Amputation induces stem cell mobilization to sites of injury during planarian regeneration.
How adult stem cell populations are recruited for tissue renewal and repair is a fundamental question of biology. Mobilization of stem cells out of their niches followed by correct migration and differentiation at a site of tissue turnover or injury are important requirements for proper tissue maintenance and regeneration. However, we understand little about the mechanisms that control this process, possibly because the best studied vertebrate adult stem cell systems are not readily amenable to in vivo observation. Furthermore, few clear examples of the recruitment of fully potent stem cells, compared with limited progenitors, are known. Here, we show that planarian stem cells directionally migrate to amputation sites during regeneration. We also show that during tissue homeostasis they are stationary. Our study not only uncovers the existence of specific recruitment mechanisms elicited by amputation, but also sets the stage for the systematic characterization of evolutionarily conserved stem cell regulatory processes likely to inform stem cell function and dysfunction in higher organisms, including humans.


Air pollution and mortality in Barcelona.
Studies conducted in Barcelona reported a short term relation between daily air pollutant values and emergency department admissions for exacerbation of chronic obstructive pulmonary diseases and asthma. Air pollution in Barcelona is mainly generated by vehicle exhaust and is below the World Health Organization air quality guidelines. The acute relation between air pollution and mortality was assessed. Daily variations in total mortality, mortality in subjects older than 70 years, and cardiovascular and respiratory mortality were related with daily variations in air pollutants for the period 1985-91, using autoregressive Poisson regression models that allow to control for temperature, relative humidity and variables handling temporal and autoregressive patterns. Black smoke and sulphur dioxide (SO2) were related to total mortality (relative risks (RR) for 100 micrograms/m3 = 1.07 and 1.13 respectively), elderly mortality (RR = 1.06 and 1.13), cardiovascular mortality (RR = 1.09 and 1.14), and respiratory mortality (RR = 1.10 and 1.13); all the associations being statistically significant, except for respiratory mortality (p = 0.07). The association between SO2 and respiratory mortality was stronger in summer (1.24, p < 0.01) than in winter (1.08, p > 0.1). Oxidant pollutants (nitrogen dioxide and ozone) were positively related with elderly mortality (RR = 1.05 and 1.09, respectively) and cardiovascular mortality (RR = 1.07 and 1.09) during the summer (p < 0.05), but not during the winter. Current air pollutant levels were related to mortality in Barcelona. These results were consistent with similar studies in other cities and coherent with previous studies with emergency room admissions in Barcelona.


Treatment of 741 Italian patients with chronic fatigue syndrome.
Chronic Fatigue Syndrome (CFS) is a distinctive syndrome characterized by specific symptoms cluster. CFS mostly affects women and often results in severe functional limitation. Its prevalence varies from 0.4 to 2.5% in the general population. In our prior studies on the clinical features of 205 CFS patients we founded immunological and brain abnormalities. In this paper we illustrate our caseload on CFS treatment. From January 2000 to December 2005, we evaluated all the patients admitted at the CFS Unit of the Aviano National Cancer Institute, for staging procedures and treatments. Patients not meeting the Fukuda diagnostic criteria were excluded. 250 male and 491 female (median age 35.5 and 39.3 years, respectively) were enrolled and treated for CFS. As expected, CFS resulted from previous infectious disease in all patients. Female patients showed to be more affected by symptoms than male patients. The treatment schedules followed by the patients included nutritional supplements alone, corticosteroids, antidepressant/sedative drugs, and antiviral/immunoglobulin drugs. Antiviral/ immunoglobulin drugs achieved the best response (15.3% positive responses vs. 8.3% negative responses; OR 0.44, CI 0.26-0.74, p = 0.002). The carrying out of 4 or more treatments showed a protective effect (OR 0.46, CI 0.28-0.77, p = 0.003). This finding was confirmed in the multivariate analysis, adjusted by type of drugs (OR 0.49, CI 0.28-0.84, p = 0.009) and number of treatments carried out (OR 0.51, CI 0.30-0.86, p = 0.01); these two variables were independent. These findings show that the antiviral/immunoglobulin approach has a longer positive disease free survival in comparison with other approaches. However, CSF still remains a difficult disease to be effectively treated.


Changes in functional coupling patterns during bimanual task performance.
Functional interaction between cortical areas may involve synchronization of activities, manifest as coherence between EEG signals. However, although EEG-EEG coherence changes when motor tasks are compared to each other or rest, there is little evidence that coherence is modulated within an action. To address this issue we used a bimanual drawer-opening task necessitating asymmetrical hand actions and comprising distinct movement phases. Pronounced modulations in EEG-EEG coherence in the beta band (>12-24 Hz) occurred with movement phase. Differences in coherence due to a switch in role of the hands were mainly observed in the alpha band (8-12 Hz). These findings suggest that inter-regional synchronization changes dynamically across task execution in line with behavioral performance.


A quantitative survey of the literature on poliovirus infection and immunity.
To examine forces that drive vaccination policy to eradicate wild- and vaccine-derived poliovirus, and to focus on the efficacy of vaccines to support decision-making and further research. We searched PubMed and Ovid databases for English-language publications, without date restrictions. We also collected references from major reviews on polio vaccine immunogenicity or protection. We conducted a meta-analysis of human immunity to polio infections using multiple non-linear regression, and built a database from a broad (but not systematic) set of polio vaccine studies (46 studies, >10000 subjects). The outcome was an immunological model representative of many different datasets. Parameters measured immunogenicity to both humoral and mucosal immune compartments for Salk and Sabin vaccines. The immunity model was more highly correlated with the data than a simpler per-dose efficacy model. The model offers new insights for immunization policy. We measured the mucosal immunogenicity of IPV to a precision that is useful in decision-making for end-game polio immunization policies.


Hospital-Level Variations in Rates of Inpatient Urinary Tract Infections in Stroke.
Background and purpose: Urinary tract infection (UTI) is one of the most common complications following stroke and has prognostic significance. UTI rates have been shown to vary between hospitals, but it is unclear whether this is due to case-mix differences or heterogeneities in care among hospitals. Methods: A prospective multi-center cohort study of acute stroke patients admitted to eight National Health Service (NHS) acute hospital trusts within the Anglia Stroke & Heart Clinical Network between 2009 and 2011 was conducted. We modeled the association between hospital (as a fixed-effect) and inpatient UTI using a multivariable logistic regression model, adjusting for established patient-level risk factors. We graphically and descriptively analyzed heterogeneities in hospital-level characteristics. Results: We included 2,241 stroke admissions in our analysis; 171 (7.6%) acquired UTI as an inpatient. UTI rates varied significantly between the eight hospitals, ranging from 3 to 11%. The hospital that had the lowest odds of UTI [odds ratio (OR) = 0.50 (95% confidence interval (CI) 0.22-.11)] in adjusted analysis, had the highest number of junior doctors and occupational therapists per five beds of all hospitals. The hospital with the highest adjusted UTI rate [OR=2.69 (1.56-4.64)] was tertiary, the largest and had the highest volume of stroke patients, lowest number of stroke unit beds per 100 admissions, and the highest number of hospital beds per CT scanner. Conclusions: There is hospital-level variation in post-stroke UTI. Our results suggest the potential influence of service characteristics independently of patient-level factors which may be amenable to be addressed to improve the ultimate stroke outcome.


Living arrangements among older people: an overview of trends in Europe and the USA.
This article compares the trends in living arrangements of older people in several European countries and in the United States. Trends and cross-country variability in several factors that could account for these cross-national differences, including marital status, fertility, labour force participation and attitudes, are also examined. In most countries the proportion of older people living alone increased substantially between 1970 and 1990. However the increase in living alone stabilised or even declined between 1990 and 2000 in most of the countries analysed indicating a possible reversal in the trend. Increases in proportions of older women who are married and reductions in the proportions childless may partially explain this. Considerable variability in both trends and levels of older people's living arrangements was seen especially between north-western and southern European countries. These variations mirrored contrasts in attitudes towards residential care and parent-child coresidence between the countries.


Anal and dry sex in commercial sex work, and relation to risk for sexually transmitted infections and HIV in Meru, Kenya.
To examine the practices of anal intercourse and dry sex within a cohort of female sex workers (FSWs) in Kenya, focusing on the prevalence and perceived risk of the practices, demographic and behavioural correlates, and association with sexually transmitted infections (STI). A survey was conducted among FSWs in Meru, Kenya, with 147 participants randomly sampled from an existing cohort of self identified FSWs. 40.8% of participants reported ever practising anal intercourse and 36.1% reported ever practising dry sex. Although the majority of women surveyed believed anal intercourse and dry sex to be high risk practices for HIV infection compared with vaginal sex, about one third of women reported never or rarely using condoms during anal intercourse, and about 20% never or rarely using condoms during dry sex. Reported consistent condom use was lower with both of these practices than with penile-vaginal intercourse. Anal intercourse was associated with experience of recent forced sexual intercourse, while dry sex was not. Anal intercourse was almost always initiated by clients, whereas dry sex was likely to be initiated by the women themselves. Sex workers reported charging higher fees for both practices than for vaginal intercourse. Both practices were associated with reported symptoms and diagnoses of STI. Both anal intercourse and dry sex were common in this sample, and although perceived as high risk practices, were not adequately protected with condom use. Education and other interventions regarding these high risk sexual behaviours need to be translated into safer practices, particularly consistent condom use, even in the face of financial vulnerability.


Enhanced Solar-to-Hydrogen Generation with Broadband Epsilon-Near-Zero Nanostructured Photocatalysts.
The direct conversion of solar energy into fuels or feedstock is an attractive approach to address increasing demand of renewable energy sources. Photocatalytic systems relying on the direct photoexcitation of metals have been explored to this end, a strategy that exploits the decay of plasmonic resonances into hot carriers. An efficient hot carrier generation and collection requires, ideally, their generation to be enclosed within few tens of nanometers at the metal interface, but it is challenging to achieve this across the broadband solar spectrum. Here the authors demonstrate a new photocatalyst for hydrogen evolution based on metal epsilon-near-zero metamaterials. The authors have designed these to achieve broadband strong light confinement at the metal interface across the entire solar spectrum. Using electron energy loss spectroscopy, the authors prove that hot carriers are generated in a broadband fashion within 10 nm in this system. The resulting photocatalyst achieves a hydrogen production rate of 9.5 µmol h-1 cm-2 that exceeds, by a factor of 3.2, that of the best previously reported plasmonic-based photocatalysts for the dissociation of H2 with 50 h stable operation.


De-moralized: Glucksberg in the malaise.
Ten years down the road, what is the enduring significance of the "assisted suicide" cases, Washington v. Glucksberg and Vacco v. Quill? The cases reflect an unusually earnest, but nonetheless unsuccessful, attempt by the Supreme Court to grapple with a profound moral issue. So, why was the Court unable to provide a more satisfying justification for its conclusions? This Article, written for a symposium on the tenth anniversary of Glucksberg, discusses that question. Part I examines some of the flaws in reasoning in the Glucksberg and Quill opinions and suggests that these flaws stem from the opinion writers' inability to recognize and articulate their underlying normative assumptions. More specifically, both the Justices and the lower court judges, on both sides of the issue, evidently attributed normative significance to something like a "natural course of life" (even when they denied doing so), but none were willing or able to make this attribution explicit. Part II discusses the modern separation of moral reasoning from the metaphysical or theological perspectives that might once have endowed "nature" with normative significance, and it suggests that the deficiencies in Glucksberg-Quill are evidence of how that separation renders moral reasoning problematic. The Conclusion wonders whether in this situation, a renewed emphasis on formalism or tradition might make legal reasoning less unacceptable.


Prenatal diagnosis of beta-thalassaemia and other haemoglobinopathies in India.
This paper reports prenatal diagnosis of 787 fetuses of beta-thalassaemia and other haemoglobinopathies in Indian high-risk communities. DNA based diagnosis was offered in the first, as well as the second trimester, in 489 pregnancies (with five twins) on fetal tissues such as chorionic villus (CV) and amniocytes using the amplification refractory mutation system (ARMS) and restriction fragment length polymorphism (RFLP) techniques. Two hundred and ninety-two women (with one twin), who either presented late in the second trimester or whose DNA diagnosis was not informative, were offered prenatal diagnosis using globin chain synthesis (GCS) on fetal blood cells. Maternal contamination of fetal DNA was ruled out by variable number tandem repeat (VNTR) analysis using sites in four different genes (Apo-B, D1S-80, Ig-JH and Ha-ras), while contamination of fetal blood was checked by a particle size distribution channelyzer. Using both techniques we were able to offer complete diagnosis in 99.8% cases. Out of 494 fetuses tested by DNA analysis, 135 were found to be normal, 201 were carriers, whereas 146 were affected. Out of 293 fetuses analysed by GCS, 215 were unaffected and 71 were affected. In this study, both fetuses were tested in twin pregnancies, of which three required selective termination of one fetus. Because of social, religious taboos and family influences, genetic counselling was found to be an important guideline for couples selecting options for prenatal diagnosis. Our experience suggests that because of late presentation by many couples to the diagnostic centres, in developing countries like India, both the techniques of DNA analysis and GCS should be made available at major referral centres for maximum benefit to couples.


Herpes simplex virus encephalitis update.
HSV is the most frequently identified cause of infectious encephalitis, in Western countries. This article is an update on the topic based on a review of recent studies from 2017 to 2018. Acyclovir is still the first line treatment, and no new drugs are currently available for clinical use. The major considerations for HSV encephalitis are as follows: point one, clinical evaluation remains the most important factor, as though CSF HSV PCR has a good sensitivity, in a small proportion of patients the initial testing might be negative. MRI brain is the first line imaging test, and mesial temporal lobe involvement and other typical findings are important for diagnosis; point 2, there should be emphasis on sequela, short-term, and long-term outcomes, and not just case fatality rated in future studies and clinical management. Auto-immune encephalitis can be triggered by HSV, and should be considered in patients who are not responding to treatment; point 3, future studies should be on better management of sequela, and better treatment regimens including those targeting the immune response. Autoimmune encephalitis is a clearly identified complication of HSV encephalitis. Inflammatory mechanisms are linked to the clinical presentation as well as severity and poor outcome. Initial corticosteroid therapy has to be evaluated in order to prevent complications.


Human INT6/eIF3e is required for nonsense-mediated mRNA decay.
The mammalian integration site 6 (INT6) protein has been implicated in breast carcinogenesis and characterized as the eIF3e non-core subunit of the translation initiation factor eIF3, but its role in this complex is not known. Here, we show that INT6 knockdown by RNA interference strongly inhibits nonsense-mediated messenger RNA decay (NMD), which triggers degradation of mRNAs with premature stop codons. In contrast to the eIF3b core subunit, which is required for both NMD and general translation, INT6 is only necessary for the former process. Consistent with such a role, immunoprecipitation experiments showed that INT6 co-purifies with CBP80 and the NMD factor UPF2. In addition, several transcripts known to be upregulated by UPF1 or UPF2 depletion were also found to be sensitive to INT6 suppression. From these observations, we propose that INT6, in association with eIF3, is involved in routing specific mRNAs for degradation.


A fast soluble carbon-free molecular water oxidation catalyst based on abundant metals.
Traditional homogeneous water oxidation catalysts are plagued by instability under the reaction conditions. We report that the complex [Co4(H2O)2(PW9O34)2]10-, comprising a Co4O4 core stabilized by oxidatively resistant polytungstate ligands, is a hydrolytically and oxidatively stable homogeneous water oxidation catalyst that self-assembles in water from salts of earth-abundant elements (Co, W, and P). With [Ru(bpy)3]3+ (bpy is 2,2'-bipyridine) as the oxidant, we observe catalytic turnover frequencies for O2 production > or = 5 s(-1) at pH = 8. The rate's pH sensitivity reflects the pH dependence of the four-electron O2-H2O couple. Extensive spectroscopic, electrochemical, and inhibition studies firmly indicate that [Co4(H2O)2(PW9O34)2]10- is stable under catalytic turnover conditions: Neither hydrated cobalt ions nor cobalt hydroxide/oxide particles form in situ.


Infrasound sensitizes human glioblastoma cells to cisplatin-induced apoptosis.
The development of nontoxic agents that can selectively enhance the cytotoxicity of chemotherapy is an important aim in oncology. This study evaluates the ability of infrasound exposure to sensitize glioblastoma cells to cisplatin-induced apoptosis. The infrasound was delivered using a device designed to replicate the unique infrasound emissions measured during external Qigong treatments. Human glioblastoma cell lines harboring wild-type p53 (U87) or mutant p53 (U251, SF210, and SF188) were treated in culture with cisplatin, infrasound emissions, or the combination of the 2 agents. Induction of apoptosis was quantified after 24 hours by flow cytometry following annexin V/propidium iodide staining. Infrasound emissions alone, delivered at moderate levels (~10 mPa) with dynamic frequency content (7-13 Hz), did not induce apoptosis, yet combining infrasound with cisplatin augmented the induction of apoptosis by cisplatin in all the 4 cell lines (P < .05). Increased cellular uptake of the fluorophore calcein associated with infrasound exposure was quantified by fluorescence microscopy as well as flow cytometry, demonstrating increased cell membrane permeability. The 4 cell lines differed in the degree to which infrasound exposure increased calcein uptake, and these differences were predictive of the extent to which infrasound enhanced cisplatin-induced apoptosis. When exposed to specific frequencies, membrane permeabilization also appeared to be differentially responsive for each cell line, suggesting the potential for selective targeting of tissue types using isolated infrasonic frequencies. Additionally, the pressure amplitudes used in this study were several orders of magnitude less than those used in similar studies involving ultrasound and shock waves. The results of this study provide support for using infrasound to enhance the chemotherapeutic effects of cisplatin in a clinical setting.


A possible mechanism of metabolic regulation in Gibberella fujikuroi using a mixed carbon source of glucose and corn oil inferred from analysis of the kinetics data obtained in a stirrer tank bioreactor.
A nonstructured model was used to study the dynamics of gibberellic acid production in a stirred tank bioreactor. Experimental data were obtained from submerged batch cultures of Gibberella fujikuroi (CDBB H-984) grown in varying ratios of glucose-corn oil as the carbon source. The nitrogen depletion effect was included in mathematical model by considering the specific kinetic constants as a linear function of the normalized nitrogen consumption rate. The kinetics of biomass growth and consumption of phosphate and nitrogen were based on the logistic model. The traditional first-order kinetic model was used to describe the specific consumption of glucose and corn oil. The nitrogen effect was solely included in the phosphate and corn oil consumption and biomass growth. The model fit was satisfactory, revealing the dependence of the kinetics with respect to the nitrogen assimilation rate. Through simulations, it was possible to make diagrams of specific growth rate and specific rate of substrate consumptions, which was a powerful tool for understanding the metabolic interactions that occurred during the various stages of fermentation process. This kinetic analysis provided the proposal of a possible mechanism of regulation on growth, substrate consumptions, and production of gibberellic acid (GA3 ) in G. fujikuroi.


E-cadherin expression in primary and metastatic gastric cancer: down-regulation correlates with cellular dedifferentiation and glandular disintegration.
Expression of the epithelial cell adhesion molecule E-cadherin in primary and metastatic gastric carcinoma was examined using immunohistochemical analyses. Compared to normal mucosa, 92% of the primary tumors (n = 60) showed reduced E-cadherin expression, suggesting that down-regulation of this cell adhesion molecule is a common early event in gastric tumorigenesis. No significant correlation was found between E-cadherin expression and tumor diameter, lymphatic vessel invasion, Borrmann classification, lymph node status, or manifest metastases. Although advanced tumors (tumor stage 3/4) showed a loss of E-cadherin-positive cells (< or = 50% cells/lesion, P = 0.0168), the most significant correlation was observed between low E-cadherin expression and cellular dedifferentiation (grading 3/4, P = 0.0001) and disintegration of tissue architecture (Lauren and WHO classifications, P = 0.0001). Low E-cadherin expression (< or = 50% cells/lesion) was associated with tumor recurrence (P = 0.0013) and mortality (P = 0.0246). E-cadherin expression in metastatic lesions (n = 58) also correlated with the degree of glandular differentiation (P = 0.0001). Significant correlation (rs = 0.686) was observed between E-cadherin expression in primary and metastatic lesions from individual patients (n = 39). However, while metastases derived from E-cadherin-negative tumors remained negative, those originating from E-cadherin-positive tumors frequently demonstrated increased levels of expression. Evaluation of multiple metastases in 11 patients revealed uniformly strong E-cadherin expression in liver metastases, suggesting a possible regulatory role of the microenvironment.


Predictive properties of serum-prostate-specific antigen testing in a community-based setting.
Most studies that have described the sensitivity and specificity of prostate-specific antigen (PSA) as a screening test have been conducted in urology practice settings or in media-based screening programs. The control patients from these settings may have a higher prevalence of urologic disorders that increase serum PSA levels than that of the general population in which screening efforts might take place, leading to biased estimates of sensitivity and specificity. To determine the sensitivity and specificity of serum PSA levels for the early detection of prostate cancer in a population-based setting. This population-based case-control study was conducted in Olmsted County, Minnesota, where the Rochester Epidemiology Project could identify all incident cases of prostate cancer through passive surveillance of medical care provided to local residents. Case patients were all 177 men (age range, 50-79 years) who were newly diagnosed as having prostate cancer from 1990 through 1992 and had a prediagnostic serum PSA determination (90% of all incident cases). Control patients were randomly selected from the Olmsted County population and had undergone a clinical examination to exclude prostate cancer. The median (25th and 75th percentiles) of serum PSA levels was 9.4 ng/mL (5.4 and 18.6 ng/mL, respectively) for case patients and 1.2 ng/mL (0.7 and 2.1 ng/mL, respectively) for control patients (P < .001). When sensitivity was plotted against 1-specificity, the area under the receiver operating characteristic curve was 0.94 (SE, 0.01). The predictive power declined somewhat with age, with areas under the curve of 0.96, 0.94, and 0.90 for men in their 50s, 60s, and 70s, respectively. When cases were restricted to the 155 men with clinically localized disease, the area under the curve was essentially unchanged (0.94; SE, 0.01) and still much greater than the estimates of 0.75 that were reported from urology practice- and media-based settings. In a community-based setting, serum PSA levels provide better discrimination between men with and without clinically localized prostate cancer than has been observed in studies that were conducted in urologic practices. These results suggest that previous decision analyses may have underestimated the predictive value of PSA for the detection of prostate cancer in a primary care or community-wide screening program.


Efficient algorithms for multidimensional global optimization in genetic mapping of complex traits.
We present a two-phase strategy for optimizing a multidimensional, nonconvex function arising during genetic mapping of quantitative traits. Such traits are believed to be affected by multiple so called quantitative trait loci (QTL), and searching for d QTL results in a d-dimensional optimization problem with a large number of local optima. We combine the global algorithm DIRECT with a number of local optimization methods that accelerate the final convergence, and adapt the algorithms to problem-specific features. We also improve the evaluation of the QTL mapping objective function to enable exploitation of the smoothness properties of the optimization landscape. Our best two-phase method is demonstrated to be accurate in at least six dimensions and up to ten times faster than currently used QTL mapping algorithms.


Determination of contraction-induced changes in elbow flexor cross-sectional area for evaluating muscle size-strength relationship during contraction.
The aims of this study were to determine contraction-induced changes in the elbow flexor cross-sectional area (CSA) and to examine whether the maximal CSA during a high-intensity contraction is more closely related to the strength than that at rest in the elbow flexors. Fourteen young male subjects participated in this study. The elbow flexor CSAs were measured at sites from 1 cm proximal to 6 cm distal to the reference site (60% of the upper arm length from the acromial process of the scapula to the lateral epicondyle of the humerus) (every 1 cm; 8 sampling sites) using magnetic resonance imaging, at rest and during 10, 20, 40, 60, and 80% of maximal voluntary contraction (MVC) of isometric elbow flexion. The elbow flexor CSA changed greatly during low-intensity contractions, and this contraction-induced change was small over 60%MVC. Compared with at rest, greater CSA around the muscle belly and smaller CSA in the distal portion of the elbow flexors were found in contracted conditions. The MVC strength was significantly correlated with the maximal CSAs at rest and each contraction level, but stepwise multiple regression analysis selected only that during 80%MVC as a significant contributor for estimating the MVC strength. These results suggest that, in the elbow flexors, the contraction-induced change in the CSA reaches its peak under high contractile level and that the maximal CSA during 80%MVC is more closely related to the MVC strength than that at rest.


Factors regulating primary producers' assemblages in Posidonia oceanica (L.) Delile ecosystems over the past 1800 years.
Posidonia oceanica (L.) Delile meadows are highly productive coastal marine ecosystems that provide multiple ecosystem services. The seagrass is not always the major contributor to total primary production, however, little is known about long-term changes in the composition of primary producers within seagrass meadows. Understanding compositional shifts within the community of primary producers is crucial to evaluate how climate and anthropogenic change affect the functioning of seagrass ecosystems. Here we analysed marker pigment composition in seagrass cores from two bays of the Cabrera Island (Balearic Islands, Spain) to asses long-term changes in phototrophic community composition and production in seagrass meadows, and identify the environmental factors triggering those changes. The proxy dataset was explored using principal component analyses (PCA): one including the pigment dataset to look for associations between producers' groups, and another one combining the pigment dataset with plausible local and global regulatory factors to assess the environmental drivers of change. Analyses of characteristic pigments and morphological fossils (cysts) showed that the abundance of dinoflagellates increased over the last 150-300 years, coeval with a rise in solar irradiance and air temperature. When compared among embayments, pigments from cyanobacteria predominated in seagrass meadows located at Es Port, a sheltered bay receiving higher terrestrial runoff; whereas pigments from diatoms, seagrasses and rodophytes were more common at Santa Maria, an exposed bay with clearer waters. Water depth also played a role in controlling the phototrophic community composition, with greater abundance of diatoms in the shallowest waters (<5 m). Overall, our results suggested that historical and spatial variation in seagrass meadows' phototrophic community composition was influenced by the interaction between local factors (catchment-bay characteristics) and global climate processes (energy influx). Together these patterns forecast how marine primary producers and seagrass ecosystem structure may respond to future global warming.


Heterogeneity of insulin-like growth factor-I affinity for the insulin-like growth factor-II receptor: comparison of natural, synthetic and recombinant DNA-derived insulin-like growth factor-I.
Although insulin-like growth factors (IGF) I and II bind with high affinity to structurally discrete receptors, they bind with a lesser affinity to each other's receptor. We have evaluated the affinity of five different IGF-I preparations (three natural IGF-I preparations, one synthetic preparation, and one recombinant DNA-derived) for the IGF-II receptor in rat placental membranes, 18-54,SF cells and BRL-3A cells. In all tissues tested, the natural IGF-I preparations demonstrated an affinity for the IGF-II receptor which was 10-20% that of IGF-II. However, the recombinant and synthetic IGF-I preparations exhibited substantially lower affinities than natural IGF-I for this receptor, with only 10-25% reduction in (125-I)iodo IGF-II binding at peptide concentrations up to 400 ng/ml. Radioimmunoassay of the natural IGF-I preparations with an antibody directed against the unique C-peptide region of IGF-II demonstrated that contamination of IGF-I preparations with immunoreactive IGF-II could not exceed 5%. These results demonstrate that IGF-I purified from human plasma has a different affinity for the IGF-II receptor than does synthetic or recombinant IGF-I. Furthermore, these data are consistent with the hypothesis that IGF-I, itself, may be heterogeneous, and that subforms may vary in their affinities for the IGF receptors. Alternatively, IGF-I preparations which have been considered to be pure may be contaminated with small amounts of IGF-II, resulting in overestimation of the affinity of IGF-I for the type II IGF receptor.


18F-Mefway PET imaging of serotonin 1A receptors in humans: a comparison with 18F-FCWAY.
The purpose of this research is to evaluate the prospects for the use of 4-(trans-18F-fluoranylmethyl)-N-[2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl]-N-pyridin-2-ylcyclohexane-1-carboxamide (18F-Mefway) in comparison to 18F-trans-4-fluoro-N-2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl]-N-(2-pyridyl)cyclohexanecarboxamide (18F-FCWAY) for the quantification of 5-HT1A receptors in human subjects. Five healthy male controls were included for two positron emission tomography (PET) studies: 18F-FCWAY PET after the pretreatment with 500 mg of disulfiram and two months later, 18F-Mefway PET without disulfiram. Regional time-activity curves (TACs) were extracted from nine cortical and subcortical regions in dynamic PET images. Using cerebellar cortex without vermis as reference tissue, in vivo kinetics for both radioligands were compared based on the distribution volume ratio (DVR) calculated by non-invasive Logan graphical analysis and area under the curve ratio of the TACs (AUC ratio). Although the pattern of regional uptakes in the 18F-Mefway PET was similar to that of the 18F-FCWAY PET (highest in the hippocampus and lowest in the cerebellar cortex), the amount of regional uptake in 18F-Mefway PET was almost half of that in 18F-FCWAY PET. The skull uptake in 18F-Mefway PET was only 25% of that in 18F-FCWAY PET with disulfiram pretreatment. The regional DVR values and AUC ratio values for 18F-Mefway were 17-40% lower than those of 18F-FCWAY. In contrast to a small overestimation of DVR values by AUC ratio values (< 10%) in 18F-FCWAY PET, the overestimation bias of AUC ratio values was much higher (up to 21%) in 18F-Mefway PET. As 18F-Mefway showed lower DVR values and greater overestimation bias of AUC ratio values, 18F-Mefway may appear less favorable than 18F-FCWAY. However, in contrast to 18F-FCWAY, the resistance to in vivo defluorination of 18F-Mefway obviates the need for the use of a defluorination inhibitor. Thus, 18F-Mefway may be a good candidate PET radioligand for 5-HT1A receptor imaging in human.


Contractile properties of the striated adductor muscle in the bay scallop Argopecten irradians at several temperatures.
The isometric and isotonic contractile properties of the cross-striated adductor muscle of the bay scallop (Argopecten irradians) were measured in vitro at 10, 15 and 20 degrees C. The length at which twitch force was maximal as a function of the closed length in situ (L0/Lcl) averaged 1.38 +/- 0.01 (mean +/- S.E.M.) at 10 degrees C. This length is very close to the typical length at maximum gape during natural swimming at this temperature. Passive force was very low over the range of lengths measured here; at L0, passive force averaged approximately 0.08 N cm-2, or only 0.5% of the corresponding peak twitch force. The mean peak isometric twitch force (Ptw,max) at 10 degrees C was 21.43 +/- 0.68 N cm-2 (S.E.M.), and the ratio of peak twitch force to tetanic force (Ptw,max/P0) averaged 0.89 +/- 0.01. Temperature did not affect either twitch force (Ptw), once fatigue was taken into account, or Ptw,max/P0. In contrast, the time-related properties of twitch contractions (latent period, tL; time to peak tension, tPtw; and time from peak tension to half-relaxation, t50%R) were positively modified by temperature at all temperatures measured (Q10 > 1.8). All three properties were more temperature-sensitive over the range 10-15 degrees C than over the range 15-20 degrees C. The force-velocity relationships of the striated adductor muscle were fitted to the hyperbolic-linear (HYP-LIN) equation. The force-velocity curves of the striated adductor muscle of the scallop were strongly influenced by temperature. Maximal velocity at zero force (Vmax), and therefore maximal power output, increased significantly with temperature. The Q10 over the temperature range 10-15 degrees C (1.42) was significantly lower than that over the range 15-20 degrees C (2.41). The shape of the force-velocity relationship, assessed through comparisons of the power ratio (Wmax/VmaxP0), was not influenced by temperature.


Defining the epithelial stem cell niche in skin.
Many adult regenerative cells divide infrequently but have high proliferative capacity. We developed a strategy to fluorescently label slow-cycling cells in a cell type-specific fashion. We used this method to purify the label-retaining cells (LRCs) that mark the skin stem cell (SC) niche. We found that these cells rarely divide within their niche but change properties abruptly when stimulated to exit. We determined their transcriptional profile, which, when compared to progeny and other SCs, defines the niche. Many of the >100 messenger RNAs preferentially expressed in the niche encode surface receptors and secreted proteins, enabling LRCs to signal and respond to their environment.


Psychometric Evaluation of a Fear of COVID-19 Scale in China: Cross-sectional Study.
At the very beginning of the COVID-19 pandemic, information about fear of COVID-19 was very limited in Chinese populations, and there was no standardized and validated scale to measure the fear associated with the pandemic. This cross-sectional study aimed to adapt and validate a fear scale to determine the levels of fear of COVID-19 among the general population in mainland China and Hong Kong. A web-based questionnaire platform was developed for data collection; the study instruments were an adapted version of the 8-item Breast Cancer Fear Scale ("Fear Scale") and the 4-item Patient Health Questionnaire. The internal construct validity, convergent validity, known group validity, and reliability of the adapted Fear Scale were assessed, and descriptive statistics were used to summarize the participants' fear levels. A total of 2822 study participants aged 18 years or older were included in the analysis. The reliability of the adapted scale was satisfactory, with a Cronbach α coefficient of .93. The item-total correlations corrected for overlap were >0.4, confirming their internal construct validity. Regarding convergent validity, a small-to-moderate correlation between the Fear Scale and the 4-item Patient Health Questionnaire scores was found. Regarding known group validity, we found that the study participants who were recruited from Hong Kong had a higher level of fear than the study participants from mainland China. Older adults had a higher level of fear compared with younger adults. Furthermore, having hypertension, liver disease, heart disease, cancer, anxiety, and insomnia were associated with a higher fear level. The descriptive analysis found that more than 40% of the study participants reported that the thought of COVID-19 scared them. About one-third of the study participants reported that when they thought about COVID-19, they felt nervous, uneasy, and depressed. The psychometric properties of the adapted Fear Scale are acceptable to measure the fear of COVID-19 among Chinese people. Our study stresses the need for more psychosocial support and care to help this population cope with their fears during the pandemic.


Orientation in the cuttlefish Sepia officinalis: response versus place learning.
Several studies have demonstrated that mammals, birds and fish use comparable spatial learning strategies. Unfortunately, except in insects, few studies have investigated spatial learning mechanisms in invertebrates. Our study aimed to identify the strategies used by cuttlefish (Sepia officinalis) to solve a spatial task commonly used with vertebrates. A new spatial learning procedure using a T-maze was designed. In this maze, the cuttlefish learned how to enter a dark and sandy compartment. A preliminary test confirmed that individual cuttlefish showed an untrained side-turning preference (preference for turning right or left) in the T-maze. This preference could be reliably detected in a single probe trial. In the following two experiments, each individual was trained to enter the compartment opposite to its side-turning preference. In Experiment 1, distal visual cues were provided around the maze. In Experiment 2, the T-maze was surrounded by curtains and two proximal visual cues were provided above the apparatus. In both experiments, after acquisition, strategies used by cuttlefish to orient in the T-maze were tested by creating a conflict between the formerly rewarded algorithmic behaviour (turn, response learning) and the visual cues identifying the goal (place learning). Most cuttlefish relied on response learning in Experiment 1; the two strategies were used equally often in Experiment 2. In these experiments, the salience of cues provided during the experiment determined whether cuttlefish used response or place learning to solve this spatial task. Our study demonstrates for the first time the presence of multiple spatial strategies in cuttlefish that appear to closely parallel those described in vertebrates.


Evidence for the treatment of borderline personality disorder.
The treatment of patients with borderline personality disorder (BPD) is notoriously difficult. Psychotherapeutic and pharmacological strategies have been investigated, and a few have shown promise. Dialectical behavior therapy (DBT) may be helpful in decreasing suicidal behavior and improving symptomatology, although the data are not strong, and the actual "type" of DBT employed may influence the outcomes. Although there are a variety of studies investigating a number of different medications for the treatment of BPD, there are few randomized, double-blind, placebo-controlled trials. Furthermore, the evidence base is limited by small sample size and variability in inclusion criteria and outcome measures among the different studies. Further study is needed with larger, randomized, placebo-controlled trials to clearly demonstrate benefit of any pharmacotherapy. To date, there is suggestion from some studies that neuroleptics, carbamazepine, monoamine oxidase inhibitors, and selective serotonin reuptake inhibitors may be effective, and there is evidence that benzodiazepines are detrimental. The role of electroconvulsive therapy remains unclear.


Macroscopic brain asymmetry is changed along the antero-posterior axis in schizophrenia.
Anatomical asymmetry may be altered in schizophrenia, but the changes are subtle and in some studies undetected perhaps due to methodological limitations. In a postmortem MRI study (23 patients, 20 controls), we used a geometric mesh technique to define the cortical surface and to separate two components of brain asymmetry: hemisphere shift, conceived as the position of an entire hemisphere relative to the other (which may be reversed in situs inversus), and the distribution of tissue within the hemisphere along the antero-posterior axis ("volume torque"). Only volume torque was changed in schizophrenia-in comparison subjects, the coronal section of maximal left hemisphere volume was more anteriorly placed than on the right [and correlated with left superior temporal gyrus (STG) volume], and, in patients, it was more posterior (showing a reversed correlation with left STG volume). The findings validate a new approach to cerebral asymmetry. Assessments of cerebral asymmetry in psychosis should account for, or exclude, hemisphere shift, which is not changed, and focus on the second component, A-P volume distribution; the findings point to an anomaly of relative hemispheric development that may have pathophysiological significance.


UK Renal Registry 18th Annual Report: Chapter 12 Epidemiology of Reported Infections amongst Patients Receiving Dialysis for Established Renal Failure in England 2013 to 2014: a Joint Report from Public Health England and the UK Renal Registry.
From 1st May 2013 to 30th April 2014 there were 35 episodes of Methicillin resistant Staphylococcus aureus (MRSA) bacteraemia in established renal failure patients on dialysis. This is now fairly stable year-on-year equating to a rate of 0.15 episodes per 100 dialysis patient years, following an initial decline in rates from 4.0 episodes per 100 dialysis patient years in 2005 when reporting began. Methicillin sensitive Staphylococcus aureus (MSSA) bacteraemia rates were slightly higher this year at 2.23 per 100 dialysis patient years (compared with 1.59 episodes per 100 dialysis patient years last year) with 526 episodes of blood stream infection reported. In 2005, the first year this was reported, there were 1,114 MSSA bacteraemias in 54 centres. There were 247 Clostridium difficile infection episodes with a rate of 1.05 per 100 dialysis patient years, slightly higher than last year at 0.55 episodes per 100 dialysis patient years. Escherichia coli infections occurred at a rate of 1.49 per 100 dialysis patient years, very similar to the rate reported last year (1.32 episodes per 100 dialysis patient years). This report has utilised a new methodology to identify cases, linking all established renal failure cases known to the UK Renal Registry (UKRR) with all infections reported to Public Health England and avoids the need for the local microbiology team to flag the patient as a renal patient. This may have increased the reliability of diagnosis at the UKRR level. In each infection for which access data were collected, the presence of a central venous catheter appeared to correlate with increased risk.


Association of Newly Developed Right Bundle Branch Block with Graft Rejection Following Heart Transplantation.
We aimed to examine associations between right bundle branch block (RBBB) following heart transplantation (HT) and graft rejection. We investigated 51 patients who underwent endomyocardial biopsies, electrocardiogram, right-side cardiac catheterization, and echocardiography at 1 month and 1 year after HT. We classified patients into four groups according to the development of RBBB, based on electrocardiogram at 1 month and 1 year: 1) sustained RBBB, 2) disappeared RBBB, 3) newly developed RBBB, and 4) sustained non-RBBB. The RBBB was defined as an RSR' pattern in V1 with a QRS duration ≥100 ms on electrocardiogram. The newly developed RBBB group (n=13, 25.5%) had a higher rate of new onset graft rejection (from grade 0 to grade ≥1R, 30.8% vs. 10.0% vs. 21.4%, p=0.042) at 1 year, compared with sustained RBBB (n=10, 19.6%) and sustained non-RBBB group (n=28, 54.9%). In contrast, the incidence of resolved graft rejection (from grade ≥1R to grade 0) was higher in the sustained RBBB group than the newly developed RBBB and sustained non-RBBB groups (70.0% vs. 7.7% vs. 25.0%, p=0.042). Left atrial volume index was significantly higher in the newly developed RBBB group than the sustained RBBB and sustained non-RBBB groups (60.6±25.9 mL/m² vs. 36.0±11.0 mL/m² vs. 38.4±18.1 mL/m², p=0.003). Close monitoring for new development of RBBB at 1 year after HT, which was associated with a higher incidence of new onset graft rejection, may be helpful to identify high risk patients for graft rejection.


Why large-scale climate indices seem to predict ecological processes better than local weather.
Large-scale climatic indices such as the North Atlantic Oscillation are associated with population dynamics, variation in demographic rates and values of phenotypic traits in many species. Paradoxically, these large-scale indices can seem to be better predictors of ecological processes than local climate. Using detailed data from a population of Soay sheep, we show that high rainfall, high winds or low temperatures at any time during a 3-month period can cause mortality either immediately or lagged by a few days. Most measures of local climate used by ecologists fail to capture such complex associations between weather and ecological process, and this may help to explain why large-scale, seasonal indices of climate spanning several months can outperform local climatic factors. Furthermore, we show why an understanding of the mechanism by which climate influences population ecology is important. Through simulation we demonstrate that the timing of bad weather within a period of mortality can have an important modifying influence on intraspecific competition for food, revealing an interaction between climate and density dependence that the use of large-scale climatic indices or inappropriate local weather variables might obscure.


High-dose topotecan, melphalan, and cyclophosphamide (TMC) with stem cell support: a new regimen for the treatment of advanced ovarian cancer.
The goal of this study was to determine the optimal dose of topotecan when used in combination with high-dose melphalan and cyclophosphamide (TMC), and to assess the toxicity and efficacy of the regimen in patients with advanced ovarian cancer. Fifty-three patients with persistent or recurrent ovarian cancer were treated. Disease status at study entry included: platinum-sensitive recurrent disease (15 patients), platinum-resistant or refractory recurrent disease (15 patients), positive second-look surgery (16 patients), failure to achieve a primary clinical complete response (CR) (7 patients). Following stem cell mobilization and collection, patients were given cyclophosphamide 1 g/m(2)/day on Days -6, -5, -4; melphalan 70 mg/m(2)/day on Days -3, -2; and topotecan at escalating doses from 1.25 to 4.0 mg/m(2)/day on Days -6 to -2. Peripheral blood stem cells were infused on Day 0. The optimal topotecan dose selected for future trials was 4.0 mg/m(2)/day x 5 days. The regimen had acceptable toxicity with no regimen-related death. Toxicity (Bearman toxicity criteria) was limited mostly to grade 1-2 mucositis and diarrhea. The overall response rate of patients with measurable or evaluable disease was 93%. Median survival has not yet been reached, but with a median follow up of 18 months (range: 11-37) 77% of patients are alive. With a topotecan dose of 4.0 mg/m(2)/day x 5 days, the TMC regimen has acceptable toxicity and produces high response rates. In the setting of ovarian cancer, high-dose chemotherapy should be administered only as part of well-designed clinical trials. TMC should be considered a potential regimen for future randomized trials in patients with advanced ovarian cancer.


Pediatric Emergency Provider Sexually Transmitted Infection Screening Practices in Adolescents With Oropharyngeal or Anorectal Chief Complaints.
Sexually transmitted infections (STIs) may present with oropharyngeal or anorectal symptoms. Little is known about the evaluation of adolescents with these complaints in the pediatric emergency department (PED). This study aimed to determine the frequency of and factors associated with STI consideration and testing in this population. Retrospective chart review of patients aged 13 to 18 years who presented to an urban PED with oropharyngeal or anorectal chief complaints between June 2014 and May 2015. Sexually transmitted infection consideration was defined as sexual history documentation, documentation of STI in differential diagnosis, and/or diagnostic testing. Multivariate logistic regression models were used to identify factors associated with consideration. Of 767 visits for oropharyngeal (89.4%), anorectal (10.4%), or both complaints, 153 (19.9%) had STI consideration. Of the 35 visits (4.6%) that included gonorrhea and/or chlamydia testing, 12 (34.3%) included testing at the anatomic site of complaint. Of those 12 tests, 50.0% were the incorrect test. Patients with older age (adjusted odds ratio [aOR] = 1.5, 95% confidence interval [CI] = 1.3-1.7), female sex (aOR = 1.6, 95% CI = 1.03-2.5), or anorectal complaints (aOR = 2.4, 95% CI = 1.3-4.3) were more likely to have STI consideration. In an urban PED, only 20% of visits for adolescents with oropharyngeal or anorectal symptoms included STI consideration. Testing was performed in only 5% of cases and often at an inappropriate anatomic site or with the incorrect test. Interventions to increase awareness of appropriate STI consideration and testing for individuals presenting with possible extragenital complaints may help reduce STIs among adolescents.


Quality of life in head and neck cancer patients: validation of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-H&N35.
The aim of this study was to define the scales and test the validity, reliability, and sensitivity of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-H&N35, a questionnaire designed to assess the quality of life of head and neck (H&N) cancer patients in conjunction with the general cancer-specific EORTC QLQ-C30. Questionnaires were given to 500 H&N cancer patients from Norway, Sweden, and the Netherlands as part of two prospective studies. The patients completed the questionnaires before, during (Norway and Sweden only), and after treatment, yielding a total of 2070 completed questionnaires. The compliance rate was high, and the questionnaires were well accepted by the patients. Seven scales were constructed (pain, swallowing, senses, speech, social eating, social contact, sexuality). Scales and single items were sensitive to differences between patient subgroups with relation to site, stage, or performance status. Most scales and single items were sensitive to changes, with differences of various magnitudes according to the site in question. The internal consistency, as assessed by Cronbach's alpha coefficient, varied according to assessment point and within subsamples of patients. A low overall alpha value was found for the speech and the senses scales, but values were higher in assessments of patients with laryngeal cancer and in patients with nose, sinus, and salivary gland tumors. Scales and single items in the QLQ-H&N35 seem to be more sensitive to differences between groups and changes over time than do the scales and single items in the core questionnaire. The QLQ-H&N35, in conjunction with the QLQ-C30, provides a valuable tool for the assessment of health-related quality of life in clinical studies of H&N cancer patients before, during, and after treatment with radiotherapy, surgery, or chemotherapy.


The cystic fibrosis gene and its product CFTR.
Cystic fibrosis is the commonest, fatal, inherited disease of caucasian populations occurring with a frequency of 1 in 2000 live births. The CF gene spans about 230 kb of genomic DNA and encodes a protein of 1480 amino acids named the cystic fibrosis transmembrane conductance regulator (CFTR). The primary sequence predicts that CFTR is an ABC type protein with twelve transmembrane spans, two nucleotide binding domains and a cytoplasmic regulatory domain. CFTR functions as a cyclic AMP-regulated, low conductance, chloride channel in epithelial cells, but other roles are possible. Failure of the CFTR channel in CF reduces epithelial salt and water secretion, leading to a dehydration of epithelial surfaces which initiates the pathology of the disease.


ST segment "hump" during exercise testing and the risk of sudden cardiac death in patients with hypertrophic cardiomyopathy.
The appearance of a discrete upward deflection of the ST segment termed "the ST hump sign" (STHS) during exercise testing has been associated with resting hypertension and exaggerated blood pressure response to exercise. We investigated the prevalence and clinical significance of this sign in a population of patients with hypertrophic cardiomyopathy. Eighty-one patients with hypertrophic cardiomyopathy (HCM) who underwent cardiopulmonary exercise testing were followed in a retrospective cohort study for a mean period of 5.3 years. The appearance of the STHS at the peak of exercise testing was observed in 42 patients (52%), particularly in the inferior and the lateral leads. Patients with the STHS had higher fractional shortening and maximum left ventricular wall thickness and exhibited more frequently outflow tract gradient >30 mmHg at rest. Furthermore, the presence of STHS was a strong independent predictor of the risk of sudden cardiac death (SCD), as the latter occurred in eight of the patients with this sign (8/42, 19%) and in none of the patients without it (0/39, 0%) (P < 0.001). The appearance of a "hump" at the ST segment during exercise testing appears to be a risk factor for SCD in patients with HCM. However, further studies are necessary to validate this finding in larger populations and to elucidate the mechanism of the appearance of the "hump."


Detection of left ventricular dysfunction after acute myocardial infarction: comparison of clinical, echocardiographic, and neurohormonal methods.
The SAVE study showed that captopril improves mortality in patients with left ventricular dysfunction after myocardial infarction and that this benefit occurred even in patients with no clinically overt heart failure. On the basis of this, it seems important to identify correctly which patients have left ventricular dysfunction after a myocardial infarction. The objective was to compare various methods of identifying patients with left ventricular dysfunction (left ventricular ejection fraction, LVEF, < or = 40%) after acute myocardial infarction. The methods compared were echocardiography (quantitative and qualitative visual assessment), clinical evaluation (subjective assessment and three clinical score methods), and measurement of plasma concentrations of cardiac natriuretic peptide hormones (atrial and brain natriuretic peptides, ANP and BNP). Cross sectional study of left ventricular function in patients two to eight days after acute myocardial infarction. Coronary care unit of a teaching hospital. 75 survivors of a recent myocardial infarction aged 40 to 88 with no history of cardiac failure and without cardiogenic shock at the time of entry to the study. Sensitivities and specificities of the various methods of detecting left ventricular dysfunction were calculated by comparing them with a cross sectional echocardiographic algorithm for LVEF. Clinical impression was poor at identifying LVEF < 40% (sensitivity 46%). Clinical scoring improved this figure somewhat (modified Peel index sensitivity 64%). Qualitative visual assessment echocardiography was a more sensitive method (sensitivity 82%) for detecting LVEF < 40%. Plasma BNP concentration was also a sensitive measure for detecting left ventricular dysfunction (sensitivity 84%) but plasma ANP concentration was much poorer (sensitivity 64%). Left ventricular dysfunction is easily and reliably detected by echocardiographic measurement of LVEF and also by a quick qualitative echocardiographic assessment but is likely to be missed by clinical assessment alone. High concentrations of plasma BNP maybe another useful indicator of left ventricular dysfunction, particularly in hospitals where not all patients can be screened by echocardiography or radionuclide ventriculography after myocardial infarction.


Assertive community treatment: an update of randomized trials.
Results of randomized clinical trials of assertive community treatment for seriously mentally ill patients published between 1990 and 1994 are reviewed to synthesize the state of knowledge about this research and to clarify continuing research directions. Randomized trials of interventions that used treatment principles and practices consistent with the Program for Assertive Community Treatment model or close adaptations whose results were published since 1990 were identified by literature searches using MEDLINE and PsychLit and by contact with investigators of ongoing trials. Controlled clinical trials have been conducted with a wide range of severely mentally ill populations, including patients in Great Britain, patients with recent-onset schizophrenia, veterans, dually diagnosed clients, and homeless persons. Methodological improvements in some studies include increased attention to monitoring the experimental and comparison interventions, as well as larger sample sizes and longer duration of the clinical trials than in earlier efficacy trials. Strong positive effects of assertive community treatment on hospital days and on patient and family satisfaction were found. Gains in functional outcomes, such as employment, may require interventions specifically targeted to these outcomes. Questions about the role of assertive community treatment as time-limited treatment, as an adjunct to other services and treatment, or as a comprehensive and continuous service system for adults with severe mental illness require further research. The growing research base should provide valuable information on costs, outcomes, and indications for assertive community treatment that can be evaluated by policy-makers.


Clinical and Surgical Predictors of Complications Following Surgery for the Treatment of Cervical Spondylotic Myelopathy: Results From the Multicenter, Prospective AOSpine International Study of 479 Patients.
Surgery for cervical spondylotic myelopathy (CSM) is generally safe and effective. Nonetheless, complications occur in 11% to 38% of patients. Knowledge of important predictors of complications will help clinicians identify high-risk patients and institute prevention and management strategies. To identify clinical and surgical predictors of perioperative complications in CSM patients. Four hundred seventy-nine surgical CSM patients were enrolled in the prospective CSM-International study at 16 sites. A panel of physicians reviewed all adverse events and classified each as related or unrelated to surgery. Univariate analyses were performed to determine differences between patients who experienced a perioperative complication and those who did not. A complication prediction rule was developed using multiple logistic regression. Seventy-eight patients experienced 89 perioperative complications (16.25%). On univariate analysis, the major clinical risk factors were ossification of the posterior longitudinal ligament (OPLL) (P = .055), number of comorbidities (P = .002), comorbidity score (P = .006), diabetes mellitus (P = .001), and coexisting gastrointestinal (P = .039) and cardiovascular (P = .046) disorders. Patients undergoing a 2-stage surgery (P = .002) and those with a longer operative duration (P = .001) were at greater risk of perioperative complications. A final prediction model consisted of diabetes mellitus (odds ratio [OR] = 1.96, P = .060), number of comorbidities (OR = 1.20, P = .069), operative duration (OR = 1.07, P = .002), and OPLL (OR = 1.75, P = .040). Surgical CSM patients have a higher risk of perioperative complications if they have a greater number of comorbidities, coexisting diabetes mellitus, OPLL, and a longer operative duration. Surgeons can use this information to discuss the risks and benefits of surgery with patients, to plan case-specific preventive strategies, and to ensure appropriate management in the perioperative period. BMI, body mass indexCSM, cervical spondylotic myelopathymJOA, modified Japanese Orthopaedic AssociationOPLL, ossification of the posterior longitudinal ligament.


The hypogonadal mouse: reproductive functions restored by gene therapy.
The hypogonadal (hpg) mouse lacks a complete gonadotropin-releasing hormone (GnRH) gene and consequently cannot reproduce. Introduction of an intact GnRH gene into the genome of these mutant mice resulted in complete reversal of the hypogonadal phenotype. Transgenic hpg/hpg homozygotes of both sexes were capable of mating and producing offspring. Pituitary and serum concentrations of luteinizing hormone, follicle-stimulating hormone, and prolactin were restored to those of normal animals. Immunocytochemistry and in situ hybridization showed that GnRH expression was restored in the appropriate hypothalamic neurons of the transgenic hpg animals, an indication of neural-specific expression of the introduced gene.


High-performance membrane chromatography of serum and plasma membrane proteins.
Porous discs made of poly(glycidyl methacrylate) were used for high-performance membrane chromatography (HPMC) of proteins. In model experiments, separations of standard proteins by anion-exchange HPMC using a DEAE disc were carried out. The influences of sample distribution and disc diameter and thickness on separation performance were studied. The separation disc allowed a scaling-up from analytical (diameter 10 mm) to semi-preparative (diameter 50 mm) dimensions. In an application study, separations with anion-exchange and affinity HPMC were carried out using different complex samples such as rat serum and plasma membrane proteins. In all experiments the results on poly(glycidyl methacrylate) discs were comparable to those achieved on adequate high-performance liquid chromatographic (HPLC) columns. However, the separations on HPMC discs could be carried out faster than corresponding separations on HPLC columns. The pressure drop on the discs was low even at high flow-rates. The experiments show that the poly(glycidyl methacrylate) discs used are especially suitable for the isolation of proteins and other biopolymers which occur in a diluted state in complex mixtures.


Anti-tumor effect of murine renal cell carcinoma cells genetically modified to express B7-1 combined with cytokine secreting fibroblasts.
Recently, many experiments have shown that the expression of the costimulatory molecule B7-1 on tumor cells can induce tumor-specific immunity. These results suggest that tumor cells modified to express costimulatory molecules can be used as a potential tumor vaccine. For this purpose, we transduced B7-1 gene into renal adenocarcinoma cells of spontaneous origin (Renca) in BALB/c mouse using the retroviral vector system. Our results indicated that approximately 60% of cells expressed B7-1 gene product using the retroviral vector system, and that B7-1 transduction did not affect the expression of MHC molecules on tumor cells nor the in vitro growth rate of tumor cells, but only in vivo tumorigenicity. As for the antitumor effect on the remote site, there were no significant differences among parental Renca, Renca lac Z and Renca B7-1 sublines, although tumors grew a little more slowly in the mice injected with Renca B7-1 cells as a vaccine. Even if the growth of tumors was significantly delayed in the mice treated by Renca B7-1 as a vaccine combined with the injection of BALB/c3T3 IL-12 near to the tumor on the same or following day, no significant antitumor effects were observed when the Renca B7-1 cells were injected as a vaccine compared with cytokines near the vaccine site. These results indicated that B7-1 gene transduction can decrease the tumorigenicity of murine renal cell carcinoma cells, but fails to induce sufficient antitumor response when it is used as a tumor vaccine. It is necessary to develop immunogenicity, by such means as irradiation or a combination of appropriate cytokines, to stimulate effective tumor immunity in a therapeutic setting.


Epidemiology and impact of imipenem resistance in Acinetobacter baumannii.
Acinetobacter baumannii is an emerging gram-negative pathogen that can cause healthcare-acquired infections among patients. Treatment is complicated for cases of healthcare-acquired infection with A. baumannii resistant to imipenem. To elucidate the risk factors for imipenem-resistant A. baumannii (IRAB) infection or colonization and to identify the effect of resistance on clinical and economic outcomes. We analyzed data from 2 medical centers of the University of Pennsylvania. Longitudinal trends in the prevalence of IRAB clinical isolates were characterized during the period from 1989 through 2004. For A. baumannii isolates obtained from 2001 through 2006, a case-control study was conducted to investigate the association between prior carbapenem use and IRAB infection or colonization, and a cohort study was performed to identify the effect of IRAB infection or colonization on mortality, length of stay after culture, and hospital cost after culture. From 1989 through 2004, the annual prevalence of IRAB isolates ranged from 0% to 21%. During the period from 2001 through 2006, there were 386 unique patients with A. baumannii isolates, and 89 (23.1%) had IRAB isolates. Prior carbapenem use was independently associated with IRAB infection or colonization (adjusted odds ratio, 3.04 [95% confidence interval, 1.07-8.65]). There was a borderline significant association between IRAB infection or colonization and mortality, although this association was limited to isolates recovered from blood samples (adjusted odds ratio, 5.30 [95% confidence interval, 0.81-34.59]). Compared with patients with imipenem-susceptible A. baumannii infection or colonization, patients with IRAB infection or colonization had a longer hospital stay after culture (median, 21 vs 16 days; P = .07) and greater hospital charges after culture (mean, $334,516 vs $276,059; P = .03). After controlling for patient location in an intensive care unit, transfer from another facility, and length of hospital stay before culture, there was no longer an independent association between IRAB infection or colonization and higher cost after culture and length of stay after positive culture result. Many A. baumannii isolates exhibit imipenem resistance, which is strongly associated with prior use of carbapenems. Given the high mortality rate associated with A. baumannii infection or colonization, interventions to curb further emergence of cases of IRAB infection and strategies to optimize therapy are needed.


A telehealth intervention to promote healthy lifestyles after stroke: The Stroke Coach protocol.
Rationale Recurrent stroke is prevalent and associated with high mortality rates, disability, and social and economic costs. Adequate management of risk factors may reduce recurrent stroke; however, many stroke survivors have poor control of risk factors. We have developed a theoretically sound and evidence-based lifestyle modification program called the Stroke Coach, a telephone-based self-management program to improve control of risk factors. Hypothesis Individuals who participate in Stroke Coach will achieve more lifestyle improvements than individuals in an attention controlled Memory Training Program. Design In this single blind randomized controlled trial, 126 community-living stroke survivors will be randomized to Stroke Coach or the attention control group. Participants randomized to the six-month Stroke Coach will receive seven telephone lifestyle coaching sessions, self-management education and practice, and a self-monitoring kit, comprised of a health report card, with blood pressure and activity monitors. Study Outcomes The primary outcome will be measured using the Health Promoting Lifestyle Profile II. Secondary outcomes include behavioral and physiological risk factors, quality of life, cognitive status, health and social service use. Measurements will be taken at baseline, immediately after the intervention and six-month post-intervention. Summary The results of this trial will add to our understanding of the use of self-management to improve control of risk factors, and may facilitate the development of a larger trial evaluating the effect of Stroke Coach on endpoints such as recurrent stroke or cardiac events as the primary outcome.


Effect of isotretinoin treatment on plasma holotranscobalamin, vitamin B12, folic acid, and homocysteine levels: non-controlled study.
Isotretinoin (Iso) has been used for the treatment of acne. Some previous studies reported elevated homocysteine (Hcy) levels after treatment with Iso. Some side effects have clinical presentations similar to vitamin B12, folic acid deficiencies, and hyperhomocysteinemia. In the present study we evaluated the plasma Hcy levels, the vitamins involved in its metabolism (vitamin B12 and folic acid), and holotranscobalamin (HoloTC), a transport system for vitamin B12 absorption in patients receiving Iso treatment for acne vulgaris. A total of 66 patients with acne vulgaris between the ages of 18 and 40 years were included. Screening for hemoglobin, creatinine, SGOT, SGPT, total cholesterol, triglycerides, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and very low-density lipoprotein cholesterol (VLDL-C), folic acid, vitamin B12, Hcy, and HoloTC were done just before initiation (pretreatment) and after four months of Iso treatment (posttreatment). Posttreatment vitamin B12, folic acid, and HoloTC levels were significantly lower while Hcy levels were significantly higher compared with initial values. Posttreatment total cholesterol, LDL-C, triglycerides, VLDL-C, SGPT, and SGOT levels were also higher, and HDL-C levels were lower compared with initial values while there was no change in hemoglobin levels during Iso treatment. We found that Iso usage might cause decreased vitamin B12, folic acid, and HoloTC. These Iso side effects might contribute to the missing link between Iso usage, hyperhomocysteinemia, and neuropsychiatric disorders. Trials may be made with the aim of demonstrating (clearly) if starting vitamin B12 and folic acid replacement therapies with Iso treatment initialization could be useful for preventing hyperhomocysteinemia and possibly related disorders.


Why is CA3 more vulnerable than CA1 in experimental models of controlled cortical impact-induced brain injury?
One interesting finding of controlled cortical impact (CCI) experiments is that the CA3 region of the hippocampus, which is positioned further from the impact than the CA1 region, is reported as being more injured. The current literature has suggested a positive correlation between brain tissue stretch and neuronal cell loss. However, it is counterintuitive to assume that CA3 is stretched more during CCI injury. Recent mechanical studies of the brain have reported on a level of spatial heterogeneity not previously appreciated-the finding that CA1 was significantly stiffer than all other regions tested and that CA3 was one of the most compliant. We hypothesized that mechanical heterogeneity of anatomical structures could underlie the proposed heterogeneous mechanical response and hence the pattern of cell death. As such, we developed a three-dimensional finite element (FE) rat brain model representing detailed hippocampal structures and simulated various CCI experiments. Four groups of material properties based on recent experiments were tested. In group 1, hyperelastic material properties were assigned to various hippocampal structures, with CA3 more compliant than CA1. In group 2, linear viscoelastic material properties were assigned to hippocampal structures, with CA3 more compliant than CA1. In group 3, the hippocampus was represented by homogenous linear viscoelastic material properties. In group 4, a homogeneous nonlinear hippocampus was adopted. Simulation results demonstrated that for CCI with a 5-mm diameter, flat shape impactor, CA3 experienced increased tensile strains over a larger area and to a greater magnitude than did CA1 for group 1, which best explained why CA3 is more sensitive to CCI injury. However, for groups 2-4, the total volume with high strain (>30%) in CA3 was smaller than that in CA1. The FE rat brain model, with detailed hippocampal structures presented here, will help to engineer desired experimental neurotrauma models by virtually characterizing brain biomechanics before testing.


Nutraceuticals and Blood Pressure Control: Results from Clinical Trials and Meta-Analyses.
Beyond the well-known effects on blood pressure (BP) of the dietary approaches to stop hypertension (DASH) and the Mediterranean diets, a large number of studies has investigated the possible BP lowering effect of different dietary supplements and nutraceuticals, the most part of them being antioxidant agents with a high tolerability and safety profile. In particular relatively large body of evidence support the use of potassium, L-arginine, vitamin C, cocoa flavonoids, beetroot juice, coenzyme Q10, controlled-release melatonin, and aged garlic extract. However there is a need for data about the long-term safety of a large part of the above discussed products. Moreover further clinical research is advisable to identify between the available active nutraceuticals those with the best cost-effectiveness and risk-benefit ratio for a large use in general population with low-added cardiovascular risk related to uncomplicated hypertension.


Ovarian cancer stem-like cells show induced translineage-differentiation capacity and are suppressed by alkaline phosphatase inhibitor.
Spheroid formation is one property of stem cells-such as embryo-derived or neural stem cells-that has been used for the enrichment of cancer stem-like cells (CSLCs). However, it is unclear whether CSLC-derived spheroids are heterogeneous or whether they share common embryonic stemness properties. Understanding these features might lead to novel therapeutic approaches. Ovarian carcinoma is a deadly disease of women. We identified two types of spheroids (SR1 and SR2) from ovarian cancer cell lines and patients' specimens according to their morphology. Both types expressed stemness markers and could self-renew and initiate tumors when a low number of cells were used. Only SR1 could differentiate into multiple-lineage cell types under specific induction conditions. SR1 spheroids could differentiate to SR2 spheroids through epithelial-mesenchymal transition. Alkaline phosphatase (ALP) was highly expressed in SR1 spheroids, decreased in SR2 spheroids, and was absent in differentiated progenies in accordance with the loss of stemness properties. We verified that ALP can be a marker for ovarian CSLCs, and patients with greater ALP expression is related to advanced clinical stages and have a higher risk of recurrence and lower survival rate. The ALP inhibitor, levamisole, disrupted the self-renewal of ovarian CSLCs in vitro and tumor growth in vivo. In summary, this research provides a plastic ovarian cancer stem cell model and a new understanding of the cross-link between stem cells and cancers.This results show that ovarian CSLCs can be suppressed by levamisole. Our findings demonstrated that some ovarian CSLCs may restore ALP activity, and this suggests that inhibition of ALP activity may present a new opportunity for treatment of ovarian cancer.


PacCYP707A2 negatively regulates cherry fruit ripening while PacCYP707A1 mediates drought tolerance.
Sweet cherry is a non-climacteric fruit and its ripening is regulated by abscisic acid (ABA) during fruit development. In this study, four cDNAs (PacCYP707A1-4) encoding 8'-hydroxylase, a key enzyme in the oxidative catabolism of ABA, were identified in sweet cherry fruits using tobacco rattle virus-induced gene silencing (VIGS) and particle bombardment approaches. Quantitative real-time PCR confirmed significant down-regulation of target gene transcripts in VIGS-treated cherry fruits. In PacCYP707A2-RNAi-treated fruits, ripening and fruit colouring were promoted relative to control fruits, and both ABA accumulation and PacNCED1 transcript levels were up-regulated by 140%. Silencing of PacCYP707A2 by VIGS significantly altered the transcripts of both ABA-responsive and ripening-related genes, including the ABA metabolism-associated genes NCED and CYP707A, the anthocyanin synthesis genes PacCHS, PacCHI, PacF3H, PacDFR, PacANS, and PacUFGT, the ethylene biosynthesis gene PacACO1, and the transcription factor PacMYBA. The promoter of PacMYBA responded more strongly to PacCYP707A2-RNAi-treated fruits than to PacCYP707A1-RNAi-treated fruits. By contrast, silencing of PacCYP707A1 stimulated a slight increase in fruit colouring and enhanced resistance to dehydration stress compared with control fruits. These results suggest that PacCYP707A2 is a key regulator of ABA catabolism that functions as a negative regulator of fruit ripening, while PacCYP707A1 regulates ABA content in response to dehydration during fruit development.


Gabapentin in the treatment of fibromyalgia: a randomized, double-blind, placebo-controlled, multicenter trial.
To assess the efficacy and safety of gabapentin in patients with fibromyalgia. A 12-week, randomized, double-blind study was designed to compare gabapentin (1,200-2,400 mg/day) (n=75 patients) with placebo (n=75 patients) for efficacy and safety in treating pain associated with fibromyalgia. The primary outcome measure was the Brief Pain Inventory (BPI) average pain severity score (range 0-10, where 0=no pain and 10=pain as bad as you can imagine). Response to treatment was defined as a reduction of >or=30% in this score. The primary analysis of efficacy for continuous variables was a longitudinal analysis of the intent-to-treat sample, with treatment-by-time interaction as the measure of effect. Gabapentin-treated patients displayed a significantly greater improvement in the BPI average pain severity score (P=0.015; estimated difference between groups at week 12=-0.92 [95% confidence interval -1.75, -0.71]). A significantly greater proportion of gabapentin-treated patients compared with placebo-treated patients achieved response at end point (51% versus 31%; P=0.014). Gabapentin compared with placebo also significantly improved the BPI average pain interference score, the Fibromyalgia Impact Questionnaire total score, the Clinical Global Impression of Severity, the Patient Global Impression of Improvement, the Medical Outcomes Study (MOS) Sleep Problems Index, and the MOS Short Form 36 vitality score, but not the mean tender point pain threshold or the Montgomery Asberg Depression Rating Scale. Gabapentin was generally well tolerated. Gabapentin (1,200-2,400 mg/day) is safe and efficacious for the treatment of pain and other symptoms associated with fibromyalgia.


Monotonicity is a key feature of genotype-phenotype maps.
It was recently shown that monotone gene action, i.e., order-preservation between allele content and corresponding genotypic values in the mapping from genotypes to phenotypes, is a prerequisite for achieving a predictable parent-offspring relationship across the whole allele frequency spectrum. Here we test the consequential prediction that the design principles underlying gene regulatory networks are likely to generate highly monotone genotype-phenotype maps. To this end we present two measures of the monotonicity of a genotype-phenotype map, one based on allele substitution effects, and the other based on isotonic regression. We apply these measures to genotype-phenotype maps emerging from simulations of 1881 different 3-gene regulatory networks. We confirm that in general, genotype-phenotype maps are indeed highly monotonic across network types. However, regulatory motifs involving incoherent feedforward or positive feedback, as well as pleiotropy in the mapping between genotypes and gene regulatory parameters, are clearly predisposed for generating non-monotonicity. We present analytical results confirming these deep connections between molecular regulatory architecture and monotonicity properties of the genotype-phenotype map. These connections seem to be beyond reach by the classical distinction between additive and non-additive gene action.


With a Little Help From My Family: A Mixed-Method Study on the Outcomes of Family Support and Workload.
Our aim was to investigate some predictors and outcomes of family-to-work enrichment (FWE) via a mixed-method approach. We sampled 447 married employees of an Italian factory. Survey results from Study 1 showed that emotional support from family positively predicted FWE, while this latter mediated the associations between the former on one side, and work engagement and life satisfaction on the other. Moreover, extra-household support directly associated positively with life satisfaction. Evidence from 20 anthropological in-depth interviews (Study 2) returned a more complex picture, highlighting the gendered role of partners inside couples, the importance of kinship support, the sense and the value of filiation and parenthood in their connection with job roles, the complex and continuous interplay between family and life domains. In combination, results from both studies stressed the importance of family support; additionally, evidences from Study 2 suggested that FWE could be better understood taking into account crossover dynamics and the compresence of work-to-family enrichment and conflict. In sum, these studies contributed to shed light on FWE dynamics, an under-researched topic in Italy, whose knowledge could be of great empirical and practical value.


Retrospective Analysis of Safety of Vedolizumab in Patients With Inflammatory Bowel Diseases.
There are few real-world data on the safety of vedolizumab for treatment of Crohn's disease (CD) or ulcerative colitis (UC). We quantified rates and identified factors significantly associated with infectious and non-infectious adverse events in clinical practice. We performed a retrospective review of data from a multicenter consortium database (from May 2014 through June 2017). Infectious and non-infectious adverse events were defined as those requiring antibiotics, hospitalization, vedolizumab discontinuation, or resulting in death. Rates were quantified as proportions and events per 100 patient years of exposure (PYE) or follow up (PYF). We performed multivariable logistic regression analyses to identify factors significantly associated with events and reported as odds ratios (OR) with 95% CIs. Our analysis comprised 1087 patients (650 with CD and 437 with UC; 55% female; median age, 37 years) with 861 PYE and 955 PYF. Infections were observed in 68 patients (6.3%; 7.9 per 100 PYE, 7.1 per 100 PYF); gastrointestinal infections (n = 31, 2.4 per 100 PYE, 2.2 per 100 PYF) and respiratory infections (n = 14, 1.6 per 100 PYE, 1.5 per 100 PYF) were the most common. Arthralgias were the most common non-infectious adverse events (n = 31, 2.9%; 3.6 per 100 PYE). Two patients developed malignancies (squamous cell skin cancer and colorectal cancer; 0.23 per 100 PYE, 0.21 per 100 PYF). Active smoker status (OR, 3.39) and number of concomitant immunosuppressive agents (corticosteroids or immunomodulators; OR, 1.72 per agent) used were independently associated with infections. In a retrospective cohort study of patients with IBD, we found vedolizumab to be well tolerated with an overall favorable safety profile. Active smoking and concomitant use of immunosuppressive agents were independently associated with infections.


Band-limited angular spectrum numerical propagation method with selective scaling of observation window size and sample number.
Band-limited angular spectrum (BLAS) methods can be used for simulating the diffractional propagation in the near field, the far field, the tilted system, and the nonparaxial system. However, it does not allow free sample interval on the output calculation window. In this paper, an improved BLAS method is proposed. This new algorithm permits a selective scaling of observation window size and sample number on the observation plane. The method is based on the linear convolution, which can be calculated by fast Fourier transform effectively.


No improvement of survival with reduced- versus high-intensity conditioning for allogeneic stem cell transplants in Ewing tumor patients.
Outcomes of Ewing tumor (ET) patients treated with allogeneic stem cell transplantation (allo-SCT) were compared regarding the use of reduced-intensity conditioning (RIC) and high-intensity conditioning (HIC) regimens as well as human leukocyte antigen (HLA)-matched and HLA-mismatched grafts. We retrospectively analyzed data of 87 ET patients from the European Group for Blood and Marrow Transplantation, Pediatric Registry for Stem Cell Transplantations, Asia Pacific Blood and Marrow Transplantation and MetaEICESS registries treated with allo-SCT. Fifty patients received RIC (group A) and 37 patients received HIC (group B). Twenty-four patients received HLA-mismatched grafts and 63 received HLA-matched grafts. Median overall survival was 7.9 months [±1.24, 95% confidence interval (CI) 5.44-10.31] for group A and 4.4 months (±1.06, 95% CI 2.29-6.43) for group B patients (P = 1.3). Death of complications (DOC) occurred in 4 of 50 (0.08) and death of disease (DOD) in 33 of 50 (0.66) group A and in 16 of 37 (0.43) and 17 of 37 (0.46) group B patients, respectively. DOC incidence was decreased (P < 0.01) and DOD/relapse increased (P < 0.01) in group A compared with group B. HLA mismatch was not generally associated with graft-versus-Ewing tumor effect (GvETE). There was no improvement of survival with RIC compared with HIC due to increased DOD/relapse incidence after RIC despite less DOC incidence. This implicates general absence of a clinically relevant GvETE with current protocols.


Prognostic impact of C-reactive protein-albumin ratio for the lethality in castration-resistant prostate cancer.
This study aimed to assess the clinical value of C-reactive protein-albumin ratio (CAR) at the initiation of first-line treatment for castration-resistant prostate cancer (CRPC). We identified 221 CRPC patients treated with either androgen-signaling inhibitors (ASIs: abiraterone and enzalutamide) or docetaxel as the first-line treatment. The value of CAR was evaluated at the initiation of first-line treatment. The optimal cutoff value of CAR for the prediction of lethality was defined by the receiver operating characteristic curve and the Youden Index. The primary endpoints of the study included overall survival (OS) and cancer-specific survival (CSS). The median age was 74 years. The optimal cutoff value of CAR in newly diagnosed CRPC patients was 0.5 (CAR > 0.5: n = 77 and CAR ≤ 0.5: n = 144). The 3-year OS and CSS rate in patients with CAR > 0.5 were significantly lower than those with CAR ≤ 0.5 (OS: 30.9% vs 55.5%, p < 0.001) (CSS: 42.5% vs 65.4%, p < 0.001). A multivariate analysis consistently demonstrated that CAR was an independent predictor for both OS and CSS. When stratified by the first-line treatments, patients with CAR > 0.5 has significantly shorter CSS than those with CAR ≤ 0.5 in abiraterone (median of 23 vs 49 months, p < 0.001) and enzalutamide (median of 23 vs 41 months, p = 0.0016), whereas no difference was observed in patients treated with docetaxel as the first-line treatment (median of 34 and 37 months, p = 0.7708). Despite the limited cohort size and retrospective design, increased CAR seemed to serve as an independent predictor of OS and CSS for patients newly diagnosed with CRPC.


Stereotactic radiosurgery for brain metastases: a case-matched study comparing treatment results for patients 80 years of age or older versus patients 65-79 years of age.
Recently, an increasing number of patients with brain metastases, even patients over 80 years of age, have been treated with stereotactic radiosurgery (SRS). However, there is little information on SRS treatment results for patients with brain metastases 80 years of age and older. The authors undertook this study to reappraise whether SRS treatment results for patients 80 years of age or older differ from those of patients who are 65-79 years old. This was an institutional review board-approved, retrospective cohort study. Among 2552 consecutive brain metastasis patients who underwent SRS during the 1998-2011 period, we studied 165 who were 80 years of age or older (Group A) and 1181 who were age 65-79 years old (Group B). Because of the remarkable disproportion in patient numbers between the 2 groups and considerable differences in pre-SRS clinical factors, the authors conducted a case-matched study using the propensity score matching method. Ultimately, 330 patients (165 from each group, A and B) were selected. For time-to-event outcomes, the Kaplan-Meier method was used to estimate overall survival and competing risk analysis was used to estimate other study end points, as appropriate. Although the case-matched study showed that post-SRS median survival time (MST, months) was shorter in Group A patients (5.3 months, 95% CI 3.9-7.0 months) than in Group B patients (6.9 months, 95% CI 5.0-8.1 months), this difference was not statistically significant (HR 1.147, 95% CI 0.921-1.429, p = 0.22). Incidences of neurological death and deterioration were slightly lower in Group A than in Group B patients (6.3% vs 11.8% and 8.5% vs 13.9%), but these differences did not reach statistical significance (p = 0.11 and p = 0.16). Furthermore, competing risk analyses showed that the 2 groups did not differ significantly in cumulative incidence of local recurrence (HR 0.830, 95% CI 0.268-2.573, p = 0.75), rates of repeat SRS (HR 0.738, 95% CI 0.438-1.242, p = 0.25), or incidence of SRS-related complications (HR 0.616, 95% CI 0.152-2.495, p = 0.49). Among the Group A patients, post-SRS MSTs were 11.6 months (95% CI 7.8-19.6 months), 7.9 months (95% CI 5.2-10.9 months), and 2.8 months (95% CI; 2.4-4.6 months) in patients whose disease status was modified-recursive partitioning analysis (RPA) Class(es) I+IIa, IIb, and IIc+III, respectively (p < 0.001). Our results suggest that patients 80 years of age or older are not unfavorable candidates for SRS as compared with those 65-79 years old. Particularly, even among patients 80 years and older, those with modified-RPA Class I+IIa or IIb disease are considered to be favorable candidates for more aggressive treatment of brain metastases.


Ethics in Children's Dental Treatment under General Anesthesia at the Lebanese University.
In pediatric dentistry, general anesthesia is required for dental treatment. The treatment modalities are often linked to the patient's medical conditions. However, ethical values might influence the decisions of the treatment. To compare the treatment modalities under general anesthesia between healthy children and children with special needs (CSN) and to assess the ethical principles. An analytical retrospective study, approximately 64 patients including 26 CSN and 38 healthy children from 3 to 12 years of age, who underwent general anesthesia (GA) for dental treatment, was performed. The treatment modalities for each tooth were noted, such as fissure sealant, composite, pulp treatment, stainless steel crowns restorations, and extraction. Statistical analysis was performed to evaluate the implementation of the four principles of ethics. Statistical analyses were performed with the Statistical Package for the Social Sciences (SPSS), version 20, (Los Angeles, California), with 95% confidence interval of the difference. The significance level was set at P < 0.05 valued. A total of 40.6% of the sample were CSN and 59.4% were healthy with extremely high dental fear and anxiety. Thirty-five children were <6 years old. Only 11.4% of them were CSN; 29 children were ≥6 years old and 75.9% were CSN. For 56 of 64 of the patients, the treatment plan has not been respected irrespective of the medical condition. A total of three of the eight treatment plans that have been respected were for the CSN and five for the healthy children. Under general anesthesia, the medical condition of the patient did not alter the dental treatment type. The four principles of ethics were respected as well in CSN as in healthy ones.


Deciphering genomic alterations in colorectal cancer through transcriptional subtype-based network analysis.
Both transcriptional subtype and signaling network analyses have proved useful in cancer genomics research. However, these two approaches are usually applied in isolation in existing studies. We reason that deciphering genomic alterations based on cancer transcriptional subtypes may help reveal subtype-specific driver networks and provide insights for the development of personalized therapeutic strategies. In this study, we defined transcriptional subtypes for colorectal cancer (CRC) and identified driver networks/pathways for each subtype. Applying consensus clustering to a patient cohort with 1173 samples identified three transcriptional subtypes, which were validated in an independent cohort with 485 samples. The three subtypes were characterized by different transcriptional programs related to normal adult colon, early colon embryonic development, and epithelial mesenchymal transition, respectively. They also showed statistically different clinical outcomes. For each subtype, we mapped somatic mutation and copy number variation data onto an integrated signaling network and identified subtype-specific driver networks using a random walk-based strategy. We found that genomic alterations in the Wnt signaling pathway were common among all three subtypes; however, unique combinations of pathway alterations including Wnt, VEGF and Notch drove distinct molecular and clinical phenotypes in different CRC subtypes. Our results provide a coherent and integrated picture of human CRC that links genomic alterations to molecular and clinical consequences, and which provides insights for the development of personalized therapeutic strategies for different CRC subtypes.