Generating and exploiting polarity in bacteria.
Bacteria are often highly polarized, exhibiting specialized structures at or near the ends of the cell. Among such structures are actin-organizing centers, which mediate the movement of certain pathogenic bacteria within the cytoplasm of an animal host cell; organized arrays of membrane receptors, which govern chemosensory behavior in swimming bacteria; and asymmetrically positioned septa, which generate specialized progeny in differentiating bacteria. This polarization is orchestrated by complex and dynamic changes in the subcellular localization of signal transduction and cytoskeleton proteins as well as of specific regions of the chromosome. Recent work has provided information on how dynamic subcellular localization occurs and how it is exploited by the bacterial cell. The main task of a bacterial cell is to survive and duplicate itself. The bacterium must replicate its genetic material and divide at the correct site in the cell and at the correct time in the cell cycle with high precision. Each kind of bacterium also executes its own strategy to find nutrients in its habitat and to cope with conditions of stress from its environment. This involves moving toward food, adapting to environmental extremes, and, in many cases, entering and exploiting a eukaryotic host. These activities often involve processes that take place at or near the poles of the cell. Here we explore some of the schemes bacteria use to orchestrate dynamic changes at their poles and how these polar events execute cellular functions. In spite of their small size, bacteria have a remarkably complex internal organization and external architecture. Bacterial cells are inherently asymmetric, some more obviously so than others. The most easily recognized asymmetries involve surface structures, e.g., flagella, pili, and stalks that are preferentially assembled at one pole by many bacteria. "New" poles generated at the cell division plane differ from old poles from the previous round of cell division. Even in Escherichia coli, which is generally thought to be symmetrical, old poles are more static than new poles with respect to cell wall assembly (1), and they differ in the deposition of phospholipid domains (2). There are many instances of differential polar functions; among these is the preferential use of old poles when attaching to host cells as in the interaction of Bradyrhizobium with plant root hairs (3) or the polar pili-mediated attachment of the Pseudomonas aeruginosa pathogen to tracheal epithelia (4). An unusual polar organelle that mediates directed motility on solid surfaces is found in the nonpathogenic bacterium Myxococcus xanthus. The gliding motility of this bacterium is propelled by a nozzle-like structure that squirts a polysaccharide-containing slime from the pole of the cell (5). Interestingly, M. xanthus, which has nozzles at both poles, can reverse direction by closing one nozzle and opening the other in response to end-to-end interactions between cells.


Proteomics study of N-acetylcysteine response in H1N1-infected cells by using mass spectrometry.
The pathology of A/Puerto Rico/8/1934 (H1N1) infection associated with the interaction of virus and its host cells is not clear. N-Acetylcysteine (NAC) is an antioxidant as well as a premier antitoxin and immune support substance. A high dose of NAC was recently reported for a therapy of H1N1 (2009) influenza pneumonia. NAC was used as a small-molecule organic probe to investigate the protein expression of human lung carcinoma cell line (A549) infected by influenza virus A/Puerto Rico/8/1934 (H1N1). Differential proteins were identified from MALDI-TOF MS and Q-TOF MS/MS analyses. The obtained results showed that NAC kept cells away from apoptosis. Virus-infected cells were arrested in G0/G1 phase. The lowest cell population of G0/G1 phase was detected when the cells were treated by 10 mM NAC for one day. Application of MS-based proteomics allowed the identification of the differential proteins. Software analysis showed that four proteins had close relationship. The results indicated that NAC as a small-molecule probe might effect the protein expression of A549 cells infected by the H1N1 virus.


A Novel Surgical Approach to Mechanical Circulatory Support in Univentricular Infants.
Historically, the options for mechanical circulatory support in infants, particularly those with single-ventricle physiology, have been limited and outcomes have generally been poor. We report a new approach implemented for long-term support in a series of such patients. This study is a single-center case series of 7 patients with single-ventricle physiology after stage 1 palliation supported with mechanical circulatory support using a novel technique, between May 2014 and September 2015. Our technique included modification and implantation of commercially available pediatric cannulae into the common atrium and the ascending aorta or reconstructed neoaorta and utilization of a centrifugal extracorporeal pump. Median circulatory support duration was 64 days (range, 35 to 99). One adverse neurologic event was observed in 1 patient, and bleeding requiring reoperation in 2 patients. Support to recovery, decision, or heart transplantation was accomplished in all cases. Of all patients, 43% were successfully discharged home. Our experience shows that long-term extracorporeal mechanical circulatory support of patients with underlying single-ventricle physiology after stage 1 palliation is feasible utilizing our technique. This approach overcomes several major challenges encountered in these patients, such as high flow requirement and stability of the cannulae, and allows extubation, rehabilitation, and at times, myocardial recovery.


Chinese consensus guidelines for diagnosis and management of gastrointestinal stromal tumor.
In order to further promote the standardization of diagnosis and treatment of gastrointestinal stromal tumor (GIST) in China, the members of Chinese Society of Clinical Oncology (CSCO) Expert Committee on GIST thoroughly discussed the key contents of the consensus guidelines, and voted on the controversial issue. In final, the Chinese consensus guidelines for the diagnosis and management of GIST (2017 edition) was formed on the basis of 2013 edition consensus guidelines, which is hereby announced. The consensus included the pathological diagnosis, recurrence risk classification evaluation, targeted agent therapy, surgery and principles of surveillance of GIST.


Selective blockade of CD28 on human T cells facilitates regulation of alloimmune responses.
T cells are central to the detrimental alloresponses that develop in autoimmunity and transplantation, with CD28 costimulatory signals being key to T cell activation and proliferation. CTLA4-Ig molecules that bind CD80/86 and inhibit CD28 costimulation offer an alternative immunosuppressive treatment, free from some of the chronic toxicities associated with calcineurin inhibition. However, CD80/86 blockade by CTLA4-Ig also results in the loss of coinhibitory CTLA4 signals that are critical to the regulation of T cell activation. Here, we show that a nonactivating monovalent anti-CD28 that spares CTLA4 signaling is an effective immunosuppressant in a clinically relevant humanized mouse transplant model. We demonstrate that selective CD28 blockade prolongs human skin allograft survival through a mechanism that includes a reduction in the cellular graft infiltrate. Critically, selective CD28 blockade promotes Treg function in vivo and synergizes with adoptive Treg therapy to promote transplant survival. In contrast to CTLA4-Ig treatment, selective CD28 blockade promotes regulation of alloimmune responses and facilitates Treg-based cellular therapy.


Effects of temperature on excluded volume-promoted cyclization and concatemerization of cohesive-ended DNA longer than 0.04 Mb.
The 0.048502 megabase (Mb), primarily double-stranded DNA of bacteriophage lambda has single-stranded, complementary termini (cohesive ends) that undergo either spontaneous intramolecular joining to form open circular DNA or spontaneous intermolecular joining to form linear, end-to-end oligomeric DNAs (concatemers); concatemers also cyclize. In the present study, the effects of polyethylene glycol (PEG) on the cyclization and concatemerization of lambda DNA are determined at temperatures that, in the absence of PEG, favor dissociation of cohesive ends. Circular and linear lambda DNA, monomeric and concatemeric, are observed by use of pulsed field agarose gel (PFG) electrophoresis. During preparation of lambda DNA for these studies, hydrodynamic shear-induced, partial dissociation of joined cohesive ends is fortuitously observed. Although joined lambda cohesive ends progressively dissociate as their temperature is raised in the buffer used here (0.1 M NaCl, 0.01 M sodium phosphate, pH 7.4, 0.001 M EDTA), when PEG is added to this buffer, raising the temperature sometimes promotes joining of cohesive ends. Conditions for promotion of primarily either cyclization or concatemerization are described. Open circular DNAs as long as a 7-mer are produced and resolved. The concentration of PEG required to promote joining of cohesive ends decreases as the molecular weight of the PEG increases. The rate of cyclization is brought, the first time, to values that are high enough to be comparable to the rate observed in vivo. For double-stranded DNA bacteriophages that have a linear replicative form of DNA (bacteriophage T7, for example), a suppression, sometimes observed here, of cyclization mimics a suppression of cyclization previously observed in vivo. The PEG, temperature effects on DNA joining are explained by both the excluded volume of PEG random coils and an increase in this excluded volume that occurs when temperature increases.


Does this child have appendicitis?
Evaluation of abdominal pain in children can be difficult. Rapid, accurate diagnosis of appendicitis in children reduces the morbidity of this common cause of pediatric abdominal pain. Clinical evaluation may help identify (1) which children with abdominal pain and a likely diagnosis of appendicitis should undergo immediate surgical consultation for potential appendectomy and (2) which children with equivocal presentations of appendicitis should undergo further diagnostic evaluation. To systematically assess the precision and accuracy of symptoms, signs, and basic laboratory test results for evaluating children with possible appendicitis. We searched English-language articles in MEDLINE (January 1966-March 2007) and the Cochrane Database, as well as physical examination textbooks and bibliographies of retrieved articles, yielding 2521 potentially relevant articles. Studies were included if they (1) provided primary data on children aged 18 years or younger in whom the diagnosis of appendicitis was considered; (2) presented medical history data, physical examination findings, or basic laboratory data; and (3) confirmed or excluded appendicitis by surgical pathologic findings, clinical observation, or follow-up. Of 256 full-text articles examined, 42 met inclusion criteria. Twenty-five of 42 studies were assigned a quality level of 3 or better. Data from these studies were independently extracted by 2 reviewers. In children with abdominal pain, fever was the single most useful sign associated with appendicitis; a fever increases the likelihood of appendicitis (likelihood ratio [LR], 3.4; 95% confidence interval [CI], 2.4-4.8) and conversely, its absence decreases the chance of appendicitis (LR, 0.32; 95% CI, 0.16-0.64). In select groups of children, in whom the diagnosis of appendicitis is suspected and evaluation undertaken, rebound tenderness triples the odds of appendicitis (summary LR, 3.0; 95% CI, 2.3-3.9), while its absence reduces the likelihood (summary LR, 0.28; 95% CI, 0.14-0.55). Midabdominal pain migrating to the right lower quadrant (LR range, 1.9-3.1) increases the risk of appendicitis more than right lower quadrant pain itself (summary LR, 1.2; 95% CI, 1.0-1.5). A white blood cell count of less than 10,000/microL decreases the likelihood of appendicitis (summary LR, 0.22; 95% CI, 0.17-0.30), as does an absolute neutrophil count of 6750/microL or lower (LR, 0.06; 95% CI, 0.03-0.16). Symptoms and signs are most useful in combination, particularly for identifying children who do not require further evaluation or intervention. Although the clinical examination does not establish a diagnosis of appendicitis with certainty, it is useful in determining which children with abdominal pain warrant immediate surgical evaluation for consideration of appendectomy and which children may warrant further diagnostic evaluation. More child-specific, age-stratified data are needed to improve the utility of the clinical examination for diagnosing appendicitis in children.


Smell identification ability: changes with age.
Smell identification ability was measured in 1955 persons ranging in age from 5 to 99 years. On the average, women outperformed men at all ages, and nonsmokers outperformed smokers. Peak performance occurred in the third through fifth decades and declined markedly after the seventh. More than half of those 65 to 80 years old evidenced major olfactory impairment. After 80 years, more than three-quarters evidenced major impairment. Given these findings, it is not surprising that many elderly persons complain that food lacks flavor and that the elderly account for a disproportionate number of accidental gas poisoning cases each year.


Optical absorption enhancement of hybrid-plasmonic-based metal-semiconductor-metal photodetector incorporating metal nanogratings and embedded metal nanoparticles.
We propose and numerically demonstrate a high absorption hybrid-plasmonic-based metal semiconductor metal photodetector (MSM-PD) comprising metal nanogratings, a subwavelength slit and amorphous silicon or germanium embedded metal nanoparticles (NPs). Simulation results show that by optimizing the metal nanograting parameters, the subwavelength slit and the embedded metal NPs, a 1.3 order of magnitude increase in electric field is attained, leading to 28-fold absorption enhancement, in comparison with conventional MSM-PD structures. This is 3.5 times better than the absorption of surface plasmon polariton (SPP) based MSM-PD structures employing metal nanogratings and a subwavelength slit. This absorption enhancement is due to the ability of the embedded metal NPs to enhance their optical absorption and scattering properties through light-stimulated resonance aided by the conduction electrons of the NPs.


[Shared decision making in mental health care; evaluation of the added value for patients and clinicians].
Although the evidence is expanding, in mental health care shared decision making (SDM) is not widely applied. Moreover, little is known about the use of routine outcome monitoring (ROM) and eHealth in SDM.
 AIM: PhD research on the added value of SDM using ROM and eHealth for patients and clinicians in mental health care.
 METHOD: Three studies: 1. a literature research and a cross-sectional study on decisional conflict; 2. ROM implementation research and a cluster randomised trial on shared decision making using ROM (Breakthrough program); 3. a cluster randomised trial on shared decision making during the intake (regional).
 RESULTS: The interventions did not lead to reduced decisional conflict for all patient groups. Decisional conflict gives insight into the patient's perspective on the quality of the decision making process and decisions being made. Only patients with depression, who participated in the national trial, reported less decisional conflict. This trial did not show a higher level of SDM, but did show increased usage of rom in clinical practice. Although the regional trial showed no results on decisional conflict, the application of SDM and treatment outcomes improved.
 CONCLUSION: SDM in mental health care needs further improvement. We recommend investigating how to support patients better, taking into account the role that suits them.


Chara buckellii, a Euryhaline Charophyte from an Unusual Saline Environment : III. Time Course of Turgor Regulation.
The time course of turgor regulation of the euryhaline giant-celled alga, Chara buckellii, is presented. Isolated intermodal cells were challenged by increasing or decreasing the external osmotic pressure by 150 milliosmoles per kilogram with all ions in the media or by dilution, respectively. Regulation following hypotonic stress was complete within 48 hours whereas regulation following hypertonic stress required between 96 and 144 hours. The change in internal osmotic pressure could be entirely accounted for by changes in vacuolar KCl in response to hypotonic stress, but this ion pair only accounted for 45% of the change in response to hypertonic stress. The membrane potential of C. buckellii is normally hyperpolarized with respect to the equilibrium potential for K(+) (E(K)). The membrane depolarized to a level close to E(K) in response to hypotonic treatment and this was accompanied by a transient increase in membrane conductance. In response to hypertonic stress, the membrane hyperpolarized transiently, then repolarized to a level close to the control. This was accompanied by a temporary decrease in membrane conductance. The data are discussed with respect to the ecological significance of the time course and ion transport mechanisms during turgor regulation.


Heterospecific Neighbor Plants Impact Root Microbiome Diversity and Molecular Function of Root Fungi.
Within the forest community, competition and facilitation between adjacent-growing conspecific and heterospecific plants are mediated by interactions involving common mycorrhizal networks. The ability of plants to alter their neighbor's microbiome is well documented, but the molecular biology of plant-fungal interactions during competition and facilitation has not been previously examined. We used a common soil-plant bioassay experiment to study molecular plant-microbial interactions among rhizosphere communities associated with Pinus taeda (native host) and Populus trichocarpa (non-native host). Gene expression of interacting fungal and bacterial rhizosphere communities was compared among three plant-pairs: Populus growing with Populus, Populus with Pinus, and Pinus with Pinus. Our results demonstrate that heterospecific plant partners affect the assembly of root microbiomes, including the changes in the structure of host specific community. Comparative metatranscriptomics reveals that several species of ectomycorrhizal fungi (EMF) and saprotrophic fungi exhibit different patterns of functional and regulatory gene expression with these two plant hosts. Heterospecific plants affect the transcriptional expression pattern of EMF host-specialists (e.g., Pinus-associated Suillus spp.) on both plant species, mainly including the genes involved in the transportation of amino acids, carbohydrates, and inorganic ions. Alteration of root microbiome by neighboring plants may help regulate basic plant physiological processes via modulation of molecular functions in the root microbiome.


Hybrid Monte Carlo-diffusion method for light propagation in tissue with a low-scattering region.
The heterogeneity of the tissues in a head, especially the low-scattering cerebrospinal fluid (CSF) layer surrounding the brain has previously been shown to strongly affect light propagation in the brain. The radiosity-diffusion method, in which the light propagation in the CSF layer is assumed to obey the radiosity theory, has been employed to predict the light propagation in head models. Although the CSF layer is assumed to be a nonscattering region in the radiosity-diffusion method, fine arachnoid trabeculae cause faint scattering in the CSF layer in real heads. A novel approach, the hybrid Monte Carlo-diffusion method, is proposed to calculate the head models, including the low-scattering region in which the light propagation does not obey neither the diffusion approximation nor the radiosity theory. The light propagation in the high-scattering region is calculated by means of the diffusion approximation solved by the finite-element method and that in the low-scattering region is predicted by the Monte Carlo method. The intensity and mean time of flight of the detected light for the head model with a low-scattering CSF layer calculated by the hybrid method agreed well with those by the Monte Carlo method, whereas the results calculated by means of the diffusion approximation included considerable error caused by the effect of the CSF layer. In the hybrid method, the time-consuming Monte Carlo calculation is employed only for the thin CSF layer, and hence, the computation time of the hybrid method is dramatically shorter than that of the Monte Carlo method.


Comparative genomics of the SOX9 region in human and Fugu rubripes: conservation of short regulatory sequence elements within large intergenic regions.
Campomelic dysplasia (CD), a human skeletal malformation syndrome with XY sex reversal, is caused by heterozygous mutations in and around the gene SOX9. SOX9 has an extended 5' control region, as indicated by CD translocation breakpoints scattered over 1 Mb proximal to SOX9 and by expression data from mice transgenic for human SOX9-spanning yeast artificial chromosomes. To identify long-range regulatory elements within the SOX9 5' control region, we compared approximately 3.7 Mb and 195 kb of sequence around human and Fugu rubripes SOX9, respectively. We identified only seven and five protein-coding genes in the human and F. rubripes sequences, respectively. Four of the F. rubripes genes have been mapped in humans; all reside on chromosome 17 but show extensive intrachromosomal gene shuffling compared with the gene order in F. rubripes. In both species, very large intergenic distances separate SOX9 from its directly flanking genes: 2 Mb and 500 kb on either side of SOX9 in humans, and 68 and 97 kb on either side of SOX9 in F. rubripes. Comparative sequence analysis of the intergenic regions revealed five conserved elements, E1-E5, up to 290 kb 5' to human SOX9 and up to 18 kb 5' to F. rubripes SOX9, and three such elements, E6-E8, 3' to SOX9. Where available, mouse sequences confirm conservation of the elements. From the yeast artificial chromosome transgenic data, elements E3-E5 are candidate enhancers for SOX9 expression in limb and vertebral column, and 8 of 10 CD translocation breakpoints separate these elements from SOX9.


Paradoxical effect of chronic fentanyl treatment on naltrexone-induced supersensitivity and upregulation.
The present study sought to evaluate the influence of chronic opioid antagonist treatment upon the discriminative stimulus and analgesic effects of the opioid receptor agonist fentanyl. Male Wistar rats were trained to discriminate fentanyl (0.04 mg/kg) from saline in a two-lever food reinforced paradigm. After acquisition of the discrimination, they were implanted with osmotic minipumps which delivered either naltrexone (0.07 mg/h) or distilled water, and the sensitivity of discrimination was assessed at various times after pump removal. The influence of chronic naltrexone treatment upon the antinociceptive effects of fentanyl was assessed in drug-naive (control) rats and in rats which had received fentanyl in the same dosage schedule as those in drug discrimination experiments. Chronic infusion of naltrexone for 7 days did not modify the dose-response curve for the fentanyl vs. saline discrimination. Algesiometric tests revealed a significant increase in the antinociceptive effect of fentanyl in control rats after naltrexone treatment. In contrast, such supersensitivity was not observed in rats which had previously received fentanyl injections. Autoradiographic data revealed a naltrexone-induced upregulation of mu opioid receptors in control animals. Paradoxically, this effect was significantly increased in fentanyl-pretreated rats. These data suggest that prior drug experience can affect the development of antagonist-induced supersensitivity to the behavioral actions of opioid agonists. Furthermore, it would appear that after chronic agonist treatment the phenomena of opioid receptor upregulation and functional supersensitivity are dissociated.


Riboflavin Has Neuroprotective Potential: Focus on Parkinson's Disease and Migraine.
With the huge negative impact of neurological disorders on patient's life and society resources, the discovery of neuroprotective agents is critical and cost-effective. Neuroprotective agents can prevent and/or modify the course of neurological disorders. Despite being underestimated, riboflavin offers neuroprotective mechanisms. Significant pathogenesis-related mechanisms are shared by, but not restricted to, Parkinson's disease (PD) and migraine headache. Those pathogenesis-related mechanisms can be tackled through riboflavin proposed neuroprotective mechanisms. In fact, it has been found that riboflavin ameliorates oxidative stress, mitochondrial dysfunction, neuroinflammation, and glutamate excitotoxicity; all of which take part in the pathogenesis of PD, migraine headache, and other neurological disorders. In addition, riboflavin-dependent enzymes have essential roles in pyridoxine activation, tryptophan-kynurenine pathway, and homocysteine metabolism. Indeed, pyridoxal phosphate, the active form of pyridoxine, has been found to have independent neuroprotective potential. Also, the produced kynurenines influence glutamate receptors and its consequent excitotoxicity. In addition, methylenetetrahydrofolate reductase requires riboflavin to ensure normal folate cycle influencing the methylation cycle and consequently homocysteine levels which have its own negative neurovascular consequences if accumulated. In conclusion, riboflavin is a potential neuroprotective agent affecting a wide range of neurological disorders exemplified by PD, a disorder of neurodegeneration, and migraine headache, a disorder of pain. In this article, we will emphasize the role of riboflavin in neuroprotection elaborating on its proposed neuroprotective mechanisms in opposite to the pathogenesis-related mechanisms involved in two common neurological disorders, PD and migraine headache, as well as, we encourage the clinical evaluation of riboflavin in PD and migraine headache patients in the future.


Neurophysiological responses to angiotensin-(1-7).
The aim of this study was to investigate the action of the heptapeptide angiotensin-(1-7) on the spontaneous activity of paraventricular neurons using microiontophoresis. Recent immunocytochemical investigations have shown that this product of angiotensin I is predominantly located in cells and fibers of the forebrain and brain stem. Our results show that most neurons in the paraventricular nucleus are excited by angiotensin-(1-7) at a dose of 50-80 nA. In comparison with angiotensin II or angiotensin III, the onset of response and the occurrence of the maximal effect were significantly delayed. With higher doses of angiotensin-(1-7), there was a decrease in latency and a dose-dependent increase in firing frequency. Of all the angiotensin compounds tested, angiotensin III was the most potent. Preliminary results obtained with an angiotensin antagonist show that the action of angiotensin II, angiotensin III, and angiotensin-(1-7) is blocked by the angiotensin receptor subtype 2 antagonist CGP 42112A. Because the angiotensin-(1-7) system in the brain is associated with central vasopressinergic pathways, vasopressin was tested in a similar way. Neurons in the paraventricular nucleus that were excited by iontophoretically applied angiotensins showed a weak response to vasopressin. Occasionally, a small excitatory action was observed. Our results support the hypothesis that the heptapeptide angiotensin-(1-7) is a biologically active neuropeptide. The data also suggest that amino terminal fragments of angiotensin II are not inactive degradation products.


Perceived barriers in accessing food among recent Latin American immigrants in Toronto.
In Canada, recent immigrant households experience more food insecurity than the general population, but limited information is available about the personal, cultural, and social factors that contribute to this vulnerability. This study focused on recent Latin American (LA) immigrants to explore their perceived barriers in acquiring safe, nutritious, and culturally-appropriate food. A cross-sectional mixed-method design was applied to collect information from a convenience sample of 70 adult Spanish/Portuguese speakers who had arrived in Toronto within the last five years. Face-to-face interviews were conducted with primary household caregivers to obtain responses about barriers to acquiring food for their households; data were analyzed using a thematic analysis technique. Four main categories of barriers were identified: limited financial resources; language difficulty; cultural food preferences; and poor knowledge of available community-based food resources and services. Inadequate income was the main impediment in accessing adequate food, and was related to affordability of food items, accessibility of food outlets and transportation cost, and limited time for grocery shopping due to work conditions. Language barriers affected participants' ability to obtain well-paid employment and their awareness about and access to available community-based food resources. Cultural barriers were related to food preferences and limited access to culturally-appropriate foods and resources. The main barrier to food security among our sample of LA newcomers to Toronto is limited financial resources, highlighting the need for policies and strategies that could improve their financial power to purchase sufficient, nutritious, and culturally-acceptable food. Linguistic barriers and limited information among newcomers suggest the need to provide linguistically- and culturally-appropriate information related to community-based food programs and resources, as well as accessible subsidized English language programs, in the community and at workplaces. Participatory community-based food programs can augment, in a socially acceptable manner, food resources and reduce the social stigma attached to food charity. Finally, it is crucial to monitor and evaluate existing social and community-based services for their accessibility, cultural appropriateness and diversity, and effectiveness.


Acquired Solitary Glomangiomyoma on the Forearm: A Rare Case Report.
Glomus tumours are benign lesions which are frequently seen on hand (particularly subungual region). In this report a 52-year-old male patient with glomangiomyoma on the left forearm has been presented. With a preliminary diagnosis of haemangioma, a subcutaneous well-circumscribed nodular lesion of the patient was excised. On histomorphological examination glomus cells, vascular structures and spindle-shaped smooth muscle cells were seen around it. Immunohistochemistry of smooth muscle cells and glomus cells showed positivity for smooth muscle actin. By means of these findings, the patient was diagnosed with glomangiomyoma. Glomus tumours are rare in the forearm (In the literatüre there are two cases). Moreover, glomangiomyomas are the least common histomorphological type of glomus tumour and are generally seen in the lower extremity. In the literature, a few cases of glomangioma and solitary glomus tumour has been described on the forearm histologically and only a few glomangiomyoma cases on forearm location. We have presented the glomangiomyoma on the forearm as a rarely-seen case. Early diagnosis of the glomangiomyoma on the forearm is of importance for the prevention of morbidity.


Advanced practice nursing roles: development, implementation and evaluation.
The aim of this paper is to discuss six issues influencing the introduction of advanced practice nursing (APN) roles: confusion about APN terminology, failure to define clearly the roles and goals, role emphasis on physician replacement/support, underutilization of all APN role domains, failure to address environmental factors that undermine the roles, and limited use of evidence-based approaches to guide their development, implementation and evaluation. Health care restructuring in many countries has led to substantial increases in the different types and number of APN roles. The extent to which these roles truly reflect advanced nursing practice is often unclear. The misuse of APN terminology, inconsistent titling and educational preparation, and misguided interpretations regarding the purpose of these roles pose barriers to realizing their full potential and impact on health. Role conflict, role overload, and variable stakeholder acceptance are frequently reported problems associated with the introduction of APN roles. Challenges associated with the introduction of APN roles suggests that greater attention to and consistent use of the terms of the terms advanced nursing practice, advancement and advanced practice nursing is required. Advanced nursing practice refers to the work or what nurses do in the role and is important for defining the specific nature and goals for introducing new APN roles. The concept of advancement further defines the multi-dimensional scope and mandate of advanced nursing practice and distinguishes differences from other types of nursing roles. Advanced practice nursing refers to the whole field, involving a variety of such roles and the environments in which they exist. Many barriers to realizing the full potential of these roles could be avoided through better planning and efforts to address environmental factors, structures, and resources that are necessary for advanced nursing practice to take place. Recommendations for the future introduction of APN roles can be drawn from this paper. These include the need for a collaborative, systematic and evidence-based process designed to provide data to support the need and goals for a clearly defined APN role, support a nursing orientation to advanced practice, promote full utilization of all the role domains, create environments that support role development, and provide ongoing evaluation of these roles related to predetermined goals.


Cost-effectiveness of nurse-led self-help for recurrent depression in the primary care setting: design of a pragmatic randomised controlled trial.
Major Depressive Disorder is a leading cause of disability, tends to run a recurrent course and is associated with substantial economic costs due to increased healthcare utilization and productivity losses. Interventions aimed at the prevention of recurrences may reduce patients' suffering and costs. Besides antidepressants, several psychological treatments such as preventive cognitive therapy (PCT) are effective in the prevention of recurrences of depression. Yet, many patients find long-term use of antidepressants unattractive, do not want to engage in therapy sessions and in the primary care setting psychologists are often not available. Therefore, it is important to study whether PCT can be used in a nurse-led self-help format in primary care. This study sets out to test the hypothesis that usual care plus nurse-led self-help for recurrent depression in primary care is feasible, acceptable and cost-effective compared to usual care only. Patients are randomly assigned to 'nurse-led self-help treatment plus usual care' (134 participants) or 'usual care' (134 participants). Randomisation is stratified according to the number of previous episodes (2 or 3 previous episodes versus 4 or more). The primary clinical outcome is the cumulative recurrence rate of depression meeting DSM-IV criteria as assessed by the Structured-Clinical-Interview-for-DSM-IV- disorders at one year after completion of the intervention. Secondary clinical outcomes are quality of life, severity of depressive symptoms, co-morbid psychopathology and self-efficacy. As putative effect-moderators, demographic characteristics, number of previous episodes, type of treatment during previous episodes, age of onset, self-efficacy and symptoms of pain and fatigue are assessed. Cumulative recurrence rate ratios are obtained under a Poisson regression model. Number-needed-to-be-treated is calculated as the inverse of the risk-difference. The economic evaluation is conducted from a societal perspective, both as a cost-effectiveness analysis (costs per depression free survival year) and as a cost-utility analysis (costs per quality adjusted life-year). The purpose of this paper is to outline the rationale and design of a nurse-led, cognitive therapy based self-help aimed at preventing recurrence of depression in a primary care setting. Only few studies have focused on psychological self-help interventions aimed at the prevention of recurrences in primary care patients. NTR3001 (http://www.trialregister.nl).


Umbilical Cord Blood Mesenchymal Stem Cells as an Infertility Treatment for Chemotherapy Induced Premature Ovarian Insufficiency.
Premature ovarian insufficiency (POI) is a challenging disease, with limited treatment options at the moment. Umbilical cord blood mesenchymal stem cells (UCMSCs) have demonstrated promising regenerative abilities in several diseases including POI. A pre-clinical murine case versus vehicle control randomized study. Two experiments ran in parallel in each of the three groups. The first was to prove the ability of UCMSCs in restoring ovarian functions. The second was to prove improved fertility. A total of 36 mice were randomly assigned; 6 mice into each of 3 groups for two experiments. Group 1 (control), group 2 (sham chemotherapy), group 3 (stem cells). In the first experiment, post-UCMSCs treatment (group 3) showed signs of restored ovarian function in the form of increased ovarian weight and estrogen-dependent organs (liver, uterus), increased follicular number, and a significant decrease in FSH serum levels (p < 0.05) compared to group 2, and anti-Mullerian hormone (AMH) serum levels increased (p < 0.05) in group 3 versus group 2. Immuno-histochemistry analysis demonstrated a higher expression of AMH, follicle stimulating hormone receptor (FSHR) and Inhibin A in the growing follicles of group 3 versus group 2. In the second experiment, post-UCMSCs treatment (group 3) pregnancy rates were higher than group 2, however, they were still lower than group 1. We demonstrated the ability of UCMSCs to restore fertility in female cancer survivors with POI and as another source of stem cells with therapeutic potentials.


Cortical localization of the Galpha protein GPA-16 requires RIC-8 function during C. elegans asymmetric cell division.
Understanding of the mechanisms governing spindle positioning during asymmetric division remains incomplete. During unequal division of one-cell stage C. elegans embryos, the Galpha proteins GOA-1 and GPA-16 act in a partially redundant manner to generate pulling forces along astral microtubules. Previous work focused primarily on GOA-1, whereas the mechanisms by which GPA-16 participates in this process are not well understood. Here, we report that GPA-16 is present predominantly at the cortex of one-cell stage embryos. Using co-immunoprecipitation and surface plasmon resonance binding assays, we find that GPA-16 associates with RIC-8 and GPR-1/2, two proteins known to be required for pulling force generation. Using spindle severing as an assay for pulling forces, we demonstrate that inactivation of the Gbeta protein GPB-1 renders GPA-16 and GOA-1 entirely redundant. This suggests that the two Galpha proteins can activate the same pathway and that their dual presence is normally needed to counter Gbetagamma. Using nucleotide exchange assays, we establish that whereas GPR-1/2 acts as a guanine nucleotide dissociation inhibitor (GDI) for GPA-16, as it does for GOA-1, RIC-8 does not exhibit guanine nucleotide exchange factor (GEF) activity towards GPA-16, in contrast to its effect on GOA-1. We establish in addition that RIC-8 is required for cortical localization of GPA-16, whereas it is not required for that of GOA-1. Our analysis demonstrates that this requirement toward GPA-16 is distinct from the known function of RIC-8 in enabling interaction between Galpha proteins and GPR-1/2, thus providing novel insight into the mechanisms of asymmetric spindle positioning.


Is it useful to combine sputum cytology and low-dose spiral computed tomography for early detection of lung cancer in formerly asbestos-exposed power industry workers?
Low-dose spiral computed tomography (LDSCT) in comparison to conventional chest X-ray proved to be a highly sensitive method of diagnosing early stage lung cancer. However, centrally located early stage lung tumours remain a diagnostic challenge. We determined the practicability and efficacy of early detection of lung cancer when combining LDSCT and sputum cytology. Of a cohort of 4446 formerly asbestos exposed power industry workers, we examined a subgroup of 187 (4.2%) high risk participants for lung cancer at least once with both LDSCT and sputum cytology. After the examination period the participants were followed-up for more than three years. The examinations resulted in the diagnosis of lung cancer in 12 participants (6.4%). Six were in clinical stage I. We found 10 non-small cell lung carcinomas and one small cell lung carcinoma. Sputum specimens showed suspicious pathological findings in seven cases and in 11 cases the results of LDSCT indicated malignancies. The overall sensitivity and specificity of sputum cytology was 58.0% and 98% with positive (PPV) and negative (NPV) predictive values of 70% and 97%. For LDSCT we calculated the sensitivity and specificity of 92% and 97%. The PPV and NPV were 65% and 99% respectively. Our results confirmed that in surveillance programmes a combination of sputum cytology and LDSCT is well feasible and accepted by the participants. Sputum examination alone is not effective enough for the detection of lung cancer, especially at early stage. Even in well- defined risk groups highly exposed to asbestos, we cannot recommend the use of combined LDSCT and sputum cytology examinations as long as no survival benefit has been proved for the combination of both methods. For ensuring low rates of false-positive and false-negative results, programme planners must closely cooperate with experienced medical practitioners and pathologists in a well-functioning interdisciplinary network.


Cancer treatment by magneto-mechanical effect of particles, a review.
Cancer treatment by magneto-mechanical effect of particles (TMMEP) is a growing field of research. The principle of this technique is to apply a mechanical force on cancer cells in order to destroy them thanks to magnetic particles vibrations. For this purpose, magnetic particles are injected in the tumor or exposed to cancer cells and a low-frequency alternating magnetic field is applied. This therapeutic approach is quite new and a wide range of treatment parameters are explored to date, as described in the literature. This review explains the principle of the technique, summarizes the parameters used by the different groups and reports the main in vitro and in vivo results.


Basal ganglia volumes in first-episode schizophrenia and healthy comparison subjects.
Previous studies suggest that dysfunction of cortico-striato-pallido-thalamic (CSPT) circuitry may be involved in the pathophysiology of schizophrenia but also show that basal ganglia structure is highly plastic and may be influenced by antipsychotic treatments. Controversy remains about whether basal ganglia pathology can be detected in vivo among treatment-naïve patients. We conducted a magnetic resonance imaging (MRI) study to examine basal ganglia structures and the limbic forebrain in first episode schizophrenia and healthy comparison subjects. Fifty-one patients with first-episode schizophrenia and 28 healthy comparison subjects participated in the study. A high-resolution, special contrast (white matter nulling) MRI sequence was used to measure the caudate nucleus, nucleus accumbens, putamen, and subcommissural limbic forebrain. Volumes of the basal ganglia regions of interest (adjusted for total brain volume and age) did not differ significantly between the groups. Age correlated significantly with caudate and putamen volumes bilaterally in the healthy comparison group, but not among patients. The findings suggest that there are no volumetric abnormalities in basal ganglia before treatment in first-episode schizophrenia. The lack of a negative correlation between age and striatal volume among patients may implicate illness-associated factors that alter normal age-related changes in basal ganglia size.


Emotional and psychological effects of physician-assisted suicide and euthanasia on participating physicians.
This is a review and evaluation of medical and public literature regarding the reported emotional and psychological effects of participation in physician-assisted suicide (PAS) and euthanasia on the involved physicians. Articles in medical journals, legislative investigations and the public press were obtained and reviewed to determine what has been reported regarding the effects on physicians who have been personally involved in PAS and euthanasia. The physician is centrally involved in PAS and euthanasia, and the emotional and psychological effects on the participating physician can be substantial. The shift away from the fundamental values of medicine to heal and promote human wholeness can have significant effects on many participating physicians. Doctors describe being profoundly adversely affected, being shocked by the suddenness of the death, being caught up in the patient's drive for assisted suicide, having a sense of powerlessness, and feeling isolated. There is evidence of pressure on and intimidation of doctors by some patients to assist in suicide. The effect of countertransference in the doctor-patient relationship may influence physician involvement in PAS and euthanasia. Many doctors who have participated in euthanasia and/or PAS are adversely affected emotionally and psychologically by their experiences.


Frequency-chirped dynamic nuclear polarization with magic angle spinning using a frequency-agile gyrotron.
We demonstrate that frequency-chirped dynamic nuclear polarization (DNP) with magic angle spinning (MAS) improves the enhancement of nuclear magnetic resonance (NMR) signal beyond that of continuous-wave (CW) DNP. Using a custom, frequency-agile gyrotron we implemented frequency-chirped DNP using the TEMTriPol-1 biradical, with MAS NMR at 7 T. Frequency-chirped microwaves yielded a DNP enhancement of 137, an increase of 19% compared to 115 recorded with CW. The chirps were 120 MHz-wide and centered over the trityl resonance, with 7 W microwave power incident on the sample (estimated 0.4 MHz electron spin Rabi frequency). We describe in detail the design and fabrication of the frequency-agile gyrotron used for frequency-chirped MAS DNP. Improvements to the interaction cavity and internal mode converter yielded efficient microwave generation and mode conversion, achieving >10 W output power over a 335 MHz bandwidth with >110 W peak power. Frequency-chirped DNP with MAS is expected to have a significant impact on the future of magnetic resonance.


Statistical methodology of phase III cancer clinical trials: advances and future perspectives.
The methodology for conducting cancer clinical trials has undergone enormous changes over the past 25-30 years since the EORTC Data Center was created. The purpose of this paper is to highlight and to provide a historical perspective for the main methodological concepts, both practical and theoretical, which form the basis for the design and analysis of phase III cancer clinical trials within the EORTC Data Center. Some statistical aspects of other associated topics such as quality of life, health economics, meta-analysis and treatment outcome will also be briefly discussed. Finally, some future perspectives and topics for further statistical methodological research will be presented in order to spur statisticians to meet the challenge of efficiently designing and analysing the clinical trials of tomorrow.


A quantitative investigation of hippocampal pyramidal cell size, shape, and variability of orientation in schizophrenia.
Hippocampal abnormalities have been described in patients with schizophrenia, with disarray of pyramidal cells being one of the more intriguing findings. Controversy exists regarding whether disarray is present in the brains from schizophrenics in the Yakovlev collection at the Armed Forces Institute of Pathology, Washington, DC. We examined for disarray the CA1 region of the midhippocampus of 17 schizophrenics and 32 controls from this collection using computerized determination of neuronal angle and directional statistical analysis of the variability of neuronal angle. Neuronal area and shape were also assessed. We found no differences between patients and controls in these measures. Possible methodological reasons for the discrepancy between our and others' findings are discussed, as well as directions for further research into possible pathological study of the hippocampus and related structures in schizophrenia.


The impact of sexually transmissible infection programs in remote Aboriginal communities in Australia: a systematic review.
To systematically review evaluations of the impact of sexually transmissible infection (STI) programs delivered by primary health care services in remote Aboriginal communities. PubMed, Google Scholar, InfoNet, Cochrane Controlled Trials Register, Australian New Zealand Clinical Trial Registry, conference proceedings and bulletins were searched to April 2011 using variations of the terms 'Aboriginal', 'programs' and 'STI'. The primary outcome of interest in the review was the change in bacterial STI infection prevalence in the target age group assessed through cross-sectional screening studies over a 5-year period or more. The characteristics of the primary health care service, STI programs and other clinical service outcomes were also described. Twelve reports described four distinct STI programs in remote communities and their impact on STI prevalence. In the Anangu Pitjantjatjara Yankunytjatjara (APY) lands of northern South Australia, there was a reduction in the age-adjusted chlamydia and gonorrhoea prevalence by 58% and 67%, respectively (1996-2003). In the Tiwi Islands of Northern Territory (NT), chlamydia and gonorrhoea positivity decreased by 94% and 34%, respectively (2002-2005). In the Ngaanyatjarra Lands of Western Australia, crude chlamydia and gonorrhoea prevalence decreased by 36% and 48%, respectively (2001-2005), and in the central Australian region of NT, there was no sustained decline in crude prevalence (2001-2005). In three of the four programs, there was some evidence that clinical best practice and well coordinated sexual health programs can reduce STI prevalence in remote Aboriginal communities.


The heart tube forms and elongates through dynamic cell rearrangement coordinated with foregut extension.
In the initiation of cardiogenesis, the heart primordia transform from bilateral flat sheets of mesoderm into an elongated midline tube. Here, we discover that this rapid architectural change is driven by actomyosin-based oriented cell rearrangement and resulting dynamic tissue reshaping (convergent extension, CE). By labeling clusters of cells spanning the entire heart primordia, we show that the heart primordia converge toward the midline to form a narrow tube, while extending perpendicularly to rapidly lengthen it. Our data for the first time visualize the process of early heart tube formation from both the medial (second) and lateral (first) heart fields, revealing that both fields form the early heart tube by essentially the same mechanism. Additionally, the adjacent endoderm coordinately forms the foregut through previously unrecognized movements that parallel those of the heart mesoderm and elongates by CE. In conclusion, our data illustrate how initially two-dimensional flat primordia rapidly change their shapes and construct the three-dimensional morphology of emerging organs in coordination with neighboring morphogenesis.


[Historical note: in homage to Lister].
Joseph Lister, who disputes with Klebs the third place as the Father of Microbiology, was just about to remain without a bacteria immortalizing his ñame. Thanks to Seeliger, now Listeria is used for identifying the genus that Pirie had already named Listerella in 1927. Through a quick review of the history of Listeria monocytogenes, we get to know the principal facts in the lives of Pirie and Seeliger, investigators with absolutely different characters. We also review a brief history of the life of the great researcher Lister, whose profound human qualities are described.


Nucleotide specificities of anterograde and retrograde organelle transport in Reticulomyxa are indistinguishable.
Membrane-bound organelles move bidirectionally along microtubules in the freshwater ameba, Reticulomyxa. We have examined the nucleotide requirements for transport in a lysed cell model and compared them with kinesin and dynein-driven motility in other systems. Both anterograde and retrograde transport in Reticulomyxa show features characteristic of dynein but not of kinesin-powered movements: organelle transport is reactivated only by ATP and no other nucleoside triphosphates; the Km and Vmax of the ATP-driven movements are similar to values obtained for dynein rather than kinesin-driven movement; and of 15 ATP analogues tested for their ability to promote organelle transport, only 4 of them did. This narrow specificity resembles that of dynein-mediated in vitro transport and is dissimilar to the broad specificity of the kinesin motor (Shimizu, T., K. Furusawa, S. Ohashi, Y. Y. Toyoshima, M. Okuno, F. Malik, and R. D. Vale. 1991. J. Cell Biol. 112: 1189-1197). Remarkably, anterograde and retrograde organelle transport cannot be distinguished at all with respect to nucleotide specificity, kinetics of movement, and the ability to use the ATP analogues. Since the "kinetic fingerprints" of the motors driving transport in opposite directions are indistinguishable, the same type of motor(s) may be involved in the two directions of movement.


Lymphocytic insulitis in a juvenile dog with diabetes mellitus.
Autoimmune diabetes has never been described in a juvenile dog, whereas serological evidence has established its development in adult dogs. Diabetes mellitus was diagnosed in a 3-mo-old Donge de Bordeaux dog suffering from persistent hyperglycemia and concurrent insulinopenia. Histological analysis of the pancreas revealed inflammatory lesions in 40% of the islets of Langerhans, with infiltration predominantly by T lymphocytes (more than 90%), either at the edge (peri-insulitis: 10%) or in the islets (insulitis: 30%). The remaining 60% of the islets showed a marked atrophy due to massive beta cell loss with no loss of alpha cells. This pattern is quite similar to that observed in humans in which a characteristic insulitis containing high numbers of T lymphocytes is found in 20% of the islets at diabetes diagnosis. By contrast, in rodent models, nearly 70% of the islets of Langerhans show inflammation at diagnosis and macrophages and dendritic cells predominate in the inflammatory lesions. This is the first report of lymphocytic insulitis in a juvenile dog exhibiting diabetes mellitus. Our observations suggest an autoimmune origin for the disease in this dog that is similar to human type 1 diabetes mellitus, for which there is no accurate spontaneous large animal model.


Should healthcare reform be 'color-blind'? Addressing the barriers to improving minority health.
The scandalous disparity between the health indicators for minority and nonminority and poor and nonpoor populations is of such long standing that it has lost th power to shock. The authors review the landmark studies of the past year which document discrimination in the healthcare system. They reiterate the most compelling statistics of mortality, birth, the AIDS epidemic, destructive health habits, and poverty. They trace the impact of healthcare policy on these vulnerable populations and address the myth that malpractice claims are filed more frequently by the poor. They conclude that equality is instrumental to the improvement of the nation's health demographics; the persistence of economic, social, and political discrimination will continue to create barriers even if financial access is assured through a pluralistic approach to healthcare reform. Ultimately, they predict that any healthcare reform that does not address minority issues is doomed to fail if all three areas driving the national "crisis"--access, cost, and quality--do not encompass minority-specific healthcare strategies.


Developing Familiarity in a New Duo: Rehearsal Talk and Performance Cues.
Context and Aims: Social and cognitive processes underlying individual classical musicians' and duo performers' preparation for performance have been explored using longitudinal case studies. Social processes can be inferred from rehearsal talk and recent studies have focused on its content and nature. Cognitive processes can be inferred from score annotations representing musicians' thoughts while practicing, rehearsing (rehearsal features), and playing or singing from memory (performance cues). We report three studies conducted by two practitioner-researchers: (1) of rehearsal talk; (2) of rehearsal features and thoughts while performing; and (3) a triangulation (as it were) of the two kinds of data to gauge the potential for rehearsal talk to predict the use of performance cues. Methods: A singer and viola player formed a new duo to prepare two songs, new to them both, for two performances on the same day and a third performance 10 months later. Their practice and rehearsal sessions, over the course of seven days, were recorded and transcribed. The musicians annotated copies of the scores after rehearsing and after each performance. Each musician performed one of the two songs from memory. First, verbal data were coded and analyzed using two frameworks for categorizing socio-emotional interactions and musical dimensions, respectively. Second, their annotations were categorized and compared, and finally the frameworks were combined so that correlations between rehearsal talk and performance cues could be calculated. Results: The musicians' verbal interactions were positive and task-related; significant changes over time were observed only in the extent to which they showed solidarity toward each other. Analysis of their annotations illustrates similarities and differences between their attention to specific features of the music while rehearsing and performing, particularly from memory. Rehearsal talk predicted performance cues in the third performance, but not the first or second. Conclusion: Musicians' talk cannot be assumed to reflect musicians' actions. The study of musicians' verbal interactions may be less useful for determining cognitive than social processes underlying preparation for performance. Nevertheless, the study provides a detailed snapshot of classical musicians' "real world" preparation for performance, highlighting the role of spontaneity in performance, and underlining differences between what happens in the studio and what can happen on stage.


Self-assessed outcome at two to four years after shoulder hemiarthroplasty with concentric glenoid reaming.
Active and young individuals with glenohumeral arthritis who are treated with total glenohumeral arthroplasty are at risk for loosening or wear of the prosthetic glenoid component. This study tests the hypothesis that patients with severe glenohumeral arthritis have improvement in self-assessed shoulder comfort and function at two to four years after treatment with the combination of humeral hemiarthroplasty and concentric glenoid reaming without tissue or prosthetic component interposition. Thirty-seven consecutive patients (thirty-eight shoulders), with a mean age of fifty-seven years, who were managed by one surgeon were enrolled in this prospective study. The procedure consisted of an uncemented humeral hemiarthroplasty combined with reaming of the glenoid to a diameter 2 mm larger than that of the prosthetic humeral head. The duration of follow-up ranged from two to four years (average, 2.7 years) for thirty-five shoulders. Self-assessed comfort and function was documented with use of the Simple Shoulder Test, and radiographs were evaluated. Thirty-two shoulders demonstrated improved comfort and function according to patient self-assessment, one demonstrated no change, and two had worse function following the procedure. The total number of Simple Shoulder Test functions that could be performed increased from 4.7 (of a possible 12.0) before surgery to 9.4 at the time of the final follow-up. The patients demonstrated significant improvement in ten of the twelve individual functions of the Simple Shoulder Test (p < 0.022 to p < 0.00001). With the numbers studied, gender, diagnosis, age, glenoid wear, and preoperative glenoid erosion did not significantly affect final shoulder function or overall improvement. The range of motion was significantly improved for all individuals (p < 0.00001). Radiographically, twenty-two patients had a joint space between the glenoid bone and the humeral prosthesis at the time of final follow-up. These shoulders had significantly better function than those without a preserved joint space (p < 0.017). There were no surgical complications and no revisions to total shoulder arthroplasty. At a minimum follow-up of two years, a selected series of patients who had humeral hemiarthroplasty with concentric glenoid reaming for the treatment of glenohumeral arthritis showed significant improvement in self-assessed shoulder comfort and function. Further study, however, is needed before routine application of this procedure can be recommended. Therapeutic Level IV.


The hard road to data interpretation: 3 or 6 months of adjuvant chemotherapy for patients with stage III colon cancer?
Six months of adjuvant oxaliplatin-based chemotherapy is standard for patients with stage III colon cancer following surgery. However, oxaliplatin is associated with peripheral neurotoxicity which worsens over treatment duration. Consequently, a shorter treatment duration, if equally effective, would be extremely beneficial. A pooled analysis of data for 12 834 stage III colon cancer patients, from six randomised phase III trials of adjuvant therapy, the International Duration Evaluation of Adjuvant chemotherapy study, was carried out and the results presented at the ASCO Annual Meeting 2017. To clarify the potential impact of these results on clinical practice, ESMO decided to sponsor a special session at their 2017 Annual Meeting dedicated to achieving a more meaningful interpretation of the results. Medical oncologists from Europe, the United States and Asia selected for their involvement in the trials, together with an independent statistician and an independent clinician, were invited to provide their independent interpretations of the results and contribute to a moderated panel discussion. The pooled analysis evaluated the non-inferiority of 3 versus 6 months of adjuvant FOLFOX/CAPOX therapy but not the non-inferiority of 3 months CAPOX versus 6 months FOLFOX therapy. There was strong evidence of an interaction between the choice of regimen (CAPOX or FOLFOX) and duration of treatment. Patients were classified as either 'fighters' or 'fatalists', and 3-month CAPOX was considered standard for patients classified as fatalists even if they had high-risk disease. However, patients classified as 'fighters' would only receive 3 months of CAPOX if they had low-risk disease but would always receive 6 months of CAPOX/FOLFOX if they had T4 disease. The panel was split on whether they would advocate 3 or 6 months CAPOX therapy based on high-risk N2 disease. The main drivers of the duration of treatment were choice of regimen and patient attitude, with risk, based mainly on T4 stage, having less influence.


Double duty for Rac1 in epidermal wound healing.
During cutaneous wound healing, increased proliferation and migration of epidermal keratinocytes is essential for efficient re-epithelialization of the wound and restoration of barrier function to the skin. Although numerous cell culture studies have identified intracellular signaling proteins that control proliferation and migration in response to extracellular cues from the wound microenvironment, confirming their importance in wound healing requires appropriate in vivo models. The Rho-family guanosine triphosphatase (GTPase) Rac1 is an effector of cellular responses to growth factors, cytokines, and adhesion proteins present in wounds, and it has long been suspected to be an important regulator of wound healing. Two different genetic models now confirm an essential role for Rac1 in wound healing and, further, identify a dual role for Rac1 in promoting keratinocyte migration and proliferation during wound re-epithelialization. This sets the stage for determining which of the known Rac1 pathways are critical for wound repair in vivo and for linking these pathways to specific integrin or growth factor receptors that mediate cellular responses to cues from the wound environment. Together with studies that implicate Rac1 in maintaining epidermal stem cell populations, these findings lay the foundation for identifying distinct epidermal compartments from which Rac1 controls different aspects of wound re-epithelialization.


Hallucinogens and dissociative agents naturally growing in the United States.
It is usually believed that drugs of abuse are smuggled into the United States or are clandestinely produced for illicit distribution. Less well known is that many hallucinogens and dissociative agents can be obtained from plants and fungi growing wild or in gardens. Some of these botanical sources can be located throughout the United States; others have a more narrow distribution. This article reviews plants containing N,N-dimethyltryptamine, reversible type A monoamine oxidase inhibitors (MAOI), lysergic acid amide, the anticholinergic drugs atropine and scopolamine, or the diterpene salvinorin-A (Salvia divinorum). Also reviewed are mescaline-containing cacti, psilocybin/psilocin-containing mushrooms, and the Amanita muscaria and Amanita pantherina mushrooms that contain muscimol and ibotenic acid. Dangerous misidentification is most common with the mushrooms, but even a novice forager can quickly learn how to properly identify and prepare for ingestion many of these plants. Moreover, through the ever-expanding dissemination of information via the Internet, this knowledge is being obtained and acted upon by more and more individuals. This general overview includes information on the geographical range, drug content, preparation, intoxication, and the special health risks associated with some of these plants. Information is also offered on the unique issue of when bona fide religions use such plants as sacraments in the United States. In addition to the Native American Church's (NAC) longstanding right to peyote, two religions of Brazilian origin, the Santo Daime and the Uniao do Vegetal (UDV), are seeking legal protection in the United States for their use of sacramental dimethyltryptamine-containing "ayahuasca."


Five-Year Real-World Outcomes of Occult and Classic Choroidal Neovascularization: Data From the Fight Retinal Blindness! Project.
To compare 5-year real-world outcomes of eyes with classic and occult choroidal neovascularization (CNV) treated with anti-vascular endothelial growth factor (anti-VEGF) injections. Retrospective analysis from a prospectively designed observational database. Treatment-naïve eyes diagnosed with occult or minimally or predominantly classic CNV that commenced anti-VEGF treatment between January 2007 and December 2012 were identified from a registry of neovascular age-related macular degeneration (nAMD) treatment outcomes. Baseline characteristics, visual acuity (VA) at 5 years, change in VA, time to first inactivation, number of injections, and proportion of visits graded with active nAMD over the 5 years were compared between the 3 groups. A total of 1929 eyes from 1730 subjects (1196 occult, 289 minimally classic, and 444 predominantly classic CNV) were analyzed. Baseline VA (mean [standard deviation]) was higher in occult CNVs (56.9 [17.4] letters) than in minimally (52.9 [19.7] letters) and predominantly (49.1 [19.9] letters) classic CNVs (P = .003 and P < .0001, respectively). VA change was similar across the groups. At 5 years eyes with occult CNVs still had better VA than other CNVs. Age, lesion size, and baseline VA, but not CNV type, significantly affected final VA in the multivariate model. Predominantly classic CNVs became inactive sooner and were overall less active than other CNV types. The number of injections received was similar across the groups. Eyes with occult CNVs had overall a better VA than other CNVs. The difference in final VA was not significant after adjusting for baseline VA. Five-year outcomes and treatment patterns were not affected by the lesion type.


3D-CT anatomy for VATS segmentectomy.
Segmentectomy has become a widely adopted surgical procedure, with recent reports describing the use of video-assisted thoracoscopic surgery (VATS) and robotic surgery. A major feature of segmentectomy is that it requires a three-dimensional (3D) understanding of the patient's pulmonary structure and a thorough preoperative analysis of the patient's individual anatomy. Here, we present our method for VATS segmentectomy based on 3D-computed tomography (3D-CT), with a review of the literature. We focus on techniques for 3D-CT reconstruction, analyses of the individual anatomy and anomalies, preoperative simulations of the procedure and surgical margin, and intraoperative navigation with 3D-CT images. We also reference the roles of members of our multi-disciplinary surgical team.


The Effects of Textured Insoles on Cortical Activity and Quiet Bipedal Standing With and Without Vision: An EEG Study.
Wearing textured insoles (TIs) can reduce static postural sway, but the neurophysiological mechanisms by which these changes occur are not well understood. To address this issue, cortical activity was investigated in this study using electroencephalography (EEG) recordings from 19 scalp locations, in 15 healthy young adults (5 females; mean age = 27 ± 4.09 years) during quiet bipedal standing, under different insole conditions (textured versus smooth), with and without vision. Compared to smooth insoles (SIs), TIs significantly reduced postural sway in two measures; anterior-posterior range and standard deviation. In the EEG data, whole-head analyses showed cortical activity in the upper alpha power band was significantly reduced for textured compared to SIs. Exploratory analyses revealed this effect was significant both with and without vision, and was more pronounced over the parietal, compared to central regions, and over central compared to frontal regions. This trend was observed in low alpha and theta bands, but the effect of insole type was not significant. Textured insoles thus appear to affect not only balance outcomes but also cortical activity. The cortical activity adaptation may represent greater information becoming readily available at the cortical level, enhancing the representation of the body in space.


Implications of stroke for caregiver outcomes: findings from the ASPIRE-S study.
Informal caregivers are vital to the long-term care and rehabilitation of stroke survivors worldwide. However, caregiving has been associated with negative psychological outcomes such as anxiety and depression, which leads to concerns about caregiver as well as stroke survivor well-being. Furthermore, caregivers may not receive the support and service provision they require from the hospitals and community. This study examines caregiver psychological well-being and satisfaction with service provision in the context of stroke. Caregiver data were collected as part of the ASPIRE-S study, a prospective study of secondary prevention and rehabilitation which assessed stroke patients and their carers at six-months post stroke. Carer assessment included measurement of demographics, satisfaction with care (UK Healthcare Commission National Patient Survey of Stroke Care), psychological distress (Hospital Anxiety and Depression Scale), and vulnerability (Vulnerable Elders Scale). Logistic regression analyses and chi-squared tests were performed using stata version 12. Analyses from 162 carers showed substantial levels of dissatisfaction (37·9%) with community and hospital services, as well as notable levels of anxiety (31·3%) and depressive symptoms (18·8%) among caregivers. Caregiver anxiety was predicted by stroke survivor anxiety (OR = 3·47, 95% CI 1·35-8·93), depression (OR = 5·17, 95% CI 1·83-14·58), and stroke survivor cognitive impairment (OR 2·35, 95% CI 1·00-5·31). Caregiver depression was predicted by stroke survivor anxiety (OR = 4·41, 95% CI 1·53-12·72) and stroke survivor depression (OR = 6·91, 95% CI 2·26-21·17). Findings indicate that caregiver and stroke survivor well-being are interdependent. Thus, early interventions, including increased training and support programs that include caregivers, are likely to reduce the risk of negative emotional outcomes.


Genetic association analysis of complex diseases incorporating intermediate phenotype information.
Genetic researchers often collect disease related quantitative traits in addition to disease status because they are interested in understanding the pathophysiology of disease processes. In genome-wide association (GWA) studies, these quantitative phenotypes may be relevant to disease development and serve as intermediate phenotypes or they could be behavioral or other risk factors that predict disease risk. Statistical tests combining both disease status and quantitative risk factors should be more powerful than case-control studies, as the former incorporates more information about the disease. In this paper, we proposed a modified inverse-variance weighted meta-analysis method to combine disease status and quantitative intermediate phenotype information. The simulation results showed that when an intermediate phenotype was available, the inverse-variance weighted method had more power than did a case-control study of complex diseases, especially in identifying susceptibility loci having minor effects. We further applied this modified meta-analysis to a study of imputed lung cancer genotypes with smoking data in 1154 cases and 1137 matched controls. The most significant SNPs came from the CHRNA3-CHRNA5-CHRNB4 region on chromosome 15q24-25.1, which has been replicated in many other studies. Our results confirm that this CHRNA region is associated with both lung cancer development and smoking behavior. We also detected three significant SNPs--rs1800469, rs1982072, and rs2241714--in the promoter region of the TGFB1 gene on chromosome 19 (p = 1.46×10(-5), 1.18×10(-5), and 6.57×10(-6), respectively). The SNP rs1800469 is reported to be associated with chronic obstructive pulmonary disease and lung cancer in cigarette smokers. The present study is the first GWA study to replicate this result. Signals in the 3q26 region were also identified in the meta-analysis. We demonstrate the intermediate phenotype can potentially enhance the power of complex disease association analysis and the modified meta-analysis method is robust to incorporate intermediate phenotype or other quantitative risk factor in the analysis.


Dehydroepiandrosterone (DHEA) supplementation for cognitive function .
In view of the theoretical rationale for beneficial effects of DHEA and DHEAS on cognitive function in ageing and dementia, we have undertaken a thorough investigation of well-conducted studies in this area. This will provide a basis for confirmation of any effect of DHEA/S administration in humans in properly controlled trials. The review will also provide a scientific basis for effective dosage, acceptable route and duration of administration, and side effect profiles. This review is especially pertinent at this time as DHEA is currently being sold in large quantities in health food stores, particularly in the USA. In some cases the recommended dose is different for men and women (50mg/day for men and 25mg/day for women) and the basis for this recommendation needs to be explored. To establish whether administration of DHEA, or its sulphate, DHEAS, improves cognitive function or reduces the rate of decline of cognitive function in normal older adults or in individuals with dementia. Relevant electronic databases, journals, personal communications and conference abstracts were searched for randomised controlled trials investigating the effects of DHEA/S on cognition in older adults. All relevant randomised controlled trials of DHEA/S were considered for inclusion in the review. Data for the specified outcomes were independently extracted by two reviewers (FAH & JvN) and cross-checked. Any discrepancies were discussed and resolved. No data pooling was undertaken owing to the lack of availability of the relevant statistics. There are four included studies, three cognition in normal older people, and Barnhart 1999 in perimenopausal women with decreased well-being. There were no studies in dementia. There were a few significant findings. Wolf 1997 found significant improvement following DHEA compared with placebo in both immediate recall (MD 0.8, 95% CI 0.16, 1.44) and delayed recall (MD 0.9, 95% CI 0.09, 1.71) of a visual memory test in women, estimated in a crossover trial after 2 weeks of treatment with each of DHEA and placebo. However there was no significant improvement in men, nor a significant effect on a verbal memory test. There was also no significant effect on four other cognitive tests. Wolf 1998 (2) found that placebo group performance deteriorated significantly on a test of selective attention following a psychosocial stressor (p<0.05), while deterioration was not evident in the DHEA group (p=0.85) after two weeks of treatment. However, when compared to placebo, DHEA produced a significant impairment on a visual memory test (p<0.01) following the stressor. No significant effect was found on a third cognitive task. Effects were not found on tasks when administered in the absence of a stressor. Barnhart 1999 employed three cognitive measures and found no significant effect of DHEA compared with placebo at 3 months. Findings to date suggest that DHEA replacement seems to be well tolerated with an absence of significant side-effects. The data offer no support at present for an improvement in memory or other aspects of cognitive function following DHEA treatment in normal older people. In view of the growing public enthusiasm for DHEA supplementation, particularly in the USA, and the possibility that any neuroprotective effect of DHEA/S may only be evident in the long term, there is a need to undertake high quality trials in which the duration of DHEA treatment is longer than one year, and the number of participants is large enough to detect effects if they exist. Recently, trials of DHEA supplementation in Alzheimer's Disease (USA), post-menopausal women (USA), normal older men (UK), and a one-year trial in normal older men and women (France) have been completed. As soon as the results are available these studies will be included in the review.


Multiple magnon modes and consequences for the Bose-Einstein condensed phase in BaCuSi2O6.
The compound BaCuSi2O6 is a quantum magnet with antiferromagnetic dimers of S=1/2 moments on a quasi-2D square lattice. We have investigated its spin dynamics by inelastic neutron scattering experiments on single crystals with an energy resolution considerably higher than in an earlier study. We observe multiple magnon modes, indicating clearly the presence of magnetically inequivalent dimer sites. The more complex spin Hamiltonian revealed in our study leads to a distinct form of magnon Bose-Einstein condensate phase with a spatially modulated condensate amplitude.


Disproportionate cardiac hypertrophy during early postnatal development in infants born preterm.
BackgroundAdults born very preterm have increased cardiac mass and reduced function. We investigated whether a hypertrophic phenomenon occurs in later preterm infants and when this occurs during early development.MethodsCardiac ultrasound was performed on 392 infants (33% preterm at mean gestation 34±2 weeks). Scans were performed during fetal development in 137, at birth and 3 months of postnatal age in 200, and during both fetal and postnatal development in 55. Cardiac morphology and function was quantified and computational models created to identify geometric changes.ResultsAt birth, preterm offspring had reduced cardiac mass and volume relative to body size with a more globular heart. By 3 months, ventricular shape had normalized but both left and right ventricular mass relative to body size were significantly higher than expected for postmenstrual age (left 57.8±41.9 vs. 27.3±29.4%, P<0.001; right 39.3±38.1 vs. 16.6±40.8, P=0.002). Greater changes were associated with lower gestational age at birth (left P<0.001; right P=0.001).ConclusionPreterm offspring, including those born in late gestation, have a disproportionate increase in ventricular mass from birth up to 3 months of postnatal age. These differences were not present before birth. Early postnatal development may provide a window for interventions relevant to long-term cardiovascular health.


Homogenization of freshwater lakes: Recent compositional shifts in fish communities are explained by gamefish movement and not climate change.
Globally, lake fish communities are being subjected to a range of scale-dependent anthropogenic pressures, from climate change to eutrophication, and from overexploitation to species introductions. As a consequence, the composition of these communities is being reshuffled, in most cases leading to a surge in taxonomic similarity at the regional scale termed homogenization. The drivers of homogenization remain unclear, which may be a reflection of interactions between various environmental changes. In this study, we investigate two potential drivers of the recent changes in the composition of freshwater fish communities: recreational fishing and climate change. Our results, derived from 524 lakes of Ontario, Canada sampled in two periods (1965-1982 and 2008-2012), demonstrate that the main contributors to homogenization are the dispersal of gamefish species, most of which are large predators. Alternative explanations relating to lake habitat (e.g., area, phosphorus) or variations in climate have limited explanatory power. Our analysis suggests that human-assisted migration is the primary driver of the observed compositional shifts, homogenizing freshwater fish community among Ontario lakes and generating food webs dominated by gamefish species.


The Relationship between caffeine and coffee consumption and exfoliation glaucoma or glaucoma suspect: a prospective study in two cohorts.
We examined the association between caffeine and caffeinated beverage consumption in relation to the risk of exfoliation glaucoma or exfoliation glaucoma suspect (EG/EGS). We followed 78,977 women from the Nurses' Health Study (NHS) and 41,202 men from the Health Professionals Follow-up Study (HPFS) who were at least 40 years of age, did not have glaucoma, and reported undergoing eye examinations from 1980 (NHS) or 1986 (HPFS) to 2008. Information on consumption of caffeine-containing beverages and potential confounders were repeatedly ascertained in validated follow-up questionnaires. Confirmation with medical record review revealed 360 incident EG/EGS cases. Multivariate rate ratios (RRs) for EG/EGS were calculated in each cohort and then pooled using meta-analytic techniques. Compared with participants whose cumulatively updated total caffeine consumption was <125 mg/day, participants who consumed ≥ 500 mg/day had a trend toward increased risk of EG/EGS that was not statistically significant (RR = 1.43; 95% confidence interval [CI], 0.98-2.08); P trend = 0.06). Compared to abstainers, those who drank ≥ 3 cups of caffeinated coffee daily were at increased risk of EG/EGS (RR = 1.66; 95% CI, 1.09-2.54; P trend = 0.02). These results were not materially altered after adjustment for total fluid intake. Associations were stronger among women with a family history of glaucoma (P interaction = 0.06 for coffee; P interaction = 0.03 for caffeine). We did not find associations with consumption of other caffeinated products (caffeinated soda, caffeinated tea, decaffeinated coffee or chocolate) and risk of EG/EGS (P trend ≥ 0.31). We observed a positive association between heavier coffee consumption with risk of EG/EGS in this large prospective study.


Bioactive chemicals from carrot (Daucus carota) juice extracts for the treatment of leukemia.
Overwhelming evidence indicates that consumption of fruits and vegetables with antioxidant properties correlates with reduced risk for cancers, including leukemia. Carrots contain beneficial agents, such as β-carotene and polyacetylenes, which could be effective in the treatment of leukemia. This study investigated the effect of carrot juice extracts on myeloid and lymphoid leukemia cell lines together with normal hematopoietic stem cells. Leukemia cell lines and nontumor control cells were treated with carrot juice extracts for up to 72 hours in vitro. Induction of apoptosis was investigated by using annexin V/propidium iodide staining followed by flow cytometric analysis, and results were confirmed by using 4'-6-diamidino-2-phenylindole morphology. Effects on cellular proliferation were investigated via cell cycle analysis and cell counts. Treatment of leukemia cell lines with carrot juice extract induced apoptosis and inhibited progression through the cell cycle. Lymphoid cell lines were affected to a greater extent than were myeloid cell lines, and normal hematopoietic stem cells were less sensitive than most cell lines. This study has shown that extracts from carrots can induce apoptosis and cause cell cycle arrest in leukemia cell lines. The findings suggest that carrots may be an excellent source of bioactive chemicals for the treatment of leukemia.


Reinterpretation of a previously described Jehol bird clarifies early trophic evolution in the Ornithuromorpha.
STM35-3 from the Yixian Formation is the only Early Cretaceous ornithuromorph preserving direct evidence of granivory. The crop contains numerous seeds and the preservation of gastroliths presumably within the ventriculus indicates this diet was paired with the presence of a gastric mill as in living granivorous birds. STM35-3 was originally referred to Hongshanornis longicresta, member of a diverse clade of small, basal ornithuromorphs with elongate hindlimbs known as the Hongshanornithidae. Hindlimb proportions suggest that hongshanornithids were wading birds, an ecological inference somewhat in conflict with direct evidence suggesting Hongshanornis fed on seeds. However, close inspection of STM35-3 reveals that the specimen represents a new species not closely related to hongshanornithids, distinguished by large forelimbs that exceed the length of the hindlimbs, robust and narrow coracoids, and a delicate edentulous rostrum. By contrast, all hongshanornithids have hindlimbs that far exceed the length of the forelimbs, coracoids with wide sternal margins, and small teeth throughout the upper and lower jaws. Reinterpretation of this new taxon, Eogranivora edentulata gen. et sp. nov, helps to clarify trophic driven patterns of tooth loss within the Ornithuromorpha. Apparent loss of the hallux may represent the first such occurrence in a Mesozoic bird and suggests a highly terrestrial lifestyle.


Retrospective evaluation of revised criteria for the diagnosis of Alzheimer's disease using a cohort with post-mortem diagnosis.
The criteria currently used to diagnose Alzheimer's disease (AD) require the presence of dementia, i.e. cognitive impairment sufficient to affect normal social and/or occupational function. Dubois et al. (Dubois et al., 2007) have recently proposed a set of revised criteria that may aid the diagnosis of the earlier stages of AD, and do not require the presence of dementia. We aimed to evaluate the new predementia-AD criteria through their retrospective application to the OPTIMA cohort with post-mortem (PM) confirmed diagnoses. The criteria were evaluated for sensitivity and specificity using cognitive, neuroimaging and cerebrospinal fluid data and clinical information for exclusion criteria. Limitations in choice of cognitive test, use of CT scans rather than MRI and missing CSFs affected the outcomes. Analyses were carried out for the whole cohort (n = 243) and on a mild-stage subgroup (n = 99) defined by MMSE ≥ 21. Of the four options for fulfilling the revised-criteria, the best results for the whole cohort were achieved using memory and CSF data with exclusion criteria applied (.68 sensitivity and .93 specificity). The pattern was similar for the mild cohort, but with lower sensitivity. Specificities of 1.0 were reached with supportive criteria, CSF and CSF plus MTL. The revised-criteria, when applied to our cohort, offer good specificity and reasonable sensitivity when compared with the gold standard of PM diagnosis. The criteria were not more effective for early stage dementia.


Improving quality in clinical placement studies in nursing homes (QUALinCLINstud): the study protocol of a participatory mixed-methods multiple case study design.
Improved quality in clinical supervision and assessment of student nurses in nursing home clinical placements is vitally important to effective recruitment and preparation for this healthcare sector. Knowledge regarding supervision and assessment practices within these settings is limited. Also, knowledge of evolving e-learning tools on the quality and effectiveness of these educational practices seems to be absent. The aim of the "Improving quality in clinical placement studies in nursing homes" (QUALinCLINstud) study is to develop and evaluate how a web-based programme can optimise supervision, assessment and learning during nursing home placements. The study applies a participatory, mixed-methods case study design, organised in four work packages (WPs). WP1 will explore how the nurse education institution address the quality of student nurses' clinical placements in nursing homes. In WP2, clinical supervision and assessment practices will be explored, and described from multiple stakeholder perspectives. In WP3, based on the findings from WP1 and WP2, a web-based pedagogical supervision and assessment programme will be developed through a developmental co-productive process between nurse education institutions, practice settings and student nurses. In WP4, the web-based programme will be pilot-tested and evaluated through a mixed-methods approach. A range of data collection procedures will be used throughout the project, for example, questionnaires, interviews, observations and workshops. The ethical conduct of the study is approved by the Norwegian Centre for Research Data (2018/61309 and 489776). The results will be disseminated through scientific articles, three PhD theses, presentations at national and international conferences, and through publicly accessible trade journals and newspapers. The results will generate knowledge to inform supervision and assessment practices in nursing home placements. Moreover, the study will generate knowledge concerning the developmental process of a web-based supervision and assessment programme, and the value of e-learning tools applied in clinical nursing education.


Clauberg's eponym and crimes against humanity.
Scientific journals are ethically bound to cite Professor Dr. Carl Clauberg's Nazi medical crimes against humanity whenever the eponym Clauberg is used. Modern articles still publish the eponym citing only the rabbit bioassy used in developing progesterone agonists or antagonists for birth control. Clauberg's Nazi career is traced to his having subjected thousands of Jewish women at the Ravensbruck and Auschwitz-Birkenau death camps to cruel, murderous sterilization experiments that are enthusiastically described by incriminating letters (reproduced here) between him and the notorious Nazi Reichsführer-SS Heinrich Himmler. The experiments were carried out in women's block 10 in Auschwitz-Birkenau where Clauberg's colleague Dr. Josef Mengele worked alongside. After Germany lost World War II in 1945 Mengele fled to South America, where he lived to an old age. Clauberg was caught by Russian soldiers, put on trial in the Soviet Union for his crimes against humanity, and imprisoned in 1948. In 1955 he was repatriated to Germany, once again imprisoned for his crimes, and belatedly expelled from the German Medical Association. To estimate the contemporary usage of the names Mengele and Clauberg, Internet hits were recorded for Clauberg C or Mengele J (with and without adding the term Auschwitz) with the Google and Scirus search engines. The ratios of hits for combinations of these terms reveal that relative to Mengele, Clauberg's name is barely known. We propose that journals and books printing the eponym Clauberg cite its derivation and reference to the convicted Nazi criminal. The present article can serve for such citations.


Secondary allergic T cell responses are regulated by dendritic cell-derived thrombospondin-1 in the setting of allergic eye disease.
Allergic eye disease, as in most forms of atopy, ranges in severity among individuals from immediate hypersensitivity to a severe and debilitating chronic disease. Dendritic cells play a key role in stimulating pathogenic T cells in allergen re-exposure, or secondary responses. However, molecular cues by dendritic cells underpinning allergic T cell response levels and the impact that this control has on consequent severity of allergic disease are poorly understood. Here, we show that a deficiency in thrombospondin-1, a matricellular protein known to affect immune function, has subsequent effects on downstream T cell responses during allergy, as revealed in an established mouse model of allergic eye disease. More specifically, we demonstrate that a thrombospondin-1 deficiency specific to dendritic cells leads to heightened secondary T cell responses and consequent clinical disease. Interestingly, whereas thrombospondin-1-deficient dendritic cells augmented activity of allergen-primed T cells, this increase was not recapitulated with naïve T cells in vitro. The role of dendritic cell-derived thrombospondin-1 in regulating secondary allergic T cell responses was confirmed in vivo, as local transfer of thrombospondin-1-sufficient dendritic cells to the ocular mucosa of thrombospondin-1 null hosts prevented the development of augmented secondary T cell responses and heightened allergic eye disease clinical responses. Finally, we demonstrate that topical instillation of thrombospondin-1-derived peptide reduces T cell activity and clinical progression of allergic eye disease. Taken together, this study reveals an important modulatory role of dendritic cell-derived thrombospondin-1 on secondary allergic T cell responses and suggests the possible dysregulation of dendritic cell-derived thrombospondin-1 expression as a factor in allergic eye disease severity.


Vitamin B6 and immune competence.
Animal and human studies suggest that vitamin B6 deficiency affects both humoral and cell-mediated immune responses. Lymphocyte differentiation and maturation are altered by deficiency, delayed-type hypersensitivity responses are reduced, and antibody production may be indirectly impaired. Although repletion of the vitamin restores these functions, megadoses do not produce benefits beyond those observed with moderate supplementation. Additional human studies indicate that vitamin B6 status may influence tumor growth and disease processes. Deficiency of the vitamin has been associated with immunological changes observed in the elderly, persons infected with human immunodeficiency virus (HIV), and those with uremia or rheumatoid arthritis. Future research efforts should focus on establishing the mechanism underlying the effects of vitamin B6 on immunity and should attempt to establish safe intake levels that optimize immune response.


Evaluation of claims-based computable phenotypes to identify heart failure patients with preserved ejection fraction.
The purpose of this analysis was to develop and validate computable phenotypes for heart failure (HF) with preserved ejection fraction (HFpEF) using claims-type measures using the Rochester Epidemiology Project. This retrospective study utilized an existing cohort of Olmsted County, Minnesota residents aged ≥ 20 years diagnosed with HF between 2007 and 2015. The gold standard definition of HFpEF included meeting the validated Framingham criteria for HF and having an LVEF ≥ 50%. Computable phenotypes of claims-type data elements (including ICD-9/ICD-10 diagnostic codes and lab test codes) both individually and in combinations were assessed via sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) with respect to the gold standard. In the Framingham-validated cohort, 2,035 patients had HF; 1,172 (58%) had HFpEF. One in-patient or two out-patient diagnosis codes of ICD-9 428.3X or ICD-10 I50.3X had 46% sensitivity, 88% specificity, 84% PPV, and 54% NPV. The addition of a BNP/NT-proBNP test code reduced sensitivity to 35% while increasing specificity to 91% (PPV = 84%, NPV = 51%). Broadening the diagnostic codes to ICD-9 428.0, 428.3X, and 428.9/ICD-10 I50.3X and I50.9 increased sensitivity at the expense of decreasing specificity (diagnostic code-only model: 87% sensitivity, 8% specificity, 56% PPV, 30% NPV; diagnostic code and BNP lab code model: 61% sensitivity, 43% specificity, 60% PPV, 45% NPV). In an analysis conducted to mimic real-world use of the computable phenotypes, any one in-patient or out-patient code of ICD-9 428/ICD-10 150 among the broader population (N = 3,755) resulted in lower PPV values compared with the Framingham cohort. However, one in-patient or two out-patient instances of ICD-9 428.0, 428.9, or 428.3X/ICD-10 150.3X or 150.9 brought the PPV values from the two cohorts closer together. While some misclassification remains, the computable phenotypes defined here may be used in claims databases to identify HFpEF patients and to gain a greater understanding of the characteristics of patients with HFpEF.