[Comparison of IgA class reticulin and endomysial antibodies for the diagnosis and dietary control in celiac disease].
Sensibility to gluten is a condition with high immunological reaction against gluten proteins from wheat, barley, rye and oats in individuals genetically susceptible. Celiac disease is its most frequent expression with various forms of clinical presentation. The treatment consists in gluten free diet. Although the biopsy of proximal small bowel is necessary, the importance of serological tests is increasing in the screening, diagnosis and monitoring of gluten free diet in celiac patients. The aim of this study was to investigate the presence of antiendomysium (EmA-IgA) and anti-reticulin (ARA-IgA) antibodies in 56 celiac patients (17 at diagnosis, 24 adherent to the diet and 15 with transgression to the diet). The antibodies were detected by indirect immunofluorescence, using human umbilical cord as substrate for the EmA-IgA and rat liver and kidney for the ARA-IgA. In the patients at diagnosis and in the group with transgression to the diet the total positivity was 100% for EmA-IgA and 59.4% for ARA-IgA. Antibodies were not detected in gluten-free diet patients. Among the 32 positive patients, the concordance of both tests was of 59.4% (19/32), being 40.6% (13/32) negative to ARA-IgA and positive to EmA-IgA. No patient was positive for ARA-IgA and negative for EmA-IgA. Thus, the sensitivity for EmA-IgA was of 100% and 59.4% for ARA-IgA. The association of the two tests did not improve the positivity in the samples. In conclusion, EmA-IgA can be considered the best serological test for diagnosis and follow up of celiac patients, because it presents high predictive value, high specificity and sensibility and is not expensive if using human umbilical cord as substrate.


Survival and flowering of hybrids between cultivated and wild carrots (Daucus carota) in Danish grasslands.
Many crop species are able to hybridize with related weedy or wild relatives, which could lead to transfer of cultivar genes, and among them transgenes, into wild populations. It is not clear, however, whether the hybrids and their descendants are able to survive and reproduce in natural habitats, as inherited cultivar traits may be maladaptive under such conditions. To test this, we produced hybrid (F(1)) seeds by controlled crosses between wild [see text for formula] and cultivated carrots (Daucus carota ssp. carota and ssp. sativa, respectively) and sowed them into three Danish grasslands of different age, in parallel with seeds of wild carrots. Replicate plots were sown in fall and spring. Survival and flowering of the emerging plants were monitored for the following three years. Both hybrid and wild carrots survived and flowered in highest frequency at a recently disturbed site, and much less at two older sites. Hybrids emerged in higher proportions than wild carrots in the first year and survived to similar or slightly lower frequencies at the end of the experiment. Hybrids flowered as frequently or slightly less frequently than wild plants, and developed fewer and smaller umbels. Despite a somewhat lower reproductive potential compared to wild carrots, first generation hybrids between cultivated and wild carrots are likely to survive and produce offspring in natural grasslands in Denmark. This, together with other studies, suggests that cultivar genes may transfer relatively easily into wild carrot populations.


Determination of linkage position and anomeric configuration in Hex-Fuc disaccharides using electrospray ionization tandem mass spectrometry.
Fixed-energy sequential tandem mass spectrometry (MS(n)) capabilities offered by quadrupole ion trap instruments have been explored in a systematic study of six isomers of Gal-Fucalpha-OBenzyl disaccharides. Under collision-induced dissociation (CID), sodiated molecular species generated in the positive-ion electrospray ionization mode yield simple and predictable mass spectra. Information on interglycosidic linkages and configurations can be deduced from the relative intensities of the selected diagnostic fragments arising from the glycosidic bond cleavages and corroborated by the fragments arising from cross-ring cleavages. As the CID patterns are not dependent on the number of prior tandem mass spectrometric steps, structures can be unambiguously assigned by matching the spectra with a library. The rules governing the fragmentation behavior of this class of oligosaccharides were tested for a representative isomeric disaccharide, Glcbeta1,3Fucalpha-OAllyl. The findings establish a basis for using MS(n) with a quadrupole ion trap instrument to elucidate structures of hexose-fucose subunits from more complicated oligosaccharides. Energy-resolved mass spectra were also acquired by CID tandem triple-quadrupole mass spectrometry. The breakdown behavior of the molecular ions revealed patterns which could differentiate stereoisomers of Gal-Fuc disaccharides over a range of collision energy from 20 to 50 eV.


[Methodologies of publications in the Revista de Investigación Clínica during the last 20 years].
To characterize the clinical research methods published in the Revista de Investigación Clínica for the past 20 years. Comparative study of methods used in the RIC articles published in 3-years periods representing three decades (1972-74, 1982-84, 1992-94). Out of 273 original papers, 218 (80%) were of clinical research. There was an increased percentage of longitudinal vs cross-sectional studies, with cohort and randomized clinical trials showing the largest increase. The total number of research manuscripts also increased. The clinical research methods of the papers in the RIC have shown an increased rate of designs with a higher scientific value.


Utilization of exocellular mannan from Rhodotorula glutinis as an immunoreactive antigen in diagnosis of leptospirosis.
Previously, Rhodotorula glutinis was reported to produce a large amount of exocellular mannan, having a repeating unit of -->3)-D-Manp-(1-->4)-D-Manp-(1-->. Recently, we found that antigenic polysaccharides of Leptospira biflexa serovar patoc strain Patoc I have the same repeating unit and cross-react with antisera raised against extended strains of other leptospires (K. Matsuo, E. Isogai, and Y. Araki, Carbohydr. Res., in press). This structural identity and the difficulty of producing and isolating antigens led us to confirm the usefulness of Rhodotorula mannan as an immunoreactive antigen in a serological diagnosis of leptospirosis. In the present investigation, we confirmed the structural identity of an exocellular mannan isolated from R. glutinis AHU 3479 and tried to use it as an immunoreactive antigen in a serological diagnosis of leptospirosis. From its chemical analysis and (1)H- and (13)C-labeled nuclear magnetic resonance spectrometry, the Rhodotorula mannan was confirmed to consist of the same disaccharide units. Furthermore, such a preparation was shown to immunoreact to various sera from patients suffering with leptospirosis as well as to most rabbit antiserum preparations obtained from immunization with various strains of pathogenic leptospires. Therefore, the Rhodotorula mannan preparation is useful as an immunoreactive antigen in the serological diagnosis for leptospirosis.


Protein delivery for retinal diseases: from basic considerations to clinical applications.
Because the eye is protected by ocular barriers but is also easily accessible, direct intravitreous injections of therapeutic proteins allow for specific and targeted treatment of retinal diseases. Low doses of proteins are required in this confined environment and a long time of residency in the vitreous is expected, making the eye the ideal organ for local proteic therapies. Monthly intravitreous injection of Ranibizumab, an anti-VEGF Fab has become the standard of care for patients presenting wet AMD. It has brought the proof of concept that administering proteins into the physiologically low proteic concentration vitreous can be performed safely. Other antibodies, Fab, peptides and growth factors have been shown to exert beneficial effects on animal models when administered within the therapeutic and safe window. To extend the use of such biomolecules in the ophthalmology practice, optimization of treatment regimens and efficacy is required. Basic knowledge remains to be increased on how different proteins/peptides penetrate into the eye and the ocular tissues, distribute in the vitreous, penetrate into the retinal layers and/or cells, are eliminated from the eye or metabolized. This should serve as a basis for designing novel drug delivery systems. The later should be non-or minimally invasive and should allow for a controlled, scalable and sustained release of the therapeutic proteins in the ocular media. This paper reviews the actual knowledge regarding protein delivery for eye diseases and describes novel non-viral gene therapy technologies particularly adapted for this purpose.


Pathogenesis of varicelloviruses in primates.
Varicelloviruses in primates comprise the prototypic human varicella-zoster virus (VZV) and its non-human primate homologue, simian varicella virus (SVV). Both viruses cause varicella as a primary infection, establish latency in ganglionic neurons and reactivate later in life to cause herpes zoster in their respective hosts. VZV is endemic worldwide and, although varicella is usually a benign disease in childhood, VZV reactivation is a significant cause of neurological disease in the elderly and in immunocompromised individuals. The pathogenesis of VZV infection remains ill-defined, mostly due to the species restriction of VZV that impedes studies in experimental animal models. SVV infection of non-human primates parallels virological, clinical, pathological and immunological features of human VZV infection, thereby providing an excellent model to study the pathogenesis of varicella and herpes zoster in its natural host. In this review, we discuss recent studies that provided novel insight in both the virus and host factors involved in the three elementary stages of Varicellovirus infection in primates: primary infection, latency and reactivation.


Tri-Clustered Tensor Completion for Social-Aware Image Tag Refinement.
Social image tag refinement, which aims to improve tag quality by automatically completing the missing tags and rectifying the noise-corrupted ones, is an essential component for social image search. Conventional approaches mainly focus on exploring the visual and tag information, without considering the user information, which often reveals important hints on the (in)correct tags of social images. Towards this end, we propose a novel tri-clustered tensor completion framework to collaboratively explore these three kinds of information to improve the performance of social image tag refinement. Specifically, the inter-relations among users, images and tags are modeled by a tensor, and the intra-relations between users, images and tags are explored by three regularizations respectively. To address the challenges of the super-sparse and large-scale tensor factorization that demands expensive computing and memory cost, we propose a novel tri-clustering method to divide the tensor into a certain number of sub-tensors by simultaneously clustering users, images and tags into a bunch of tri-clusters. And then we investigate two strategies to complete these sub-tensors by considering (in)dependence between the sub-tensors. Experimental results on a real-world social image database demonstrate the superiority of the proposed method compared with the state-of-the-art methods.


Dendritic cell nuclear protein-1, a novel depression-related protein, upregulates corticotropin-releasing hormone expression.
The recently discovered dendritic cell nuclear protein-1 is the product of a novel candidate gene for major depression. The A allele encodes full-length dendritic cell nuclear protein-1, while the T allele encodes a premature termination of translation at codon number 117 on chromosome 5. In the present study we investigate whether the two forms of dendritic cell nuclear protein-1 might act on corticotropin-releasing hormone, which plays a crucial role in the stress response and in the pathogenesis of depression. The messenger RNA expression of dendritic cell nuclear protein-1 appeared to be increased in the laser micro-dissected paraventricular nucleus of patients with depression compared with control subjects. Dendritic cell nuclear protein-1 was also found to be co-localized with corticotropin-releasing hormone in paraventricular nucleus neurons. Moreover, full-length dendritic cell nucleus protein-1 bound to and transactivated the promoter of corticotropin-releasing hormone in human embryonic kidney 293 cells. We propose that full-length dendritic cell nucleus protein-1 may play a role in the pathogenesis of depressive disorders by enhancing corticotropin-releasing hormone expression in the hypothalamic paraventricular nucleus.


[Formation of the population composition of a stationary cell culture and the participation of nonproliferating cells with a doubled DNA content in regulating its density].
The conditions of the cultivation of chick embryo diploid cells were alternated (prolonged maintenance with or without medium replacement, with or without consequent cell replating in fresh medium). In different times of culture growth, the cell DNA content was assessed by cytophotometry; the percentage of non-labeled mitoses after incubating the cells with 3H-thymidine and colcemide, as well as the cell density were determined. The phenomenon, detected earlier, of the accumulation of cells containing 4c DNA during the transition of the culture from logarithmic into the stationary phase of growth, was confirmed. These cells were shown to differ in their ability to survive in conditions of stationary culture and by proliferative potential. The fraction of cells reversibly arrested in G2-period was described, by which fraction the change of the cell population size is occurring after the decrease of its proliferation rate. The transitional stage is distinguished at the beginning of the stationary phase of culture growth. During this stage the stabilization of structural and numerical composition of the population is taking place.


Duodenal bicarbonate secretion: eradication of Helicobacter pylori and duodenal structure and function in humans.
Eradication of Helicobacter pylori expedites duodenal ulcer healing and prevents recurrences. Most patients with duodenal ulcers have impaired proximal duodenal mucosal bicarbonate secretion (DMBS). In patients with inactive, healed duodenal ulcers and normal subjects, the effect of H. pylori infection on DMBS and proximal duodenal secretory function and structure were examined. DMBS was quantitated before and after eradication of H. pylori. Mucosal structure (duodenal bulb histopathology) and function (DMBS at rest and stimulated, effect of active vs. healed ulcer and of age) were determined in patients with duodenal ulcers and normal subjects. In patients with duodenal ulcers, H. pylori eradication normalized proximal DMBS. Histological examination of duodenal biopsy samples was comparable in patients with duodenal ulcers and normal subjects without apparent relationship between inflammation and DMBS. Significantly impaired DMBS occurred in response to all agonists tested (luminal acid, prostaglandin E2, and cephalic-vagal stimulation) in patients with duodenal ulcers, suggesting a generalized secretory defect. Neither the presence of active (vs.inactive) ulcer nor age significantly affected bicarbonate secretion. In patients with duodenal ulcers, eradication of H. pylori normalized proximal DMBS and may thereby reduce ulcer recurrences. Altered DMBS in patients with duodenal ulcers was unrelated to histopathologic abnormalities. Impaired bicarbonate secretion in patients with duodenal ulcers could be caused by a cellular and/or physiological regulatory transport defect possibly related to H. pylori.


Internationalism and nationalism: the Rockefeller Foundation, public health, and malaria in Italy, 1923-1951.
The Rockefeller Foundation's support of malaria control and public health in Italy over three decades, the 1920s, 1930s and 1940s, was one of the foundation's most successful collaborations in its history. Nearly one-sixth of the funds the Rockefeller Foundation allocated for malaria programs was spent in Italy in those years. Outstanding research, a new and important institution, and decided improvements in public health were historically-significant results. The three most important episodes of this American-Italian relationship were the operations of the Stazione Sperimentale per la Lotta Antimalarica, the founding of the Istituto Superiore di Sanità, and the campaign to eradicate mosquitoes in Sardinia. In each of these episodes there was a tension between the international aspects and national aspects of the partnership that to some degree limited its success.


Dynamic vibrotactile signals for forward collision avoidance warning systems.
Four experiments were conducted in order to assess the effectiveness of dynamic vibrotactile collision-warning signals in potentially enhancing safe driving. Auditory neuroscience research has demonstrated that auditory signals that move toward a person are more salient than those that move away. If this looming effect were found to extend to the tactile modality, then it could be utilized in the context of in-car warning signal design. The effectiveness of various vibrotactile warning signals was assessed using a simulated car-following task. The vibrotactile warning signals consisted of dynamic toward-/away-from-torso cues (Experiment 1), dynamic versus static vibrotactile cues (Experiment 2), looming-intensity- and constant-intensity-toward-torso cues (Experiment 3), and static cues presented on the hands or on the waist, having either a low or high vibration intensity (Experiment 4). Braking reaction times (BRTs) were significantly faster for toward-torso as compared to away-from-torso cues (Experiments 1 and 2) and static cues (Experiment 2). This difference could not have been attributed to differential responses to signals delivered to different body parts (i.e., the waist vs. hands; Experiment 4). Embedding a looming-intensity signal into the toward-torso signal did not result in any additional BRT benefits (Experiment 3). Dynamic vibrotactile cues that feel as though they are approaching the torso can be used to communicate information concerning external events, resulting in a significantly faster reaction time to potential collisions. Dynamic vibrotactile warning signals that move toward the body offer great potential for the design of future in-car collision-warning system.


α2-chimaerin is required for Eph receptor-class-specific spinal motor axon guidance and coordinate activation of antagonistic muscles.
Axonal guidance involves extrinsic molecular cues that bind growth cone receptors and signal to the cytoskeleton through divergent pathways. Some signaling intermediates are deployed downstream of molecularly distinct axon guidance receptor families, but the scope of this overlap is unclear, as is the impact of embryonic axon guidance fidelity on adult nervous system function. Here, we demonstrate that the Rho-GTPase-activating protein α2-chimaerin is specifically required for EphA and not EphB receptor signaling in mouse and chick spinal motor axons. Reflecting this specificity, the loss of α2-chimaerin function disrupts the limb trajectory of extensor-muscle-innervating motor axons the guidance of which depends on EphA signaling. These embryonic defects affect coordinated contraction of antagonistic flexor-extensor muscles in the adult, indicating that accurate embryonic motor axon guidance is critical for optimal neuromuscular function. Together, our observations provide the first functional evidence of an Eph receptor-class-specific intracellular signaling protein that is required for appropriate neuromuscular connectivity.


Association between age and survival following major amputation. The Scottish Vascular Audit Group.
To determine whether age is associated with survival following major amputation and whether this association is independent or simply reflects selection bias in amputation level. Computer linkage of routine discharge and death data on the 2759 patients undergoing major amputation in Scotland between 1989 and 1993 for peripheral arterial disease. Cox's proportional hazards model and multivariate logistic regression analysis using death as the outcome variable and age, sex, urgency, amputation level and recent arterial reconstructive surgery as predictor variables. Proximal amputation was more common in older patients. Survival was associated with both age (p < 0.001) and amputation level (p < 0.001). Age was an independent predictor of death at 30 days (p < 0.0001), 6 months (p < 0.001), 12 months (p < 0.0001) and 2 years (p < 0.0001) postoperation. Survival following amputation was poor, with only half the patients alive at 2 years. Above-knee amputation was associated with poorer survival, presumably due to the presence of more severe and widespread disease, and was undertaken more commonly in older patients. However, age remained a predictor of survival after adjustment for amputation level. Higher early mortality suggest that a worse prognosis in elderly patients cannot be attributed wholly to actuarial considerations.


Biological therapies for the treatment of psoriasis in pediatrics.
Psoriasis is a multifactorial, immune-mediated condition with predominant skin involvement. It may develop at any age. In one-third of patients, the first symptoms of psoriasis start during childhood or adolescence. A marked impairment of the quality of life of patients and their caregivers is often associated. Databases including PubMed and Clinicaltrials.gov were used to identify clinical studies involving pediatric patients with psoriasis. In the last few years, the implementation of therapy with drugs targeting cytokines like interleukin (IL)-12/23 and IL-17A has expanded the number of available therapeutic options in pediatric psoriasis. This review focuses on the latest evidence on the clinical efficacy and safety profile of drugs licensed for severe pediatric psoriasis. Increasing knowledge about the pathogenetic mechanisms underlying pediatric psoriasis is leading to an improvement in disease management. Effective treatment is crucial in patients affected with moderate to severe disease to reduce the burden of the disease and avoid stigmatization. The treatment of pediatric psoriasis remains challenging for specific clinical subtypes, when difficult areas are involved, after resistance to multiple treatments, and when psoriatic arthritis is associated. A personalized approach and a thorough understanding of the disease are required to advance pediatric psoriasis care.


Analysis of bioactive compounds in seven citrus cultivars.
Chemical content in peels of fruits belonging to cultivars of Clementine mandarin (Fino, Loretina and Marisol), Satsume mandarin (Owari), Navel orange (Navelate and Navelina) and Common orange (Valencia Late) groups have been analyzed. The influence of the variety on the content of bioactive constituents at the varietal level is discussed. Rind contents showed similar tendencies for the majority of compounds although Satsume group presented the highest amounts on the flavanone glycosides hesperidin and narirutin, as well as the highest amounts of the carotenoid and β-cryptoxanthin, comparing with the remaining varieties studied. Both mandarin and orange varieties studied showed similar tendencies concerning to other phenolic compounds and total ascorbic acid concentrations. Limonene was the most abundant peel essential oil in all cultivars studied, followed by myrcene. Calcium and potassium were the dominant macronutrients for each cultivar studied, although the proportion of the individual nutrients ranged among different cultivars.


Absolute transcript levels of thioredoxin- and glutathione-dependent redox systems in Saccharomyces cerevisiae: response to stress and modulation with growth.
We report the co-ordinated fine-tune of mRNA molecules that takes place in yeast (Saccharomyces cerevisiae) in response to diverse environmental stimuli. We performed a systematic and refined quantification of the absolute expression patterns of 16 genes coding for thioredoxin- and glutathione-dependent redox system components. Quantifications were performed to examine the response to oxidants, to sudden temperature upshifts and in association with metabolic changes accompanying culture growth and to explore the contribution of mRNA decay rates to the differences observed in basal expression levels. Collectively, these quantifications show (i) vast differences in the steady-state amounts of the investigated transcripts, cTPxI being largely overexpressed compared with GPX1 during the exponential phase and GPX2 beyond this growth stage; (ii) drastic changes in the relative abundance of the transcripts in response to oxidants and heat shock; and (iii) a unique temporal expression profile for each transcript as cells proceed from exponential to stationary growth phase, yet with some general trends such as maximal or near-maximal basal amounts of most mRNA species at early growth stages when glucose concentration is high and cells are actively growing. Moreover, the results indicate that (i) the half-lives of the investigated transcripts are longer and distributed within a narrower range than previously reported global mRNA half-lives and (ii) transcriptional initiation may play an important role in modulating the significant alterations that most mRNAs exhibit in their steady-state levels along with culture growth.


Health equity, care access and quality in headache - part 2.
Headache disorders are a global public health concern affecting diverse populations. This review examines headache service organizations in low-, middle-, and high-income countries. It addresses global challenges in pharmacological headache treatment, with a focus on safety, tolerability, reproductive and child health, and outlines disparities in accessing innovative treatments worldwide. Organized headache services are essential due to the wide prevalence and varying severity of headache disorders. The tiered headache service model is globally recognized, although its implementation varies based on financial and workforce considerations. Headache burden affects well-being, causing disability, economic challenges, and work limitations, irrespective of location or income. All nations still require improved diagnosis and treatment, and the majority of countries face obstacles including limited access, awareness, economic barriers, and inadequate health policies. Provided adequate internet availability, telemedicine could help improve health equity by expanding access to headache care, since it can offer patients access to services without lengthy waiting times or extensive travel and can provide healthcare unavailable in underserved areas due to staff shortages. Numerous health disparities restrict global access to many headache medications, especially impacting individuals historically excluded from randomized controlled trials, such as those with cardiovascular and cerebrovascular conditions, as well as pregnant women. Furthermore, despite advancements in researching migraine treatments for young patients, the options for treatment remain limited. Access to headache treatment relies on factors like medication availability, approval, financial coverage, and healthcare provider expertise. Inadequate public awareness leads to neglect by policymakers and undertreatment by patients and healthcare providers. Global access discrepancies are exacerbated by the introduction of novel disease-specific medications, particularly impacting Asian, African, and Latin American nations excluded from clinical trials. While North America and Europe experience broad availability of migraine treatments, the majority of countries worldwide lack access to these therapies. Healthcare disparities, treatment access, and medication availability are concerning issues in headache medicine. Variations in national healthcare systems impact headache management, and costly innovative drugs are widening these gaps. Healthcare practitioners and experts should acknowledge these challenges and work towards minimizing access barriers for equitable global headache care in the future.


Challenges regarding informed consent in recruitment to clinical research: a qualitative study of clinical research nurses' experiences.
Clinical research nurses (CRNs) have first-hand experience with ethical challenges and play a crucial role in upholding ethical conduct and adherence to the principles of informed consent in clinical research. This study explores the ethical challenges encountered by CRNs in the process of obtaining informed consent for clinical research. A qualitative exploratory design. Semistructured interviews (n = 14) were conducted with diverse CRNs in Sweden. These CRNs covered a wide range of research fields, including pharmaceutical and academic studies, interventions, and observational research, spanning different trial phases, patient categories, and medical conditions. The interviews were analysed using inductive qualitative content analysis. The analysis identified three main categories: (i) threats to voluntariness, (ii) measures to safeguard voluntariness, and (iii) questionable exclusion of certain groups. CRNs face challenges due to time constraints, rushed decisions, information overload, and excessive reliance on physicians' recommendations. Overestimating therapeutic benefits in stages of advanced illness emerged as a risk to voluntariness. CRNs outlined proactive solutions, such as allowing ample decision-making time and offering support, especially for terminally ill patients. Concerns were also voiced about excluding certain demographics, such as those with language barriers or cognitive impairments. In conclusion, upholding ethical research standards requires recognising various factors affecting patient voluntariness. Researchers and CRNs should prioritise refining the informed consent process, overcoming participation challenges, and aligning scientific rigour with personalised care. Additionally, a concerted effort is vital to meet the diverse needs of patient populations, including equitable inclusion of individuals with language barriers or cognitive limitations in clinical studies. These findings have significant implications for enhancing the ethics of clinical research and advancing person-centred care.


Oncogenic Activation of Nrf2, Though as a Master Antioxidant Transcription Factor, Liberated by Specific Knockout of the Full-Length Nrf1α that Acts as a Dominant Tumor Repressor.
Liver-specific knockout of Nrf1 in the mouse leads to spontaneous development of non- alcoholic steatohepatitis with dyslipidemia, and then its deterioration results in hepatoma, but the underlying mechanism remains elusive to date. A similar pathological model is reconstructed here by using human Nrf1α-specific knockout cell lines. Our evidence has demonstrated that a marked increase of the inflammation marker COX2 definitely occurs in Nrf1α-/- cells. Loss of Nrf1α leads to hyperactivation of Nrf2, which results from substantial decreases in Keap1, PTEN and most of 26S proteasomal subunits in Nrf1α-/- cells. Further investigation of xenograft model mice showed that malignant growth of Nrf1α-/--derived tumors is almost abolished by silencing of Nrf2, while Nrf1α+/⁺-tumor is markedly repressed by an inactive mutant (i.e., Nrf2-/-ΔTA), but largely unaffected by a priori constitutive activator (i.e., caNrf2ΔN). Mechanistic studies, combined with transcriptomic sequencing, unraveled a panoramic view of opposing and unifying inter-regulatory cross-talks between Nrf1α and Nrf2 at different layers of the endogenous regulatory networks from multiple signaling towards differential expression profiling of target genes. Collectively, Nrf1α manifests a dominant tumor-suppressive effect by confining Nrf2 oncogenicity. Though as a tumor promoter, Nrf2 can also, in turn, directly activate the transcriptional expression of Nrf1 to form a negative feedback loop. In view of such mutual inter-regulation by between Nrf1α and Nrf2, it should thus be taken severe cautions to interpret the experimental results from loss of Nrf1α, Nrf2 or both.


[Methodology used in the original articles on smoking in 4 Spanish medical journals (1985-1996)].
Planning being the one factor entailed in doing any research that has the greatest bearing on the quality of the findings thereof, and the cigarette smoking habit being a prime topic for research, a description is provided of the methodological aspects of the original articles on the cigarette smoking habit which have been published in four Spanish medical journals. A descriptive study was conducted regarding the original articles on the cigarette smoking habit from Spanish centers which were published in 1985-1996 in the journals Atención Primaria (Primary Care), Medicina Clínica (Clinical Medicine) (Barcelona), Revista Española de Salud Pública (Spanish Public Health Journal) and Revista Clínica Española (Spanish Clinical Journal). Most of the 154 original articles studied dealt with the topics of smoking patterns (31.8%) and the cigarette smoking habit as a risk factor (27.3%) and were conducted within a municipal scope (41.7%) or provincial scope (36.1%) with subjects from primary care (71.6%) who visited the doctor (20.8%) falling within the age 25-65 group (30.4%) or over age 15 (27.0%). Surveys were used for collecting the data (38.3%) and were conducted throughout a 12-month period (24.5%) or longer (19.3%). The types most frequently used were descriptive (67.5%), retrospective (79.2%) and cross-sectional (81.8%). Spanish research on the cigarette smoking habit must cover certain subjects which have not been dealt with in sufficient depth and must invest greater care regarding certain methodological aspects which will improve the quality of the publications, this being a need also brought to fore in other studies.


A weighting analogue to pair matching in propensity score analysis.
Propensity score (PS) matching is widely used for studying treatment effects in observational studies. This article proposes the method of matching weights (MWs) as an analog to one-to-one pair matching without replacement on the PS with a caliper. Compared with pair matching, the proposed method offers more efficient estimation, more accurate variance calculation, better balance, and simpler asymptotic analysis. A statistical test for the misspecification of the PS model is proposed for balance checking purposes. An augmented version of the MW estimator is developed that has the double robust property, that is, the estimator is consistent, if either the outcome model or the PS model is correct. The proposed method is studied in simulations and illustrated through a real data example.


Reduction of Somatic Tinnitus Severity is Mediated by Improvement of Temporomandibular Disorders.
Successful orofacial treatment can reduce tinnitus severity in patients with somatic tinnitus (ST). However, it is still unclear to what extent the degree of reduction in temporomandibular disorders (TMD) actually contributes to the decrease in tinnitus severity after orofacial treatment. Therefore, the aim of this study was to analyze the mediating effect of reduction in TMD pain on the improvement of tinnitus severity after multidisciplinary orofacial treatment. A total of 80 patients with moderate to severe ST attributed to the temporomandibular region, were recruited from a tertiary tinnitus clinic. At baseline, patients were randomly assigned to the orofacial treatment group or to the control group. Both groups received a minimum of information and advice regarding their tinnitus complaints. The orofacial treatment group received orofacial physical therapy complemented with occlusal splints when needed, while the control group received no other treatment. A mediation analysis was performed according to the steps described by Baron and Kenny and the proportion of the mediating effect was calculated for the potential mediator: "change in TMD pain," measured by a one-point decrease in TMD pain screener score. Our analysis showed that 35% of the observed decrease in tinnitus severity can be attributed to a reduction in TMD pain. A significant total effect of orofacial treatment compared with control on the change in tinnitus functional index (TFI) score was found (B = 0.253 p = 0.025 Cl for B = 1.265-18.576). Orofacial treatment was also significantly related to the change in TMD pain (Exp (B) = 2.800, p = 0.034 Cl for Exp B 1.081-7.251). Additionally, the change in TMD pain screener score was significantly related to the change in TFI score (B = -0.273 p = 0.016 Cl for B = -19.875 to -2.119). Reduction of TMD pain is a mediating factor in the decrease of tinnitus severity after multidisciplinary orofacial treatment. Orofacial treatment can be used to decrease tinnitus severity in patients with TMD related somatic tinnitus.


Initial stress-kick is required for fluid shear stress-induced rate dependent activation of bone cells.
The shear stress induced by the loading-mediated flow of interstitial fluid through the lacuno-canalicular network is a likely stimulus for bone cell adaptive responses. Furthermore, the magnitude of the cellular response is related to the rate of mechanical loading rather than its magnitude. Thus, bone cells might be very sensitive to sudden stress-kicks, as occuring e.g., during impact loading. There is evidence that cells change stiffness under stress, which might make them more sensitive to subsequent loading. We studied the influence of a stress-kick on the mechanosensitivity of MC3T3-E1 osteoblast-like cells under different peak shear rate conditions, as measured by nitric oxide production. MC3T3-E1 bone cells were treated with steady or pulsating fluid shear stress (PFSS) for 5 min with different peak rates (9.70, 17.5, and 22.0 Pa Hz) using varying frequencies (5 and 9 Hz), and amplitudes (0.70 and 0.31 Pa). PFSS treatment was done with or without fluid flow pretreatment phase, which removed the initial stress-kick by first applying a slow fluid flow increase. Nitric oxide production in response to fluid shear stress was rate dependent, but necessitated an initial stress-kick to occur. This suggests that high-rate stimuli condition bone cells to be more sensitive for high-frequency, low-amplitude loads.


Biochemical, antimicrobial susceptibility and genotyping studies on Corynebacterium urealyticum isolates from diverse sources.
Thirty-two isolates of Corynebacterium urealyticum, isolated between 1991 and 1995, were studied by biochemical tests, phospholipid content, analysis of fatty and mycolic acids, ribotyping, whole-cell protein patterns and antimicrobial susceptibility to six antibiotics. Nineteen isolates were from human and human-related sources (HHRS); the remainder were from animal and animal-related sources (AARS). Most C. urealyticum isolates were similar in their biochemical and whole-cell protein profiles, although most HHRS isolates were alkaline phosphatase-positive (84%) and produced almost identical protein patterns, whereas AARS isolates were quite diverse. The qualitative composition of cellular fatty acids was identical for all isolates examined. Twelve different ribotypes were obtained with HindIII producing four-to-seven bands. Ribotypes 8, 9 and 10 were predominant in isolates from HHRS, whereas in isolates from AARS, ribotypes 5 and 6 predominated. AARS isolates were significantly less antibiotic-resistant, in comparison with HHRS isolates. Ribotyping appeared to be the most useful tool for strain characterisation.


Transcervical intrauterine levobupivacaine or lidocaine infusion for pain control during endometrial biopsy.
Endometrial biopsy is a common procedure for the investigation of many gynecological disorders including abnormal uterine bleeding, postmenopausal bleeding, abnormal cytology and infertility. Most women experience some degree of discomfort and pain during the procedure. Pain may occur during dilation of the cervix for insertion of the catheter and during endometrial biopsy, which further aggravates pain by inducing uterine contraction. To determine pain levels during endometrial biopsy by comparing intrauterine instillation of levobupivacaine or lidocaine with placebo in a randomized, double-blinded trial in pre- and postmenopausal women. Ninety patients were allocated to either control or experimental groups before endometrial biopsy. The trial medication was intrauterine anesthesia, either 5 mL 0.9% saline (control group), or 5 mL 0.5% levobupivacaine or 2% lidocaine (experimental groups). Resident doctors used the same endometrial biopsy technique to minimize the risk of technical variation. All tissue specimens were sent for cytopathological examination. The pathologists, who were blinded to the study solution, analyzed all tissue specimens. The primary outcome measure was pain experienced during the procedure. Pain was assessed using a 10 cm visual analogue pain scale. All observed adverse effects were recorded until the patients were discharged. Pain scores of the intrauterine lidocaine and levobupivacaine groups were found to be significantly lower than the control group. There was no difference between the levobupivacaine and lidocaine groups with regard to pain scores. There was a moderately positive correlation between pain scores and endometrial thickness. No complications were observed due to the procedure. Most of the biopsy results were proliferative and secretory endometrium. Insufficient material causing inconclusive results was observed mostly in the control group. Transcervical intrauterine topical instillation of levobupivacaine or lidocaine causes pain relief during endometrial biopsy. However, further studies are needed to evaluate the effectiveness of intrauterine anesthesia, to determine optimal concentration, volume and waiting time according to the type of local anesthetic agent, and to assess the applicability of the method to other intrauterine procedures.


Accuracy of Multi-Slice Spiral Computed Tomography for Preoperative Tumor Node Metastasis (TNM) Staging of Colorectal Carcinoma.
BACKGROUND With the advances in imaging technologies, multi-slice spiral computed tomography (MSCT) has demonstrated superiority in the diagnosis and staging of colorectal carcinoma. In the current study, preoperative TNM staging of colorectal carcinoma by using MSCT was conducted and compared with the corresponding postoperative pathological examination findings, in order to evaluate the accuracy of preoperative MSCT for TNM staging. MATERIAL AND METHODS Combinations of biphasic or triphasic enhanced-phase MSCT scans were obtained for 76 patients with colorectal carcinoma, and the TNM stage was determined based on imaging reconstruction from various angles and perspectives to display the size, location, and affected range of tumors. The preoperative TNM stage was compared with the postoperative pathological stage, and the consistency between the 2 methods was tested by the k test using SPSS 17.0 software. RESULTS Among the different combinations of enhanced-phase MSCT scanning, triphasic MSCT imaging, comprising the arterial, portal venous, and delayed phases, showed the highest accuracy rates, at 81.6% (62/76), 82.89% (63/76), and 96.1% (73/76) for T, N, and M staging, respectively, with k values of 0.72, 0.65, and 0.56, respectively, indicating consistency with the postoperative pathological staging. CONCLUSIONS Combined MSCT scanning comprising the arterial phase, portal venous phase, and delayed phase showed satisfying consistency with the postoperative pathological analysis results for TNM staging of colorectal carcinoma. Thus, MSCT is an important clinical value for improving the accuracy of TNM staging and for planning the appropriate colorectal cancer treatment.


Efficacy, adverse events, and inter-drug comparison of mepolizumab and reslizumab anti-IL-5 treatments of severe asthma - a systematic review and meta-analysis.
Background: New, complex, and expensive therapies targeting Interleukin-5 (IL-5) to treat severe eosinophilic asthma are emerging. Objective: To assess efficacy, adverse events, and inter-drug comparison of mepolizumab and reslizumab for treating severe eosinophilic asthma. Design: A systematic review and meta-analysis on randomized, placebo-controlled, clinical trials elucidating two critical (exacerbation rate and oral corticosteroid (OCS) use) and six important clinical outcomes on the efficacy and safety of mepolizumab and reslizumab. Results: Five studies (N = 2197) contributed with data for exacerbation rate, showing a reduction of 53% (95% CI 46; 59) in favour of anti-IL-5, corresponding to -0.94 annual exacerbations (95% CI -1.08;-0.82), thus exceeding the predefined minimal clinical important difference (MCID) of 25% reduction of the estimated ≥2 annual exacerbations. Quality of evidence was considered moderate, with low heterogeneity in study findings (I2 = 0%). One study (N = 135) contributed with data on percentage of patients experiencing ≥50% reduction inoral corticosteroid treatment, showing an effect of 20% (95% CI 2.3;47) in favour of anti-IL-5 treatment (mepolizumab), thus exceeding the predefined MCID of 10%. Quality of evidence was considered low. Compared to placebo, anti-IL-5 showed significant improvements in lung function, asthma control, and asthma-related quality of life, but below the MCIDs. No differences were observed for serious adverse events and number of patients, who dropped out. No studies evaluating sickleave or head-to-head comparisons were identified. By indirect comparison, we found no significant difference between mepolizumab and reslizumab in any ofthe predefined clinical outcomes. OCS treatment reduction could not be compared due to lack of reslizumab studies investigating this outcome. Conclusions: Mepolizumab and reslizumab provide significant and clinically relevant improvements in exacerbation rate and OCS reduction. Indirect, inter-study comparisons revealed no differences between the anti-IL-5 drugs in efficacy or safety measures.


Immunocytology shows the presence of tobacco etch virus P3 protein in nuclear inclusions.
Intracellular localization studies of various potyvirus proteins have been made in hope of finding clues to their function(s). Immunocytological studies localized many of the tobacco etch virus (TEV)-encoded proteins in infected cells. We used antiserum against the nonstructural P3 protein of TEV to determine the subcellular location of the P3 protein in ultrathin sections of virus-infected cells. Immunogold labeling with the antiserum showed labels associated with nucleoli, nuclei, or NIs, Absorption of antiserum with purified NIs or P3 protein resulted in no labeling. TEV NIs are known to contain a bifunctional genome-linked protein-viral proteinase (NIa-VPg) and RNA-dependent RNA polymerase (NIb). It appeared that the TEV P3 protein was a third nonstructural viral protein of NIs of TEV if the NIa-VPg is considered one protein. The presence of P3 in NIs was also supported by Western blot assays. P3 protein in the nucleolus and nucleus could indicate that it, too, is involved in early stages of viral replication.


Identification of Zirconia Particle Uptake in Human Osteoblasts by ToF-SIMS Analysis and Particle-Size Effects on Cell Metabolism.
As the use of zirconia-based nano-ceramics is rising in dentistry, the examination of possible biological effects caused by released nanoparticles on oral target tissues, such as bone, is gaining importance. The aim of this investigation was to identify a possible internalization of differently sized zirconia nanoparticles (ZrNP) into human osteoblasts applying Time-of-Flight Secondary Ion Mass Spectrometry (ToF-SIMS), and to examine whether ZrNP exposure affected the metabolic activity of the cells. Since ToF-SIMS has a low probing depth (about 5 nm), visualizing the ZrNP required the controlled erosion of the sample by oxygen bombardment. This procedure removed organic matter, uncovering the internalized ZrNP and leaving the hard particles practically unaffected. It was demonstrated that osteoblasts internalized ZrNP within 24 h in a size-dependent manner. Regarding the cellular metabolic activity, metabolization of alamarBlue by osteoblasts revealed a size- and time-dependent unfavorable effect of ZrNP, with the smallest ZrNP exerting the most pronounced effect. These findings point to different uptake efficiencies of the differently sized ZrNP by human osteoblasts. Furthermore, it was proven that ToF-SIMS is a powerful technique for the detection of zirconia-based nano/microparticles that can be applied for the cell-based validation of clinically relevant materials at the nano/micro scale.


Video. Transumbilical single-incision laparoscopic surgery for sigmoid colon cancer.
Transumbilical single-incision laparoscopic surgery is an emerging concept that could offer excellent cosmetic results [1]. The authors describe an index case of curatively intended resection of early-stage sigmoid colon cancer using this technique [2, 3]. A 75-year-old woman with a body mass index of 24 underwent surgery by two colorectal surgeons who had hundreds of experiences with laparoscopic colorectal surgery. Three 5-mm ports were placed linearly in the vertical 2-cm skin incision in the umbilicus. Almost all the procedures were performed with usual laparoscopic instruments such as a 5-mm flexible laparoscope and the Harmonic ACE (Ethicon Endo-Surgery, Cincinnati, OH, USA). Also, the operative procedures were much the same as in usual laparoscopic surgery. The sigmoid colon was mobilized using a medial approach. Then the root of the superior rectal artery and inferior mesenteric vein were divided using the EnSeal tissue sealing and hemostasis system (SurgRx, Inc. Redwood City, CA, USA). Low-profile trocars were mandatory to minimize interferences among instruments. The rectum was divided 5 cm distal to the lesion with one firing of an endoscopic stapler. The specimen was extracted through a 2-cm transumbilical laparotomy. End-to-side anastomosis using a circular stapler was performed intraabdominally, and air tightness was confirmed by the anastomotic leak test. The operative time was 192 min. There was no intra- or postoperative morbidity. Altogether, 20 cm of sigmoid was resected with negative tumor margins, and 14 lymph nodes were harvested. The patient started receiving meals and was discharged on postoperative days 2 and 7, respectively. The final pathology showed Tis, N0, M0, stage 0. The scar was invisible at 1 month. Single-incision laparoscopic colectomy is feasible and safe for selected patients and gives a favorable cosmetic result. By well-trained surgeons, this technique could be a realistic option for colorectal cancer surgery.


Immobilization of goitred gazelles (Gazella subgutterosa) and Arabian mountain gazelles (Gazella gazella) with xylazine-ketamine.
Xylazine combined with ketamine successfully immobilized free-ranging and captive goitred gazelles (Gazella subgutterosa) and Arabian mountain gazelles (Gazella gazella). One hundred thirty immobilizations were performed on 58 individuals. When administered i.m. via dart to free-ranging gazelles, xylazine (125 mg/ml) combined with ketamine (100 mg/ml) produced smooth induction and recovery. Mountain gazelles required higher dosages (11.7-15.2 mg/kg xylazine and 9.3-12.2 mg/kg ketamine) than goitred gazelles (6.8-7.4 mg/kg xylazine and 5.4-5.9 mg/kg ketamine). For manually restrained captive gazelles of both species, i.v. xylazine (11 mg/ml) combined with i.v. ketamine (44 mg/ml) immobilized the gazelles at considerably lower doses (0.4-1.0 mg/kg xylazine and 1.4-3.9 mg/kg ketamine). These anesthetic combinations are useful alternatives to ultrapotent narcotics in these gazelle species.


Chemoprevention by grape seed extract and genistein in carcinogen-induced mammary cancer in rats is diet dependent.
Many popular dietary supplements are enriched in polyphenols such as the soy isoflavones, tea catechins, and resveratrol (from grape skins), each of which has been shown to have chemopreventive activity in cellular models of cancer. The proanthocyanidins, which are oligomers of the catechins, are enriched in grape seeds and form the basis of the dietary supplement grape seed extract (GSE). Evidence suggests that the proanthocyanidins may be metabolized to the monomeric catechins. This study was carried out to determine whether GSE added to rodent diets protected against carcinogen-induced mammary tumorigenesis in rats and whether this was affected by the composition of the whole diet. Female rats were begun on 5%, 1.25%, or 0% (control) GSE-supplemented diets at age 35 d. At age 50 d they were administered 7,12-dimethylbenz[a]anthracene (DMBA) in sesame oil at 80 mg/kg body weight. They were weighed and monitored weekly for tumor development until 120 d after DMBA administration. Administration of GSE in AIN-76A diet did not show any protective activity of GSE against DMBA-induced breast cancer. However, administration of GSE in a laboratory dry food diet (Teklad 4% rodent diet) resulted in a 50% reduction in tumor multiplicity. In similar experiments, genistein administered in AIN-76A diet also failed to show chemopreventive activity against the carcinogen N-methyl-N-nitrosourea; however, when administered at the same dose in the Teklad 4% rodent diet, genistein exhibited significant chemopreventive activity (44-61%). These results demonstrate that GSE is chemopreventive in an animal model of breast cancer; moreover, the diet dependency of the chemopreventive activity for both GSE and genistein suggests that whether or not a compound is chemopreventive may depend on the diet in which the agent is administered.


Matching profiles of masked perpetrators: a pilot study.
Seventeen male volunteers were photographed laterally with and without a tight-fitting balaclava. We then matched these photographs in blind trials. The matches were performed in two separate trials: as side-by-side comparisons, and by using superimposition. In both trials we graded the matches as good, possible and no fit. We found a very high true identification rate of 94% using superimposition, i.e. whether a match judged as good was in fact the correct match. The correct exclusion rate was also high, 94%, when using superimposition, i.e. when no match was found this was in fact correct. However, even though we were often correct in judging the best fit, we often had several possible matches for each case, which means that comparing profiles is not very selective. As such, using superimposition to compare the profile of a masked perpetrator with lateral photos of one or more suspects may indicate the possible matches, and perhaps even the best match, which may be helpful in police investigations, but it would not carry enough weight to be used as evidence per se. This study only focused on the profile. Future studies will use surface laser scans to analyse congruence between masked and unmasked subjects using the whole head.


Effects of congenital hearing loss and cochlear implantation on audiovisual speech perception in infants and children.
Cochlear implantation has recently become available as an intervention strategy for young children with profound hearing impairment. In fact, infants as young as 6 months are now receiving cochlear implants (CIs), and even younger infants are being fitted with hearing aids (HAs). Because early audiovisual experience may be important for normal development of speech perception, it is important to investigate the effects of a period of auditory deprivation and amplification type on multimodal perceptual processes of infants and children. The purpose of this study was to investigate audiovisual perception skills in normal-hearing (NH) infants and children and deaf infants and children with CIs and HAs of similar chronological ages. We used an Intermodal Preferential Looking Paradigm to present the same woman's face articulating two words ("judge" and "back") in temporal synchrony on two sides of a TV monitor, along with an auditory presentation of one of the words. The results showed that NH infants and children spontaneously matched auditory and visual information in spoken words; deaf infants and children with HAs did not integrate the audiovisual information; and deaf infants and children with CIs initially did not initially integrate the audiovisual information but gradually matched the auditory and visual information in spoken words. These results suggest that a period of auditory deprivation affects multimodal perceptual processes that may begin to develop normally after several months of auditory experience.


Interlaboratory comparison of assessments of Alzheimer disease-related lesions: a study of the BrainNet Europe Consortium.
This interlaboratory study evaluated the reproducibility of the assessments of neuritic plaques and neurofibrillary tangles (NFTs)--the hallmark lesions of Alzheimer disease--and compared the staining between the BrainNet Europe centers. To reduce the topography-related inconsistencies in assessments, we used a 2-mm tissue microarray (TMA) technique. The TMA block included 42 core samples taken from 21 paraffin blocks. The assessments were done on Bielschowsky and Gallyas silver stains using an immunohistochemical (IHC) method with antibodies directed to beta-amyloid (IHC/Abeta) and hyperphosphorylated tau (IHC/HPtau). The staining quality and the assessments differed between the participants, being most diverse with Bielschowsky (good/acceptable stain in 53% of centers) followed by Gallyas (good/acceptable stain in 57%) and IHC/Abeta (good/acceptable stain in 71%). The most uniform staining quality and assessment was obtained with the IHC/HPtau method (good/acceptable stain in 94% of centers). The neuropathologic diagnostic protocol (Consortium to Establish a Registry for Alzheimer Disease, Braak and Braak, and the National Institute of Aging and Reagan [NIA-Reagan] Institute) that was used significantly influenced the agreement, being highest with NIA-Reagan (54%) recommendations. This agreement was improved by visualization of NFTs using the IHC/HPtau method. Therefore, the IHC/HPtau methodology to visualize NFTs and neuropil threads should be considered as a method of choice in a future diagnostic protocol for Alzheimer disease.


TWEAK: a novel biomarker for lupus nephritis?
Renal involvement is common in systemic lupus erythematosus. Early diagnosis of lupus nephritis (LN), allowing the instigation of appropriate therapy, remains an important clinical challenge. Current biomarkers in clinical practice are less than ideal, lacking both sensitivity and specificity. In the previous issue of Arthritis Research & Therapy, Schwartz and colleagues demonstrated the potential value of urinary TNF-like weak inducer of apoptosis (uTWEAK) as a biomarker for LN. They showed that uTWEAK is elevated in subjects with LN at diagnosis compared with those with systemic lupus erythematosus but no renal disease, and correlates with the degree of clinical disease activity. These data are thought-provoking and provide the platform for future longer-term studies.


A single-tube multiplexed assay for detecting ALK, ROS1, and RET fusions in lung cancer.
Approximately 7% of non-small cell lung carcinomas (NSCLCs) harbor oncogenic fusions involving ALK, ROS1, and RET. Although tumors harboring ALK fusions are highly sensitive to crizotinib, emerging preclinical and clinical data demonstrate that patients with ROS1 or RET fusions may also benefit from inhibitors targeting these kinases. Using a transcript-based method, we designed a combination of 3' overexpression and fusion-specific detection strategies to detect ALK, ROS1 and RET fusion transcripts in NSCLC tumors. We validated the assay in 295 NSCLC specimens and showed that the assay is highly sensitive and specific. ALK results were 100% concordant with fluorescence in situ hybridization (FISH) (n = 52) and 97.8% concordant with IHC (n = 179) [sensitivity, 96.8% (95% CI 91.0%-98.9%); specificity, 98.8% (95% CI 93.6%-99.8%)]. For ROS1 and RET, we also observed 100% concordance with FISH (n = 46 and n = 15, respectively). We identified seven ROS1 and 14 RET fusion-positive tumors and confirmed the fusion status by RT-PCR and FISH. One RET fusion involved a novel partner, cutlike homeobox 1 gene (CUX1), yielding an in-frame CUX1-RET fusion. ROS1 and RET fusions were significantly enriched in tumors without KRAS/EGFR/ALK alterations. ALK/ROS1/RET/EGFR/KRAS alterations were mutually exclusive. As a single-tube assay, this test shows promise as a more practical and cost-effective screening modality for detecting rare but targetable fusions in NSCLC.


Hydroxyapatite microspheres used as a drug delivery system for gliosarcoma strain 9l/Lacz treatment by photodynamic therapy protocols.
Hydroxyapatite (HAp) presents similarities with the human bone structure and presents properties such as biodegradability, biocompatibility, and osteoconductivity, which favors its use in prostheses implants and enables its use as a vehicle for the delivery of photosensitizers (PS) from systems of release (DDS) for photodynamic therapy applications Methods: In this work was to synthesized hydroxyapatite microspheres (meHAp), encapsulated with chloroaluminium phthalocyanine (ClAlPc), for DDS. meHAp was synthesized using vaterite as a template. The drug was encapsulated by mixing meHAp and a 50.0 mg.mL-1 ClAlPc solution. Photochemical, photophysical, and photobiological studies characterized the system. The images from the SEM analysis showed the spherical form of the particles. All spectroscopic results showed excellent photophysical parameters of the drug studied when served in the meHAp system. The incorporation efficiency was 57.8 %. The trypan blue exclusion test results showed a significant reduction (p < 0.05) in cell viability for the groups treated with PDT at all concentrations above 250 μg.mL-1. In 9 L/lacZ gliosarcoma cells, PDT mediated at concentrations from 250 to 62.5 µg.mL-1 reduced cell viability by more than 98 %. In the cell internalization study, it was possible to observe the internalization of phthalocyanines at 37 °C, with the accumulation of PS in the cytoplasm and inside the nucleus in the two tested concentrations. From all the results presented throughout the article, the meHAp system shows promise for use as a modified release system (DSD) in photodynamic therapy.


Response of key soil parameters during compost-assisted phytostabilization in extremely acidic tailings: effect of plant species.
Phytostabilization of mine tailings acts to mitigate both eolian dispersion and water erosion events which can disseminate barren tailings over large distances. This technology uses plants to establish a vegetative cover to permanently immobilize contaminants in the rooting zone, often requiring addition of an amendment to assist plant growth. Here we report the results of a greenhouse study that evaluated the ability of six native plant species to grow in extremely acidic (pH ∼ 2.5) metalliferous (As, Pb, Zn: 2000-3000 mg kg(-1)) mine tailings from Iron King Mine Humboldt Smelter Superfund site when amended with a range of compost concentrations. Results revealed that three of the six plant species tested (buffalo grass, mesquite, and catclaw acacia) are good candidates for phytostabilization at an optimum level of 15% compost (w/w) amendment showing good growth and minimal shoot accumulation of metal(loid)s. A fourth candidate, quailbush, also met all criteria except for exceeding the domestic animal toxicity limit for shoot accumulation of zinc. A key finding of this study was that the plant species that grew most successfully on these tailings significantly influenced key tailings parameters; direct correlations between plant biomass and both increased tailings pH and neutrophilic heterotrophic bacterial counts were observed. We also observed decreased iron oxidizer counts and decreased bioavailability of metal(loid)s mainly as a result of compost amendment. Taken together, these results suggest that the phytostabilization process reduced tailings toxicity as well as the potential for metal(loid) mobilization. This study provides practical information on plant and tailings characteristics that is critically needed for successful implementation of assisted phytostabilization on acidic, metalliferous mine tailings sites.


Clinical characteristics of 161 cases of corona virus disease 2019 (COVID-19) in Changsha.
In December 2019, a new type of coronavirus-infected pneumonia broke out in Wuhan and spread rapidly to other parts of the country. The purpose of this study was to investigate the clinical features of coronavirus disease 2019 (COVID-19). A retrospective analysis was performed on the confirmed cases of COVID-19, who were admitted to the North Hospital of Changsha first Hospital (Changsha Public Health treatment Center) from January 17 to February 7, 2020. The median age of COVID-19 patients was 45 years (range 33.5-57). The male patients accounted for 49.7%, 64.6% of the patients had a history of exposure in Wuhan, and 31.7% had family aggregation. The median days of onset were six, and the incidence of severe illness was 18.6%. Compared with the non-severe group, the severe group showed statistical significance in older age, hypertension, bilateral lung plaque shadow, decrease in lymphocyte count, increase in C-reactive protein (CRP), aspartate aminotransferase (AST), lactate dehydrogenase, and creatine kinase. Age, combined hypertension, oxygenation index, double lung patch, decreased lymphocyte count, and elevated levels of C-reactive protein, aspartate aminotransferase, lactate dehydrogenase, and creatine kinase can be used as predictors of the disease severity.


Flow and diffusion measurements in natural porous media using magnetic resonance imaging.
Flow and diffusion of water in natural porous media, quartz sand, and calcareous gravel were measured using a 1.5-T clinical magnetic resonance tomograph. The spatial resolution of the dynamic measurements was 1.32 x 1.32 x 5 mm3, and the time between two cross-sectional measurements was approximately 10 s. The measured coefficients of molecular diffusion for water were in good agreement with theoretical data. Flow was measured without any tracer at velocities between 0.15 and 6.67 mm/s. The results, based on a calibration within one part of the column, were in good agreement with data obtained from a tracer experiment and from a numerical model. It was possible to measure the flow velocity in larger pores and preferential flow paths directly. The results of the flow measurements in smaller pores reflected the mean velocity within that volume element. In that case the obtained values were close to the average linear velocity. Since the time resolution is high a monitoring of flow processes is possible. The pore space was imaged with a spatial resolution of 0.5 x 0.5 x 0.5 mm3. Here, the porosity of pores that are larger than 0.2 mm can be measured directly; for smaller pores a calibration is necessary.


Prevalence of Skin and Skin-Related Diseases in the Rochester Epidemiology Project and a Comparison with Other Published Prevalence Studies.
In Olmsted County, Minn., USA, reliable, population-based epidemiologic research studies can be performed because of a unique medical records linkage system, the Rochester Epidemiology Project (REP). Our objective was to summarize the epidemiologic data describing the prevalence of skin and skin-related diseases derived from the REP and to compare the findings with those from other studies worldwide. Retrospectively, we reviewed the results of population-based REP studies reporting the prevalence of skin and skin-related diseases over more than 4 decades and compared them to other published prevalences globally. Prevalences from the REP reported per 100,000 persons were as follows: hidradenitis suppurativa, 130.0; psoriasis, 700.0; psoriatic arthritis in 1992, 100.0, and in 2000, 160.0; Behçet disease, 5.2; scleroderma, 13.8; dermatomyositis, 21.42; systemic lupus erythematosus (SLE), from 30.5 to 122.0 suspected SLE, 32.8; combined SLE, 41.8; discoid lupus erythematosus, 27.6, and cutaneous lupus erythematosus, 70.4 and 73.2 (from 2 studies). Many of the population-based prevalences of specific skin and skin-related diseases derived from the REP are different from those estimated globally. Suggested reasons for disparity in the prevalences globally may include differences in the type of reported prevalence, study methodology, geographic areas, ethnic groups, age distribution, and socioeconomic status.


Extensive genetic heterogeneity in the neuroblastoma cell line NB(TU)1.
A neuroblastoma cell line displaying genetically unique features was established from a stage III case of a 20-month-old girl. Southern blotting by the probe pTNB6, which contains exon 1 of the N-myc gene, showed that the primary tumor had in total 4 aberrant bands beside the normal amplified band. The established cell line NB(TU)1 had an aberrant N-myc band (9.0 kb) in addition to the normal band (2.9 kb). Cytogenetic analysis revealed that NB(TU)1 has a composite karyotype composed of at least 7 related karyotypes, which are pseudo-diploid and contain complex chromosomal abnormalities, including translocations, deletions and homogeneously staining regions (HSRs). Such extensive abnormalities were considered to be prominent among known neuroblastoma cell lines, and it was suggested that NB(TU)1 had acquired a certain type of genetic instability. Analysis of N-myc bands in 11 clones of NB(TU)1 showed that the intensity ratio of the normal-sized band (2.9 kb) and the aberrant one (9.0 kb) markedly varied among clones. Moreover, 3 clones showed an additional band with the size of 3.7 kb, which was detectable neither in the parent NB(TU)1 nor in the primary tumor. Thus, NB(TU)1 was shown to be composed of heterogeneous cell components. To further detect such ongoing chromosomal instability, we examined micronuclei formation. NB(TU)1 yielded a larger number of micronuclei than 5 other neuroblastoma cell lines. We conclude that NB(TU)1 has acquired genetic instability detectable by both Southern blotting and cytogenetic analysis.


Optimal persistent currents for interacting bosons on a ring with a gauge field.
We study persistent currents for interacting one-dimensional bosons on a tight ring trap, subjected to a rotating barrier potential, which induces an artificial U(1) gauge field. We show that, at intermediate interactions, the persistent current response is maximal, due to a subtle interplay of effects due to the barrier, the interaction, and quantum fluctuations. These results are relevant for ongoing experiments with ultracold atomic gases on mesoscopic rings.


The effectiveness of additional long-term use of bottle-positive expiratory pressure in chronic obstructive pulmonary disease: A single-blind, randomized study.
This study aimed to investigate the long-term use of bottle-positive expiratory pressure (PEP) in addition to breathing exercises as a home-based rehabilitation aid on exercise capacity, spirometric parameters, and quality of life in chronic obstructive pulmonary disease (COPD) patients. From a total of 30 patients with stable moderate-to-severe COPD, 24 (22 males, 2 females; mean age: 62.4+7.2 years; range, 40 to 75 years) were included in the final study and randomized into two groups: the group that performed breath retaining techniques and the group that was instructed to use the bottle-PEP in addition to these techniques. Patients were evaluated with modified Medical Research Council scale, COPD assessment test (CAT), spirometry, St. George`s Respiratory Questionnaire (SGRQ), and 6-min walk distance (6MWD) before, three months and six months after the initiation of the program. In the bottle-PEP group, patients` mean 6MWD increased from 380.6±67.6 to 444.1±22.0 m (p=0.002), the mean CAT score decreased from 17.8±36.8 to 12.9±6.2 (p=0.03), and the mean SGRQ total score significantly decreased from 57.1±23.1 to 47.6±21.9 (p<0.05) after three months. The improvement in 6MWD continued in six months but disappeared in SGRQ and CAT scores. In the exercise group, only the 6MWD improved, and there were no significant improvements in other parameters regardless of time. There were no significant differences between the groups in any of the parameters at any follow-up session. While bottle-PEP does not significantly contribute when added to breathing exercises in patients with moderate-to-severe COPD in improving function and quality of life, it can be used as a safe choice in patients` home rehabilitation programs.


Endocrine epidemiology of male breast cancer (review).
Male carcinoma of the breast is not a common clinical problem, but is of interest in the wider context of female as well as male breast cancer etiology. This review discusses recognized and suspected epidemiology associations of male breast cancer, and relates these to potential endocrine factors. It is concluded that altered estrogen production and metabolism, perhaps in part related to body weight in early adulthood, may prove to be the major hormonal involvement in male breast cancer. Future studies should incorporate the more recently developed approaches to investigating estrogen metabolism and bioactivity, and include familial benign and malignant breast disease.


Silver nitrate ingestion: report of a case with an uneventful course and review of the literature.
Silver nitrate is commonly recognized for the toxic effects followed by the direct contact with the skin and mucosa known as argyria, but there is surprisingly little information about the adverse effects of silver nitrate after ingestion. Since only a few cases were reported in the literature, the aim of this case is to enrich the little experience existent about the possible effects of silver nitrate ingestion. We describe the case of a 15-year-old female who intentionally ingested 15cc of silver nitrate solution in a suicidal attempt. The clinical picture included an excruciating burning sensation in her throat and nostrils followed by vomiting and poor oral intake. The presence of a whitish membrane on the oral and buccal mucosa without bleeding or erosions was the only remarkable finding at physical examination. Unlike the rest of the cases described in the literature the clinical and endoscopic follow up of the patient was benign and without sequela or signs of oesophageal damage. Even though very uncommon, it is very important for physicians to keep in mind the possible toxic effects and appropriate management of silver nitrate ingestion. The outcome is not always devastating as reported, and a good early approach and follow up is important in the anticipation of sequela.


Racial-Ethnic Comparison of Guideline-Adherent Gynecologic Cancer Care in an Equal-Access System.
To compare receipt of National Comprehensive Cancer Network Guideline-adherent treatment for gynecologic cancers, inclusive of uterine, cervical, and ovarian cancer, between non-Hispanic White women and racial-ethnic minority women in the equal-access Military Health System. We accessed MilCanEpi, which links data from the Department of Defense Central Cancer Registry and Military Health System Data Repository administrative claims data, to identify a cohort of women aged 18-79 years who were diagnosed with uterine, cervical, or ovarian cancer between January 1, 1998, and December 31, 2014. Information on tumor stage, grade, and histology was used to determine which treatment(s) (surgery, chemotherapy, radiotherapy) was indicated for each patient according to the National Comprehensive Cancer Network Guidelines during the period of the data (1998-2014). We compared non-Hispanic Black, Asian, and Hispanic women with non-Hispanic White women in their likelihood to receive guideline-adherent treatment using multivariable logistic regression models given as adjusted odds ratios (aORs) and 95% CIs. The study included 3,354 women diagnosed with a gynecologic cancer of whom 68.7% were non-Hispanic White, 15.6% Asian, 9.0% non-Hispanic Black, and 6.7% Hispanic. Overall, 77.8% of patients received guideline-adherent treatment (79.1% non-Hispanic White, 75.9% Asian, 69.3% non-Hispanic Black, and 80.5% Hispanic). Guideline-adherent treatment was similar in Asian compared with non-Hispanic White patients (aOR 1.18, 95% CI 0.84-1.48) or Hispanic compared with non-Hispanic White women (aOR 1.30, 95% CI 0.86-1.96). Non-Hispanic Black patients were marginally less likely to receive guideline-adherent treatment compared with non-Hispanic White women (aOR 0.73, 95% CI 0.53-1.00, P=.011) and significantly less likely to receive guideline-adherent treatment than either Asian (aOR 0.65, 95% CI 0.44-0.97) or Hispanic patients (aOR 0.56, 95% CI 0.34-0.92). Racial-ethnic differences in guideline-adherent care among patients in the equal-access Military Health System suggest factors other than access to care contributed to the observed disparities.


Effect of β-carotene on cancer cell stemness and differentiation in SK-N-BE(2)C neuroblastoma cells.
Neuroblastoma is a solid tumor often diagnosed in childhood. While there have been intense efforts to develop a treatment for neuroblastoma, current therapies remain unsuccessful due to high rate of resistance and metastasis. Most cancers originate from a subset of self-renewing cells, primarily cancer stem cells (CSCs), which establish a tumor through continuous self-renewal and differentiation. The successful elimination of CSCs is an important goal in the development of effective strategies to achieve complete remission for cancers. Although β-carotene has been associated with several anticancer mechanisms, the efficacy of β-carotene against CSCs remains unclear. In the present study, β-carotene was shown to reduce cell growth and induce neuronal cell differentiation, concomitant with a marked increase in the phosphorylation of extracellular signal-regulated kinases (ERK) (p42/p44). More importantly, β-carotene inhibited self-renewal characteristics of CSCs and decreased expression of several stem cell markers. Levels of mRNA and protein of Drosophila delta-like 1 homolog (Drosophila) (DLK1) were downregulated following treatment with β-carotene. In addition, knockdown of DLK1 by siRNA enhanced the inhibitory effect of β-carotene on colony formation of neuroblastoma cells. β-carotene also potentiated the effect of cisplatin on the self-renewal characteristics of CSCs in neuroblastoma, revealing that β-carotene has the capacity to resensitize cells to cisplatin cytotoxicity by directly targeting CSCs. In conclusion, β-carotene was shown to strongly increase the anticancer efficacy against neuroblastoma cancer stem-like cells. Moreover, these results suggest that the targeting of CSCs is a novel mechanism of β-carotene. Thus, β-carotene is a potential chemotherapeutic reagent for this cancer.


[Meningococcus group carrier status in Chinese recruits].
During the period, May 1974 approximately April 1975, 4 groups of Chinese basic training recruits from different cities in Taiwan were examined for cases of nasopharyngeal Neisseria meningitidis. Before training the carrier rate of N. meningitidis was 13.7%. However, 7 approximately 8 weeks after training the carrier rate had increased to 20%. The majority of strains isolated were serogroup A. However, serogroups C and B, in that order of frequency, were also isolated. Only four strains were serologically untypable. Of 344 strains tested for drug susceptibility, 186 (54.1)% of these strains were found to be resistant to sulfadiazine.


Prepubertal gonad investment modulates thymus function: evidence in a teleost fish.
Thymus plasticity following gonadectomy or sex hormone replacement has long since exemplified sex hormone effects on the immune system in mammals and, to a lesser extent, in 'lower vertebrates', including amphibians and fish. Nevertheless, the underlying physiological significances as well as the ontogenetic establishment of this crosstalk remain largely unknown. Here, we used a teleost fish, the European sea bass, Dicentrarchus labrax, to investigate: (1) whether the regulation of thymus plasticity relies on resource trade-off with somatic growth and reproductive investment and (2) if the gonad-thymus interaction takes place during gonadal differentiation and development. Because gonadal development and, supposedly, thymus function in sea bass depend on environmental changes associated with the winter season, we evaluated thymus changes (foxn1 expression, and thymocyte and T cell content) in juvenile D. labrax raised for 1 year under either constant or fluctuating photoperiod and temperature. Importantly, in both conditions, intensive gonadal development following sex differentiation coincided with a halt of thymus growth, while somatic growth continued. To the best of our knowledge, this is the first study showing that gonadal development during prepuberty regulates thymus plasticity. This finding may provide an explanation for the initiation of the thymus involution related to ageing in mammals. Comparing fixed and variable environmental conditions, our work also demonstrates that the extent of the effects on the thymus, which are related to reproduction, depend on ecophysiological conditions, rather than being directly related to sexual maturity and sex hormone levels.


Utility of a commercial nonstructural protein 1 antigen capture kit as a dengue virus diagnostic tool.
Annually, over 2.5 billion people are at risk for infection with dengue virus (DENV), while between 50 and 100 million people contract the infection. There is an urgent need for alternative diagnostic tools that can detect DENV during acute infection. Recent studies have shown that DENV nonstructural protein 1 (NS1) is detectable in the blood as early as the onset of symptoms and persists well into the convalescent phase of the infection. We evaluated the utility of the Bio-Rad Platelia DENV NS1 antigen capture kit in combination with real-time reverse transcriptase PCR (RT-PCR) and an IgM antibody capture enzyme-linked immunosorbent assay (MAC-ELISA) for refining a new algorithm for the diagnosis of acute- or convalescent-phase DENV infection with a single clinical sample. We tested the Bio-Rad kit with three panels of sera. These panels were designed to evaluate the sensitivities of the NS1 kit for (i) early-convalescent-phase samples, (ii) acute-phase samples with false-negative PCR results, and (iii) IgM-negative convalescent-phase samples from patients with confirmed secondary DENV infections. Results show that NS1 can be detected in 22% of serum samples collected more than 10 days after the onset of illness and in 22% of samples that did not elicit an IgM response. Additionally, NS1 was detected in 37% of the tested acute-phase samples with false-negative PCR results, suggesting that NS1 detection may be valuable in increasing the sensitivity of current acute-phase diagnostics. These results will improve diagnosis with a single acute-phase or early-convalescent-phase sample for disease surveillance and clinical diagnosis.


The liaison brain for voluntary movement: the supplementary motor area.
An account of the origin of the term liaison brain leads on to an historical account of its usage, particularly in voluntary movement. Empirical evidence was provided by the readiness potential of Kornhuber and associates, which even indicated a key role for the supplementary motor area, SMA. It was found by Brinkman and Porter that in voluntary movement many neurones of the SMA were activated probably up to 200 msec before the pyramidal tract discharge. Then came the (133)Xe investigations of regional cerebral blood flow by Roland and associates to reveal that there was neuronal activity in the SMA of both sides during a continued series of voluntary movements, and that his even occurred when the movement was being thought of but not executed. The microstructure and connectivities of the SMAS are considered in relationship to its proposed key role in being excited by the mental act of intention and then calling up the appropriate motor programs to give the desired movement: each mental intention would act on the SMA in a specific manner; the SMA has an 'inventory' and the 'addresses' of stored subroutines of all learnt motor programs and so is able to institute the desired movement by its neuronal connectivites. In conclusion there is a general account of the concept of the liaison brain both for intention and perception.


Effect of pH on metabolism of alpha-ketoglutarate by renal cortical mitochondria.
The effect of acid-base perturbations on mitochondrial alpha-ketoglutarate (alpha-KG) metabolism was quantitated by measuring the nitrogen and carbon metabolites of glutamine. alpha-KG metabolized was calculated as the difference between alpha-KG production from glutamine (glutamate deamination plus transamination) and alpha-KG accumulation in the medium. Under all experimental conditions accumulation in the medium of malate plus aspartate was altered similarly to the calculated change in alpha-KG metabolism. Mitochondria from rats with chronic acidosis were compared to pair-fed controls. Chronic acidosis resulted in increased alpha-KG production and its intramitochondrial concentration; the rate of conversion of alpha-KG to succinate was unchanged. When mitochondria from normal animals were incubated at pH 7.0, 7.4, and 7.7, the amount of alpha-KG metabolized was altered, but the magnitude and direction of the response was dependent on the concentration of glutamine (0.5, 1.0, or 5.0 mM). A low pH depressed production but stimulated the subsequent metabolism of alpha-KG, whereas an alkaline pH acted in the opposite fashion. The overall response at a given glutamine concentration depended on which effect predominated. Accordingly, chronic acidosis does not induce adaptive changes, but pH, per se, directly alters intramitochondrial alpha-KG metabolism.


High-Efficiency Ion-Exchange Doping of Conducting Polymers.
Molecular doping-the use of redox-active small molecules as dopants for organic semiconductors-has seen a surge in research interest driven by emerging applications in sensing, bioelectronics, and thermoelectrics. However, molecular doping carries with it several intrinsic problems stemming directly from the redox-active character of these materials. A recent breakthrough was a doping technique based on ion-exchange, which separates the redox and charge compensation steps of the doping process. Here, the equilibrium and kinetics of ion exchange doping in a model system, poly(2,5-bis(3-alkylthiophen-2-yl)thieno(3,2-b)thiophene) (PBTTT) doped with FeCl3 and an ionic liquid, is studied, reaching conductivities in excess of 1000 S cm-1 and ion exchange efficiencies above 99%. Several factors that enable such high performance, including the choice of acetonitrile as the doping solvent, which largely eliminates electrolyte association effects and dramatically increases the doping strength of FeCl3 , are demonstrated. In this high ion exchange efficiency regime, a simple connection between electrochemical doping and ion exchange is illustrated, and it is shown that the performance and stability of highly doped PBTTT is ultimately limited by intrinsically poor stability at high redox potential.


Cavity-QED assisted attraction between a cavity mode and an exciton mode in a planar photonic-crystal cavity.
The photoluminescence spectra from a quantum-dot exciton weakly-coupled to a planar photonic-crystal cavity is experimentally investigated by temperature tuning. Significant resonance shifts of the cavity mode are observed as the cavity mode spectrally approaches that of the exciton mode, showing the appearance of cavity-to-exciton attraction or mode pulling. Cavity-mode spectral shifts are also found theoretically using a master equation model that includes incoherent pump processes for the coupled exciton and cavity, pure dephasing, and allows for photon emission via radiation modes and the leaky cavity mode. Both experiments and theory show clear cavity mode spectral shifts in the photoluminescence spectra, when certain coupling parameters are met. However, discrepancies between the experimental data and theory, including more pronounced spectral shifts in the measurements, indicate that other unknown mode-pulling effects may also be occurring.


Equity of access in the spatial distribution of GPs within an Australian metropolitan city.
Equitable access to primary health care is a key objective for health policy makers. In Australia, poor access to primary care providers has been well documented for many rural areas, yet the distribution of general practitioners (GPs) in metropolitan regions remains relatively unknown. Traditional methods of determining geographic access to GPs are limited as they rely on simple population to provider ratios within artificial administrative borders and, among other things, fail to take into account patients that utilise close-by facilities outside of these borders. This study utilised specialised geographic information systems to examine the equity of access to GPs in an Australia capital city (Adelaide). Results showed that by Australian standards, residents of metropolitan Adelaide have low GP ratios. However, an inequitable spatial distribution of GPs within metropolitan Adelaide was found, with ~16% of residents considered to be living in areas of GP workforce shortage. Residents in the outer suburbs and those with lower social economic status appeared to be the most disadvantaged. It is recommended that future studies employ specialised GIS techniques as they provide a more accurate measurement of variations in spatial accessibility to primary care within metropolitan cities.


CYP19 (aromatase): exploring the scaffold flexibility for novel selective inhibitors.
Several derivatives out of a series of antifungal agents exhibited a good inhibitory potency against aromatase as well as a fairly good selectivity toward CYP17, even if lacking H-bond accepting substituents. Their common structural feature is a flexible backbone that did not fit into previously reported CYP19 models. Thus, a ligand-based approach was exploited to develop a novel statistically robust, self-consistent and predictive 3D-QSAR model herein proposed as a helpful tool to design new aromatase inhibitors.


The therapeutic effect of engineered phage, derived protein and enzymes against superbug bacteria.
Defending against antibiotic-resistant infections is similar to fighting a war with limited ammunition. As the new century unfolded, antibiotic resistance became a significant concern. In spite of the fact that phage treatment has been used as an effective means of fighting infections for more than a century, researchers have had to overcome many challenges of superbug bacteria by manipulating phages and producing engineered enzymes. New enzymes and phages with enhanced properties have a significant impact on the ability to fight antibiotic-resistant infections, which is considered a window of hope for the future. This review, therefore, illustrates not only the challenges caused by antibiotic resistance and superbug bacteria but also the engineered enzymes and phages that are being developed to solve these issues. Our study found that engineered phages, phage proteins, and enzymes can be effective in treating superbug bacteria and destroying the biofilm caused by them. Combining these engineered compounds with other antimicrobial substances can increase their effectiveness against antibiotic-resistant bacteria. Therefore, engineered phages, proteins, and enzymes can be used as a substitute for antibiotics or in combination with antibiotics to treat patients with superbug infections in the future.


Methods, results, and lessons learned from process evaluation of the high 5 school-based nutrition intervention.
This article describes the process evaluation of High 5, a school-based intervention targeting fruit and vegetable consumption among fourth graders and their families. The outcome evaluation involved 28 schools randomized to intervention or control conditions. The intervention included classroom, family, and cafeteria components. Process evaluation was completed on each of these components by using observations, self-report checklists, surveys, and other measures. Results indicated high implementation rates on the classroom activities. Moderate family involvement was attained, perhaps diminishing intervention effects on parent consumption. Cafeterias provided environmental cues, and fruit and vegetable offerings as directed by the program. A lower dose of the intervention was delivered to schools with larger African American enrollments and lower-income families. This article provides insights into the effective elements of a school-based dietary intervention and provides suggestions for process evaluation in similar studies.


Referral to aftercare following inpatient withdrawal treatment and readmission: retrospective chart review of patients with substance use disorders.
Aftercare following inpatient withdrawal treatment improves the prognosis and prevents future readmissions in patients with substance use disorders. According to the stepped care approach, the setting and intensity of aftercare should be adjusted to the patients' specific needs and resources. This study evaluated the real-life referral to different types of aftercare in Switzerland and the rate of inpatient readmission within a 1-year follow-up. All substance use disorder patients admitted for inpatient withdrawal treatment in a Swiss psychiatric hospital between January and December 2016 (n = 497) were included in this retrospective study. Clinical and sociodemographic characteristics were extracted from the electronic medical records and their impact on the likelihood of being referred to a particular type of aftercare (general practitioner, psychiatric outpatient care, psychiatric day clinic, inpatient rehabilitation programme) was evaluated. For each type of referral, we determined the readmission rate within one year after discharge. In the sample of substance use disorder patients (mean age 41 years; 69% male), alcohol use disorder was by far the most frequent substance use disorder. Most patients were referred to psychiatric outpatient care (39.8%), followed by a general practitioner (31.0%), inpatient rehabilitation (19.3%) and psychiatric day clinic (9.9%). Patient characteristics that point to an unfavourable course of disease, including higher symptom severity, history of more than two previous admissions, compulsory admission and treatment discontinuation, were associated with a higher likelihood to be referred to lower-level aftercare (general practitioner, psychiatric outpatient care), whereas patients with lower symptom severity, fewer than two previous admissions, voluntary admission and regular discharge were more likely to be referred to high-intensity aftercare (psychiatric day clinic, inpatient rehabilitation). The readmission rate after one year did not differ between the different settings of aftercare (range 40.4-42.9%). The findings of this study suggest that patients suffering from severe substance use disorders and/or from an unfavourable course of disease who would benefit from a more intensive aftercare setting, such as psychiatric day clinics or inpatient rehabilitation programs, might be under-treated, whereas patients with a rather favourable prognosis might similarly benefit from a less intensive treatment setting, such as psychiatric outpatient care. Regarding the comparable readmission rates, we recommend considering more efficient resource management by promoting stepped care approaches for substance use disorders and establishing standardised placement criteria in Switzerland.


A combretastatin-mediated decrease in neutrophil concentration in peripheral blood and the impact on the anti-tumor activity of this drug in two different murine tumor models.
The vascular disrupting agent combretastatin A-4 disodium phosphate (CA4P) induces fluctuations in peripheral blood neutrophil concentration. Because neutrophils have the potential to induce both vascular damage and angiogenesis we analyzed neutrophil involvement in the anti-tumoral effects of CA4P in C3H mammary carcinomas in CDF1 mice and in SCCVII squamous cell carcinomas in C3H/HeN mice. Flow cytometry analyses of peripheral blood before and up to 144 h after CA4P administration (25 and 250 mg/kg) revealed a decrease 1 h after treatment, followed by an early (3-6 h) and a late (>72 h) increase in the granulocyte concentration. We suggest that the early increase (3-6 h) in granulocyte concentration was caused by the initial decrease at 1 h and found that the late increase was associated with tumor size, and hence independent of CA4P. No alterations in neutrophil infiltration into the C3H tumor after CA4P treatment (25 and 250 mg/kg) were found. Correspondingly, neutrophil depletion in vivo, using an anti-neutrophil antibody, followed by CA4P treatment (25 mg/kg) did not increase the necrotic fraction in C3H tumors significantly. However, by increasing the CA4P dose to 250 mg/kg we found a significant increase of 359% in necrotic fraction when compared to neutrophil-depleted mice; in mice with no neutrophil depletion CA4P induced an 89% change indicating that the presence of neutrophils reduced the effect of CA4P. In contrast, neither CA4P nor 1A8 affected the necrotic fraction in the SCCVII tumors significantly. Hence, we suggest that the initial decrease in granulocyte concentration was caused by non-tumor-specific recruitment of neutrophils and that neutrophils may attenuate CA4P-mediated anti-tumor effect in some tumor models.