Calreticulin variant stratified driver mutational status and prognosis in essential thrombocythemia.
About 85% of patients with essential thrombocythemia (ET) harbor one of three driver mutations: JAK2, calreticulin (CALR), and MPL; the remaining ( ∼15%) are wild type for all three mutations and are referred to as being "triple negative." Furthermore, CALR mutations in ET are structurally classified as type 1/type 1-like or type 2/type 2-like variants. The objective of the current study was to examine the impact of CALR mutation variant stratified driver mutational status on overall (OS), myelofibrosis-free (MFFS), thrombosis-free, and leukemia-free survival (LFS) in ET; 495 patients (median age 58 years; 61% females) with ET were fully annotated for the their driver mutational status: 321 (65%) harbored JAK2, 109 (22%) CALR, and 12 (2%) MPL mutations and 11% were triple-negative. Among the 109 CALR-mutated cases, 52% were classified as type 1/type 1-like and 48% as type 2/type 2-like. In univariate analysis, triple-negative patients displayed the best and MPL mutated the worst OS (P = 0.007); however, the difference in OS was no longer apparent on multivariable analysis that included age and sex as covariates (P = 0.5). LFS was also similar among the different mutational groups (P = 0.6) whereas MFFS was significantly shorter in MPL-mutated patients on both univariate and multivariable analyses (age-adjusted P = 0.02; HR 7.9, 95% CI 2.0-31.5). Also in multivariable analysis that included thrombosis history, age, and cardiovascular risk factors, the presence of JAK2 or MPL mutations was independently associated with higher risk of thrombosis (P = 0.02; HR 1.9, 95% CI 1.1-3.4). In conclusion, driver mutational status in ET does not appear to influence overall or LFS, even after CALR variant stratification. However, the presence of MPL mutations might be associated with a higher risk of fibrotic transformation and the presence of JAK2/MPL mutations with higher risk of thrombosis.


Outcomes of Unconstrained Proximal Interphalangeal Joint Arthroplasty: A Systematic Review.
Background: Unconstrained pyrocarbon and metal-on-polyethylene (MoP) proximal interphalangeal (PIP) joint arthroplasty is an increasingly popular alternative to silicone implants and arthrodesis. This systematic review appraises their outcomes. Methods: 30 studies comprising 1,324 joints (813 pyrocarbon, 511 MoP) were included. Mean patient age was 59 years (38 to 78) and mean follow-up period was 54 months (1.2 to 380). Results: There were mean improvements of 4.5 points (2 to 6.9) in pain Visual Analogue Score, 10.5° (-26 to 58) in range of motion (ROM), 3.1 kg (-4 to 7) in grip strength, 0.6 kg (-1.5 to 2) in pinch strength, and 18 points (-3 to 29) in the Disabilities of the Arm, Shoulder and Hand score, with no significant differences between implant types. ROM gains, in particular, deteriorated over time. Clinical complications were frequent (23%), and significantly more common with pyrocarbon, as were radiographic complications. However, most were mild-moderate and did not necessarily correlate with negative outcomes or dissatisfaction. Overall reoperation rate was 21%, and revision rate 11%, both more frequent with pyrocarbon. Most revisions were within 24 months, beyond which survival was maintained up to ten years. Conclusions: Unconstrained PIP joint arthroplasty is effective at improving pain scores, active ROM, grip/pinch strength, and patient reported outcome measures, particularly in patients with osteoarthritis. Results are generally maintained at least to the medium term, although gains diminish in the longer term. Complication and early revision rates are high, particularly with pyrocarbon implants. The majority of patients express positive attitudes to arthroplasty, with significant improvements in patient-reported outcome measures for both pyrocarbon and MoP implants. Patients with post-traumatic and inflammatory arthropathy are generally less satisfied. There is currently insufficient data to recommend one implant type over another, although the early-to-medium term results of MoP implants are promising. Prospective surveillance via small joint registries is recommended.


Public engagement on ethical principles in allocating scarce resources during an influenza pandemic.
To investigate the views of students, support staff and academic staff at the University of Alberta in Edmonton, Canada on the allocation of scarce resources during an influenza pandemic to discover if there were any shared values. A web-based questionnaire was circulated to students, support staff and academic staff asking them how they would rank the priority of eleven different groups for access to scarce resources. They were also asked to select one of seven priority access plans. The highest priority was given to health care workers by 89% of respondents, closely followed by emergency workers (85%). Only 12.7% of respondents gave politicians high priority. Respondents favored the "Save the most lives" priority access (39.9%) (N=5220). Current policies in place for the allocation of scarce resources during an influenza pandemic may not properly reflect the views of the general public. Further public consultation should be undertaken in order to uncover how they would allocate scarce resources.


Protein kinase Cbeta selective inhibitor LY333531 attenuates diabetic hyperalgesia through ameliorating cGMP level of dorsal root ganglion neurons.
Streptozocin (STZ)-induced diabetic rats show hyperalgesia that is partially attributed to altered protein kinase C (PKC) activity. Both attenuated neuronal nitric oxide synthase (nNOS)-cGMP system and tetrodotoxin-resistant (TTX-R) Na channels in dorsal root ganglion neurons may be involved in diabetic hyperalgesia. We examined whether PKCbeta inhibition ameliorates diabetic hyperalgesia and, if so, whether the effect is obtained through action on neurons by testing nociceptive threshold in normal and STZ-induced diabetic rats treated with or without PKCbeta-selective inhibitor LY333531 (LY) and by assessing the implication of LY in either nNOS-cGMP system or TTX-R Na channels of isolated dorsal root ganglion neurons. The decreased nociceptive threshold in diabetic rats was improved either after 4 weeks of LY treatment or with a single intradermal injection into the footpads. The treatment of LY for 6 weeks significantly decreased p-PKCbeta and ameliorated a decrease in cGMP content in dorsal root ganglia of diabetic rats. The latter effect was confirmed in ex vivo condition. The treatment with NO donor for 4 weeks also normalized both diabetic hyperalgesia and decreased cGMP content in dorsal root ganglions. The expressions of nNOS and TTX-R Na channels were not changed with LY treatment. These results suggest that LY is effective for treating diabetic hyperalgesia through ameliorating the decrease in the nNOS-cGMP system.


One Health Approach to Address Zoonotic Diseases.
The world of animals, humans, and environment is interlinked, giving rise to a number of benefits as well as a spread in zoonosis and multifactorial chronic diseases. With the emergence of antimicrobial resistances and environmental pollution, addressing these diseases needs an interdisciplinary and intersectoral expertise. "One Health (OH)" refers to such collaboration between local, national, and global experts from public health, health care, forestry, veterinary, environmental, and other related disciplines to bring about optimal health for humans, animals, and environment. The concept of OH is still in embryonic stage in India and increasingly gaining importance. The Government of India has taken some initiatives to tackle burgeoning problems such as antimicrobial resistance, zoonotic diseases, and food safety using the OH approach, but there are several challenges at the level of implementation. The major bottlenecks in implementing OH include absence of a legal framework to implement OH, poor coordination among different governmental and private agencies, lack of proper surveillance of animal diseases, poor data-sharing mechanism across sectors, and limited budget. Implementing systematic zoonotic surveillance; regulated antibiotic use among humans and animals; development of a zoonotic registry in the country; constitution of a wide network of academic, research, pharmaceutical, and various implementation stakeholders from different sectors is the need of the hour to effectively use OH in order to combat increasing zoonotic diseases.


Examining the associations among severity of injunctive drinking norms, alcohol consumption, and alcohol-related negative consequences: the moderating roles of alcohol consumption and identity.
This study examined a range of injunctive norms for alcohol use and related consequences from less severe behaviors (e.g., drinking with friends) to more severe behaviors (e.g., drinking enough alcohol to pass out), and their relationship with alcohol consumption and alcohol-related negative consequences among college students. In addition, this research aimed to determine whether these relationships between injunctive norms and consequences were moderated by alcohol consumption and level of identification with the typical same-gender college student. A random sample (N = 1,002) of undergraduates (56.9% women) completed a Web-based survey that was comprised of measures of drinking behavior, perceived approval of drinking behaviors that ranged in severity (i.e., injunctive norms), and level of identification with the typical same-gender college student. Results suggest that the association between negative consequences and injunctive drinking norms depend on one's own drinking behavior, identification with other students, and the severity of the alcohol use and related consequences for which injunctive norms are assessed. Findings are discussed in terms of false consensus and false uniqueness effects, and deviance regulation perspectives. Implications for preventive interventions are discussed.


Secondary structure and 1H, 15 N & 13C resonance assignments of the periplasmic domain of OutG, major pseudopilin from Dickeya dadantii type II secretion system.
The ability to interact and adapt to the surrounding environment is vital for bacteria that colonise various niches and organisms. One strategy developed by Gram-negative bacteria is to secrete exoprotein substrates via the type II secretion system (T2SS). The T2SS is a proteinaceous complex spanning the bacterial envelope that translocates folded proteins such as toxins and enzymes from the periplasm to the extracellular milieu. In the T2SS, a cytoplasmic ATPase elongates in the periplasm the pseudopilus, a non-covalent polymer composed of protein subunits named pseudopilins, and anchored in the inner membrane by a transmembrane helix. The pseudopilus polymerisation is coupled to the secretion of substrates. The T2SS of Dickeya dadantii secretes more than 15 substrates, essentially plant cell wall degrading enzymes. In D. dadantii, the major pseudopilin or the major subunit of the pseudopilus is called OutG. To better understand the mechanism of secretion of these numerous substrates via the pseudopilus, we have been studying the structure of OutG by NMR. Here, as the first part of this study, we report the 1H, 15N and 13C backbone and sidechain chemical shift assignment of the periplasmic domain of OutG and its NMR derived secondary structure.


Understanding clinician connections to inform efforts to promote high-quality inflammatory bowel disease care.
Highly connected individuals disseminate information effectively within their social network. To apply this concept to inflammatory bowel disease (IBD) care and lay the foundation for network interventions to disseminate high-quality treatment, we assessed the need for improving the IBD practices of highly connected clinicians. We aimed to examine whether highly connected clinicians who treat IBD patients were more likely to provide high-quality treatment than less connected clinicians. We used network analysis to examine connections among clinicians who shared patients with IBD in the Veterans Health Administration between 2015-2018. We created a network comprised of clinicians connected by shared patients. We quantified clinician connections using degree centrality (number of clinicians with whom a clinician shares patients), closeness centrality (reach via shared contacts to other clinicians), and betweenness centrality (degree to which a clinician connects clinicians not otherwise connected). Using weighted linear regression, we examined associations between each measure of connection and two IBD quality indicators: low prolonged steroids use, and high steroid-sparing therapy use. We identified 62,971 patients with IBD and linked them to 1,655 gastroenterologists and 7,852 primary care providers. Clinicians with more connections (degree) were more likely to exhibit high-quality treatment (less prolonged steroids beta -0.0268, 95%CI -0.0427, -0.0110, more steroid-sparing therapy beta 0.0967, 95%CI 0.0128, 0.1805). Clinicians who connect otherwise unconnected clinicians (betweenness) displayed more prolonged steroids use (beta 0.0003, 95%CI 0.0001, 0.0006). The presence of variation is more relevant than its magnitude. Clinicians with a high number of connections provided more high-quality IBD treatments than less connected clinicians, and may be well-positioned for interventions to disseminate high-quality IBD care. However, clinicians who connect clinicians who are otherwise unconnected are more likely to display low-quality IBD treatment. Efforts to improve their quality are needed prior to leveraging their position to disseminate high-quality care.


Network-Derived Radioresistant Breast Cancer Target with Candidate Inhibitors from Brown Algae: A Sequential Assessment from Target Selection to Quantum Chemical Calculation.
Despite significant progress in early detection and treatment, a few aggressive breast cancers still exhibit resistance to therapy. This study aimed to identify a therapeutic target for radioresistant breast cancer (RRbc) through a protein network from breast cancer genes and to evaluate potent phytochemicals against the identified target. Our approach includes the integration of differential expression genes from expression datasets to create a protein network and to use survival analysis to identify the crucial RRbc protein in order to discover a therapeutic target. Next, the phytochemicals sourced from brown algae were screened through molecular docking, ADME (absorption, distribution, metabolism, and excretion), molecular dynamics (MD) simulation, MM-GBSA, and quantum mechanics against the identified target. As a result of our protein network investigation, the proto-oncogene c-KIT (KIT) protein was identified as a potent radioresistant breast cancer target. Further, phytochemical screening establishes that nahocol-A1 from brown algae has high binding characteristics (-8.56 kcal/mol) against the KIT protein. Then, quantum chemical analysis of nahocol-A1 provided insights into its electronic properties favorable for protein binding. Also, MD simulation comprehends the conformational stability of the KIT-nahocol-A1 complex. Overall, our findings suggest nahocol-A1 could serve as a promising therapeutic candidate for radioresistant breast cancer.


An Improved InSAR Image Co-Registration Method for Pairs with Relatively Big Distortions or Large Incoherent Areas.
Co-registration is one of the most important steps in interferometric synthetic aperture radar (InSAR) data processing. The standard offset-measurement method based on cross-correlating uniformly distributed patches takes no account of specific geometric transformation between images or characteristics of ground scatterers. Hence, it is inefficient and difficult to obtain satisfying co-registration results for image pairs with relatively big distortion or large incoherent areas. Given this, an improved co-registration strategy is proposed in this paper which takes both the geometric features and image content into consideration. Firstly, some geometric transformations including scale, flip, rotation, and shear between images were eliminated based on the geometrical information, and the initial co-registration polynomial was obtained. Then the registration points were automatically detected by integrating the signal-to-clutter-ratio (SCR) thresholds and the amplitude information, and a further co-registration process was performed to refine the polynomial. Several comparison experiments were carried out using 2 TerraSAR-X data from the Hong Kong airport and 21 PALSAR data from the Donghai Bridge. Experiment results demonstrate that the proposed method brings accuracy and efficiency improvements for co-registration and processing abilities in the cases of big distortion between images or large incoherent areas in the images. For most co-registrations, the proposed method can enhance the reliability and applicability of co-registration and thus promote the automation to a higher level.


Dopamine release from nigral transplants visualized in vivo in a Parkinson's patient.
Synaptic dopamine release from embryonic nigral transplants has been monitored in the striatum of a patient with Parkinson's disease using [11C]-raclopride positron emission tomography to measure dopamine D2 receptor occupancy by the endogenous transmitter. In this patient, who had received a transplant in the right putamen 10 years earlier, grafts had restored both basal and drug-induced dopamine release to normal levels. This was associated with sustained, marked clinical benefit and normalized levels of dopamine storage in the grafted putamen. Despite an ongoing disease process, grafted neurons can thus continue for a decade to store and release dopamine and give rise to substantial symptomatic relief.


[Combined litholytic therapy of urate nephrolithiasis].
The authors present the analysis of therapy of 72 patients under 70 years of age (40 males - 55.6%, 32 females - 44.4%) with urate nephrolithiasis. Recurrent nephrolithiasis occurred in 51 (70.8%) patients, metabolic disturbances were registered in 38 (52.8%) patients. Efficacy of litholytic therapy with blemoren was 58.3%. In the rest cases the concrements were removed by extracorporeal shock-wave lithotripsy (ESWL). The authors believe that in concrements more than 2 cm in size ESWL should be made in the presence of internal stent, while litholytic therapy prior to ESWL improves treatment results even if ineffectiveness of the former.


Aluminum elution and precipitation in glass vials: effect of pH and buffer species.
Inorganic extractables from glass vials may cause particle formation in the drug solution. In this study, the ability of eluting Al ion from borosilicate glass vials, and tendencies of precipitation containing Al were investigated using various pHs of phosphate, citrate, acetate and histidine buffer. Through heating, all of the buffers showed that Si and Al were eluted from glass vials in ratios almost the same as the composition of borosilicate glass, and the amounts of Al and Si from various buffer solutions at pH 7 were in the following order: citrate > phosphate > acetate > histidine. In addition, during storage after heating, the Al concentration at certain pHs of phosphate and acetate buffer solution decreased, suggesting the formation of particles containing Al. In citrate buffer, Al did not decrease in spite of the high elution amount. Considering that the solubility profile of aluminum oxide and the Al eluting profile of borosilicate glass were different, it is speculated that Al ion may be forced to leach into the buffer solution according to Si elution on the surface of glass vials. When Al ions were added to the buffer solutions, phosphate, acetate and histidine buffer showed a decrease of Al concentration during storage at a neutral range of pHs, indicating the formation of particles containing Al. In conclusion, it is suggested that phosphate buffer solution has higher possibility of forming particles containing Al than other buffer solutions.


Prevention of Herpes Zoster: A Focus on the Effectiveness and Safety of Herpes Zoster Vaccines.
Infection with varicella zoster virus typically occurs in children and it can cause primary varicella infection or "chickenpox", or it can reactivate later in life and cause herpes zoster or "shingles". Herpes zoster mainly occurs in older adults, causing a reduction in activities of daily living, impacting quality of life, and may lead to serious complications, including chronic pain. Two vaccines are marketed to prevent herpes zoster: the live zoster vaccine and the non-live, recombinant zoster vaccine. The pre-licensure clinical trials show the efficacy of the live zoster vaccine to be between 50 and 70% and for the recombinant vaccine to be higher at 90 to 97%. Real-world effectiveness studies, with a follow-up of approximately 10 years, were reviewed in this article. These data corroborated the efficacy studies, with vaccine effectiveness being 46% and 85% for the live and recombinant vaccines, respectively. Safety data from the effectiveness studies show similar results to the clinical trials with mostly local injection-site reactions and mild systemic reactions seen with both vaccines, although in larger proportions with the recombinant vaccine. Rare adverse events, occurring less than 1% of the time, have been seen with both vaccine types and include disseminated herpes zoster with the live zoster vaccine and Guillain-Barré syndrome with the recombinant vaccine. The wider use of preventative measures with vaccines will reduce the herpes zoster burden of illness seen in older adults.


Inhibition of interleukin-1beta-stimulated production of matrix metalloproteinases by hyaluronan via CD44 in human articular cartilage.
To investigate the mechanism of the inhibitory action of hyaluronan (HA) on interleukin-1beta (IL-1beta)-stimulated production of matrix metalloproteinases (MMPs) in human articular cartilage. IL-1beta was added to normal and osteoarthritic (OA) human articular cartilage in explant culture to stimulate MMP production. Articular cartilage was incubated or preincubated with a clinically used form of 800-kd HA to assess its effect on IL-1beta-induced MMPs. Levels of secreted MMPs 1, 3, and 13 in conditioned media were detected by immunoblotting; intracellular MMP synthesis in chondrocytes was evaluated by immunofluorescence microscopy. Penetration of HA into cartilage tissue and its binding to CD44 were analyzed by fluorescence microscopy using fluoresceinated HA. Blocking experiments with anti-CD44 antibody were performed to investigate the mechanism of action of HA. Treatment and pretreatment with 800-kd HA at 1 mg/ml resulted in significant suppression of IL-1beta-stimulated production of MMPs 1, 3, and 13 in normal and OA cartilage explant culture. Fluorescence histocytochemistry revealed that HA penetrated cartilage tissue and localized in the pericellular matrix around chondrocytes. HA-binding blocking experiments using anti-CD44 antibody demonstrated that the association of HA with chondrocytes was mediated by CD44. Preincubation with anti-CD44 antibody, which suppressed IL-1beta-stimulated MMPs, reversed the inhibitory effect of HA on MMP production that was induced by IL-1beta in normal and OA cartilage. This study demonstrates that HA effectively inhibits IL-1beta-stimulated production of MMP-1, MMP-3, and MMP-13, which supports the clinical use of HA in the treatment of OA. The action of HA on IL-1beta may involve direct interaction between HA and CD44 on chondrocytes.


State-of-the-Art Computations of Vertical Ionization Potentials with the Extended Koopmans' Theorem Integrated with the CCSD(T) Method.
The accurate computation of ionization potentials (IPs), within 0.10 eV, is one of the most challenging problems in modern computational chemistry. The extended Koopmans' theorem (EKT) provides a systematic direct approach to compute IPs from any level of theory. In this study, the EKT approach is integrated with the coupled-cluster singles and doubles with perturbative triples [CCSD(T)] method for the first time. For efficiency, the density-fitting (DF) approximation is employed for electron repulsion integrals. Further, the EKT-CCSD(T) method is applied to a set of 23 molecules, denoted as IP23, for comparison with the experimental ionization potentials. For the IP23 set, the EKT-CCSD(T) method, along with the aug-cc-pV5Z basis set, provides a mean absolute error of 0.05 eV. Hence, our results demonstrate that direct computations of IPs at high-accuracy levels can be achieved with the EKT-CCSD(T) method. We believe that the present study may open new avenues in IP computations.


Alteration in urinary matrix metalloproteinase-9 to tissue inhibitor of metalloproteinase-1 ratio predicts recurrence in nonmuscle-invasive bladder cancer.
The purpose is to assess the prognostic significance of matrix metalloproteinase (MMP)-9 in patients with bladder cancer using a combination of ELISA (to measure MMP-9 in voided urine) and immunohistochemistry (to study MMP-9 in bladder tumors). The relationship between MMP-9 and its principal inhibitor, tissue inhibitor of metalloproteinase (TIMP)-1 (in voided urine samples) was also studied. A total of 134 patients with bladder tumors (7 cis, 76 T(a), 27 T(1), 24 T(2)-T(4); 40 G1, 43 G2, and 44 G3), 33 patients with benign urological conditions, and 36 healthy volunteers was studied. Samples from 106 patients with bladder cancer and 12 controls were stained for MMP-9. Clinical follow-up data were available on 116 patients (median: 25 months; range: 4-36 months). MMP-9 was present in all urine samples analyzed. There were no differences between patients with cancer and patients with benign disorders. However, patients had significantly higher urinary MMP-9 than normal volunteers (P = 0.0167). Urinary MMP-9 was associated with bladder tumors of advanced stage (P = 0.0065) and large size (P < 0.0001) but not with grade (P = 0.14), multiplicity (P = 0.31), recurrence (P = 0.55), progression (P = 0.83), or survival (P = 0.55). Low MMP-9:TIMP-1 ratios in patients with nonmuscle-invasive tumors were associated with higher recurrence rates (P = 0.0035). Sixty percent (64 of 106) of bladder tumor specimens expressed MMP-9 compared with none of 12 normal urothelial biopsies (P < 0.0001). MMP-9 staining was associated with tumor size (P = 0.014), disease progression (P = 0.005), and poor disease-specific survival (P = 0.022) but was unrelated to tumor stage (P = 0.46), grade (P = 0.26), multiplicity (P = 0.85), or recurrence rate (P = 0.62). High urinary MMP-9 levels are associated with large bladder tumors. A low urinary MMP-9:TIMP-1 ratio may indicate a higher risk of intraluminal nonmuscle-invasive tumor recurrence and may assist in planning follow-up surveillance protocols.


Alpha interferon inhibits early stages of the human immunodeficiency virus type 1 replication cycle.
In this study, we have analyzed the effect of human alpha interferon (IFN-alpha) on a single replication cycle of human immunodeficiency virus type 1 (HIV-1) infection in the lymphocytic cell line CEM-174, which is highly sensitive to the antiviral effects of IFN. Pretreatment of cells with 50 to 500 U of recombinant human IFN-alpha per ml resulted in a marked reduction in viral RNA and protein synthesis. The effect of IFN-alpha was dose dependent and was amplified in multiple infection cycles. IFN-induced inhibition of viral protein synthesis could be detected only when cells were treated with IFN-alpha prior to infection or when IFN-alpha was added up to 10 h postinfection, but not if IFN-alpha was added at the later stages of HIV-1 replication cycle or after the HIV-1 infection was already established. Analysis of the integrated HIV-1 provirus showed a marked decrease in the levels of proviral DNA in IFN-treated cells. Thus, in contrast to the previous studies on established HIV-1 infection in T cells, in which the IFN block appeared to be at the posttranslational level, during de novo infection, IFN-alpha interferes with an early step of HIV-1 replication cycle that occurs prior to the integration of the proviral DNA. These results indicate that the early IFN block of HIV-1 replication, which has been previously observed only in primary marcophages, can also be detected in the IFN-sensitive T cells, indicating that the early IFN block is not limited to macrophages.


A soluble protein related to the HER-2 proto-oncogene product is released from human breast carcinoma cells.
Amplified expression of p185HER-2, the protein product of the HER-2/neu proto-oncogene, appears to be involved in carcinogenesis of human mammary epithelial cells. Our data suggest that an extracellular 130 Kda glycoprotein released from breast carcinoma cells may be related to the ectodomain of p185HER-2: (1) Both cellular p185HER-2 and extracellular p130, when reduced and alkylated, reacted with antipeptide antibody against the N-terminus of the HER-2 protein [alpha N(HER-21)] and reactivity was blocked by cognate peptide; (2) Neither p130 nor other extracellular proteins reacted with antiserum against the C-terminus of p185HER-2 [alpha C(HER-2)]; (3) Partial proteolysis of p185HER-2 generated an immunoreactive fragment of 130 kDa that was similar to extracellular p130; (4) Both p130 and p185HER-2 contained carbohydrate that bound to Con-A Sepharose; (5) The amount of p130 released from breast cells corresponded to the levels of expression of cellular p185HER-2. Release of the ectodomain of p185HER-2 from breast carcinoma cells may be involved in their malignant growth and may be a useful marker for assessing the expression of p185HER-2 in human tumors.


Preventive care in the emergency department: diagnosis and management of smoking and smoking-related illness in the emergency department: a systematic review.
Smoking remains the leading preventable cause of morbidity and mortality in the United States. The efficacy of emergency department (ED)-based patient screening and counseling for smoking cessation is not currently known. To perform a structured, systematic review of the medical literature to assess the efficacy of limited screening and counseling for tobacco use cessation among adults in the primary care and ED settings, and develop recommendations for emergency physicians based on these data. A two-person template-driven review of all English-language articles from Medline, the Cochrane Database, and two recent smoking cessation guidelines, with evidence graded according to the scheme of the U.S. Preventive Services Task Force (USPSTF), was performed. Recommendations were developed, and strength graded, based on this evidence. Of 2,078 citations reviewed, 16 were selected for inclusion, based on their methodologic strength and relevance to emergency medicine. Routine physician screening and counseling may increase quit rates at 6-12 months from 3% (usual care) to 8-11%. Interventions include brief counseling (<3 minutes), possibly supplemented with self-help literature, nicotine replacement therapy (NRT), and follow-up telephone calls. Strong evidence exists, in the primary care setting, that smoking cessation screening and counseling are effective. Limited data exist for ED-based practice, but, based on the burden of disease, relative ease of intervention, and likely efficacy, routine screening of all patients for tobacco use and referral of smokers to primary care and cessation programs are recommended.


Bilateral recurrent orbital inflammation associated with retroperitoneal fibrosclerosis.
Orbital inflammation initially presented in a patient who five years later developed renal obstruction from retroperitoneal fibrosclerosis. Biopsy revealed infiltration of chronic lymphocytic cells in the orbit and dense fibrous connective tissue in the pelvis. Episodes of proptosis were controlled with systemic steroids and non-steroidal anti-inflammatory agents. The hydronephrosis was relieved by intraperitonisation of the ureters. Similarities to previously reported cases are discussed. This case shows the importance of searching for systemic disease in patients with orbital inflammatory disease and informing the patients of the possibility of future systemic manifestations of their disease.


Parent-child conversations about literacy: a longitudinal, observational study.
Conversations about literacy-related matters with parents can help prepare children for formal literacy instruction. We studied these conversations using data gathered from fifty-six US families as they engaged in daily activities at home. Analyzing conversations when children were aged 1;10, 2;6, 3;6, and 4;2, we found that explicit talk about the elements and processes of reading and writing occurred even when children were less than two years old and became more common as children grew older. The majority of literacy-related conversations included talk about alphabet letters. Literacy-related conversations occurred in a variety of contexts, not only book-reading. There were few differences as a function of family socioeconomic status in the proportion of utterances during the sessions that occurred in literacy-related conversations. At older ages, however, children in families of lower socioeconomic status bore more of the conversational burden than children in families of higher status.


Local languages, the succesor method, and a step towards a general methodology for the inference of regular grammars.
A methodology is proposed for the inference of regular grammars from positive samples of their languages. It is mainly based on the generative mechanism associated with local languages, which allows us to obtain arbitrary regular languages by applying morphic operators to local languages. The actual inference procedure of this methodology consists of obtaining a local language associated with the given positive sample. This procedure, which is very simple, is always the same, regardless of the problem considered, while the task-dependent features that are desired for the inferred languages, are specified through the definition of certain task-appropriate symbol renaming functions (morphisms).


IgE-mediated asthma and rhinitis I: a role of allergen exposure?
Exposures to airborne protein antigens, aeroallergens, may cause sensitization with production of Th2-dependent antibodies, including IgE. The IgE antibodies and associated cellular responses are responsible for the allergic airway diseases, allergic rhinitis and allergic asthma, which are increasing in societies with Western life style. Aeroallergens may have different potential to sensitize exposed subjects. Thus, there are only a limited number of important groups of aeroallergens, which are those from house dust mites, cockroaches, pets, pollens, and moulds. Allergy follows to a certain extent the pharmacological/toxicological paradigm of dose-response relationship. Unlike effects of pharmacologically and toxicologically active substances, allergens elicit their adverse effects in a two-stage process. In the first stage the immunologically naïve individual is sensitized to the allergen. In the second stage renewed exposure to the allergen elicits the disease response. Also, high concentrations of aeroallergens may induce immunological tolerance. The scientific literature suggests that many environmental factors contribute to the increase in sensitization and development of airway allergies. Nevertheless, the dose-response relationships apply (within certain limits) both to the sensitization itself and to the exacerbation of the diseases. This suggest that exposure reduction may be one of the methods for reduction of risk, in relation to control of the allergic airway diseases.


Factors associated with and impact of burnout in nursing and residential home care workers for the elderly.
Numbers of elderly people worldwide continue to grow. Increasingly these individuals require nursing and residential care to meet their needs. Nursing is an occupation associated with burnout amongst its workforce, associated with increases of emotional exhaustion, depersonalisation and decreases in personal accomplishment. This review of literature provides a more detailed picture of the associations and predictors of burnout within this setting, and also considers the implications this holds for patient care, before providing recommendations for managers of such settings. Literature searches were conducted across a range of academic databases with a series of relevant keywords. Examination of search results suggested several factors relating to staff burnout including occupational aspects, types of setting, staff perceptions, coping strategies, education and training and the impact of burnout on care delivery. Studies from across the globe suggest that burnout is prevalent amongst staff working in nursing and residential homes caring for elderly people, with implications for the patients, staff and homecare providers. Factors associated with burnout appear to include perceptions of job stress and occupational aspects, as well as the types of coping mechanisms staff employ. Managing grief associated with death of patients at work, as well as staff perceptions of both clients and their illnesses also appear related to burnout as well as the specific type of healthcare setting.


The implications of vitamin D deficiency on COVID-19 for at-risk populations.
Novel coronavirus disease 2019 (COVID-19) has spread to > 10 000 000 individuals in a short time. With no pharmacological agents successfully implemented to control the outbreak, the use of less invasive nonpharmacological agents, such as vitamin D, are increasingly being studied. This purpose of this article is to determine the current knowledge about the risk of COVID-19 development for populations at risk for vitamin D deficiency, including individuals living with overweight and obesity, those of older age, and racial or ethnic minorities. Despite the documented impact of vitamin D on viral disease prevention, many subgroups at risk for contracting COVID-19 are also known to have increased rates of vitamin D deficiency. Because vitamin D is most commonly obtained from sunlight, when interpreted alongside the stay-at-home orders, the importance of identifying safe approaches to obtain sufficient vitamin D is apparent. Furthermore, elucidating the cause-and-effect relationship between vitamin D and COVID-19, including optimal dosing for COVID-19 outcomes, is also warranted for immediate investigation.


Determinants of early versus late cardiac death in patients undergoing coronary artery bypass graft surgery.
Most analyses of risk factors affecting survival after coronary artery bypass graft surgery have not differentiated among factors that influence early and late survival. For this reason, a multiphase model was applied to survival data from 2,967 patients undergoing a first coronary artery bypass graft at the Duke University Medical Center between 1969 and 1984. There were 709 deaths during follow-up to 19.6 years. The data were analyzed using a multivariable survival model that separates the underlying hazard function into as much as three different phases, each incorporating separate risk factors. Two distinct phases were detected. One phase dominated early survival (0-1 year), and the second phase dominated late survival (greater than 1 year). Surgery performed earlier in our experience was associated with elevated risk of dying in both phases but with different magnitudes, whereas lower ejection fraction, greater extent of coronary disease, older age, conduction abnormality, and history of hypertension were associated with elevated risk of dying similarly in both phases (p less than 0.05). Severity of angina symptoms and lower weight were associated with an elevated risk of dying only in the early phase (p less than 0.05; because few of the patients were obese, estimates of the relative risk of morbid obesity could not be estimated), whereas vascular disease, diabetes, and extent of myocardial damage were associated with an elevated risk of dying only in the late phase (p less than 0.05). These data illustrate both the differential influence of risk factors over time and the importance of multiphase models.


Metrics and textural features of MRI diffusion to improve classification of pediatric posterior fossa tumors.
Qualitative radiologic MR imaging review affords limited differentiation among types of pediatric posterior fossa brain tumors and cannot detect histologic or molecular subtypes, which could help to stratify treatment. This study aimed to improve current posterior fossa discrimination of histologic tumor type by using support vector machine classifiers on quantitative MR imaging features. This retrospective study included preoperative MRI in 40 children with posterior fossa tumors (17 medulloblastomas, 16 pilocytic astrocytomas, and 7 ependymomas). Shape, histogram, and textural features were computed from contrast-enhanced T2WI and T1WI and diffusivity (ADC) maps. Combinations of features were used to train tumor-type-specific classifiers for medulloblastoma, pilocytic astrocytoma, and ependymoma types in separation and as a joint posterior fossa classifier. A tumor-subtype classifier was also produced for classic medulloblastoma. The performance of different classifiers was assessed and compared by using randomly selected subsets of training and test data. ADC histogram features (25th and 75th percentiles and skewness) yielded the best classification of tumor type (on average >95.8% of medulloblastomas, >96.9% of pilocytic astrocytomas, and >94.3% of ependymomas by using 8 training samples). The resulting joint posterior fossa classifier correctly assigned >91.4% of the posterior fossa tumors. For subtype classification, 89.4% of classic medulloblastomas were correctly classified on the basis of ADC texture features extracted from the Gray-Level Co-Occurence Matrix. Support vector machine-based classifiers using ADC histogram features yielded very good discrimination among pediatric posterior fossa tumor types, and ADC textural features show promise for further subtype discrimination. These findings suggest an added diagnostic value of quantitative feature analysis of diffusion MR imaging in pediatric neuro-oncology.


Separation of signal transduction and adaptation functions of the aspartate receptor in bacterial sensing.
In order to investigate the functions of stimulus recognition, signal transduction, and adaptation, the aspartate receptor gene for bacterial chemotaxis in Salmonella typhimurium has been sequenced and modified. A carboxyl-terminal truncated receptor was shown to bind aspartate and to transmit a signal to change motility behavior. However, the truncated receptor showed greatly reduced methyl-accepting capacity, and did not allow adaptation to the sensory stimulation. The separation of receptor functions by alteration of primary structure emphasizes that the receptor is directly involved in adaptation and is not solely a device for transmitting a signal across a membrane.


Wearable Activity Trackers That Motivate Women to Increase Physical Activity: Mixed Methods Study.
Physical inactivity is a significant public health concern, particularly among women in the United States. Wearable activity trackers (WATs) have been proposed as a potential solution to increase awareness of and engagement in physical activity (PA). However, to be effective, WATs must include features and designs that encourage daily use. This study aims to explore the features and designs of WATs that appeal to women and determine whether devices with these attributes are effective motivators for women to be physically active. A mixed methods study guided by the self-determination theory was conducted among 15 women. Participants trialed 3 WATs with influence in their respective accessory domains: Apple Watch for the wrist; Oura Ring for the finger; and Bellabeat Leaf Urban for multiple sites (it can be worn as a bracelet, necklace, or clip). Participants documented their daily PA levels and rated their satisfaction with each device's comfort, features, and motivational effect. Focus groups were also conducted to gather additional feedback and experiences within the a priori areas of comfort, features, and motivation. Behavioral Regulation in Exercise Questionnaire-2 scores indicated that most participants (14/15, 93%) were motivated at baseline (amotivation score: mean 0.13, SD 0.45), but on average, participants did not meet the national minimum PA guidelines according to the self-reported Physical Activity Vital Sign questionnaire (moderate to vigorous PA score: mean 144, SD 97.5 min/wk). Mean WAT wear time was 16.9 (SD 4.4) hours, 19.4 (SD 5.3) hours, and 20.4 (SD 4.7) hours for Apple Watch, Bellabeat Leaf Urban, and Oura Ring, respectively. During focus groups, participants reinforced their quantitative ratings and rankings of the WATs based on personal experiences. Participants shared a variety of both activity-related and non-activity-related features that they look for in a motivating device. When considering what the ideal WAT would be for a woman, participants suggested features of (1) comfort, (2) extended battery life, (3) durability, (4) immediate PA feedback, (5) intuitive PA sensing, and (6) programmability. This study is the first to specifically address women's experiences with and preferences for different types of WATs. Those who work with women should realize how they view WATs and the role they play in motivation to be active.


Tensor-based Feature Extraction for Pupil Recognition in Cataract Surgery.
Cataract surgery remains the definitive treatment for cataracts, which are a major cause of preventable blindness worldwide. Adequate and stable dilation of the pupil are necessary for the successful performance of cataract surgery. Pupillary instability is a known risk factor for cataract surgery complications, and the accurate segmentation of the pupil from surgical video streams can enable the analysis of intraoperative pupil changes in cataract surgery. However, pupil segmentation performance can suffer due to variations in surgical illumination, obscuration of the pupil with surgical instruments, and hydration of the lens material intraoperatively. To overcome these challenges, we present a novel method called tensor-based pupil feature extraction (TPFE) to improve the accuracy of pupil recognition systems. We analyzed the efficacy of this approach with experiments performed on a dataset of 4,560 intraoperative annotated images from 190 cataract surgeries in human patients. Our results indicate that TPFE can identify features relevant to pupil segmentation and that pupil segmentation with state-of-the-art deep learning models can be significantly improved with the TPFE method.


Gluten-free diet improves iron-deficiency anaemia in patients with coeliac disease.
Two cases of newly-diagnosed asymptomatic coeliac disease with 3 years of unexplained severe iron-deficiency anaemia are presented. Oral iron supplementation had no effect on their serum iron levels and, therefore, had no influence on their anaemia. Upper gastrointestinal endoscopy confirmed normal macroscopic findings. Duodenal biopsies revealed subtotal villous atrophy of the mucosa of the small intestine. A strict gluten-free diet led to an increase in serum iron, resolution of anaemia, and restitution of normal mucosal morphology. Thus, severe iron-deficiency anaemia associated with asymptomatic coeliac disease is responsible to gluten-free diet.


Quantification of [18F]DPA-714 binding in the human brain: initial studies in healthy controls and Alzheimer's disease patients.
Fluorine-18 labelled N,N-diethyl-2-(2-[4-(2-fluoroethoxy)phenyl]-5,7-dimethylpyrazolo[1,5-α]pyrimidine-3-yl)acetamide ([(18)F]DPA-714) binds to the 18-kDa translocator protein (TSPO) with high affinity. The aim of this initial methodological study was to develop a plasma input tracer kinetic model for quantification of [(18)F]DPA-714 binding in healthy subjects and Alzheimer's disease (AD) patients, and to provide a preliminary assessment whether there is a disease-related signal. Ten AD patients and six healthy subjects underwent a dynamic positron emission tomography (PET) study along with arterial sampling and a scan protocol of 150 minutes after administration of 250 ± 10 MBq [(18)F]DPA-714. The model that provided the best fits to tissue time activity curves (TACs) was selected based on Akaike Information Criterion and F-test. The reversible two tissue compartment plasma input model with blood volume parameter was the preferred model for quantification of [(18)F]DPA-714 kinetics, irrespective of scan duration, volume of interest, and underlying volume of distribution (VT). Simplified reference tissue model (SRTM)-derived binding potential (BPND) using cerebellar gray matter as reference tissue correlated well with plasma input-based distribution volume ratio (DVR). These data suggest that [(18)F]DPA-714 cannot be used for separating individual AD patients from healthy subjects, but further studies including TSPO binding status are needed to substantiate these findings.


[Measurement of left atrial and ventricular volumes in real-time 3D echocardiography. Validation by nuclear magnetic resonance].
The measurement of the left ventricular ejection fraction is important for the evaluation of cardiomyopathy and depends on the measurement of left ventricular volumes. There are no existing conventional echocardiographic means of measuring the true left atrial and ventricular volumes without mathematical approximations. The aim of this study was to test anew real time 3-dimensional echocardiographic system of calculating left atrial and ventricular volumes in 40 patients after in vitro validation. The volumes of the left atrium and ventricle acquired from real time 3-D echocardiography in the apical view, were calculated in 7 sections parallel to the surface of the probe and compared with atrial (10 patients) and ventricular (30 patients) volumes calculated by nuclear magnetic resonance with the simpson method and with volumes of water in balloons placed in a cistern. Linear regression analysis showed an excellent correlation between the real volume of water in the balloons and volumes given in real time 3-dimensional echocardiography (y = 0.94x + 5.5, r = 0.99, p < 0.001, D = -10 +/- 4.5 ml). A good correlation was observed between real time 3-dimensional echocardiography and nuclear magnetic resonance for the measurement of left atrial and ventricular volumes (y = 0.95x - 10, r = 0.91, p < 0.001, D = -14.8 +/- 19.5 ml and y = 0.87x + 10, r = 0.98, P < 0.001, D = -8.3 +/- 18.7 ml, respectively. The authors conclude that real time three-dimensional echocardiography allows accurate measurement of left heart volumes underlying the clinical potential of this new 3-D method.


Dysregulation of arcuate nucleus preproneuropeptide Y mRNA in diet-induced obese rats.
Neuropeptide Y (NPY) neurons in the hypothalamic arcuate nucleus (ARC) produce metabolic and physiological effects that promote the development and maintenance of obesity. In turn, NPY metabolism in these neurons is inhibited by dopamine release. In this study, ARC prepro-NPY mRNA and ARC/median eminence (ME) dopamine turnover were assessed in chow-fed male Sprague-Dawley rats prone to develop diet-induced obesity (DIO) or to be diet resistant (DR) when fed a high-energy (HE) diet. By in situ hybridization, DIO-prone rats had 39% more ARC NPY mRNA expression than DR-prone rats under chow-fed conditions. DIO-prone rat ARC/ME dopamine levels were 14% higher, but dopamine half-life was 176% longer and turnover was 59% less than DR-prone rats. Neither a 48-h fast nor 50% energy intake restriction for 5 days affected the already increased ARC NPY mRNA levels in DIO-prone rats. Both manipulations increased NPY expression to the level of DIO-prone rats in DR-prone rats by 23 and 35%, respectively. Finally, when fed HE diet for 2 wk, neither DIO- nor DR-prone rats altered their ARC NPY expression despite the development of obesity and hyperinsulinemia in DIO rats. Thus DIO-prone rats overexpress and fail to regulate ARC NPY mRNA to energy restriction or hyperinsulinemia. This dysregulation is possibly secondary to reduced inhibition because of defective ARC/ME dopamine turnover. Both may be important predisposing factors in the development of DIO.


[Complement fixation activity of immunoglobulin G in ethylene glycol solutions].
Affinity of IgG to the first complement factor C1q was found out to increase in 10-30% glycol solutions. Analytical ultracentrifugation and turbidity data showed that IgG molecules do not aggregate at such concentrations of glycol. The complement-binding effect may be caused by a conformational transition in the IgG molecules.


Interaction of the prostaglandin and renin-angiotensin systems in isolated rat glomeruli.
Renal glomeruli were isolated from rat kidneys using a passive mechanical sieving technique. Suspensions of 40-50 mg glomeruli were placed in glass chambers and superfused by a modified Krebs-Ringer solution. Effluent collections of 10-min fractions were measured for renin or prostaglandin (PG) E2 concentration using radioimmunoassays. The perfusate was altered to contain either the beta-adrenergic agonist isoproterenol, angiotensin II, or arachidonic acid. Isoproterenol at 1.78 or 8.1 X 10(-4) M produced a significant release of renin, but the concentration of PGE2 was unaffected. Isoproterenol-stimulated renin release was blocked by 1.2 X 10(-4) M propranolol but was unaffected by 6.3 X 10(-6) M meclofenamate. Angiotensin II at 4 or 40 X 10(-9) M altered neither renin nor PGE2. Arachidonic acid administered at 1.6 or 16.0 X 10(-5) M produced a marked increase in PG synthesis and stimulated a significant release of renin. Treatment of glomeruli with 6.3 X 10(-6) M meclofenamate attenuated PGE2 synthesis and abolished renin release, but 1.2 X 10(-4) M propranolol had no effect on PG synthesis or the coincident release of renin. These results give direct evidence of an interrelating mechanism between renal prostaglandins and renin release that is independent of external tubular or hemodynamic stimuli and show that the beta-adrenergic pathway of renin stimulation is independent of any modifying influence exerted by prostaglandins.


Regulatory defects in liver and intestine implicate abnormal hepcidin and Cybrd1 expression in mouse hemochromatosis.
Individuals with hereditary hemochromatosis suffer from systemic iron overload due to duodenal hyperabsorption. Most cases arise from a founder mutation in HFE (845G-->A; ref. 2) that results in the amino-acid substitution C282Y and prevents the association of HFE with beta2-microglobulin. Mice homozygous with respect to a null allele of Hfe (Hfe-/-) or homozygous with respect to the orthologous 882G-->A mutation (Hfe(845A/845A)) develop iron overload that recapitulates hereditary hemochromatosis in humans, confirming that hereditary hemochromatosis arises from loss of HFE function. Much work has focused on an exclusive role for the intestine in hereditary hemochromatosis. HFE deficiency in intestinal crypt cells is thought to cause intestinal iron deficiency and greater expression of iron transporters such as SLC11A2 (also called DMT1, DCT1 and NRAMP2) and SLC11A3 (also called IREG1, ferroportin and MTP1; ref. 3). Published data on the expression of these transporters in the duodenum of HFE-deficient mice and humans are contradictory. In this report, we used a custom microarray to assay changes in duodenal and hepatic gene expression in Hfe-deficient mice. We found unexpected alterations in the expression of Slc39a1 (mouse ortholog of SLC11A3) and Cybrd1, which encode key iron transport proteins, and Hamp (hepcidin antimicrobial peptide), a hepatic regulator of iron transport. We propose that inappropriate regulatory cues from the liver underlie greater duodenal iron absorption, possibly involving the ferric reductase Cybrd1.


The primary responses of murine neonatal lymph node CD4+ cells are Th2-skewed and are sufficient for the development of Th2-biased memory.
Exposure of neonatal mice to antigen often results in Th2-biased responses in later life. Examples of this Th2 tendency are (a) secondary antibody responses dominated by the Th2-associated IgG1 isotype and (b) Th2-mediated tolerance to alloantigens. We previously reported that neonates develop primary Th1 and Th2 function in the lymph nodes but exclusive Th2 primary splenic responses. Here, we have tested whether the Th2 bias of adults initially immunized as neonates is due to the early, primary Th2 polarization in the spleen. Surprisingly, removal of the spleen at birth had no affect on either IgG1-dominant secondary responses or the development of tolerance to alloantigens. Thus, neonatal lymph nodes are sufficient to generate Th2-biased function following neonatal antigen exposure. To understand how this could arise, we examined the primary Th1/Th2 responses of CD4+ lymph node cells. Unlike the balanced Th1/Th2 responses seen with total lymph node cells, the primary responses of isolated CD4+ cells were skewed to IL-4 producing function. These results suggest that the early development of Th2-dominant responses by lymph node CD4+ cells contributes substantially to the subsequent development of Th2-dominant memory in neonates.


Understanding factors associated with the trajectory of subjective cognitive complaints in groups with similar objective cognitive trajectories.
Cognitive complaints are often regarded as an early sign of Alzheimer's disease (AD) but may also occur in several other conditions and contexts. This study examines the correlates of cognitive complaint trajectories over a 5-year period in individuals who shared similar objective cognitive trajectories. We analyzed a subsample (n = 1748) of the MEMENTO cohort, consisting of individuals with subjective cognitive decline or mild cognitive impairment at baseline. Participants were stratified based on their latent MMSE trajectory over a 5-year period: "high and increasing," "subtle decline," and "steep decline." Within each of the three strata, we used a latent-class longitudinal approach to identify distinct trajectories of cognitive complaints. We then used multiple logistic regressions to examine the association between these complaint trajectories and several factors, including AD biomarkers (blood pTau/Aβ42 ratio, cortical thickness, APOE genotype), anxiety, depression, social relationships, a comorbidity-polypharmacy score, and demographic characteristics. Among participants with high and increasing MMSE scores, greater baseline comorbidity-polypharmacy scores (odds ratio (OR) = 1.30, adjusted p = 0.03) were associated with higher odds of moderate and increasing cognitive complaints (as opposed to mild and decreasing complaints). Baseline depression and social relationships also showed significant associations with the complaint pattern but did not survive correction for multiple comparisons. Among participants with subtle decline in MMSE scores, greater baseline depression (OR = 1.76, adjusted p = 0.02) was associated with higher odds of moderate and increasing cognitive complaints (versus mild and decreasing). Similarly, baseline comorbidity-polypharmacy scores and pTau/Aβ42 ratio exhibited significant associations, but they did not survive correction. Among participants with a steep decline in MMSE scores, greater baseline comorbidity-polypharmacy scores increased the odds of moderate complaints (versus mild, OR = 1.38, unadjusted p = 0.03, adjusted p = 0.32), but this effect did not survive correction for multiple comparisons. Despite similar objective cognitive trajectory, there is heterogeneity in the subjective perception of these cognitive changes. This perception was explained by both AD-related and, more robustly, non-AD-related factors. These findings deepen our understanding of the multifaceted nature of subjective cognitive complaints in individuals at risk for dementia and underscore the importance of considering a range of factors when interpreting cognitive complaints.


Rupture of the myocardium. Occurrence and risk factors.
The occurrence of myocardial rupture was studied in a well defined unselected population of patients with acute myocardial infarction, and the group of patients who died of rupture of the heart were compared with two control groups. Of a total of 3960 patients, 1746 (44%) fulfilled the diagnostic criteria for acute myocardial infarction. Rupture was defined solely on the basis of the presence of a pathological passage through part of the myocardium, either the free wall of the left ventricle or the septum, found at necropsy or during operation. Two controls were selected for each patient and matched for age and sex, one (control group A) with acute myocardial infarction having died in hospital but not of rupture (non-rupture cardiac death) and one (control group B) with acute myocardial infarction having survived the hospital stay. Necropsy was performed in 75% of all fatal cases with acute myocardial infarction. The total hospital mortality was 19%, the highest mortality being among women over 70 years (29%). Ruptures (n = 56) were found in 17% of the hospital deaths, or 3.2% of all cases of acute myocardial infarction. Women aged less than 70 had the highest incidence of rupture, 42% of deaths being due to rupture. The mean age for patients with rupture and controls was 70.5 years. The median time after admission to death was approximately 50 hours for patients and control group A. Thirty per cent of the patients with rupture occurred within 24 hours of the initial symptoms occurring. Angina and previous acute myocardial infarction were more common among control group A. Patients with rupture and control group B were mostly relatively free of previous cardiovascular or other diseases (chronic angina pectoris ( > 2 months) and previous myocardial infarction). Sustained hypertension during admission to the coronary care unit was more common in patients than in control group A. Hypotension and shock were more common among control group A. Most (79%) of the patients who subsequently ruptured did not receive any corticosteroids at all during the hospital stay. Severe heart failure and antiarrhythmic treatment were more uncommon among patients than among control group A. Patients with rupture received analgesics approximately three times a day throughout their stay. Control group B received analgesics mostly during the first 24 hours. Thus female patients, patients with first infarcts, and patients with sustained chest pain should be investigated for the possibility of rupture. As many as one third (32%) of ruptures may be subacute, and therefore time is available for diagnosis and surgery.


Effect of phase response curve skewness on synchronization of electrically coupled neuronal oscillators.
We investigate why electrically coupled neuronal oscillators synchronize or fail to synchronize using the theory of weakly coupled oscillators. Stability of synchrony and antisynchrony is predicted analytically and verified using numerical bifurcation diagrams. The shape of the phase response curve (PRC), the shape of the voltage time course, and the frequency of spiking are freely varied to map out regions of parameter spaces that hold stable solutions. We find that type 1 and type 2 PRCs can hold both synchronous and antisynchronous solutions, but the shape of the PRC and the voltage determine the extent of their stability. This is achieved by introducing a five-piecewise linear model to the PRC and a three-piecewise linear model to the voltage time course, and then analyzing the resultant eigenvalue equations that determine the stability of the phase-locked solutions. A single time parameter defines the skewness of the PRC, and another single time parameter defines the spike width and frequency. Our approach gives a comprehensive picture of the relation of the PRC shape, voltage time course, and stability of the resultant synchronous and antisynchronous solutions.


The Pseudomonas syringae type III effector HopD1 suppresses effector-triggered immunity, localizes to the endoplasmic reticulum, and targets the Arabidopsis transcription factor NTL9.
• Pseudomonas syringae type III effectors are known to suppress plant immunity to promote bacterial virulence. However, the activities and targets of these effectors are not well understood. • We used genetic, molecular, and cell biology methods to characterize the activities, localization, and target of the HopD1 type III effector in Arabidopsis. • HopD1 contributes to P. syringae virulence in Arabidopsis and reduces effector-triggered immunity (ETI) responses but not pathogen-associated molecular pattern-triggered immunity (PTI) responses. Plants expressing HopD1 supported increased growth of ETI-inducing P. syringae strains compared with wild-type Arabidopsis. We show that HopD1 interacts with the membrane-tethered Arabidopsis transcription factor NTL9 and demonstrate that this interaction occurs at the endoplasmic reticulum (ER). A P. syringae hopD1 mutant and ETI-inducing P. syringae strains exhibited enhanced growth on Arabidopsis ntl9 mutant plants. Conversely, growth of P. syringae strains was reduced in plants expressing a constitutively active NTL9 derivative, indicating that NTL9 is a positive regulator of plant immunity. Furthermore, HopD1 inhibited the induction of NTL9-regulated genes during ETI but not PTI. • HopD1 contributes to P. syringae virulence in part by targeting NTL9, resulting in the suppression of ETI responses but not PTI responses and the promotion of plant pathogenicity.


A report on the effect of commencing enfuvirtide on peripheral neuropathy.
Enfuvirtide is the first fusion inhibitor approved for use in HIV treatment and is a useful therapeutic option for highly treatment experienced individuals. Passive reporting has associated increased neuropathy rates with enfuvirtide use in some early studies but not others. The aim of this study was to describe any functional or clinical changes consistent with neuropathy among enfuvirtide users. A prospective cohort study of patients commencing or continuing enfuvirtide at a state HIV referral service, including clinical and sensory threshold monitoring, was conducted. A total of 14 patients were studied. All had advanced HIV disease and 13 (93%) had symptoms and/or signs consistent with neuropathy at baseline. Patients who entered the study on enfuvirtide-based therapy remained neurologically stable throughout follow-up. Eleven patients were assessed preand postenfuvirtide. No evidence was found for any clear effect of enfuvirtide on neuropathic symptoms, neuropathic signs, or sensory thresholds at a cohort level (p > 0.3 for all, Wilcoxon signed rank test). However, three (21%) patients experienced worsening of existing neuropathy symptoms (transient in two cases) and two (14%) patients' symptoms improved with enfuvirtide commencement. Breakthrough HIV viremia was associated with worsening symptoms in two patients at 5 and 18 months of enfuvirtide use. This study found no clear effect on peripheral nerves from enfuvirtide. Although limited by a small sample size, this study involved patients who would have been particularly vulnerable to a neurotoxin, with advanced HIV disease and a high rate of baseline neurological abnormalities. We observed no clear evidence of neurotoxicity from enfuvirtide in this population.


Colour wide field specular microscopic investigation of corneal surface disorders.
Colour wide field specular microscopy (WFSM) may be used to examine different phases of corneal surface pathology in vivo. A soft contact lens facilitates colour differentiation of cell surface variations by interference. Pathologic states may be characterised by modifications in apparent cell colour, brightness, morphology and configuration. Cell brightness is altered by interference phenomena, cell surface irregularities (microprojections), homogeneity of substances covering cells, intracellular components and changes in indices of refraction at the interfaces between the cell surface and the tear layers. Colour photography has been helpful in deciding which intensity variations may be due to interference effects.


Dermacentor reticulatus - a tick on its way from glacial refugia to a panmictic Eurasian population.
The ornate dog tick (Dermacentor reticulatus) shows a recently expanding geographic distribution. Knowledge on its intraspecific variability, population structure, rate of genetic diversity and divergence, including its evolution and geographic distribution, is crucial to understand its dispersal capacity. All such information would help to evaluate the potential risk of future spread of associated pathogens of medical and veterinary concern. A set of 865 D. reticulatus ticks was collected from 65 localities across 21 countries, from Portugal in the west to Kazakhstan and southern Russia in the east. Cluster analyses of 16 microsatellite loci were combined with nuclear (ITS2, 18S) and mitochondrial (12S, 16S, COI) sequence data to uncover the ticks' population structures and geographical patterns. Approximate Bayesian computation was applied to model evolutionary relationships among the found clusters. Low variability and a weak phylogenetic signal showing an east-west cline were detected both for mitochondrial and nuclear sequence markers. Microsatellite analyses revealed three genetic clusters, where the eastern and western cluster gradient was supplemented by a third, northern cluster. Alternative scenarios could explain such a tripartite population structure by independent formation of clusters in separate refugia, limited gene flow connected with isolation by distance causing a "bipolar pattern", and the northern cluster deriving from admixture between the eastern and western populations. The best supported demographic scenario of this tick species indicates that the northern cluster derived from admixture between the eastern and western populations 441 (median) to 224 (mode) generations ago, suggesting a possible link with the end of the Little Ice Age in Europe.


[Lethal effect of Cuban Myrtaceae on Aedes aegypti (Diptera Cuilicidae)].
The biological activity of the essential foliar oils from 2 Cuban endemic Myrtaceae: Eugenia melanadenia and Psidium rotundatum on A. aegypti larvae was evaluated for the first time at the laboratory level. The probit-log analysis of the results showed the larvicidal effect of both oils with values of CL50 = 0.0085% and CL95 = 0.0104% for E. melanadenia and CL50 = 0.0063% and CL95 = 0.0071% for O. rotundatum. Besides, the diagnostic concentration for both essential oils are given and the possible implications of these findings on field populations of A. aegypti are suggessted.


Use of molecular biomarkers to quantify the spatial distribution of effects of anticancer drugs in solid tumors.
Poor distribution of anticancer drugs within solid tumors may limit their effectiveness. Here, we characterize the distribution within solid tumors of biomarkers of drug effect. γ-H2AX, cleaved-caspase-3 or -6, and Ki67 were quantified in tumor sections in relation to blood vessels (recognized by CD31) using monoclonal antibodies and immunohistochemistry. To validate their use, we compared their time-dependent distribution with that of (i) fluorescent doxorubicin and (ii) a monoclonal antibody that detects melphalan-induced DNA adducts. The biomarkers were then used to quantify the distribution of docetaxel in relation to tumor blood vessels. Activation of γ-H2AX was evaluated following in vitro exposure of tumor cells to multiple drugs. Distributions of doxorubicin in MDA-MB-231 and MCF-7 xenografts and of melphalan-induced DNA adducts in MCF-7 and EMT-6 tumors decreased with distance from blood vessels, similar to the distributions of (i) γ-H2AX at 10 minutes, (ii) cleaved caspase-3 or -6, and (iii) change in Ki67 at 24 hours following treatment. The distribution of these biomarkers following treatment with docetaxel also decreased with increasing distance from tumor blood vessels. Activation of γ-H2AX occurred within 1 hour after exposure to several drugs in culture. Multiple anticancer drugs show a decrease in activity with increasing distance from tumor blood vessels; poor drug distribution is an important cause of drug resistance. The above biomarkers may be used in designing strategies to overcome therapeutic resistance by modifying or complementing the limited spatial distribution of drug activity in solid tumors.


Illness behavior and cultural characteristics of the gypsy population in Spain.
Gypsy population constitutes the most important ethnic minority in Spain (more than 2% of population). Our country has the third largest gypsy population in the world. Although their presence among us dates from more than 600 years ago and their culture and their health needs are very different from ours, lack of interest about this group of population has been important. The growing migration process that has happened in our country during the last years has also produced an increasing concern about the health needs of gypsies. This paper aims to summarize the scarce present medical and anthropological knowledge on gypsies. The aim is to provide the health professionals with minimal skills to avoid possible prejudices towards this ethnic group and provide them high quality health care.


Relocation of the iliac artery bifurcation to facilitate endoluminal treatment of abdominal aortic aneurysms.
To report a surgical technique to preserve the internal iliac arteries (IIAs) and facilitate endovascular repair of abdominal aortic aneurysms (AAAs) with extensive iliac artery involvement. A new iliac artery bifurcation is created surgically through an 8-cm lower left abdominal incision by implanting the IIA onto the distal external iliac artery either directly or by using a tube graft interposition. Careful technique is required to avoid embolic complications, but after relocating the bifurcation, aortic endografting can be performed, either simultaneously or staged, depending upon patient characteristics. Relocation of the iliac artery bifurcation appears to be a good alternative to preserve pelvic arterial flow in selected candidates for endoluminal AAA repair.


LCA comparison of container systems in municipal solid waste management.
The planning and design of integrated municipal solid waste management (MSWM) systems requires accurate environmental impact evaluation of the systems and their components. This research assessed, quantified and compared the environmental impact of the first stage of the most used MSW container systems. The comparison was based on factors such as the volume of the containers, from small bins of 60-80l to containers of 2400l, and on the manufactured materials, steel and high-density polyethylene (HDPE). Also, some parameters such as frequency of collections, waste generation, filling percentage and waste container contents, were established to obtain comparable systems. The methodological framework of the analysis was the life cycle assessment (LCA), and the impact assessment method was based on CML 2 baseline 2000. Results indicated that, for the same volume, the collection systems that use HDPE waste containers had more of an impact than those using steel waste containers, in terms of abiotic depletion, global warming, ozone layer depletion, acidification, eutrophication, photochemical oxidation, human toxicity and terrestrial ecotoxicity. Besides, the collection systems using small HDPE bins (60l or 80l) had most impact while systems using big steel containers (2400l) had less impact. Subsequent sensitivity analysis about the parameters established demonstrated that they could change the ultimate environmental impact of each waste container collection system, but that the comparative relationship between systems was similar.


Phylogenetic analyses of a new group of denitrifiers capable of anaerobic growth of toluene and description of Azoarcus tolulyticus sp. nov.
To understand the phylogeny and taxonomy of eight new toluene-degrading denitrifying isolates, we performed a 16S rRNA sequence analysis and a gas chromatographic analysis of their cellular fatty acids and examined some of their biochemical and physiological features. These isolates had 16s rRNA sequence signatures identical to those of members of the beta subclass of the Proteobacteria. The levels of similarity were as follows: 97.9 to 99.9% among the new isolates; 91.2 to 92.4% between the new isolates and Azoarcus sp. strain S5b2; 95.3 to 96.2% between the new isolates and Azoarcus sp. strain BH72; and 94.8 to 95.3% between the new isolates and Azoarcus indigens VB32T (T = type strain). Phylogenetic trees constructed by using the distance matrix, maximum-parsimony, and maximum-likelihood methods showed that our eight denitrifying isolates form a phylogenetically coherent cluster which represents a sister lineage of the previously described Azoarcus species. Furthermore, the fatty acid profiles, the cell morphology, and several physiological and nutritional characteristics of the eight isolates and the previously described members of the genus Azoarcus were also similar. In contrast to the previously described members of the genus Azoarcus, the eight new isolates were capable of degrading toluene under denitrifying conditions. We concluded that these toluene-degrading denitrifiers are members of a new species of the novel nitrogen-fixing genus Azoarcus. We propose the name Azoarcus tolulyticus for these toluene-degrading denitrifying isolates and designate strain Tol-4 the type strain.


Notch Signaling Inhibition by LY411575 Attenuates Osteoblast Differentiation and Decreased Ectopic Bone Formation Capacity of Human Skeletal (Mesenchymal) Stem Cells.
Chemical biology approaches using small molecule inhibitors targeting specific signaling pathways are useful tools to dissect the molecular mechanisms governing stem cell differentiation and for their possible use in therapeutic interventions. Stem cell signaling small molecule library functional screen was performed employing human bone marrow skeletal (mesenchymal) stem cells (hBMSCs). Alkaline phosphatase (ALP) activity and formation of mineralized matrix visualized by Alizarin red staining were employed as markers for osteoblastic differentiation. Global gene expression profiling was conducted using the Agilent microarray platform, and data normalization and bioinformatics were performed using GeneSpring software. Pathway analyses were conducted using the Ingenuity Pathway Analysis (IPA) tool. In vivo ectopic bone formation was performed using hBMSC mixed with hydroxyapatite-tricalcium phosphate granules that were implanted subcutaneously in 8-week-old female nude mice. Hematoxylin and eosin staining and Sirius red staining were performed to identify bone formation in vivo. Among the tested molecules, LY411575, a potent γ-secretase and Notch signaling inhibitor, exhibited significant inhibitory effects on osteoblastic differentiation of hBMSCs manifested by reduced ALP activity, mineralized matrix formation, and decreased osteoblast-specific gene expression as well as in vivo ectopic bone formation. Global gene expression profiling of LY411575-treated cells revealed changes in multiple signaling pathways, including focal adhesion, insulin, TGFβ, IL6, and Notch signaling, and decreased the expression of genes associated with functional categories of tissue development. Among the affected signaling networks were TGFβ1, SPP1, and ERK regulatory networks. We identified γ-secretase inhibitor (LY411575) as a potent regulator of osteoblastic differentiation of hBMSC that may be useful as a therapeutic option for treating conditions associated with ectopic bone formation.


Cell uptake, distribution and response to aluminium chloro sulphonated phthalocyanine, a potential anti-tumour photosensitizer.
The uptake, retention and effects of aluminium chloro sulphonated phthalocyanine (AlSPc) were measured in two cell lines, UV-2237 a murine fibrosarcoma and the non-tumorigenic NIH/3T3 fibroblast line. The behaviour of cells treated with AlSPc was compared with that of those treated with haematoporphyrin derivative (HpD), a photosensitizer often used in photodynamic therapy (PDT) of cancer. AlSPc absorbs light strongly in the red region, is taken up by cells in a dose dependent fashion and is retained in vitro over a period of days (5 days after exposure greater than 40% remains cell-associated versus less than 25% of HpD). Additionally AlSPc was less cytotoxic to cells, maintained in darkness or exposed to room light, compared to HpD (100% viability versus 0% viability 3 days after 60 min exposure to room light). However red light (approximately 600-700 nm) caused greater toxicity in AlSPc-treated cells (100%) than in similarly exposed HpD-treated cells (less than 60%). No significant differences were detected between the responses of the fibrosarcoma and the fibroblast cell lines. These characteristics of AlSPc suggest that it may prove to be a useful photosensitizer for PDT of cancer and this possibility is discussed.


A randomized controlled trial of oxygen therapy in acute myocardial infarction Air Verses Oxygen In myocarDial infarction study (AVOID Study).
The role of routine supplemental oxygen for patients with uncomplicated acute myocardial infarction (AMI) has recently been questioned. There is conflicting data on the possible effects of hyperoxia on ischemic myocardium. The few clinical trials examining the role of oxygen in AMI were performed prior to the modern approach of emergent reperfusion and advanced medical management. Air Verses Oxygen In myocarDial infarction study (AVOID Study) is a prospective, multi-centre, randomized, controlled trial conducted by Ambulance Victoria and participating metropolitan Melbourne hospitals with primary percutaneous coronary intervention capabilities. The purpose of the study is to determine whether withholding routine supplemental oxygen therapy in patients with acute ST-elevation myocardial infarction but without hypoxia prior to reperfusion decreases myocardial infarct size. AVOID will enroll 490 patients, >18 years of age with acute ST-elevation myocardial infarction of less than 12 hours duration. There is an urgent need for clinical trials examining the role of oxygen in AMI. AVOID will seek to clarify this important issue. Results from this study may have widespread implications on the treatment of AMI and the use of oxygen in both the pre-hospital and hospital settings.


Characterization of an antigen associated with the Marek's disease lymphoblastoid cell line MSB-1.
A Marek's disease lymphoblastoid cell line (MSB-1) has been analysed by immunoprecipitation for expression of tumour-associated antigen, Marek's disease virus (MDV)-specific antigens and antigens specific to avian leukosis-sarcoma viruses. Rabbit antisera raised against two independently derived cell lines after extensive absorption with normal chick cells reacted with a polypeptide of mol. wt. 40 000 (40K) in extracts of MSB-1 cells. The 40K polypeptide was not present in myeloblasts or in chick embryo fibroblasts (CEF) infected with MDV and did not react with antiserum raised against normal chicken thymus antigens. The possibility that the 40K polypeptide is a tumour-associated antigen is discussed. Seven MDV-specific antigens were noted in infected CEF (mol. wt. 110K, 100K, 80K, 70K, 50K, 35K and 32K) but none of these was detected in MSB-1 cells. The avian leukosis-sarcoma group-specific antigen P27gag and its precursor Pr76gag were not found in MSB-1 cells, confirming that expression of mature gag protein is not required for transformation by MDV. However, two polypeptides of unknown origin and function (mol. wt. 180K and 110K) were precipitated from MSB-1 cells with a rabbit anti-Rous sarcoma (Schmidt-Rupin, subgroup D) antiserum.


Crystallization and lamellar nanosheet formation of an aromatic dipeptoid.
An aromatic peptoid analogue of the diphenylalanine dipeptide self-assembles in aqueous solution and the first crystal structure was obtained for this class of compound. This reveals molecular packing stabilized by networks of hydrogen bonds. Free-floating nanosheet lamellar structures are observed in solution, which form via cooperative intermolecular interactions driven by π stacking.


Microarray analysis of primary epithelial and fibroblast cells in chronic rhinosinusitis without nasal polyps.
Chronic rhinosinusitis is an inflammatory condition with an as yet unknown pathophysiology. We aimed to detect clusters of differentially regulated genes in the epithelial and fibroblast cells of patients with Chronic Rhinosinusitis without nasal polyposis (CRSsNP) and healthy controls. Carefully phenotyped CRSsNP and healthy control participants were recruited. Primary cultures of isolated epithelial and fibroblast cells were established. Whole transcriptome analysis of the cells was performed using microarrays and replicated with quantitative RT-PCR and immunohistochemistry. Fibroblast cells from CRSsNP patients showed a significant upregulation (more than 2x) of the transcription factor NFE2L3 when compared to healthy controls by microarray with multiple hypothesis testing correction, qRT-PCR and immunohistochemistry. Here we have utilized microarray analysis to search for differentially expressed genes in isolated patient derived epithelial and fibroblast cells. The transcription factor NFE2L3 has been shown to be upregulated in fibroblast cells consistent with increasing evidence that fibroblasts play a key role in tissue specific inflammation within the paranasal sinuses.


Effects of CTGF Blockade on Attenuation and Reversal of Radiation-Induced Pulmonary Fibrosis.
Radiotherapy is a mainstay for the treatment of lung cancer that can induce pneumonitis or pulmonary fibrosis. The matricellular protein connective tissue growth factor (CTGF) is a central mediator of tissue remodeling. A radiation-induced mouse model of pulmonary fibrosis was used to determine if transient administration of a human antibody to CTGF (FG-3019) started at different times before or after 20 Gy thoracic irradiation reduced acute and chronic radiation toxicity. Mice (25 mice/group; 10 mice/group in a confirmation study) were examined by computed tomography, histology, gene expression changes, and for survival. In vitro experiments were performed to directly study the interaction of CTGF blockade and radiation. All statistical tests were two-sided. Administration of FG-3019 prevented (∼50%-80%) or reversed (∼50%) lung remodeling, improved lung function, improved mouse health, and rescued mice from lethal irradiation ( P < .01). Importantly, when antibody treatment was initiated at 16 weeks after thoracic irradiation, FG-3019 reversed established lung remodeling and restored lung function. CTGF blockade abrogated M2 polarized macrophage influx, normalized radiation-induced gene expression changes, and reduced myofibroblast abundance and Osteopontin expression. These results indicate that blocking CTGF attenuates radiation-induced pulmonary remodeling and can reverse the process after initiation. CTGF has a central role in radiation-induced fibrogenesis, and FG-3019 may benefit patients with radiation-induced pulmonary fibrosis or patients with other forms or origin of chronic fibrotic diseases.


Detection and modelling of time-dependent QTL in animal populations.
A longitudinal approach is proposed to map QTL affecting function-valued traits and to estimate their effect over time. The method is based on fitting mixed random regression models. The QTL allelic effects are modelled with random coefficient parametric curves and using a gametic relationship matrix. A simulation study was conducted in order to assess the ability of the approach to fit different patterns of QTL over time. It was found that this longitudinal approach was able to adequately fit the simulated variance functions and considerably improved the power of detection of time-varying QTL effects compared to the traditional univariate model. This was confirmed by an analysis of protein yield data in dairy cattle, where the model was able to detect QTL with high effect either at the beginning or the end of the lactation, that were not detected with a simple 305 day model.


Continuous ambulatory peritoneal dialysis in a pediatric population.
Seven children aged from 6 weeks to 14 years were treated for end-stage renal disease by continuous ambulatory peritoneal dialysis (CAPD) for 60 patient months. Satisfactory control of their uremia was achieved. Peritonitis was diagnosed on seven occasions (one case per 8.6 patient months) and did not interfere with continuation of dialysis or decrease peritoneal membrane permeability. Patients older than 5 years grew at rates comparable with those of patients receiving hemodialysis. Two infants receiving CAPD exhibited normal growth rates. Families demonstrated good psychosocial adjustment to the technique. Thus, CAPD seems to be a satisfactory alternative to hemodialysis for long-term therapy .


Altruism in clinical research: coordinators' orientation to their professional roles.
Research coordinators have significant responsibilities in clinical trials that often require them to find unique ways to manage their jobs, thus reshaping their professional identities. The purpose of this study was to identify how research coordinators manage role and ethical conflicts within clinical research trials. A qualitative study combining observation and 63 semistructured interviews at 25 research organizations was used. Altruism is a recurring theme in how research coordinators define and view their work. Altruism is adopted by research coordinators to: (1) Teach patient-subjects the appropriate reasons to participate in clinical research, (2) minimize the conflict between research and care, and (3) contest the undervaluation of coordinating. Altruism is a strategy used to handle the various conflicts they experience in a difficult job, and it has become part of the professional identity of clinical research coordinators.


Correlation between DNA damage responses of skin to a test dose of radiation and late adverse effects of earlier breast radiotherapy.
To correlate residual double strand breaks (DSB) 24h after 4Gy test doses to skin in vivo and to lymphocytes in vitro with adverse effects of earlier breast radiotherapy (RT). Patients given whole breast RT ⩾5years earlier were identified on the basis of moderate/marked or minimal/no adverse effects despite the absence ('RT-Sensitive', RT-S) or presence ('RT-Resistant', RT-R) of variables predisposing to late adverse effects. Residual DSB were quantified in skin 24h after a 4Gy test dose in 20 RT-S and 15 RT-R patients. Residual DSB were quantified in lymphocytes irradiated with 4Gy in vitro in 30/35 patients. Mean foci per dermal fibroblast were 3.29 (RT-S) vs 2.80 (RT-R) (p=0.137); 3.28 (RT-S) vs 2.60 (RT-R) in endothelium (p=0.158); 2.50 (RT-S) vs 2.41 (RT-R) in suprabasal keratinocytes (p=0.633); 2.70 (RT-S) vs 2.35 (RT-R) in basal epidermis (p=0.419); 12.1 (RT-S) vs 10.3 (RT-R) in lymphocytes (p=0.0052). Residual DSB in skin following a 4Gy dose were not significantly associated with risk of late adverse effects of breast radiotherapy, although exploratory analyses suggested an association in severely affected individuals. By contrast, a significant association was detected based on the in vitro response of lymphocytes.


Recursive erosion, dilation, opening, and closing transforms.
A new group of recursive morphological transforms on the discrete space Z(2) are discussed. The set of transforms include the recursive erosion transform (RET), the recursive dilation transform (RDT), the recursive opening transform (ROT), and the recursive closing transform (RCT), The transforms are able to compute in constant time per pixel erosions, dilations, openings, and closings with all sized structuring elements simultaneously. They offer a solution to some vision tasks that need to perform a morphological operation but where the size of the structuring element has to be determined after a morphological examination of the content of the image. The computational complexities of the transforms show that the recursive erosion and dilation transform can be done in N+2 operations per pixel, where N is the number of pixels in the base structuring element. The recursive opening and closing transform can be done in 14N operations per pixel based on experimental results.


A new species of Laranda Walker 1869 (Orthoptera: Grylloidea, Phalangopsidae) from remnant patches of the Brazilian Atlantic Forest.
The genus Laranda has six described species and is confined to South and Southeast of Brazil. We describe a new species and discuss the biology and distribution of the genus. The new species can be distinguished from its known congeners by the following characteristics: absence of yellow spots on pronotum and base of posterior tibiae; female copulatory papilla: sclerotization in dorsal view forming opposing acute angles, apical lobes narrow and small; male genitalia: pseudepiphallic median process short and wide; pseudepiphallic paramere with apex incurved and ectophallic fold surpassing apex of the parameres. The genus is distributed within the Atlantic Forest biome; the new species is found on tree trunks, as well as on forest leaf litter.


Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers.
All patients with EGF receptor (EGFR)-mutant lung cancers eventually develop acquired resistance to EGFR tyrosine kinase inhibitors (TKI). Smaller series have identified various mechanisms of resistance, but systematic evaluation of a large number of patients to definitively establish the frequency of various mechanisms has not been conducted. Patients with lung adenocarcinomas and acquired resistance to erlotinib or gefitinib enrolled onto a prospective biopsy protocol and underwent a rebiopsy after the development of acquired resistance. Histology was reviewed. Samples underwent genotyping for mutations in EGFR, AKT1, BRAF, ERBB2, KRAS, MEK1, NRAS and PIK3CA, and FISH for MET and HER2. Adequate tumor samples for molecular analysis were obtained in 155 patients. Ninety-eight had second-site EGFR T790M mutations [63%; 95% confidence interval (CI), 55%-70%] and four had small cell transformation (3%, 95% CI, 0%-6%). MET amplification was seen in 4 of 75 (5%; 95% CI, 1%-13%). HER2 amplification was seen in 3 of 24 (13%; 95% CI, 3%-32%). We did not detect any acquired mutations in PIK3CA, AKT1, BRAF, ERBB2, KRAS, MEK1, or NRAS (0 of 88, 0%; 95% CI, 0%-4%). Overlap among mechanisms of acquired resistance was seen in 4%. This is the largest series reporting mechanisms of acquired resistance to EGFR-TKI therapy. We identified EGFR T790M as the most common mechanism of acquired resistance, whereas MET amplification, HER2 amplification, and small cell histologic transformation occur less frequently. More comprehensive methods to characterize molecular alterations in this setting are needed to improve our understanding of acquired resistance to EGFR-TKIs.


Splenic mass of masked shrews, Sorex cinereus, in relation to body mass, sex, age, day of the year, and bladder nematode, Liniscus (=Capillaria) maseri, infection.
The spleen is an important organ of vertebrates. Splenic mass can change in response to a variety of factors. We tested whether splenic mass of masked shrews, Sorex cinereus, was related to sex, age, time of the year, or intensity of bladder nematode (Liniscus [=Capillaria] maseri) infection, after controlling for host body mass. For females, body mass was a strong predictor of splenic mass. For males, splenic masses were greater later in the year and in more heavily infected males. The latter appeared to represent a threshold response wherein only the most heavily infected individuals had enlarged spleens.


Hyaluronan and RHAMM in wound repair and the "cancerization" of stromal tissues.
Tumors and wounds share many similarities including loss of tissue architecture, cell polarity and cell differentiation, aberrant extracellular matrix (ECM) remodeling (Ballard et al., 2006) increased inflammation, angiogenesis, and elevated cell migration and proliferation. Whereas these changes are transient in repairing wounds, tumors do not regain tissue architecture but rather their continued progression is fueled in part by loss of normal tissue structure. As a result tumors are often described as wounds that do not heal. The ECM component hyaluronan (HA) and its receptor RHAMM have both been implicated in wound repair and tumor progression. This review highlights the similarities and differences in their roles during these processes and proposes that RHAMM-regulated wound repair functions may contribute to "cancerization" of the tumor microenvironment.


Enhancing perceptual and attentional skills requires common demands between the action video games and transfer tasks.
Despite increasing evidence that shows action video game play improves perceptual and cognitive skills, the mechanisms of transfer are not well-understood. In line with previous work, we suggest that transfer is dependent upon common demands between the game and transfer task. In the current study, participants played one of four action games with varying speed, visual, and attentional demands for 20 h. We examined whether training enhanced performance for attentional blink, selective attention, attending to multiple items, visual search and auditory detection. Non-gamers who played the game (Modern Combat) with the highest demands showed transfer to tasks of attentional blink and attending to multiple items. The game (MGS Touch) with fewer attentional demands also decreased attentional blink, but to a lesser degree. Other games failed to show transfer, despite having many action game characteristics but at a reduced intensity. The results support the common demands hypothesis.


Ultrasound of the Knee: Common Pathology Excluding Extensor Mechanism.
Ultrasound can be used to diagnose many types of pathology and guide various diagnostic or therapeutic procedures. The most common applications for musculoskeletal ultrasound of the knee include evaluation of the joint recesses, the extensor mechanism, and bursae including Baker's cyst. However, a role exists for ultrasound in the evaluation of cartilage, other tendons, ligaments, peripheral nerves, osseous structures, and vasculature. This article reviews common pathologies of these structures as seen with ultrasound. In addition, various ultrasound-guided procedures pertaining to these pathologies are introduced. The importance of a comprehensive evaluation is also emphasized as a method to maximize information gained from the ultrasound examination.