WNT5A expression in human breast cancer.
The Wnt family encodes secreted signaling molecules involved in cell adhesion and, by implication, cell growth. Wnt5a has been shown to behave as a putative oncogene and also as a tumour suppressor gene. This is a reflection of its role within a multi-step pathway and in the variety of ways in which its production can be stimulated or switched off. Wnt genes can be functionally separated into two classes; those that activate the canonical Wnt/beta-catenin pathway and those that activate the Wnt/Ca++ pathway. Wnt5a signals through frizzled receptors and, depending upon which frizzled receptor is present, may activate either pathway. Therefore the observed function of Wnt5a is entirely dependent upon its context, hence the confusion over its role in tumorigenesis. This study examines Wnt5a mRNA expression using RT-PCR in human breast cancer. One hundred and twenty malignant breast tumours and 33 normal breast tissues were analysed. The levels of transcription of Wnt5a were determined using real-time quantitative PCR. Levels of expression were analysed against staging, nodal involvement, grade, distant metastasis and survival over a 6-year follow-up period. Levels of Wnt5a mRNA were lower in tumours than in normal tissue (mean values: 107 vs. 62.7). They fell further with increasing stage using the Nottingham Prognostic Index. This became statistically significant when NPI3 was compared to normal tissue (p=0.043, t-test). There was a trend towards lower levels of Wnt5a in those with progressive disease, however, this did not reach statistical significance. In patients with ER-negative disease, lower levels of Wnt5a were significantly associated with a worse clinical outcome (p=0.016). There is a trend for mRNA levels to be lower in cancerous tissue and lower still in those showing more aggressive behaviour. This is consistent with the hypothesis that Wnt5a is a tumour suppressor gene with potential clinical applications.


An extinction event in planktonic Foraminifera preceded by stabilizing selection.
Unless they adapt, populations facing persistent stress are threatened by extinction. Theoretically, populations facing stress can react by either disruption (increasing trait variation and potentially generating new traits) or stabilization (decreasing trait variation). In the short term, stabilization is more economical, because it quickly transfers a large part of the population closer to a new ecological optimum. However, stabilization is deleterious in the face of persistently increasing stress, because it reduces variability and thus decreases the ability to react to further changes. Understanding how natural populations react to intensifying stress reaching terminal levels is key to assessing their resilience to environmental change such as that caused by global warming. Because extinctions are hard to predict, observational data on the adaptation of populations facing extinction are rare. Here, we make use of the glacial salinity rise in the Red Sea as a natural experiment allowing us to analyse the reaction of planktonic Foraminifera to stress escalation in the geological past. We analyse morphological trait state and variation in two species across a salinity rise leading to their local extinction. Trilobatus sacculifer reacted by stabilization in shape and size, detectable several thousand years prior to extinction. Orbulina universa reacted by trait divergence, but each of the two divergent populations remained stable or reacted by further stabilization. These observations indicate that the default reaction of the studied Foraminifera is stabilization, and that stress escalation did not lead to the emergence of adapted forms. An inherent inability to breach the global adaptive threshold would explain why communities of Foraminifera and other marine protists reacted to Quaternary climate change by tracking their zonally shifting environments. It also means that populations of marine plankton species adapted to response by migration will be at risk of extinction when exposed to stress outside of the adaptive range.


Sulfide-dependent Photoautotrophy in the Filamentous Anoxygenic Phototrophic Bacterium, Chloroflexus aggregans.
Chloroflexus aggregans is a thermophilic filamentous anoxygenic phototrophic bacterium frequently found in microbial mats in natural hot springs. C. aggregans often thrives with cyanobacteria that engage in photosynthesis to provide it with an organic substrate; however, it sometimes appears as the dominant phototroph in microbial mats without cyanobacteria. This suggests that C. aggregans has the ability to grow photoautotrophically. However, photoautotrophic growth has not been observed in any cultured strains of C. aggregans. We herein attempted to isolate a photoautotrophic strain from C. aggregansdominated microbial mats in Nakabusa hot spring in Japan. Using an inorganic medium, we succeeded in isolating a new strain that we designated "ACA-12". A phylogenetic analysis based on 16S rRNA gene and 16S-23S rRNA gene internal transcribed spacer (ITS) region sequences revealed that strain ACA-12 was closely related to known C. aggregans strains. Strain ACA-12 showed sulfide consumption along with autotrophic growth under anaerobic light conditions. The deposited elemental sulfur particles observed by microscopy indicated that sulfide oxidation occurred, similar to that in photoautotrophic strains in the related species, C. aurantiacus. Moreover, we found that other strains of C. aggregans, including the type strain, also exhibited a slight photoautotrophic growing ability, whereas strain ACA-12 showed the fastest growth rate. This is the first demonstration of photoautotrophic growth with sulfide in C. aggregans. The present results strongly indicate that C. aggregans is associated with inorganic carbon incorporation using sulfide as an electron donor in hot spring microbial mats.


Inverse method for quantitative characterisation of breast tumours from surface temperature data.
We introduce a computational method to simultaneously estimate size, location and blood perfusion of the cancerous breast lesion from the surface temperature data. A 2D computational phantom of axisymmetric tumorous breast with six tissue layers, epidermis, papillary dermis, reticular dermis, fat, gland, muscle layer and spherical tumour was used to generate surface temperature distribution and thereby estimate tumour characteristics iteratively using an inverse algorithm based on Levenberg-Marquardt method. In addition to the steady state temperature data, we modified and expanded the inverse algorithm to include transient data that can be captured by dynamic infra-red imaging. Several test cases were considered for the transient analysis, where the depth, radii and blood perfusion of tumour were varied from 11 to 30 mm, 7 to 11 mm and 0.003 to 0.01 1/s, respectively. Similar steady state temperature profile for different tumours makes it impossible to simultaneously estimate blood perfusion, size and location of tumour using steady state data alone. This becomes possible when transient data are used along with steady state data. For the cases discussed here, the estimates have errors below 1% for tumours with depths less than 20 mm, but for deeper tumours (25 mm) errors can be more than 10%. Combination of transient data and steady state data makes it possible to simultaneously estimate tumour size, location and blood perfusion. Blood perfusion is an indicator of the growth rate of the tumour and therefore its evaluation can possibly lead to the assessment of tumour malignancy.


Effects of elastin haploinsufficiency on the mechanical behavior of mouse arteries.
Supravalvular aortic stenosis (SVAS) is associated with decreased elastin and altered arterial mechanics. Mice with a single deletion in the elastin gene (ELN(+/-)) are models for SVAS. Previous studies have shown that elastin haploinsufficiency in these mice causes hypertension, decreased arterial compliance, and changes in arterial wall structure. Despite these differences, ELN(+/-) mice have a normal life span, suggesting that the arteries remodel and adapt to the decreased amount of elastin. To test this hypothesis, we performed in vitro mechanical tests on abdominal aorta, ascending aorta, and left common carotid artery from ELN(+/-) and wild-type (C57BL/6J) mice. We compared the circumferential and longitudinal stress-stretch relationships and residual strains. The circumferential stress-stretch relationship is similar between genotypes and changes <3% with longitudinal stretch at lengths within 10% of the in vivo value. At mean arterial pressure, the circumferential stress in the ascending aorta is higher in ELN(+/-) than in wild type. Although arterial pressures are higher, the increased number of elastic lamellae in ELN(+/-) arteries results in similar tension/lamellae compared with wild type. The longitudinal stress-stretch relationship is similar between genotypes for most arteries. Compared with wild type, the in vivo longitudinal stretch is lower in ELN(+/-) abdominal and carotid arteries and the circumferential residual strain is higher in ELN(+/-) ascending aorta. The increased circumferential residual strain brings the transmural strain distribution in ELN(+/-) ascending aorta close to wild-type values. The mechanical behavior of ELN(+/-) arteries is likely due to the reduced elastin content combined with adaptive remodeling during vascular development.


Stay the course: practitioner reflections on implementing family-based treatment with adolescents with atypical anorexia.
Atypical anorexia nervosa (AN) has received minimal empirical attention regarding effective diagnosis and treatment. Family-based treatment (FBT) might be a promising treatment for atypical AN, yet it is unclear as to what adaptations are needed to the current manualized FBT for AN model. The objective of the current study was to identify how FBT practitioners applied FBT for atypical AN for adolescents in their clinical practice, and if there were any implementation challenges and adaptations to the model for this population. The current study employed fundamental qualitative description, with the aim of capturing practitioners' reflections on working with adolescents with atypical AN in clinical practice. A purposeful sample of practitioners with training in FBT were recruited and each participant completed an individual, semi-structured interview. Data was analyzed using conventional content analysis. A total of 23 practitioners participated in this study. The results indicate that practitioners maintained some fidelity to manualized FBT in treating atypical AN, but they differed in their discussions around target weights, what constitutes weight restoration, and the dosage for FBT phases. Salient practice challenges included operationalizing the Diagnostic and Statistical Manual of Mental Disorders - 5th Edition (DSM-5) definition of atypical AN, identifying a 'goal weight' for adolescents and activating parents to take charge of the re-nourishment process. The results of this qualitative study demonstrate practitioner reflections on the delivery and adaptations of FBT for adolescents with atypical AN. These reflections highlight the need to establish the delivery of coherent and consistent treatment and messaging with patients and families. Further, practitioners' reflections highlight common strategies to increase the sense of urgency in parents to support their child with atypical AN.


Video technology. Use in nursing research.
Video technology is becoming more popular as a research tool because it has unique features that capture accurately and comprehensively the nature of nursing phenomena. Video technology is used extensively in nursing as an educational tool or intervention, a means of monitoring quality assurance standards, and as tool to collect research data. Videotaping is useful because is provides continuous multi-media, multisensory information about the subject and its context. Credibility for video data is based on the question of to what extent do the data or results adequately represent true behavior. The three main issues in video research that impact the credibility of data are observer bias, participant reactivity to knowledge of being videotaped, and maintenance of consistent data quality. Not all threats to credibility can be overcome. The key is to acknowledge insurmountable problems, to consider their limitations in data analysis, and to evaluate and report their effects.


Chest computerized tomography scan findings in 74 children with tuberculous meningitis in southeastern Turkey.
This prospective study was done over seven years from 1996 to 2003 to investigate the chest computed tomography scan findings along with other radiologic examinations that included chest roentgenography and cranial computed tomography in children with tuberculous meningitis (TBM). Chest roentgenography demonstrated abnormal findings in 32 cases (43%) (hilar adenopathy, 32%; miliary pattern, 18%; bronchopneumonic infiltrate, 24%), while chest computerized tomography was abnormal in 65 cases (88%; p<0.005): mediastinal and hilar lymphadenopathy were present in 46% (p<0.005); miliary pattern, in 23% (p<0.05); and bronchopneumonic infiltrate, in 23% (p<0.05). Cranial computerized tomography was abnormal in 68 cases (92%). Chest computerized tomography scan helps establish the diagnosis of TBM when chest radiography is normal or inconclusive, and it is useful in assessing children with suspected TBM.


Quantitative impact of cardiovascular risk factors and vascular closure devices on the femoral artery after repeat cardiac catheterization.
We evaluated the exact quantitative long-term impact of repeated catheterizations, vascular closure devices, and cardiovascular risk factors on the femoral artery after cardiac catheterization. A total of 2,102 available femoral angiograms from 827 consecutive patients were analyzed using caliper-based quantitative vascular analysis. These patients underwent coronary interventions between January 2005 and April 2007 and had at least one additional catheterization procedure through the ipsilateral femoral access site from December 2001 until January 2008. Multivariate analysis was performed to control for confounding variables. The primary outcome was change in artery size. The average punctured artery diameter was 6.5 +/- 2.1 mm. The average time between the first case and last follow-up was 349 days. There was no significant change of the punctured artery size over time after the index procedure (P = .15) and no change associated with the use of vascular closure devices (P = .25) after multivariate analysis. Smaller arteries were associated with female gender (-1.22 mm, P < .0001), presence of angiographic peripheral vascular disease (PVD, -1.19 mm, P < .0001), and current (-0.48 mm, P = .001) or former (-0.23 mm, P = .01) smoking status, whereas previous statin therapy was associated with an increase in artery size (+0.47 mm, P < .0001). Vascular closure devices were used less often compared with manual compression in cases preceding the first detection of angiographic PVD (P < .001). Vascular closure devices are not associated with a change in the artery size or progression of PVD. Overall, there is no change in vessel size over time after repeat catheterizations, with a decrease in vessel size associated with current and former smoking and an increase with previous statin therapy.


Association of genes involved in bile acid synthesis with the progression of primary biliary cirrhosis in Japanese patients.
Patients with primary biliary cirrhosis (PBC) exhibit a variety of clinical manifestations and patterns of disease progression. The aim of this study was to identify genetic determinants of PBC progression. A total of 52 tag single nucleotide polymorphisms (SNPs) of 11 candidate genes involved in regulating bile acid synthesis were analyzed by polymerase chain reaction (PCR)-restriction fragment length polymorphism, -high resolution melting curve analysis, or -direct DNA sequencing in 315 Japanese patients with PBC. In this study, four tag SNPs of CYP7A1 (rs1457043, rs8192870, rs3808607, and rs3824260), two tag SNPs of HNF4A (rs6017340 and 6031587), and one SNP of PPARGC1A (rs8192678) showed a significant association with PBC progression. In addition, a dual luciferase assay revealed that the polymorphism of rs3808607 in CYP7A1 altered the expression of CYP7A1 in HepG2. Specifically, the CYP7A1 promoter carrying the risk G allele for PBC progression induced higher expression of CYP7A1 under both the normal and cholestatic conditions in vitro as compared to another promoter carrying the non-risk T allele. These results suggested that the genetic variants of CYP7A1 and its transcriptional activators (HNF4A and PPARGC1A) may activate bile acid synthesis, resulting in the accumulation of bile acids in hepatocytes and eventually leading to the predisposition to PBC progression. Thus, the regulation of CYP7A1 expression may represent an attractive therapeutic target for cholestatic liver diseases including PBC.


Identifying Putative Causal Links between MicroRNAs and Severe COVID-19 Using Mendelian Randomization.
The SARS-CoV-2 (COVID-19) pandemic has caused millions of deaths worldwide. Early risk assessment of COVID-19 cases can help direct early treatment measures that have been shown to improve the prognosis of severe cases. Currently, circulating miRNAs have not been evaluated as canonical COVID-19 biomarkers, and identifying biomarkers that have a causal relationship with COVID-19 is imperative. To bridge these gaps, we aim to examine the causal effects of miRNAs on COVID-19 severity in this study using two-sample Mendelian randomization approaches. Multiple studies with available GWAS summary statistics data were retrieved. Using circulating miRNA expression data as exposure, and severe COVID-19 cases as outcomes, we identified ten unique miRNAs that showed causality across three phenotype groups of COVID-19. Using expression data from an independent study, we validated and identified two high-confidence miRNAs, namely, hsa-miR-30a-3p and hsa-miR-139-5p, which have putative causal effects on developing cases of severe COVID-19. Using existing literature and publicly available databases, the potential causative roles of these miRNAs were investigated. This study provides a novel way of utilizing miRNA eQTL data to help us identify potential miRNA biomarkers to make better and early diagnoses and risk assessments of severe COVID-19 cases.


Evaluation and mechanistic analysis of the cytotoxicity of the acyl glucuronide of nonsteroidal anti-inflammatory drugs.
The chemical reactivity of acyl glucuronide (AG) has been thought to be associated with the toxic properties of drugs containing carboxylic acid moieties, but there has been no direct evidence showing that AG formation is related to the observed toxicity. In the present study, the cytotoxicity of AGs, especially that associated with the inflammatory response, was investigated. The changes in the mRNA and protein expression levels of interleukin 8 (IL-8) and monocyte chemoattractant protein (MCP)-1 induced by the treatment of human peripheral blood mononuclear cells (PBMCs) with diclofenac (Dic), probenecid (Pro), tolmetin (Tol), ibuprofen (Ibu), naproxen (Nap), and their AGs were investigated by real-time reverse transcription polymerase chain reaction, and the viabilities of CD3+, CD14+, and CD19+ cells were measured by flow cytometry. Treatment with Dic-AG, Pro-AG, and Tol-AG significantly increased the expression levels of IL-8 and MCP-1. In addition, Dic-AG, Pro-AG, and Tol-AG significantly decreased the viability of CD14+ cells. Of these three AGs, Dic-AG showed the most potent changes, followed by Tol-AG and Pro-AG. Treatment with Ibu-AG and Nap-AG affected neither the expression levels of IL-8 and MCP-1 nor the viability of CD14+ cells. None of the drugs affected the CD3+ and CD19+ cell populations. Dic-AG increased the phosphorylation of p38 mitogen-activated protein (MAP) kinase and c-Jun N-terminal kinase (JNK)1/2. The pretreatment of peripheral blood mononuclear cells (PBMCs) with SB203580 (p38 inhibitor) significantly suppressed the Dic-AG-induced expression of inflammatory factors and cytotoxicity of CD14+ cells. In conclusion, AGs induce inflammatory responses and cytotoxicity against CD14+ cells via the p38 MAPK pathway. These factors may be useful biomarkers for evaluating the toxicity of AGs.


[Fragments of limited trypsinolysis of native alpha-actinin].
Incubation of native alpha-actinin with trypsin leads to the formation of intermediate fragments that are quite resistant to further enzyme action (M 98, 85, 80, 70, 64, 55, 38, 30, 15 kDa). Analysis of these fragments made it possible to elucidate the course of trypsinolysis and to localize the fragments in the polypeptide chain of alpha-actinin subunit.


An analysis of Medicare's Incentive Payment program for physicians in health professional shortage areas.
Medicare's Incentive Payment (MIP) program provides a 10% bonus payment to providers who treat Medicare patients in rural and urban areas where there is a shortage of generalist physicians. To examine the experience of Alaska, Idaho, North Carolina, South Carolina, and Washington with the MIP program. We determined the program's utilization and which types of physicians received payments. Retrospective cohort design, utilizing complete 1998 Medicare Part B data. Physician specialty was determined through American Medical Association data. Rural status was determined by linking the physician business ZIP code to its Rural-Urban Commuting Area code (RUCA). There were 2,220,275 patients and 39,749 providers in the cohort, including 9,769 (24.6%) generalists, 21,331 (53.7%) specialists, and 8,649 (21.8%) nonphysician providers. Over $4 million in bonus payments (median payment = $173) were made to providers in HPSAs. Specialists and urban providers received 58% and 14% of the bonus reimbursements, respectively. Two million dollars in payments were not distributed because the providers did not claim them. Over $2.8 million in bonus claims were distributed to providers who likely did not work in approved HPSA sites. The MIP bonus payments given to providers are small. Many providers who should have claimed the bonus did not, and many providers who likely did not qualify for the bonus claimed and received it. Consideration should be given to focusing and enlarging the bonus payments to specific providers, rather than rewarding all providers equally. Policy makers should also consider a system that prospectively determines provider eligibility.


Long-term venovenous extracorporeal membrane oxygenation support for acute respiratory distress syndrome after COVID-19.
Acute respiratory syndrome (ARDS) following coronavirus 2 (SARS-CoV-2) infection is a serious complication often causing irreversible lung injury associated with high mortality. Extracorporeal membrane oxygenation (ECMO) may be initiated in severe cases. We present a case of ARDS following SARS-CoV-2 infection with prolonged duration ECMO (1045 hours, 44 days) without exchanging circuit throughout the whole duration without technical complication. A 71-year-old man of acute respiratory failure secondary to SARS-CoV-2 infection was initiated on venovenous ECMO (VV-ECMO). There was no technical complication without exchanging circuit throughout the whole prolonged ECMO duration (1045 hours, 44 days). Despite a great effort to improve his lung mechanics and gas exchange, there was continued clinical and physiological deterioration unfortunately. Following family discussion and with input from the multidisciplinary team (MDT) including palliative care specialists, there was recognition of deterioration despite optimal respiratory support. Shortly thereafter planned withdrawal occurred, and the patient passed away with his family at his bedside. This case study illustrates that it may be considered to use long term ECMO as a bridge to recovery or lung transplantation of ARDS patient after SARS-CoV-2 infection with severe lung injury. Benefits from proper long-term ECMO management,it is possible of sparing to exchange circuit throughout the whole prolonged duration without technical complication. This case indicates the feasibility of using of a long term VV-ECMO as a bridge to recovery or lung transplantation of ARDS patient after secondary to coronavirus 2 (SARS-CoV-2) infection with severe lung injury without circuit exchange. The optimal duration of VV-ECMO support and optimal diagnostic modalities for critical assessment of native lung recovery or irretrievable severe lung injury still require further investigation.


Vitamin D and rheumatic diseases.
Vitamin D has some well-known effects on calcium, phosphate and bone metabolism, but it has recently shown to have many other effects, which may potentially be relevant to patients with extra-skeletal rheumatic diseases. Such effects may be justified by: 1) the presence of the vitamin D receptors also on extra-osseous cells, such as cartilage cells, sinoviocytes, muscle cells; 2) the proven role of vitamin D in the control of the transcription of genes involved in rheumatic diseases; 3) the evidence that vitamin D has multiple endocrine effects not only on calcium homeostasis; 4) the activation of vitamin D not only in the kidneys, but also in monocyte-macrophage and lymphocytic cell lines and in some epithelial cells with additional intracrine and paracrine effects. Vitamin D deficiency has been reported in numerous metabolic, degenerative, inflammatory and autoimmune rheumatic diseases. In some cases this association was also related to the risk of developing a rheumatic disease or the degree of disease activity. However there is no conclusive evidence of the efficacy of a preventive or therapeutic strategy based on vitamin D supplementation in extra-skeletal rheumatic diseases. This review aims to provide an overview of the latest evidence concerning the relationship between vitamin D and the most relevant rheumatic diseases.


Ligand protons in a frozen solution of copper histidine relax via a T1e -driven three-spin mechanism.
Davies electron-nuclear double resonance spectra can exhibit strong asymmetries for long mixing times, short repetition times, and large thermal polarizations. These asymmetries can be used to determine nuclear relaxation rates in paramagnetic systems. Measurements of frozen solutions of copper(L-histidine)(2) reveal a strong field dependence of the relaxation rates of the protons in the histidine ligand, increasing from low (g( parallel)) to high (g( perpendicular)) field. It is shown that this can be attributed to a concentration-dependent T(1e)-driven relaxation process involving strongly mixed states of three spins: the histidine proton, the Cu(II) electron spin of the same complex, and another distant electron spin with a resonance frequency differing from the spectrometer frequency approximately by the proton Larmor frequency. The protons relax more efficiently in the g( perpendicular) region, since the number of distant electrons able to participate in this relaxation mechanism is higher than in the g( parallel) region. Analytical expressions for the associated nuclear polarization decay rate Tau(een) (-1) are developed and Monte Carlo simulations are carried out, reproducing both the field and the concentration dependences of the nuclear relaxation.


Association of Surgical Treatment, Systemic Therapy, and Survival in Patients With Abdominal Visceral Melanoma Metastases, 1965-2014: Relevance of Surgical Cure in the Era of Modern Systemic Therapy.
Systemic therapy for metastatic melanoma has evolved rapidly during the last decade, and patient treatment has become more complex. To evaluate the survival benefit achieved through surgical resection of melanoma metastatic to the abdominal viscera in patients treated in the modern treatment environment. This retrospective review of the institutional melanoma database from the John Wayne Cancer Institute at Providence St Johns Health Center, a tertiary-level melanoma referral center, included 1623 patients with melanoma diagnosed as having potentially resectable abdominal metastases before (1969-2003) and after (2004-2014) advances in systemic therapy. Overall survival (OS). Of the 1623 patients identified in the database with abdominal melanoma metastases, 1097 were men (67.6%), and the mean (SD) age was 54.6 (14.6) years. Of the patients with metastatic melanoma, 1623 (320 [19.7%] in the 2004-2014 period) had abdominal metastases, including 336 (20.7%) with metastases in the gastrointestinal tract, 697 (42.9%) in the liver, 138 (8.5%) in the adrenal glands, 38 (2.3%) in the pancreas, 109 (6.7%) in the spleen, and 305 (18.8%) with multiple sites. Median OS was superior in surgical (n = 392; 18.0 months) vs nonsurgical (n = 1231; 7.0 months) patients (P < .001). The most favorable 1-year and 2-year OS was seen after surgery for gastrointestinal tract (52% and 41%) and liver (51% and 38%) metastases, respectively. Multivariable analysis found increasing age (hazard ratio [HR], 1.01; 95% CI, 1.00-1.01; P = .02) and the presence of ulceration (HR, 1.21; 95% CI, 1.01-1.45; P = .04) were associated with a worse OS. Alternatively, treatment with metastasectomy (HR, 0.59; 95% CI, 0.46-0.74; P < .001) and metastases involving the gastrointestinal tract (HR, 0.65; 95% CI, 0.48-0.87; P = .004) were associated with a better OS. The systemic treatment era did not significantly affect outcomes (HR, 0.82; 95% CI, 0.67-1.02; P = .15). Overall, patients with gastrointestinal tract metastases undergoing complete, curative resection derived the greatest benefit, with a median OS of 64 months. To our knowledge, this series is the largest single-institution experience with abdominal melanoma metastases, demonstrating that surgical resection remains an important treatment consideration even in the systemic treatment era.


Single-turnover kinetics of homoprotocatechuate 2,3-dioxygenase.
Homoprotocatechuate 2,3-dioxygenase isolated from Brevibacterium fuscum utilizes an active site Fe(II) and O(2) to catalyze proximal extradiol cleavage of the substrate aromatic ring. In contrast to other members of the ring cleaving dioxygenase family, the transient kinetics of the extradiol dioxygenase catalytic cycle have been difficult to study because the iron is nearly colorless and EPR silent. Here, it is shown that the reaction cycle kinetics can be monitored by utilizing the alternative substrate 4-nitrocatechol (4NC), which is also cleaved in the proximal extradiol position. Changes in the optical spectrum of 4NC occurring as a result of ionization, environmental changes, and ring cleavage allow both the substrate binding and product formation phases of the reaction to be studied. It is shown that substrate binding occurs in a four-step process probably involving binding to two ionization states of the enzyme at different rates. Following an initial rapid binding of the monoanionic 4NC in the active site, slower binding to the Fe(II) and conversion to the dianionic form occur. The bound dianionic 4NC reacts rapidly with O(2) in four additional steps, apparently occurring in sequence. On the basis of the optical properties of the intermediates, these steps are hypothesized to be O(2) binding to the iron, isomerization of the resulting complex, ring opening, and product release. The natural substrate appears to form the same intermediates but with much larger rate constants. These are the first transient intermediates to be reported for an extradiol dioxygenase reaction.


Optimization of screw fixation in rat bone with extracorporeal shock waves.
Screw fixation in osteoporotic patients is becoming an increasing problem in orthopaedic surgery as deterioration of cortical and cancellous bone hamper biomechanical stability and screw fixation. This might result in delayed weight-bearing or failure of instrumentation. We hypothesized that local peri-operative shock wave treatment can optimize osseointegration and subsequent screw fixation. In eight female Wistar rats, two cancellous and two cortical bone screws were implanted in both femora and tibiae. Immediately after implantation, 3.000 unfocused extracorporeal shock waves (energy flux density 0.3 mJ/mm2 ) were applied to one side. The other side served as non-treated internal control. Evaluation of osseointegration was performed after 4 weeks with the use of microCT scanning, histology with fluorochrome labeling, and pull-out tests of the screws. Four weeks after extracorporeal shock wave treatment, treated legs exhibited increased bone formation and screw fixation around cortical screws as compared to the control legs. This was corroborated by an increased pull-out of the shock wave treated cortical screws. The cancellous bone screws appeared not to be sensitive for shock wave treatment. Formation of neocortices after shock wave therapy was observed in three of eight animals. Furthermore, de novo bone formation in the bone marrow was observed in some animals. The current study showed bone formation and improved screw fixation as a result of shock wave therapy. New bone was also formed at locations remote from the screws, hence, not contributing to screw fixation. Further, research is warranted to make shock wave therapy tailor-made for fracture fixation. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:76-84, 2018.


Arts-Based Compassion Skills Training (ABCST): Channelling Compassion Focused Therapy Through Visual Arts for Australia's Indigenous Peoples.
The last 20 years have seen the development of a new form of therapy, compassion focused therapy (CFT). Although CFT has a growing evidence base, there have been few studies of CFT outside of an Anglo-European cultural context. In this paper, we ask: Might a CFT-based approach be of value for Indigenous Australians? If so, what kind of cultural adaptations might be needed? We report the findings from a pilot study of an arts-based compassion skills training (ABCST) group, in which usual CFT group processes were significantly adapted to meet the needs of Indigenous Australians. At face value, CFT appeared to be a promising approach to enhancing the social and emotional wellbeing of Australia's Indigenous peoples. However, despite initial consultations with Indigenous health professionals, the first attempts to offer a more conventional group-based CFT to Indigenous clients were largely unsuccessful. Following a review and advice from two Indigenous clients, we combined elements of CFT with visual arts to develop a new approach, "arts-based compassion skills training" (ABCST). This paper reports an evaluation of this pilot ABCST group. The group had 6 × 4 h sessions of ABCST, facilitated by two psychologists (1 Indigenous, 1 non-Indigenous) and two artists (1 Indigenous, 1 non-Indigenous). There were 10 participants, who attended between 2 and 6 sessions: five were clients, five were health professionals. Between 1 and 3 months later, six of the participants (2 clients, 4 health professionals) were interviewed. Qualitative analysis of interview data identified that two key processes-creating a positive group atmosphere and channeling compassion skills training through the medium of visual arts-led to four positive outcomes for participants: planting the seeds of new understandings, embodying the skills of compassion, strengthening relationships with others, and evolving a more self-compassionate relationship. We suggest that the preliminary results are sufficiently encouraging to warrant further development of ABCST in Indigenous communities.


Cisplatin-induced ototoxicity: effect of intratympanic dexamethasone injections.
Intratympanic (IT) application of dexamethasone will reduce ototoxicity associated with systemic cisplatin therapy. Cisplatin is a common chemotherapeutic drug often dose-limited by ototoxicity attributed to the formation of reactive oxygen and nitrogen species damaging critical inner ear structures. Steroids have been shown to reduce formation of reactive oxygen species and thus may reduce ototoxicity. In the present pilot study, we test this hypothesis by IT administration of dexamethasone in a novel murine model of cisplatin ototoxicity. Click- and pure-tone-evoked auditory brainstem responses (ABRs) in young CBA/J mice were measured. The first phase consisted of a dosing study to identify the optimal cisplatin dose for ototoxicity. In the next phase, ABR thresholds were measured in cisplatin-treated mice after 5 days of IT injection of 24 mg/ml of dexamethasone in 1 ear and normal saline in the opposite ear to serve as controls. Intraperitoneal injection of 14 mg/kg of cisplatin induces significant hearing loss (click-evoked ABR threshold elevation = 12 +/- 7 dB, mu +/- standard error of the mean) with acceptable mortality (20%). The ears that received IT dexamethasone in cisplatin-treated mice had minimal ABR threshold shifts with the click, 8 and 16 kHz of stimuli. There was no significant difference between IT dexamethasone and IT saline ears at 32 kHz. IT dexamethasone protected the mouse ear against cisplatin-induced ototoxicity in a frequency-dependent manner. The present results suggest that IT dexamethasone may be a safe, simple, and effective intervention that minimizes cisplatin ototoxicity without interfering with the chemotherapeutic actions of cisplatin.


Single Particle Tracking and Super-Resolution Imaging of Membrane-Assisted Stop-and-Go Diffusion and Lattice Assembly of DNA Origami.
DNA nanostructures offer the possibility to mimic functional biological membrane components due to their nanometer-precise shape configurability and versatile biochemical functionality. Here we show that the diffusional behavior of DNA nanostructures and their assembly into higher order membrane-bound lattices can be controlled in a stop-and-go manner and that the process can be monitored with super-resolution imaging. The DNA structures are transiently immobilized on glass-supported lipid bilayers by changing the mono- and divalent cation concentrations of the surrounding buffer. Using DNA points accumulation for imaging in nanoscale topography (DNA-PAINT) super-resolution microscopy, we confirm the fixation of DNA origami structures with different shapes. On mica-supported lipid bilayers, in contrast, we observe residual movement. By increasing the concentration of NaCl and depleting MgCl2, a large fraction of DNA structures restarts to diffuse freely on both substrates. After addition of a set of oligonucleotides that enables three Y-shaped monomers to assemble into a three-legged shape (triskelion), the triskelions can be stopped and super-resolved. Exchanging buffer and adding another set of oligonucleotides triggers the triskelions to diffuse and assemble into hexagonal 2D lattices. This stop-and-go imaging technique provides a way to control and observe the diffusional behavior of DNA nanostructures on lipid membranes that could also lead to control of membrane-associated cargos.


Uric Acid and Xanthine Levels in Pregnancy Complicated by Gestational Diabetes Mellitus-The Effect on Adverse Pregnancy Outcomes.
Uric acid (UA) levels are associated with many diseases including those related to lifestyle. The aim of this study was to evaluate the influence of clinical and anthropometric parameters on UA and xanthine (X) levels during pregnancy and postpartum in women with physiological pregnancy and pregnancy complicated by gestational diabetes mellitus (GDM), and to evaluate their impact on adverse perinatal outcomes. A total of 143 participants were included. Analyte levels were determined by HPLC with ultraviolet detection (HPLC-UV). Several single-nucleotide polymorphisms (SNPs) in UA transporters were genotyped using commercial assays. UA levels were higher within GDM women with pre-gestational obesity, those in high-risk groups, and those who required insulin during pregnancy. X levels were higher in the GDM group during pregnancy and also postpartum. Positive correlations between UA and X levels with body mass index (BMI) and glycemia levels were found. Gestational age at delivery was negatively correlated with UA and X levels postpartum. Postpartum X levels were significantly higher in women who underwent caesarean sections. Our data support a possible link between increased UA levels and a high-risk GDM subtype. UA levels were higher among women whose glucose tolerance was severely disturbed. Mid-gestational UA and X levels were not linked to adverse perinatal outcomes.


ADP-ribosylation of the GTP-binding protein RhoA blocks cytoplasmic division in human myelomonocytic cells.
To test the role of Rho GTP-binding proteins in growth regulation of human myelomonocytic tumour cells we used recombinant C3 exoenzyme of Clostridium botulinum to specifically ADP-ribosylate and inactivate Rho proteins in situ. In homogenates of HL60 cells, the C3 exoenzyme [32P]ADP-ribosylated one protein that was identified as RhoA by immunoblot and two-dimensional gel electrophoresis. [32P]ADP ribosylation of RhoA in HL60 homogenates in vitro was reduced to 10-20% when cells in culture were pretreated with C3 exoenzyme (10 micrograms, 24 h), indicating that 80-90% of RhoA could be ADP-ribosylated in situ. The C3 exoenzyme inhibited HL60 cell proliferation by up to 80% and the degree of growth inhibition correlated with the amount of in situ ADP-ribosylated RhoA in a time- and dose-dependent manner. Cell cycle analysis demonstrated that the C3 exoenzyme-treated HL60 cells accumulated in mitosis, and nuclear staining revealed binucleated cells. These findings suggest that RhoA has a key role in human myelomonocytic tumour cell growth by regulating cytoplasmic division.


Accounting for technical noise in differential expression analysis of single-cell RNA sequencing data.
Recent technological breakthroughs have made it possible to measure RNA expression at the single-cell level, thus paving the way for exploring expression heterogeneity among individual cells. Current single-cell RNA sequencing (scRNA-seq) protocols are complex and introduce technical biases that vary across cells, which can bias downstream analysis without proper adjustment. To account for cell-to-cell technical differences, we propose a statistical framework, TASC (Toolkit for Analysis of Single Cell RNA-seq), an empirical Bayes approach to reliably model the cell-specific dropout rates and amplification bias by use of external RNA spike-ins. TASC incorporates the technical parameters, which reflect cell-to-cell batch effects, into a hierarchical mixture model to estimate the biological variance of a gene and detect differentially expressed genes. More importantly, TASC is able to adjust for covariates to further eliminate confounding that may originate from cell size and cell cycle differences. In simulation and real scRNA-seq data, TASC achieves accurate Type I error control and displays competitive sensitivity and improved robustness to batch effects in differential expression analysis, compared to existing methods. TASC is programmed to be computationally efficient, taking advantage of multi-threaded parallelization. We believe that TASC will provide a robust platform for researchers to leverage the power of scRNA-seq.


Dimensionless, Scale Invariant, Edge Weight Metric for the Study of Complex Structural Networks.
High spatial and angular resolution diffusion weighted imaging (DWI) with network analysis provides a unique framework for the study of brain structure in vivo. DWI-derived brain connectivity patterns are best characterized with graph theory using an edge weight to quantify the strength of white matter connections between gray matter nodes. Here a dimensionless, scale-invariant edge weight is introduced to measure node connectivity. This edge weight metric provides reasonable and consistent values over any size scale (e.g. rodents to humans) used to quantify the strength of connection. Firstly, simulations were used to assess the effects of tractography seed point density and random errors in the estimated fiber orientations; with sufficient signal-to-noise ratio (SNR), edge weight estimates improve as the seed density increases. Secondly to evaluate the application of the edge weight in the human brain, ten repeated measures of DWI in the same healthy human subject were analyzed. Mean edge weight values within the cingulum and corpus callosum were consistent and showed low variability. Thirdly, using excised rat brains to study the effects of spatial resolution, the weight of edges connecting major structures in the temporal lobe were used to characterize connectivity in this local network. The results indicate that with adequate resolution and SNR, connections between network nodes are characterized well by this edge weight metric. Therefore this new dimensionless, scale-invariant edge weight metric provides a robust measure of network connectivity that can be applied in any size regime.


Electrically active axons degenerate when exposed to nitric oxide.
Axonal degeneration is a major cause of permanent deficit in inflammatory neurological diseases such as multiple sclerosis. Axons undergo degeneration specifically at the site of the inflammatory lesions, suggesting that locally produced inflammatory factors mediate the phenomenon. One such factor is nitric oxide (NO), which we have previously reported can cause reversible conduction block in axons. Here we confirm these observations and extend them to show that axons exhibit the early stages of wallerian degeneration if they are conducting impulses at physiological frequencies while they are exposed to the low micromolar concentrations of NO that are likely to occur at sites of inflammation. Rat dorsal roots were concurrently exposed in vivo to both NO and sustained impulse activity at 1, 50, or 100 Hz. Although our in vivo observations necessarily focused on the more acute responses, morphological examination of exposed roots at the end of the recording period revealed nodal and paranodal changes consistent with acute wallerian degeneration in roots stimulated at 50 or 100 Hz. This interpretation was confirmed in a few experiments that were prolonged to permit more obvious indicators of degeneration to develop. In these experiments the formation of myelin ovoids and frank axonolysis occurred in more than 95% of fibers. Roots stimulated at only 1 Hz appeared normal. We propose that the combination of normal impulse traffic and NO at sites of inflammation may cause axonal degeneration and that electrical activity may therefore be an important factor in causing permanent disability in patients with neuroinflammatory disorders.


Measurement of atmospheric neutral wind and temperature from Fabry-Perot interferometer data using piloted deconvolution.
Nonlinear regression techniques, when applied to sky exposures obtained using a Fabry-Perot interferometer (FPI), are able to recover atmospheric neutral wind and temperature through inversion of the resulting fringe pattern. Current inversion methods often account for temporal fluctuation of the etalon's optical path length (caused by temperature variation in the instrument housing, for example) by characterizing the system function using isolated exposures of a frequency-stabilized laser. Because these path length changes correspond directly to shifts in the fringe pattern, they can significantly increase the total wind velocity uncertainty between laser exposures. We propose an extension to current regression techniques allowing for characterization of the optical path length and measurement of neutral wind and temperature simultaneously, thus reducing the need for frequent isolated laser exposures. This is achieved by using the laser as a pilot signal that enters the aperture of the instrument during sky exposures. We show that the extension can lead to a lower variance estimator for velocity when the optical path length has a significant time-varying component. Additionally, several pragmatic physical configurations that would allow for construction of a piloted signal in a real system are tested and compared using an FPI installation at the Urbana Atmospheric Observatory.


Nationwide population-based study reveals increased malignancy risk in taiwanese liver transplant recipients.
Post-transplant malignancy is a major cause of late mortality for liver transplant recipients (LTRs). This nationwide population-based cohort study investigated the cancer type, incidence, and risk factors associated with post-transplant malignancies in 2938 Taiwanese LTRs who underwent transplantation between 1998 and 2012. Data from the National Health Insurance Research Database were extracted on the basis of the International Classification of Disease, Ninth Revision, Clinical Modification codes. Among these patients, 284 post-transplant malignancies were diagnosed. These included 99 de novo malignancies among 98 patients, yielding a standardized incidence ratio of 2.17 (95% CI, 1.76 to 2.64) compared to the general population. The most common malignancies were infection related liver cancer (19.39%), oropharyngeal cancer (19.39%), non-Hodgkin's lymphoma (9.18%), and esophageal cancer (5.10%), as well as non-infection-related prostate cancer (6.12%). Patients with recurrent malignancies had the highest mortality. Furthermore, 186 recurrent malignancies relapsed, and the commonly affected organs were the liver (83.33%), lung (4.84%), bone and bone marrow (4.30%), and intrahepatic bile ducts (2.69%). Old age, the male sex, liver cirrhosis, hepatitis B, peptic ulcer, diabetes mellitus, and pre-existing cancer were all risk factors associated with post-transplant malignancies. Recipients with biliary atresia or urea cycle metabolism disorders were protected from post-transplant malignancies. Our data revealed a significantly increased risk of malignancies in Taiwanese LTRs and suggest implementation of a careful malignancy-surveillance program and immunosuppression-minimizing strategy for high-risk patients.


Mild cognitive impairment in Parkinson's disease: the challenge and the promise.
This review addresses the literature surrounding Parkinson's disease (PD) and mild cognitive impairment (MCI). It discusses the neuropsychological, pharmaceutical, and pathological overlap, the socioeconomic impact of PD and MCI, and the value of recognizing, understanding, and treating MCI in PD. It is concluded from this review that MCI in PD does exist and should be considered in clinical and research investigations. Due to the lack of accepted clinical criteria, an inclusive operating definition of MCI in PD is proposed. Research guidelines for studying the presence of MCI in PD and evaluating the efficacy of pharmaceutical interventions are also suggested.


Decreased mutation frequencies among immunoglobulin G variable region genes during viremic HIV-1 infection.
HIV-1 infection is complicated by high rates of opportunistic infections against which specific antibodies contribute to immune defense. Antibody function depends on somatic hypermutation (SHM) of variable regions of immunoglobulin heavy chain genes (VH-D-J). We characterized the frequency of SHM in expressed IgG mRNA immunoglobulin transcripts from control and HIV-1-infected patients. We compared utilization of genes in the most prominent VH family (VH3) and mutation frequencies and patterns of cDNA from VH3-IgG genes from 10 seronegative control subjects and 21 patients with HIV-1 infection (6 without and 15 patients with detectable plasma viremia). Unique IgG VH3 family cDNA sequences (n = 1,565) were PCR amplified, cloned, and sequenced from blood. Sequences were analyzed using online (Vbase) and in-house immunoglobulin alignment resources. Mutation frequencies in the antigen-binding hypervariable complementarity determining regions (CDR1/2) of IgG class-switched B cells were lower among viremic HIV-1-infected patients vs. controls for nucleotides (CDR1/2: 10±5% vs. 13.5±6%, p = 0.03) and amino acids (CDR: 20%±10 vs. 25%±12, p = 0.02) and in structural framework regions. Mutation patterns were similar among groups. The most common VH3 gene, VH3-23, was utilized less frequently among viremic HIV-1-infected patients (p = 0.03), and overall, mutation frequencies were decreased in nearly all VH3 genes compared with controls. B cells from HIV-1-infected patients show decreased mutation frequencies, especially in antigen-binding VH3 CDR genes, and selective defects in gene utilization. Similar mutation patterns suggest defects in the quantity, but not quality, of mutator activity. Lower levels of SHM in IgG class-switched B cells from HIV-1-infected patients may contribute to the increased risk of opportunistic infections and impaired humoral responses to preventative vaccines.


Calf Vein Thrombosis Comparison of Outcomes for Axial and Muscular Venous Thrombosis.
The objective of this study was to characterize clinical features and outcomes among patients with calf deep vein thrombosis (DVT) limited to the muscular veins compared with axial veins. Consecutive patients with ultrasound confirmed acute DVT involving the calf veins (January 1, 2016-August 1, 2018) were identified from the Gonda Vascular Center ultrasound database. Patients were divided into axial or muscular groups based on thrombus location. Demographics, management, and outcomes were compared. Over the study period, there were 647 patients with calf DVT equally distributed between axial (n = 321) and muscular (n = 326) locations. Within these groups, peroneal and soleal veins were most commonly involved. Nearly all cases were provoked (97%). Synchronous pulmonary embolism (PE) were more common for axial (30.8%) compared to muscular groups (20.2%; p = 0.001); nearly one-third had no pulmonary symptoms. Anticoagulation for a median of 3 months was initiated for 85.5% of both groups. Venous thromboembolism (VTE) recurrence was more common in the axial group (15.9% vs. 7.1%, p = 0.0015) including more frequent DVT propagation (9.4% vs. 3.1%; p = 0.0017) and PE (3.4% vs. 0.6%; p = 0.0168). Major bleeding, clinically relevant nonmajor bleeding, and mortality rates did not differ between groups. Withholding anticoagulation led to more frequent thrombus propagation in the axial group (3.4% vs. 0.9%; p = 0.029). Several important features distinguish muscular from axial DVT. Axial DVT are more likely to have an associated PE and are more likely to experience recurrent VTE, particularly if anticoagulation is withheld.


Natural anti-Gal and Salmonella-specific antibodies in bile and plasma of hens differing in diet efficiency.
Specific anti-Salmonella enteritidis (SE) and natural anti-alpha-gal epitope (Galalpha1-3Galbeta-1-4GlcNAc-R; anti-Gal) antibodies were measured in plasma sample pools and individual bile specimens obtained from hens differing in diet efficiency. More SE somatic (O) and flagellar (H) antibodies were found in plasma pools from efficient hens (R-) compared with nonefficient hens (R+) after oral challenge with live SE. Mean titers of somatic agglutinins in bile were 2.3 in R- hens and 1.9 in R+ hens (P = 0.06) following live challenge. Salmonella enteritidis antibodies were also found in bile of nonchallenged hens of both types but their levels were not significantly different. Flagellar (H) agglutinin scores were higher in SE-challenged hens compared with nonchallenged hens (3.1 vs. 2.1; P < or = 0.004) but efficiency types did not differ. Bile also contained high titers of the anti-Gal antibody indicated by the agglutination of glutaraldehyde-stabilized rabbit erythrocytes. The average titer of all SE-nonexposed hens was 9.0 corresponding to 1:5,120 when corrected for the initial dilution and expressed in conventional terms. Salmonella enteritidis exposure was associated with higher anti-Gal titers. The average anti-Gal titer for all SE-exposed hens was 10.0, corresponding to 1:10,240 in conventional terms; this difference was significant (P < or = 0.016). Diet efficiency type-associated differences in anti-Gal titers were not significant. Collectively, our data indicate that diet efficiency status is not associated with compromised Salmonella-specific immune responses. Rather it appears that the immune responses of diet efficient hens (R-) are also more efficient. This is because R- hens produced higher levels of O- and H-type antibody only as the result of direct exposure to living SE. On the contrary, R+ hens produced H-type antibody because of challenge with heat-killed SE, a circumstance that will not result in disease. Moreover, the hen type difference does not seem to occur at the expense of innate immunity as measured by anti-Gal antibody levels.


Piglet innate immune response to Streptococcus suis colonization is modulated by the virulence of the strain.
Streptococcus suis is a zoonotic pathogen of swine involved in arthritis, polyserositis, and meningitis. Colonization of piglets by S. suis is very common and occurs early in life. The clinical outcome of infection is influenced by the virulence of the S. suis strains and the immunity of the animals. Here, the role of innate immunity was studied in cesarean-derived colostrum-deprived piglets inoculated intranasally with either virulent S. suis strain 10 (S10) or non-virulent S. suis strain T15. Colonization of the inoculated piglets was confirmed at the end of the study by PCR and immunohistochemistry. Fever (≥40.5 °C) was more prevalent in piglets inoculated with S10 compared to T15 at 4 h after inoculation. During the 3 days of monitoring, no other major clinical signs were detected. Accordingly, only small changes in transcription of genes associated with the antibacterial innate immune response were observed at systemic sites, with S10 inducing an earlier response than T15 in blood. Local inflammatory response to the inoculation, evaluated by transcriptional analysis of selected genes in nasal swabs, was more sustained in piglets inoculated with the virulent S10, as demonstrated by transcription of inflammation-related genes, such as IL1B, IL1A, and IRF7. In contrast, most of the gene expression changes in trachea, lungs, and associated lymph nodes were observed in response to the non-virulent T15 strain. Thus, S. suis colonization in the absence of systemic infection induces an innate immune response in piglets that appears to be related to the virulence potential of the colonizing strain.


Information filtering by coincidence detection of synchronous population output: analytical approaches to the coherence function of a two-stage neural system.
Information about time-dependent sensory stimuli is encoded in the activity of neural populations; distinct aspects of the stimulus are read out by different types of neurons: while overall information is perceived by integrator cells, so-called coincidence detector cells are driven mainly by the synchronous activity in the population that encodes predominantly high-frequency content of the input signal (high-pass information filtering). Previously, an analytically accessible statistic called the partial synchronous output was introduced as a proxy for the coincidence detector cell's output in order to approximate its information transmission. In the first part of the current paper, we compare the information filtering properties (specifically, the coherence function) of this proxy to those of a simple coincidence detector neuron. We show that the latter's coherence function can indeed be well-approximated by the partial synchronous output with a time scale and threshold criterion that are related approximately linearly to the membrane time constant and firing threshold of the coincidence detector cell. In the second part of the paper, we propose an alternative theory for the spectral measures (including the coherence) of the coincidence detector cell that combines linear-response theory for shot-noise driven integrate-and-fire neurons with a novel perturbation ansatz for the spectra of spike-trains driven by colored noise. We demonstrate how the variability of the synaptic weights for connections from the population to the coincidence detector can shape the information transmission of the entire two-stage system.


[Trigono-cervico-prostatomy. Technic, clinical and urodynamic results].
Trigono-cervico-prostatotomy (TCP) incision was performed endoscopically in 102 patients, 99 for benign hypertrophy of the prostate (BHP) less than 35 g., and 3 for bladder neck obstruction. Good results were achieved in 81.4%, symptom relief was achieved in 12.7%, and 5.8% required reoperation. The incidence of retrograde ejaculation was only 20.6%. Patient follow-up was one year. Our findings show the usefulness of ultrasound, urethroscopy and urodynamics in determining the size of the adenoma and in assessing the results achieved by the surgical technique.


Community- and health care-associated methicillin-resistant Staphylococcus aureus: a comparison of molecular epidemiology and antimicrobial activities of various agents.
The epidemiology of methicillin-resistant Staphylococcus aureus (MRSA) is changing. We determined the inhibitory and bactericidal activity of select antimicrobial agents utilizing a well-characterized group of 200 staphylococcal cassette chromosome mec (SCCmec) type IV community-associated MRSA (CAMRSA) and 50 SCCmec type II health care-associated MRSA (HAMRSA). Differences in carriage of the Panton-Valentine leukocidin (PVL) genes, agr group, and agr function in CAMRSA and HAMRSA were also examined. Pulsed-field gel electrophoresis (PFGE) patterns were determined for a subset of study strains. CAMRSA typically belonged to the USA 300 PFGE profile, were associated with high rates of PVL carriage (78%), and primarily were agr group I. Susceptibility to daptomycin, linezolid, teicoplanin, and vancomycin was 100%. In contrast, HAMRSA isolates typically belonged to the USA 100 PFGE profile, were associated with low rates of PVL carriage (8%), and primarily were agr group II. Comparing susceptibilities between the 2 types of MRSA strains, there was a 2-fold increase in MIC for daptomycin, doxycycline, teicoplanin, trimethoprim-sulfamethoxazole (TMP/SMX), and vancomycin in HAMRSA versus CAMRSA. Levofloxacin and clindamycin susceptibly decreased dramatically by 66% and 54%, respectively, against HAMRSA versus CAMRSA. With respect to agr function, 3.5% of CAMRSA and 48% of HAMRSA displayed a down-regulated agr gene cluster. The comparative bactericidal activities of daptomycin were similar to those of vancomycin and clindamycin, but were significantly greater than those of linezolid, teicoplanin, and TMP/SMX against CAMRSA at 24-h terminal end points. Further studies are warranted against a larger number of molecularly defined, geographically diverse CAMRSA to confirm these findings.


Genetic and environmental influences on cannabis use initiation and problematic use: a meta-analysis of twin studies.
Because cannabis use is associated with social, physical and psychological problems, it is important to know what causes some individuals to initiate cannabis use and a subset of those to become problematic users. Previous twin studies found evidence for both genetic and environmental influences on vulnerability, but due to considerable variation in the results it is difficult to draw clear conclusions regarding the relative magnitude of these influences. A systematic literature search identified 28 twin studies on cannabis use initiation and 24 studies on problematic cannabis use. The proportion of total variance accounted for by genes (A), shared environment (C) and unshared environment (E) in (i) initiation of cannabis use and (ii) problematic cannabis use was calculated by averaging corresponding A, C and E estimates across studies from independent cohorts and weighting by sample size. For cannabis use initiation, A, C and E estimates were 48%, 25% and 27% in males and 40%, 39% and 21% in females. For problematic cannabis use A, C and E estimates were 51%, 20% and 29% for males and 59%, 15% and 26% for females. Confidence intervals of these estimates are considerably narrower than those in the source studies. Our results indicate that vulnerability to both cannabis use initiation and problematic use was influenced significantly by A, C and E. There was a trend for a greater C and lesser A component for cannabis use initiation compared to problematic use for females.


Neural Endophenotype Assessment in Zebrafish Larvae Using Optomotor and ZebraBox Locomotion Assessment.
Due to the highly conserved genetics across the central nervous system, the easily probed visual system can act as an endophenotype for assessing neurological function. Here, we describe a psychophysics approach to assess visually driven swimming behavior in the high-throughput zebrafish genetic model system. We use the optomotor response test together with general locomotion behavior to assess neural processing while excluding motor defects related to muscle function.


Prospective comparison of transient elastography, MRI and serum scores for grading steatosis and detecting non-alcoholic steatohepatitis in bariatric surgery candidates.
Tools for the non-invasive diagnosis of non-alcoholic steatohepatitis (NASH) in morbidly obese patients with suspected non-alcoholic fatty liver disease (NAFLD) are an unmet clinical need. We prospectively compared the performance of transient elastography, MRI, and 3 serum scores for the diagnosis of NAFLD, grading of steatosis and detection of NASH in bariatric surgery candidates. Of 186 patients screened, 152 underwent liver biopsy, which was used as a reference for NAFLD (steatosis [S]>5%), steatosis grading and NASH diagnosis. Biopsies were read by a single expert pathologist. MRI-based proton density fat fraction (MRI-PDFF) was measured in an open-bore, vertical field 1.0T scanner and controlled attenuation parameter (CAP) was measured by transient elastography, using the XL probe. Serum scores (SteatoTest, hepatic steatosis index and fatty liver index) were also calculated. The applicability of MRI was better than that of FibroScan (98% vs. 79%; p <0.0001). CAP had AUROCs of 0.83, 0.79, 0.73 and 0.69 for S>5%, S>33%, S>66% and NASH, respectively. Transient elastography had an AUROC of 0.80 for significant fibrosis (F0-F1 vs. F2-F3). MRI-PDFF had AUROCs of 0.97, 0.95, 0.92 and 0.84 for S>5%, S>33%, S>66% and NASH, respectively. When compared head-to-head in the 97 patients with all valid tests available, MRI-PDFF outperformed CAP for grading steatosis (S>33%, AUROC 0.97 vs. 0.78; p <0.0003 and S>66%, AUROC 0.93 vs. 0.75; p = 0.0015) and diagnosing NASH (AUROC 0.82 vs. 0.68; p = 0.0056). When compared in "intention to diagnose" analysis, MRI-PDFF outperformed CAP, hepatic steatosis index and fatty liver index for grading steatosis (S>5%, S>33% and S>66%). MRI-PDFF outperforms CAP for diagnosing NAFLD, grading steatosis and excluding NASH in morbidly obese patients undergoing bariatric surgery. Non-invasive tests for detecting fatty liver and steatohepatitis, the active form of the disease, have not been well studied in obese patients who are candidates for bariatric surgery. The most popular tests for this purpose are Fibroscan, which can be used to measure the controlled attenuation parameter (CAP), and magnetic resonance imaging, which can be used to measure the proton density fat fraction (MRI-PDFF). We found that, when taking liver biopsy as a reference, MRI-PDFF performed better than CAP for detecting and grading fatty liver as well as excluding steatohepatitis in morbidly obese patients undergoing bariatric surgery.


Tracking of target motion using physically based modelling of organs.
In this paper, we describe a general methodology for the realistic reconstruction and animation of anatomic organs. In fact, in the scope of conformal radiotherapy and hadron therapy applications, we want to simulate the motion and the shape alteration of the internal anatomical objects and to input this knowledge to treatment planning. For the reconstruction, particle systems are used: firstly, surface shape of the considered organ is computed from a set of CT scan sections. Next, the volume defined by this surface is filled with particles. The coherency of the object is maintained due to the use of the classical Lennard-Jones inter particles force. This work permits to study the impact of the organs movement on the treatment of prostate and lung cancer. Our particle system has been suitably integrated in a radiation dose evaluation software, developed within an European BIOMED2 project and is currently supported by the French ETOILE project.


Cell Density Effects in Different Cell Culture Media and Their Impact on the Propagation of Foot-And-Mouth Disease Virus.
Foot-and-mouth disease virus (FMDV) is endemic in many parts of the world. Vaccination is an important control measure, limits viral spread, and can help to eradicate the disease. However, vaccination programs are cost-intensive because of the short shelf life of vaccines and the need for frequent re-vaccination. Animal-component-free (ACF) or chemically defined media (CDM) at high cell densities are a promising approach for the production of inexpensive high-quality vaccines, but the occurrence of cell density effects has been reported for various virus-cell systems in vaccine production. For FMDV, the use of CDM or ACF media for vaccine production has not been studied and no information about cell density effects is available. This work describes the propagation of FMDV in ACF or in CDM. Cells were grown at increasing cell densities and either 100% media exchange or addition of 30% fresh media was performed before infection with FMDV. Increasing cell densities reduced the viral titer and increased yield variability in all media except BHK300G. This effect can be mitigated by performing a 100% media exchange before infection or when using the controlled environment of a bioreactor. The media composition and also a fragile relationship between virus and cell metabolism seem to be causal for that phenomenon.


Heart failure: management of patients with left-ventricular systolic dysfunction.
More than 2 million Americans have heart failure, and about 400,000 new cases are diagnosed each year. Mortality is high, with 5-year mortality in the range of 50 percent. Many of the almost 1 million hospitalizations each year for heart failure might be prevented by improved evaluation and care. This Quick Reference Guide for Clinicians summarizes major recommendations in Heart Failure: Evaluation and Care of Patients with Left-Ventricular Systolic Dysfunction. Clinical Practice Guideline No. 11. The document was prepared by RAND, a nonprofit research and policy organization, and a private-sector panel of experts and consumers. Guideline recommendations are intended for use by a broad range of health care practitioners. The guideline recommendations are based on a combination of evidence obtained through extensive literature reviews and on expert judgment where evidence was lacking. Specific recommendations are made in the following areas: Prevention of heart failure with asymptomatic left-ventricular systolic dysfunction. Approaches to diagnosis and initial evaluation of suspected heart failure. Hospital admission and discharge criteria. Pharmacological management. Patient counseling and education. Exercise and rehabilitation. Evaluation for myocardial revascularization. Patient monitoring and followup evaluation.


Hematocrit and clinical outcome in acute cerebral infarction.
Hematocrits of 131 cerebral infarction cases were correlated with the outcome at 2 weeks. Bivariate analysis showed that cases with more intense admission deficit had lower admission hematocrit and that cases with poorer outcome had lower Day 2 and 4 hematocrits. However, multivariate analysis of several prognostic factors (including hematocrit, glycemia, blood pressure, age, and sex) showed that hematocrit was not independently related to outcome. Higher hematocrit thus is not indicative of less favorable short-term outcome.


Identification of Predictors for Hemorrhagic Transformation in Patients with Acute Ischemic Stroke After Endovascular Therapy Using the Decision Tree Model.
This study aimed to identify independent predictors for the risk of hemorrhagic transformation (HT) in arterial ischemic stroke (AIS) patients. Consecutive patients with AIS due to large artery occlusion in the anterior circulation treated with mechanical thrombectomy (MT) were enrolled in a tertiary stroke center. Demographic and medical history data, admission lab results, and Circle of Willis (CoW) variations were collected from all patients. Altogether, 90 patients were included in this study; among them, 34 (37.8%) had HT after MT. The final pruned decision tree (DT) model consisted of collateral score and platelet to lymphocyte ratios (PLR) as predictors. Confusion matrix analysis showed that 82.2% (74/90) were correctly classified by the model (sensitivity, 79.4%; specificity, 83.9%). The area under the ROC curve (AUC) was 81.7%. The DT model demonstrated that participants with collateral scores of 2-4 had a 75.0% probability of HT. For participants with collateral scores of 0-1, if PLR at admission was <302, participants had a 13.0% probability of HT; otherwise, participants had an 75.0% probability of HT. The final adjusted multivariate logistic regression analysis indicated that collateral score 0-1 (OR, 10.186; 95% CI, 3.029-34.248; p < 0.001), PLR (OR, 1.005; 95% CI, 1.001-1.010; p = 0.040), and NIHSS at admission (OR, 1.106; 95% CI, 1.014-1.205; p = 0.022) could be used to predict HT. The AUC for the model was 0.855, with 83.3% (75/90) were correctly classified (sensitivity, 79.4%; specificity, 87.3%). Less patients with HT achieved independent outcomes (mRS, 0-2) in 90 days (20.6% vs. 64.3%, p < 0.001). Rate of poor outcomes (mRS, 4-6) was significantly higher in patients with HT (73.5% vs. 19.6%; p < 0.001). Both the DT model and multivariate logistic regression model confirmed that the lower collateral status and the higher PLR were significantly associated with an increased risk for HT in AIS patients after MT. PLR may be one of the cost-effective and practical predictors for HT. Further prospective multicenter studies are needed to validate our findings.


Association between Internet overuse and aggression in Korean adolescents.
The purpose of this study was to examine the association between Internet overuse and aggression. A total of 2336 high school students (boys, 57.5%; girls, 42.5%) in South Korea completed the structured questionnaire. The severity of Internet overuse was evaluated using Young's Internet Addiction Test. Aggression was measured using the Aggression Questionnaire, a modified hostility inventory by Buss and Perry. The proportions of boys who were classified as severe addicts and moderate addicts were 2.5% and 53.7%, respectively. For girls, the corresponding proportions were 1.9% and 38.9%, respectively. manova results for univariate analysis showed that sex, duration of Internet use, most-frequently used Internet activities, level of Internet addiction, smoking, alcohol, and caffeine were significantly associated with aggression scores. From multivariate analysis, it was found that smoking, alcohol, and level of Internet addiction were independently associated with all aggressive characteristics. Internet addiction scores were also significantly associated with all aggression scores from simple and multiple linear regression analyses (parameter estimate = 0.54-0.58 for total aggression). Pearson correlation results showed that Internet addiction scores revealed the highest correlation coefficients with aggression among Internet-related factors, age, and sex. Severe Internet-addicted boys showed higher scores in all aggression characteristics than severe Internet-addicted girls, even though it was not statistically significant in every characteristic. However, there was no sex effect on the association between Internet overuse and aggression. This study shows that Internet overuse is strongly associated with aggression in adolescents.


[Effect of pancreatic juice diversion on gastric acid and gut hormone secretion].
In an effort to clarify the effect of pancreatic juice diversion (PJD) on the gastric acid and gut hormone secretion, models of PJD and non-PJD were prepared in dogs with Heidenhain pouch (HP). Two types of operative procedures, pancreatico-jejunostomy with Roux-Y reconstruction as a PJD model (RY group), and pancreatico-jejuno-duodenostomy using interposed jejunum as a non-PJD model (INT group) were carried out. The results were obtained as follows. 1. Both endocrine and exocrine function of the pancreas were preserved by either procedure. 2. Gastric acid secretion from HP after test meal ingestion was significantly increased postoperatively in RY group and was not affected in INT group. 3. Postprandial secretion of gastrin was not affected by these operative procedures in both RY and INT group. Secretion of GIP was significantly suppressed in RY group and was not changed in INT group. Secretion of enteroglucagon was significantly increased in both groups. These results indicate that significant increase of postprandial gastric secretion as shown in RY group is conceivably based on the significant suppression of GIP secretion produced by PJD.


Stomach as a source of colonization of the respiratory tract during mechanical ventilation: association with ventilator-associated pneumonia.
The aetiopathogenesis of ventilator-associated pneumonia (VAP) requires abnormal oropharyngeal and gastric colonization and the further aspiration of their contents to the lower airways. VAP develops easily if aspiration or inoculation of microorganisms occur in patients with artificial airways, in whom mechanical, cellular and/or humoral defences are altered. Well-known risk factors for gastric colonization include: alterations in gastric juice secretion; alkalinization of gastric contents; administration of enteral nutrition; and the presence of bilirubin. However, the role of the colonized gastric reservoir in the development of VAP remains debatable. Evidence in favour of the role of the stomach in the development of VAP comes mainly from randomized, controlled trials of selective gut decontamination and stress ulcer prophylaxis in the intensive care unit (ICU), in which reducing the bacterial burden of the stomach decreases the incidence of nosocomial respiratory infections. However, at least three studies of flora have found an absence of stomach origin of pneumonia occurring during mechanical ventilation. Prophylactic measures suggested to prevent VAP in relation to the gastric reservoir include: treatment for stress ulcers with sucralfate; prevention of duodenal reflux with metoclopramide; reduction of gastric burden and bacterial translocation by selective digestive decontamination; acidification of enteral feeding; and jejunal feeding. Gastro-oesophageal reflux can be prevented by using small bore nasogastric tubes and jejunal feeding. The aspiration of gastric contents can be reduced by positioning patients in a semirecumbent position, checking the patency of the tube cuff, and aspiration of subglottic secretions. The role of the stomach as a reservoir for microorganisms causing ventilator-associated pneumonia is still controversial but despite the debate, there is major evidence in the literature in favour of the gastric origin of part of these pulmonary infections.


Dynamics of Prl release in galactorrhoeic normoprolactinaemic women.
Prl responsiveness to TRH and sulpiride was evaluated in 14 galactorrhoeic normoprolactinaemic women. Radiological signs of sellar alteration were present in 6 of these patients. Pituitary responses to TRH did not differ from those obtained in a group of 16 healthy women. Serum Prl levels after sulpiride were higher in the patients than in the controls (P less than 0.01). The delta max response was 256 +/- 16 SE vs 158 +/- 10.6 ng/ml in the control group (P less than 0.01). The mean integrated area after sulpiride was also greater 20738 +/- 1263 SE ng/ml/2 h vs 13 188 +/- 408) (P less than 0.01). The markedly enhanced Prl response to sulpiride in our patients with galactorrhoea could be due to a functional disorder of the hypothalamic-pituitary axis or to a lactotrope hyperplasia.


Expression of Functional Anti-p24 scFv 183-H12-5C in HEK293T and Jurkat T Cells.
Purpose: More than half of the diagnostic and therapeutic recombinant protein production depends on mammalian-based expression system. However, the generation of recombinant antibodies remains a challenge in mammalian cells due to the disulfide bond formation and reducing cytoplasm. Therefore, the production of functional recombinant antibodies in target cell line is necessary to be evaluated before used in therapeutic application such intrabodies against HIV-1. Methods: The work was to test expression of a single-chain variable fragment (scFv) antibody against HIV-1 Capsid p24 protein in a human mammalian-based expression system using HEK293T and Jurkat T cells as a model. Three expression plasmid vectors expressing scFv 183-H12-5C were generated and introduced into HEK293T. Expression of the scFv was analyzed, while ELISA and immunoblotting analysis verified its binding. The evaluation of the recombinant antibody was confirmed by HIV-1 replication and MAGI infectivity assay in Jurkat T cells. Results: Three plasmid vectors expressing scFv 183-H12-5C was successfully engineered in this study. Recombinant antibodies scFv (~29 kDa) and scFv-Fc (~52 kDa) in the cytoplasm of HEK293T were effectively obtained by transfected the cells with engineered pCDNA3.3-mu-IgGk-scFv 183-H12-5C and pCMX2.5-scFv 183-H12-5C-hIgG1-Fc plasmid vectors respectively. scFv and scFv-Fc are specifically bound recombinant p24, and HIV-1 derived p24 (gag) evaluated by ELISA and Western blot. Jurkat T cells transfected by pCDNA3.3-scFv 183-H12-5C inhibit the replication-competent NL4-3 viral infectivity up to 60%. Conclusion: Anti-p24 scFv 183-H12-5C antibody generated is suitable to be acted as intrabodies and may serve as a valuable tool for the development of antibody-based biotherapeutics against HIV-1.


Combating melanoma: the use of photodynamic therapy as a novel, adjuvant therapeutic tool.
Metastatic malignant melanoma remains one of the most dreaded skin cancers worldwide. Numerous factors contribute to its resistance to hosts of treatment regimes and despite significant scientific advances over the last decade in the field of chemotherapeutics and melanocytic targets, there still remains the need for improved therapeutic modalities. Photodynamic therapy, a minimally invasive therapeutic modality has been shown to be effective in a number of oncologic and non-oncologic conditions. Using second-generation stable, lipophilic photosensitizers with optimised wavelengths, PDT may be a promising tool for adjuvant therapy in combating melanoma. Potential targets for PDT in melanoma eradication include cell proliferation inhibition, activation of cell death and reduction in pro-survival autophagy and a decrease in the cellular melanocytic antioxidant system. This review highlights the current knowledge with respect to these characteristics and suggests that PDT be considered as a good candidate for adjuvant treatment in post-resected malignant metastatic melanoma. Furthermore, it suggests that primary consideration must be given to organelle-specific destruction in melanoma specifically targeting the melanosomes - the one organelle that is specific to cells of the melanocytic lineage that houses the toxic compound, melanin. We believe that using this combined knowledge may eventually lead to an effective therapeutic tool to combat this highly intractable disease.


Effects of Astragalus polysaccharides on P-glycoprotein efflux pump function and protein expression in H22 hepatoma cells in vitro.
Astragalus polysaccharides (APS) are active constituents of Astragalus membranaceus. They have been widely studied, especially with respect to their immunopotentiating properties, their ability to counteract the side effects of chemotherapeutic drugs, and their anticancer properties. However, the mechanism by which APS inhibit cancer and the issue of whether that mechanism involves the reversal of multidrug resistance (MDR) is not completely clear. The present paper describes an investigation of the effects of APS on P-glycoprotein function and expression in H22 hepatoma cell lines resistant to Adriamycin (H22/ADM). H22/ADM cell lines were treated with different concentrations of APS and/or the most common chemotherapy drugs, such as Cyclophosphamid, Adriamycin, 5-Fluorouracil, Cisplatin, Etoposide, and Vincristine. Chemotherapeutic drug sensitivity, P-glycoprotein function and expression, and MDR1 mRNA expression were detected using MTT assay, flow cytometry, Western blotting, and quantitative RT-PCR. When used alone, APS had no anti-tumor activity in H22/ADM cells in vitro. However, it can increase the cytotoxicity of certain chemotherapy drugs, such as Cyclophosphamid, Adriamycin, 5-Fluorouracil, Cisplatin, Etoposide, and Vincristine, in H22/ADM cells. It acts in a dose-dependent manner. Compared to a blank control group, APS increased intracellular Rhodamine-123 retention and decreased P-glycoprotein efflux function in a dose-dependent manner. These factors were assessed 24 h, 48 h, and 72 h after administration. APS down regulated P-glycoprotein and MDR1 mRNA expression in a concentration-dependent manner within a final range of 0.8-500 mg/L and in a time-dependent manner from 24-72 h. APS can enhance the chemosensitivity of H22/ADM cells. This may involve the downregulation of MDR1 mRNA expression, inhibition of P-GP efflux pump function, or both, which would decrease the expression of the MDR1 protein.


Adolescent pregnancy, public policies, and targeted programs in Latin America and the Caribbean: a systematic review.
To present and assess evidence from Latin America and the Caribbean (LAC) on public policies and targeted programs which may have influenced variations in adolescent pregnancy or its proximate determinants, and to identify knowledge gaps that require further research. A systematic review was performed based on the 2015 PRISMA protocol. Five databases were searched for articles published between 2000 and 2019 that refer to at least one country in LAC. The outcomes of interest were adolescent pregnancy or its proximate determinants (sexual behavior, contraceptive use, and/ or abortion). Only studies exploring correlations between the outcomes of interest and public policies or targeted programs were included in the analysis. Thirty studies spanning 14 countries were selected for analysis. Twenty-three of these (77%) were not included in prior systematic reviews on adolescent pregnancy. Public policies related to conditional cash transfers and compulsory education have the strongest evidence of correlation with adolescent pregnancy prevention. Emerging research points to the potential positive impact of life-skills programs for adolescents. Evidence from public health policies and programs was limited. Further research which incorporates an intersectional analysis is needed to better understand which policies and programs could lead to steeper declines in adolescent pregnancy in the region. Evidence on effects of expanded family planning services and secondary school attainment upon adolescent pregnancy are particularly absent.


Behavioral Economics of Cigarette Purchase Tasks: Within-Subject Comparison of Real, Potentially Real, and Hypothetical Cigarettes.
Hypothetical rewards are commonly used in studies of laboratory-based tobacco demand. However, behavioral economic demand procedures require confirmation that the behavior elicited from real and hypothetical reward types are equivalent, and that results attained from these procedures are comparable to other accepted tasks, such as the hypothetical purchase task. Nineteen smokers were asked to purchase 1 week's worth of cigarettes that they would consume over the following week either at one price that incrementally increased across four weekly sessions ("real" sessions) or four prices in a single session ("potentially real" session), one of which was randomly chosen to be actualized. At each session, participants also completed a hypothetical cigarette purchase task. After each week, participants reported the number of cigarettes they actually smoked. Demand was found to be equivalent under both the real and potentially real reward conditions but statistically different from the demand captured in the hypothetical purchase task. However, the amounts purchased at specific prices in the hypothetical purchase task were significantly correlated with the amount purchased at comparable prices in the other two tasks (except for the highest price examined in both tasks of $1.00 per cigarette). Number of cigarettes consumed that were obtained outside of the study was correlated with study cigarette price. Combined, these results suggest that purchasing behavior during potentially real sessions (1) was not functionally different from real sessions, (2) imposes fewer costs to the experimenter, and (3) has high levels of both internal and external validity.


Self-reported hearing quality of life measures in pediatric cochlear implant recipients with bilateral input.
Objective: Self-reported hearing quality of life (QoL) for pediatric cochlear implant (CI) recipients was examined, asking whether 1) children with CIs have similar QoL as those with less severe hearing loss (HL); 2) children with different bilateral CI (BCI) device configurations report different QoL; and 3) do audiological, demographic and spoken language factors affect hearing QoL?Design: One hundred four children (ages 7-11 years) using bimodal devices or BCIs participated. The Hearing Environments and Reflection of Quality of Life (HEAR-QL) questionnaire, receptive language and speech perception tests were administered. HEAR-QL scores of CI recipients were compared to scores of age-mates with normal hearing and mild to profound HL.Results: HEAR-QL scores for CI participants were similar to those of children with less severe HL and did not differ with device configuration. Emotion identification and word recognition in noise correlated significantly with HEAR-QL scores.Discussion: CI recipients reported that HL hinders social participation. Better understanding of speech in noise and emotional content was associated with fewer hearing-related difficulties on the HEAR-QL.Conclusions: Noisy situations encountered in educational settings should be addressed for children with HL. The link between perception of emotion and hearing-related QoL for CI recipients should be further examined.


The effects of a topical analgesic and placebo in treatment of chronic knee pain.
Chronic knee pain is a prevalent health problem of old and middle age. The authors' objective was to determine whether a topical analgesic would reduce knee pain and improve the function of a group of 40- to 65-year-old people with chronic knee pain. The experimental design was a double-blind, randomized, placebo-controlled clinical trial. The dependent variables were knee pain, active range of motion, and isometric strength. Forty-six men and women volunteered, of whom 3 dropped out, leaving 23 in the treatment group and 20 in the placebo group. Knee pain was assessed with a visual analogue scale and the knee-pain scale for frequency and severity. Testing took place before treatment and after 21 and 35 days of treatment. The results indicated that although both groups experienced improved pain scores, there were no differences between groups over the treatment period for any of the dependent variables.


Bovid herpesvirus 2: natural spread among breeding bulls.
Sera collected over a seven year period, together with detailed health and management records, were used in a retrospective study of Bovid herpesvirus 2 (BHV-2) spread within a large herd of breeding bulls. Virus spread rapidly throughout the bulls in one barn. Transfer of infected bulls to other barns was followed by further, although sporadic, spread of virus. Spread of BHV-2 from seropositive animals to susceptible bulls in close contact led to the conclusion that reactivation and transmission of latent virus had occurred. Semen from seropositive bulls did not transmit BHV-2 to seronegative calves that were purposefully inoculated by the intranasal or intravenous routes.


[Support groups in oncology. How does the nurse intervene?].
Participation by nurses in support groups are beneficial for oncology patients and their families since they improve their degree of adaptation and they promote effective mechanisms to confront one's illness. This improvement in quality of life is reflected in patients emotional, physical, social and spiritual state; furthermore, in some cases this leads to an increase in their survival. Due to a nurse's role, oncology patients' families improve their adaptation to the situation; moreover, nurse's aid provides the necessary support to patients during their medical treatment. The authors review the existing literature about nurses' participation in support groups in order to improve a patient's and his/her family's adaptation to cancer and all it entails. With this objective in mind, the authors present the conceptual and empirical concepts of a support group along with their overall objectives and possible benefits. Finally, the authors document the role of nursing in support groups for oncology patients and their families. This study was financed by the Carlos III Health Institute as part of the Evaluation Studies of Health Technologies, reference FIS 00/10107.


Dynamics of receptor-operated Ca(2+) currents through TRPC channels controlled via the PI(4,5)P2-PLC signaling pathway.
Transient receptor potential canonical (TRPC) channels are Ca(2+)-permeable, nonselective cation channels that carry receptor-operated Ca(2+) currents (ROCs) triggered by receptor-induced, phospholipase C (PLC)-catalyzed hydrolysis of phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2]. Within the vasculature, TRPC channel ROCs contribute to smooth muscle cell depolarization, vasoconstriction, and vascular remodeling. However, TRPC channel ROCs exhibit a variable response to receptor-stimulation, and the regulatory mechanisms governing TRPC channel activity remain obscure. The variability of ROCs may be explained by their complex regulation by PI(4,5)P2 and its metabolites, which differentially affect TRPC channel activity. To resolve the complex regulation of ROCs, the use of voltage-sensing phosphoinositide phosphatases and model simulation have helped to reveal the time-dependent contribution of PI(4,5)P2 and the possible role of PI(4,5)P2 in the regulation of ROCs. These approaches may provide unprecedented insight into the dynamics of PI(4,5)P2 regulation of TRPC channels and the fundamental mechanisms underlying transmembrane ion flow. Within that context, we summarize the regulation of TRPC channels and their coupling to receptor-mediated signaling, as well as the application of voltage-sensing phosphoinositide phosphatases to this research. We also discuss the controversial bidirectional effects of PI(4,5)P2 using a model simulation that could explain the complicated effects of PI(4,5)P2 on different ROCs.


Beyond model antigens: high-dimensional methods for the analysis of antigen-specific T cells.
Adaptive immune responses often begin with the formation of a molecular complex between a T-cell receptor (TCR) and a peptide antigen bound to a major histocompatibility complex (MHC) molecule. These complexes are highly variable, however, due to the polymorphism of MHC genes, the random, inexact recombination of TCR gene segments, and the vast array of possible self and pathogen peptide antigens. As a result, it has been very difficult to comprehensively study the TCR repertoire or identify and track more than a few antigen-specific T cells in mice or humans. For mouse studies, this had led to a reliance on model antigens and TCR transgenes. The study of limited human clinical samples, in contrast, requires techniques that can simultaneously survey TCR phenotype and function, and TCR reactivity to many T-cell epitopes. Thanks to recent advances in single-cell and cytometry methodologies, as well as high-throughput sequencing of the TCR repertoire, we now have or will soon have the tools needed to comprehensively analyze T-cell responses in health and disease.


A phylogenetic study of pollinator conservatism among sexually deceptive orchids.
Orchids of the genus Chiloglottis are pollinated through the sexual deception of male wasps mainly from the genus Neozeleboria (Tiphiidae: Thynninae). The orchids mimic both the appearance and sex pheromones of wingless female thynnines but provide no reward to the deceived males. Despite the asymmetry of this interaction, strong pollinator specificity is typical. Such plant-pollinator interactions would seem to be relatively flexible in the plant's adaptive response to variation in the local pollinator resource. However, we present DNA sequence data on both orchids and wasps that demonstrate a pattern of pollinator conservatism operating at a range of taxonomic levels. Sequence data from the wasps indicate 15 of 16 Chiloglottis pollinators are closely related members of one clade of Thynninae. A pattern of congruence between orchid and wasp phylogenies is also demonstrated below the generic level, such that related orchids tend to use related thynnine wasps as specific pollinators. Comparative physiological data on the wasp responses to the floral scents of two Chiloglottis species and one outgroup, Arthrochilus, indicate similar attractive volatile chemicals are used by related orchid taxa. By extension, we infer a similarity of sex pheromone signals among related thynnines. Thus, the conservative pattern of pollinator change in sexually deceptive orchids may reflect phylogenetic patterns in the sex pheromones of their pollinators.