, tetralin or cyclohexane moiety. Seventeen members of the previously reported class of adamantane-type carboxylic acids in oil sands process water could also be identified in the sample. This study underlines the complexity of naphthenic acid isomer distributions in composite tailings and provides a useful inventory of individual acids.


Gaussian-optics-based optical modeling and characterization of a Fabry-Perot microcavity for sensing applications.
A generalized study has been carried out on the modeling of a Fabry-Perot microcavity for sensing applications. Different analytical models on transmission characteristics of a Fabry-Perot microcavity are established by using plane-wave-based techniques, such as the Macleod characteristic matrix technique, the transfer matrix technique, and Smith's technique. A novel Gaussian-optics-based model for a Fabry-Perot microcavity illuminated by a laser beam is then developed and validated. The influence of laser beam waist on microcavity optical response is investigated, and the required minimal beam waist size is explored to ensure a useful optical response for sensing applications that can be accurately predicted by plane-wave optics. Also, the perturbations of microcavity performance induced by different types of microcavity mirror imperfections are discussed, based on the novel optical model. The prototype of the proposed Fabry-Perot microcavity for sensing applications has been successfully fabricated and characterized.


Taxonomic and Functional Characterization of the Microbial Community During Spontaneous in vitro Fermentation of Riesling Must.
Although there is an extensive tradition of research into the microbes that underlie the winemaking process, much remains to be learnt. We combined the high-throughput sequencing (HTS) tools of metabarcoding and metagenomics, to characterize how microbial communities of Riesling musts sampled at four different vineyards, and their subsequent spontaneously fermented derivatives, vary. We specifically explored community variation relating to three points: (i) how microbial communities vary by vineyard; (ii) how community biodiversity changes during alcoholic fermentation; and (iii) how microbial community varies between musts that successfully complete alcoholic fermentation and those that become 'stuck' in the process. Our metabarcoding data showed a general influence of microbial composition at the vineyard level. Two of the vineyards (4 and 5) had strikingly a change in the differential abundance of Metschnikowia. We therefore additionally performed shotgun metagenomic sequencing on a subset of the samples to provide preliminary insights into the potential relevance of this observation, and used the data to both investigate functional potential and reconstruct draft genomes (bins). At these two vineyards, we also observed an increase in non-Saccharomycetaceae fungal functions, and a decrease in bacterial functions during the early fermentation stage. The binning results yielded 11 coherent bins, with both vineyards sharing the yeast bins Hanseniaspora and Saccharomyces. Read recruitment and functional analysis of this data revealed that during fermentation, a high abundance of Metschnikowia might serve as a biocontrol agent against bacteria, via a putative iron depletion pathway, and this in turn could help Saccharomyces dominate the fermentation. During alcoholic fermentation, we observed a general decrease in biodiversity in both the metabarcoding and metagenomic data. Unexpected Micrococcus behavior was observed in vineyard 4 according to metagenomic analyses based on reference-based read mapping. Analysis of open reading frames using these data showed an increase of functions assigned to class Actinobacteria in the end of fermentation. Therefore, we hypothesize that bacteria might sit-and-wait until Saccharomyces activity slows down. Complementary approaches to annotation instead of relying a single database provide more coherent information true species. Lastly, our metabarcoding data enabled us to identify a relationship between stuck fermentations and Starmerella abundance. Given that robust chemical analysis indicated that although the stuck samples contained residual glucose, all fructose had been consumed, we hypothesize that this was because fructophilic Starmerella, rather than Saccharomyces, dominated these fermentations. Overall, our results showcase the different ways in which metagenomic analyses can improve our understanding of the wine alcoholic fermentation process.


The association of psychological factors, physical activity, neuropathy, and quality of life in type 2 diabetes.
The objective of this study was to determine the relationship of sociodemographics; diabetes-related factors, including diabetes-related microvascular complications; cardiac risk factors; and psychological factors with quality of life (QOL). Participants enrolled at three sites in the Detection of Ischemia in Asymptomatic Diabetics (DIAD) study were invited to participate in this ancillary study. Questionnaires assessing psychological factors were completed by participants, and the remainder of the data was obtained as part of the DIAD study. Many participants had elevated levels of anxiety (n = 91; 82%), depressive symptoms (n = 16; 14%), anger (n = 38; 34%), and hostility (n = 17; 17%). Results of multivariate analyses conducted for each of the eight domains on the Medical Outcomes Study Short Form-36 and two Diabetes Quality of Life domains demonstrated that in the majority of models (42% to 68% of the variance explained), female sex, peripheral or autonomic neuropathy, physical inactivity, higher body mass index, and the presence of depressive symptoms and anxiety were associated with poorer QOL (p = .0001). These findings demonstrate that anxiety, depressive symptoms, and neuropathy are prevalent in older adults with type 2 diabetes. In addition, potentially important correlations were demonstrated between psychological factors, neuropathy, body mass index, and physical inactivity.


Is formocresol obsolete? A fresh look at the evidence concerning safety issues.
Concern has been expressed about the safety of formocresol use in pediatric dentistry. Formaldehyde, a primary component in formocresol, is a hazardous substance and is considered a probable human carcinogen by the International Agency for Research on Cancer, Health Canada, the Agency for Toxic Substances and Disease Registry in the U.S. Department of Health and Human Services, and the U.S. Environmental Protection Agency. Humans inhale and ingest formaldehyde daily, however, and produce formaldehyde during cellular metabolism. The human body is physiologically equipped to handle formaldehyde through multiple conversion pathways. The resultant single carbon atom released during metabolism is deposited in the "1-carbon pool," which, in turn, is used for the biosynthesis of macromolecules including DNA and RNA. Reevaluation of earlier research that examined potential health risks associated with formaldehyde exposure has shown that this research was based on flawed assumptions, which resulted in erroneous conclusions. The purpose of this review was to examine more recent research about formaldehyde metabolism, pharmacokinetics, and carcinogenicity. These results indicated that formaldehyde is probably not a potent human carcinogen under low exposure conditions. Extrapolation of these research results to pediatric dentistry suggests an inconsequential risk associated with formaldehyde use in pediatric pulp therapy.


Transmitter sensitivity of neurons assayed by autoradiography.
Ionic conductance channels that are opened by activating nicotinic acetylcholine receptors at synapses of sympathetic neurons are permeable to small organic amines. Uptake of a tritium-labeled amine through these channels can be measured by autoradiography. This provides a simple and direct way to assess the sensitivity of individual neurons to acetylcholine without using microelectrodes.


A review on the safety of one-stage circumferential ring constriction release.
The study was undertaken to investigate the use of one-stage circumferential ring-constriction release with Z-plasties regarding the safety, aesthetic appearance, and limb function. A thorough review was conducted on all English publications in PubMed during the period of 2001 through 2011. Titles and abstracts were identified using online search engine from National Library of Medicine's PubMed database under the keywords "limb constriction ring," "limb constriction band," "amniotic band," "annular constriction," and "circumferential constriction." We used Boolean operator and field of title. Evaluation was done to search indications, timing of the first surgical intervention, time interval between surgeries, patients' gender, anatomic location of the ring, wound healing problems, and scar quality. Fourteen publications met the criteria. There were 17 patients with 25 ring constrictions in total. Sixteen ring constrictions (64%) were circumferential; nine (36%) were semi-circumferential. Mean age of 14 patients treated with one-stage release was 4.8 years. Six articles mentioned about normal development of postoperative limb function. Mean age of three patients treated with staged release was 10.5 months. Two articles mentioned regained distal muscle function postoperatively. It is confirmed that surgeons may continue the practice to release circumferential CRS in one stage.


THz radiation from two electron-beams interaction within a bi-grating and a sub-wavelength holes array composite sandwich structure.
Two electron-beams' interaction in a sandwich structure composed of a bi-grating and a sub-wavelength holes array is suggested to generate THz radiation in this paper. It shows that this system takes advantage of both bi-grating and sub-wavelength holes array structures. The results demonstrate that surface waves on a bi-grating can couple with mimicking surface plasmons of a sub-wavelength holes array so that the wave-coupling is strong and the field intensity is high in this structure. Moreover, compared with the interaction in the bi-grating structure and sub-wavelength holes array structure, respectively, it shows that in this composite system the two electron-beams' interaction is more efficient and the modulation depth and radiation intensity have been enhanced significantly. The modulation depth and efficiency can reach 22% and 4%, respectively, and the starting current density is only 12 A/cm². This radiation system may provide good opportunities for development of multi-electron beam-driven THz radiation sources.


Development of an Imaging Flow Cytometry Method for Fungal Cytological Profiling and Its Potential Application in Antifungal Drug Development.
Automated imaging techniques have been in increasing demand for the more advanced analysis and efficient characterization of cellular phenotypes. The success of the image-based profiling method hinges on assays that can rapidly and simultaneously capture a wide range of phenotypic features. We have developed an automated image acquisition method for fungal cytological profiling (FCP) using an imaging flow cytometer that can objectively measure over 250 features of a single fungal cell. Fungal cells were labeled with calcofluor white and FM4-64FX, which bind to the cell wall and lipophilic membrane, respectively. Images of single cells were analyzed using IDEAS® software. We first acquired FCPs of fungal cells treated with fluconazole, amphotericin B, and caspofungin, each with a distinct mode of action, to establish FCP databases of profiles associated with specific antifungal treatment. Once fully established, we investigated the potential application of this technique as a screening methodology to identify compounds with novel antifungal activity against Candida albicans and Cryptococcus neoformans. Altogether, we have developed a rapid, powerful, and novel image-profiling method for the phenotypic characterization of fungal cells, also with potential applications in antifungal drug development.


Nonmedical factors associated with prolonged hospital length of stay in an urban homebound population.
Prolonged length of stay (LOS) is a major concern for hospitalized populations at risk for adverse events. Homebound patients are at particular risk for long stays and may have unique discharge needs because of their commitment to be cared for at home despite poor functional status. The goal of this study was to describe factors contributing to long hospitalizations in the homebound population. This retrospective observational pilot study included all 2007 discharges that occurred for patients at The Mount Sinai Hospital enrolled in the Mount Sinai Visiting Doctors Program. Long-stay patients were defined as those having an LOS 2 standard deviations above the mean. Hospitalization days were defined as "nonmedical" when patients medically ready for discharge remained in the hospital. Patients discharged immediately after determination of medical readiness were characterized as "medical stay" cases. The University HealthSystems Consortium Database was used to calculate expected LOS and the LOS ratio. Chart reviews were performed to describe long-stay cases as nonmedical or medical. The average LOS for 479 discharges was 7.84 days, with a mean LOS Ratio of 1.23. Seventeen cases were determined to be long stays. Eight of these cases (47%) were defined as nonmedical stays. These accounted for 136 days of hospitalization and 32% of total long-stay days. The most common reason for a nonmedical stay was nursing facility placement delay. Nonmedical factors accounted for nearly one-third of all long-stay days in the hospitalized homebound population. Increased interdisciplinary collaboration may help address homebound patient LOS.


Multiple effects of phorbol esters on hormone-sensitive adenylate cyclase activity in S49 lymphoma cells.
In S49 lymphoma cells, 12-O-tetradecanoyl phorbol-13-acetate (TPA) enhances adenylate cyclase activity and doubles cAMP accumulation in response to beta-adrenergic stimulation at 37 degrees C, putatively via the action of protein kinase C. At 27 degrees C, TPA has the opposite effect, inhibiting cAMP production in response to isoproterenol by approximately 25%. TPA also inhibits the response to prostaglandin E1 (PGE1), another stimulant of hormone-sensitive adenylate cyclase in these cells, by 30% at 37 degrees C and almost 50% at 27 degrees C. In contrast, TPA enhances responses to forskolin and cholera toxin at both 27 and 37 degrees C. In membranes from cells treated with TPA, PGE1-stimulated adenylate cyclase activity is inhibited by 50%, whereas the catalytic activity stimulated by NaF or forskolin is enhanced. TPA reduces the potency of both PGE1 and isoproterenol for cAMP generation by 50%. TPA causes a similar decrease in beta-adrenergic agonist affinity with no reduction in the density of either antagonist or agonist binding sites in wild type cells and in cells lacking the alpha-subunit of the stimulatory transducer protein (Gs) (cyc-) or lacking functional receptor Gs coupling (UNC). Therefore, TPA has at least three functionally distinct effects on hormone-sensitive adenylate cyclase in S49 cells: a 50% reduction in agonist affinity, attenuation of receptor-transducer coupling, and enhancement of GTP-dependent catalytic activity. We conclude that multiple and opposing effects of TPA on hormone-sensitive adenylate cyclase occur simultaneously within the same cell, affecting the responses to several agonists differently.(ABSTRACT TRUNCATED AT 250 WORDS)


Requirement for CD28 in the effector phase of allergic airway inflammation.
Central to the pathogenesis of allergic airway inflammation are the activation and differentiation of T lymphocytes. This process requires the participation of the CD28 costimulatory receptor. Blockade of CD28 has been demonstrated to prevent inflammation and airway hyperreactivity in a murine model of asthma. Whether this is due specifically to defects in initial T cell activation or whether effector responses are also impaired has not been determined. Using adoptive transfer studies of Ag-specific lymphocytes, we demonstrate that CD28 has a critical role in both the induction and effector phase of allergic airway inflammation. Transfer of in vitro activated and Th2-differentiated Ag-specific lymphocytes from wild-type hosts restored inflammation, but not tissue eosinophilia in CD28-deficient recipients. Furthermore, similarly activated and differentiated CD28-deficient lymphocytes were ineffective at mediating inflammation in wild-type recipients. Secondary cytokine and proliferative responses of activated Th2 cells were highly dependent on CD28 in vitro. Moreover, eosinophil recruitment to both the lung and peritoneum is impaired by the lack of CD28, suggesting a generalized defect in the ability of eosinophils to accumulate at sites of inflammation in vivo. These data identify a novel role for CD28 in the effector phase of allergic airway inflammation and suggest that inhibition of this pathway may be a useful therapeutic intervention in previously sensitized individuals.


Neural response telemetry reconsidered: I. The relevance of ECAP threshold profiles and scaled profiles to cochlear implant fitting.
For more than a decade, Neural Response Telemetry (NRT) has provided direct access to the electrically evoked compound action potential (ECAP) as elicited by the Nucleus cochlear implant. When used clinically during fitting, ECAP threshold profiles are applied by shifting the profile to the audible threshold and comfort level boundaries (the T- and C-level profiles, respectively). The resulting profiles, to date, have matched the curvature of the ECAP threshold profile exactly. When compared with psychophysical profiles, previous studies have shown that this approach incurs errors in program levels that are no better than flat or population mean profiles. However, C-level profiles are observed to be flatter than T-level profiles. Accordingly, ECAP threshold profiles are flattened in this study when applied at increasing stimulus levels, and the effectiveness of this approach is evaluated among other methods. In phase I, ECAP thresholds (via AutoNRT) and T- and C-levels were measured from 15 adult Nucleus Freedom implantees. Psychophysical levels were measured using pulse train stimuli at six different stimulation rates, spanning 80 to 3500 Hz. The different rates spread T- and C-levels across a range of stimulus levels. At each of these levels, a scaling factor of best fit was calculated such that the shifted ECAP threshold profile, when scaled (0 giving a flat profile, 1 giving an unmodified profile), gave the best fit to the corresponding psychophysical profile. From the 148 such T- and C-level profiles, a single profile scaling model was determined by a simple linear regression. In phase II, the model was tested on data using three separate stimulation rates (250, 900, and 2400 Hz) and 14 additional subjects. The root mean square psychophysical level mismatch of the ECAP threshold profile, the scaled ECAP threshold profile, a flat profile, and a mean population profile was calculated per subject and per stimulation rate, and the differences in the means of these calculations were compared. In phase III, 13 separate subjects evaluated the scaled ECAP-based program during a 2 wk trial, comparing the new program to a flat program and a conventional ECAP-based program with unmodified ECAP threshold profiles. A questionnaire captured their subjective preferences. In phase I, the profile scaling model constructed from the data prescribed a flattening of the ECAP threshold profile with increasing mean T- or C-level (in CL units): scale = 1.38 - 0.0043 PsychoMean. In phase II, the scaled ECAP-based profiles were found to fit the psychophysical profiles significantly better in all test configurations (typically of the order of 5% dynamic range) compared with all other profiles. In phase III, 62% of subjects preferred the scaled ECAP-based program, whereas 8% preferred the conventional ECAP-based program, 15% the flat program and 15% had no preference. Analyses of the questionnaires revealed significantly higher ratings for the scaled ECAP-based programs, whereas the conventional ECAP-based programs were not rated differently than the flat programs. The scaled ECAP threshold profile method provides a clinically significant enhancement to ECAP-based fitting methods, confirming the value of the ECAP threshold profile to cochlear implant fitting.


Rate of decline of kidney function in patients with type 2 diabetes mellitus and the associated factors: a 10-year retrospective cohort study.
This study examines the rate of decline of estimated glomerular filtration rate (eGFR) over a 10-year period and the associated risk factors in type 2 diabetes mellitus (T2DM) patients. Medical records of T2DM patients were randomly selected. The rate of fall in eGFR (simplified modification of diet in renal disease formula) was used as a measure of decline. Univariate and multivariate analysis were performed to determine the factors associated with decline of kidney function. A total of 504 patients were selected. Mean age was 57.8 ± 9 years; 65.3% were females. The mean decline rate of eGFR was 0.89 ± 2.16 mL/min/1.73 m(2)/y. Baseline proteinuria, glycosylated hemoglobin level, duration of T2DM, and Malay race were associated with faster decline in eGFR. The expected greater deterioration in kidney function in this cohort was not seen. Treatment of proteinuria and glycemia should be optimized early to retard the decline in kidney function in patients with T2DM.


Adherence to Antipsychotic Medication by Community-Based Patients With Schizophrenia in China: A Cross-Sectional Study.
Nonadherence to antipsychotic medication is a major health concern. Identification of risk factors associated with nonadherence is a useful initial step toward designing an effective intervention. This study compared the characteristics of medication-adherent and -nonadherent outpatients with schizophrenia in a Chinese community setting. In a naturalistic, multicenter, and cross-sectional design, 601 outpatients with schizophrenia served by the National Continuing Management and Intervention Program for Psychoses (the "686 program") were surveyed from June 2013 to January 2014 in four Chinese cities. On the basis of self-reported behavior, the patients were divided into medication-adherent and -nonadherent groups. Logistic regression analyses were performed to identify potential risk factors associated with nonadherence. The analyses included 554 patients, 20% of whom were considered to be nonadherent. Compared with the adherent group, the nonadherent group had a longer period of untreated psychosis (odds ratio [OR]=1.09), lower body mass index (OR=.94), higher rate of rural residency (OR=2.01), and lower monthly household income per capita (OR=.94/100 renminbi) (p<.05 by hierarchical analysis). Other characteristics (age, gender, occupation, education, marital status, living with family, age at initial presentation of symptoms, duration of illness, and type of antipsychotic medication) did not differ significantly between the groups. Medication-adherent and -nonadherent groups differed significantly in some social and treatment characteristics. These findings may be useful in informing the development of strategies for reducing medication nonadherence.


Plasmid pRQ7 from the hyperthermophilic bacterium Thermotoga species strain RQ7 replicates by the rolling-circle mechanism.
The hyperthermophilic bacterium Thermotoga species strain RQ7 harbors an 846-bp plasmid, pRQ7, with a single open reading frame. Previously published analyses of the DNA sequence of pRQ7 suggested that it may replicate by a rolling-circle (RC) replication mechanism, and this report provides experimental evidence supporting this hypothesis. Single-stranded pRQ7 DNA accumulates in strain RQ7, as evidenced by the facts that this DNA bound to nitrocellulose membranes under nondenaturing conditions, was sensitive to S1 nuclease digestion, and hybridized to only one of two homologous DNA probes specific for each strand of the plasmid. The DNA encoding the open reading frame was cloned and expressed in Escherichia coli and gave a protein with a molecular mass of 26 kDa, similar to that deduced by sequence analysis. This protein bound to a fragment of pRQ7 that contains a putative double-stranded replication region in a magnesium-dependent reaction and made this fragment sensitive to S1 nuclease activity. It did not cause this same S1 nuclease sensitivity in the remainder of pRQ7. This activity on pRQ7 DNA suggests that this protein plays a role in plasmid replication.


GPs' views and experiences of prescribing non-steroidal anti-inflammatory drugs: a qualitative study.
Non-steroidal anti-inflammatory drugs (NSAIDs) are widely prescribed in primary care despite being a high-risk drug group causing significant adverse events, yet little is known about GPs' perceptions of NSAID risks and benefits. To explore GPs' experiences with NSAID prescribing and views about the risks and benefits of this group of medicines. A qualitative, inductive study in general practice. Individual interviews with 15 GPs using a semi-structured interview guide. Interviews were audiorecorded and transcribed. An inductive, thematic approach was used for analysis. Sampling continued until data saturation was achieved. Three main themes illustrate GPs' key concerns with managing NSAID risks. The first theme was perceptions of risks and benefits of NSAIDs: GPs expressed differing attitudes towards prescribing medication generally. GPs were aware of the general risks of NSAIDs but weighed these up against specific risk factors and potential benefits for particular patients. They were most concerned about long-term use, risks for children, older people, and patients with comorbidities. The second theme was assessing and mitigating risks when prescribing NSAIDs: GPs considered gastric, cardiac, and renal risks of patients as well as drug interactions. Mitigation strategies included alternative treatment, choice and dose of NSAID, and use of gastroprotective agents. The final theme was other factors impacting on NSAID risks: particularly patient expectations and over-the-counter (OTC) availability. NSAID prescribing is a complex balance between pragmatism and potential adverse events. Given the costs of morbidity, hospitalisation, and patient demand there is an urgent need to secure a more detailed evidence base and develop practical pathways to support safer prescribing.


Technique of pulmonary vein isolation by catheter ablation.
In selected patients with atrial fibrillation, the fibrillation episodes may be initiated by single or short bursts of ectopy often originating from one or more pulmonary veins (PVs). Therefore, electrical isolation of these veins by catheter ablation is currently being explored as a treatment modality for patients with paroxysmal and even more permanent types of atrial fibrillation. At present, two different techniques are used: 1) selective ablation of electrical connections between left atrium and myocardial sleeves inside the PVs; and 2) contiguous encircling lesions around and outside the PV ostia. With both techniques, moderate to high success rates have been reported with a limited follow-up duration. Both types of procedure are very complex and require a highly skilful team. With the variable anatomy of the PVs, non-invasively acquired angiographic images may serve as a roadmap for catheter manipulation. Modern three-dimensional catheter navigation techniques can be applied to facilitate accurate catheter positioning with limited fluoroscopic exposure. Experimental and clinical research is needed to define patient selection criteria.


Evaluation of falls in older persons in the emergency department during the early Coronavirus-2019 pandemic and pre-pandemic periods.
This study aimed to investigate the clinical characteristics, outcomes and healthcare costs of older patients presented to the emergency department (ED) with falls in the periods before and during the Coronavirus disease-2019 (COVID-19) pandemic. Hospital records one year before and after the onset of the COVID-19 pandemic were retrospectively analyzed through "International Statistical Classification of Diseases-10th Revision" codes. Age, gender, falls, triage classification, length of stay (LOS) in the hospital and the ED, COVID-19 status, Glasgow Coma scale, consultations-comorbidities, injury status, outcomes in the ED, and costs were recorded. The study comprised of 3187 patients aged ≥ 65 years admitted to the ED of a university hospital between March 2019 and 2021. In terms of pre-pandemic and pandemic periods; older patients presenting with falls to the ED, consultations, Charlson Comorbidity Index, and LOS in the ED were lower in the pandemic period, but costs were higher (p = 0.03, p = 0.01, p = 0.01, p = 0.01 and p = 0.02, respectively). Hospitalization/mortality rates were higher in COVID-19 positive patients (77.2%) than in COVID-19 negative patients (4.6%) within the pandemic period and the patients in the pre-pandemic period (22.8%), and the costs, as well (both p = 0.01). Though the number of fall-related presentations of older persons to the ED, comorbidity burden, consultations, and the LOS in the ED was lower, direct costs were higher during the pandemic period, particularly for COVID-19 positive older patients admitted to ED with falls than the pre-pandemic period, and those patients were with poorer outcomes.