The two-step model of prostaglandin signal termination: in vitro reconstitution with the prostaglandin transporter and prostaglandin 15 dehydrogenase.
Termination of prostaglandin (PG) signaling has been proposed to involve carrier-mediated uptake across the plasma membrane followed by cytoplasmic oxidation. Here, we tested this hypothesis directly by coexpressing the PG uptake carrier prostaglandin transporter (PGT) in various cell types with and without human PG 15 dehydrogenase (PG15DH). In HeLa cells, which express neither PGT nor PG15DH, exogenously added PGE2 or PGF2alpha were rapidly oxidized to the 13, 14-dihydro, 15-keto metabolites only when PGT and PG15DH were coexpressed, directly confirming the two-step hypothesis. Cells expressing PG15DH that were broken open formed more PG metabolites than cells in which the PGs could gain access to PG15DH only via PGT. Similar results were obtained using the human prostate cancer cell line LNCaP, in which endogenous PG15DH is induced after exposure to dihydrotestosterone. Because PGT in vivo is expressed in renal collecting duct epithelia, we also expressed PGT in Madin-Darby canine kidney cells grown on filters, where it mediated both the active uptake of PGE2 across the apical membrane and the transepithelial transport of PGE2 to the basolateral compartment. When PG15DH was coexpressed with PGT in these epithelial monolayers, about half of the PGE2 taken up apically was oxidized to 13, 14-dihydro, 15-keto-PGE2, which in turn exited the cells nondirectionally into both the apical and basolateral compartments. Our data represent reconstitution of the longstanding model of PG metabolism consisting of sequential carrier-mediated PG uptake, cytoplasmic oxidation, and diffusional efflux of the PG metabolite.


Bayesian outbreak detection in the presence of reporting delays.
One use of infectious disease surveillance systems is the statistical aberration detection performed on time series of counts resulting from the aggregation of individual case reports. However, inherent reporting delays in such surveillance systems make the considered time series incomplete, which can be an impediment to the timely detection and thus to the containment of emerging outbreaks. In this work, we synthesize the outbreak detection algorithms of Noufaily et al. (2013) and Manitz and Höhle (2013) while additionally addressing right truncation caused by reporting delays. We do so by considering the resulting time series as an incomplete two-way contingency table which we model using negative binomial regression. Our approach is defined in a Bayesian setting allowing a direct inclusion of all sources of uncertainty in the derivation of whether an observed case count is to be considered an aberration. The proposed algorithm is evaluated both on simulated data and on the time series of Salmonella Newport cases in Germany in 2011. Altogether, our method aims at allowing timely aberration detection in the presence of reporting delays and hence underlines the need for statistical modeling to address complications of reporting systems. An implementation of the proposed method is made available in the R package surveillance as the function "bodaDelay".


The prognostic and diagnostic value of intraleukocytic malaria pigment in patients with severe falciparum malaria.
Severe falciparum malaria is a major cause of death in tropical countries, particularly in African children. Rapid and accurate diagnosis and prognostic assessment are critical to clinical management. In 6027 prospectively studied patients diagnosed with severe malaria we assess the prognostic value of peripheral blood film counts of malaria pigment containing polymorphonuclear leukocytes (PMNs) and monocytes. We combine these results with previously published data and show, in an individual patient data meta-analysis (n = 32,035), that the proportion of pigment containing PMNs is predictive of in-hospital mortality. In African children the proportion of pigment containing PMNs helps distinguish severe malaria from other life-threatening febrile illnesses, and it adds to the prognostic assessment from simple bedside examination, and to the conventional malaria parasite count. Microscopy assessment of pigment containing PMNs is simple and rapid, and should be performed in all patients hospitalised with suspected severe malaria.


Double-blind, placebo-controlled, dose-ranging trial of intravenous ketamine as adjunctive therapy in treatment-resistant depression (TRD).
Numerous placebo-controlled studies have demonstrated the ability of ketamine, an NMDA receptor antagonist, to induce rapid (within hours), transient antidepressant effects when administered intravenously (IV) at subanesthetic doses (0.5 mg/kg over 40 min). However, the optimal antidepressant dose remains unknown. We aimed to compare to active placebo the rapid acting antidepressant properties of a broad range of subanesthetic doses of IV ketamine among outpatients with treatment-resistant depression (TRD). A range of IV ketamine doses were compared to active placebo in the treatment of adult TRD over a 3-day period following a single infusion over 40 min. This was an outpatient study conducted across six US academic sites. Outpatients were 18-70 years old with TRD, defined as failure to achieve a satisfactory response (e.g., less than 50% improvement of depression symptoms) to at least two adequate treatment courses during the current depressive episode. Following a washout period, 99 eligible subjects were randomly assigned to one of the five arms in a 1:1:1:1:1 fashion: a single intravenous dose of ketamine 0.1 mg/kg (n = 18), a single dose of ketamine 0.2 mg/kg (n = 20), a single dose of ketamine 0.5 mg/kg (n = 22), a single dose of ketamine 1.0 mg/kg (n = 20), and a single dose of midazolam 0.045 mg/kg (active placebo) (n = 19). The study assessments (HAM-D-6, MADRS, SDQ, PAS, CGI-S, and CGI-I) were performed at days 0, 1, 3 (endpoint), 5, 7, 14, and 30 to assess the safety and efficacy. The overall group × time interaction effect was significant for the primary outcome measure, the HAM-D-6. In post hoc pairwise comparisons controlling for multiple comparisons, standard dose (0.5 mg/kg) and high dose (1 mg/kg) of intravenous ketamine were superior to active placebo; a low dose (0.1 mg/kg) was significant only prior to adjustment (p = 0.02, p-adj = 0.14, d = -0.82 at day 1). Most of the interaction effect was due to differences at day 1, with no significant adjusted pairwise differences at day 3. This pattern generally held for secondary outcomes. The infusions of ketamine were relatively well tolerated compared to active placebo, except for greater dissociative symptoms and transient blood pressure elevations with the higher doses. Our results suggest that there is evidence for the efficacy of the 0.5 mg/kg and 1.0 mg/kg subanesthetic doses of IV ketamine and no clear or consistent evidence for clinically meaningful efficacy of lower doses of IV ketamine. Trial Registration: NCT01920555.


Predictive error processing distinguishes between relevant and irrelevant errors after visuomotor learning.
Error processing is an important aspect of learning. The detection and online correction of an error as well as error-based adaptation of subsequent movements enables humans to improve behavior. For this improvement, it is necessary to differentiate between relevant and irrelevant errors. Behavioral adaptations are only reasonable when an error is attributed to one's own behavior and therefore regarded as relevant for subsequent adjustments, whereas irrelevant errors caused by unsystematic external influences should be disregarded. Here, we ask whether error predictions as indexed by the error-related negativity (Ne/ERN) can be used to differentiate relevant and irrelevant errors in movements with a complex visuomotor mapping. Using event-related potentials, we compared the neural activation between relevant (self-induced/internal) errors and irrelevant (externally manipulated) errors in a virtual goal-oriented throwing task. Results show that the Ne/ERN responds more strongly to self-induced errors, while the feedback-related negativity (FRN) more strongly correlates with externally manipulated errors. Moreover, subsequent behavioral adjustments were larger in the relevant compared to the irrelevant error trials. We conclude that predictive processes, marked by the Ne/ERN, can subserve error attribution in naturalistic, complex visuomotor tasks like throwing.


Safety attitudes and beliefs of junior Australian football players.
To describe the safety attitudes and beliefs of junior (aged 16-18 years) Australian football players. Six Victorian Football League Under 18 (VFL U18) clubs in Victoria, Australia. Cross sectional survey. Altogether 103 players completed a self report questionnaire about their safety beliefs and perceptions of support when injured, across three contexts in which they played: VFL U18 club, local club, and school. Although only 6% believed it was safe to play with injuries, 58% were willing to risk doing so. This increased to almost 80% when players perceived that their chances of being selected to play for a senior elite team would be adversely affected if they did not play. There were significant differences in the perceived level of support for injured players and in the ranking of safety as a high priority across the three settings. In general, the VFL U18 clubs were perceived as providing good support for injured players and giving a high priority to safety issues, but local clubs and particularly schools were perceived to address these issues less well. Junior Australian football players have certain beliefs and perceptions in relation to injury risk that have the potential to increase injuries. These negative beliefs need to be addressed in any comprehensive injury prevention strategy aimed at these players.


Hospital-level variation in inpatient cost among children receiving extracorporeal membrane oxygenation.
Pediatric extracorporeal membrane oxygenation (ECMO) varies in the way care is provided from hospital to hospital. This variability in hospital ECMO care can be represented by the variation in ECMO costs. We hypothesized that hospitals will demonstrate large variations in case-mix-adjusted ECMO inpatient costs for children requiring ECMO and higher volume hospitals will have lower associated costs. We retrospectively analyzed the inpatient cost of children receiving ECMO in 2006, 2009 and 2012, using the Healthcare Cost and Utilization Project Kids' Inpatient Database. We used a hierarchical linear regression model and the intraclass correlation coefficient to quantify how much of the difference in ECMO inpatient costs was associated with the hospital where a child received care. To do this, we adjusted for patient factors, hospital factors and potentially modifiable factors such as complications, procedures and length of stay. The median inflation-adjusted inpatient costs for children requiring ECMO were $183,000, $240,000 and $241,000 in years 2006, 2009 and 2012, respectively. The largest median cost for ECMO cases in a given hospital in a given year ($690,000) was more than 11 times that of the smallest median cost ($60,000). After case-mix adjustment, 27% of the variation in inpatient costs was associated with the hospital where ECMO care was provided. Average hospital costs were not associated with hospital ECMO volume. The large variation in ECMO inpatient costs between hospitals suggests great variation in care between hospitals, which is important because hospitals have a co-existing variation in ECMO survival rates.


Quantitative morphology of synaptic plasticity in the aging brain.
Quantitation of synaptic ultrastructural changes is of great importance in neurobiology, since merely qualitative alterations, if not extreme, are not readily detectable. In the present paper we discuss our previous and present findings on the number (numerical density: Nv), size (average length of the synaptic profiles: L) and surface contact area (surface density: Sv) of the synaptic junctions in aging rodent and human brains. We found that number and size of the synapses are in a close inverse relationship so as to maintain the total surface contact are among the nerve cells constant. These three parameters are closely related to each other, their quantitation may thus represent a reliable index of the morphological aspects of synaptic plasticity, i.e. the modification of ultrastructure occurring at synaptic membranes after transient changes in synaptic activity. During aging, the morphological plasticity of synapses appears to be seriously impaired: the number of synapses and the total surface contact area among the nerve cells are markedly reduced. However, old nerve cells seem to retain the ability to modify their synaptic endings and to partially compensate for the reduced surface density of the contact zones by expanding the average size of the persisting junctions. Our recent studies on synaptic plasticity in human brains from old and demented subjects showed that while the size of the synaptic contacts remains constant, the numerical and surface densities undergo a further decrease in demented brains relative to that in normal aging.


Visible-light-promoted synthesis of phenanthridines via an intermolecular isocyanide insertion reaction.
An isocyanide insertion reaction promoted by the combination of an amide and a photoredox is now presented. By using visible light, 6-amidophenanthridine derivatives can be prepared in good chemical yields under mild and eco-friendly reaction conditions. The reaction was shown to proceed through an electron transfer sequence by mechanistic experiments, and thus enabled the efficient production of 24 compounds, each with one new intramolecular aromatic ring obtained. The synthesized compounds were tested to embody good antitumor, antimicrobial and neuraminidase inhibitory activities.


[The neonatal hepatitis syndrome].
Syndrome of Neonatal hepatitis and atresia of extrahepatic bile ducts are the most frequent causes of jaundice with conjugated bilirubin in the small infant. The neonatal hepatitis is diagnosed by its plurietiologic character, onset in the first 3 months, subacute or chronic, potentially cirrhogenous, evolution, conjugated hyperbilirubinemia and mainly, gigantocellular hepatic transformation--the essential characteristic of the diagnosis. Etiology of neonatal hepatitis has extremely diverse causes: infectious causes, genetic diseases of metabolism, toxic causes, post-hemolytic states, neonatal acute hepatic necroses, parenteral nutrition, chromosomal anomalies, familial syndromes, etc.; there exists also a form with nonspecific cause (idiopathic form). Practically, neonatal hepatitis might often be mistaken for atresia of the extrahepatic bile ducts. In the latter case, the temporization of the surgery (bilidigestive anastomosis) for more than 2 months of cholestasis evolution leads to the appearance of hepatic cirrhosis lesions. The authors analyze various clinical, biological and histopathological elements which permit the differentiation in due time of the two situations that require different therapeutic attitudes. Except for certain situations, which allow an etiologic treatment, the main therapeutic element (pathogenic) is corticotherapy and several additional measures. The paper concludes with appreciations on the evolution, prognosis and prophylaxis possibilities.


Development of a system for genetic manipulation of Bartonella bacilliformis.
Lack of a system for site-specific genetic manipulation has severely hindered studies on the molecular biology of all Bartonella species. We report the first site-specific mutagenesis and complementation for a Bartonella species. A highly transformable strain of B. bacilliformis, termed JB584, was isolated and found to exhibit a significant increase in transformation efficiency with the broad-host-range plasmid pBBR1MCS-2, relative to wild-type strains. Restriction analyses of genomic preparations with the methylation-sensitive restriction enzymes ClaI and StuI suggest that strain JB584 possesses a dcm methylase mutation that contributes to its enhanced transformability. A suicide plasmid, pUB1, which contains a polylinker, a pMB1 replicon, and a nptI kanamycin resistance cassette, was constructed. An internal 508-bp fragment of the B. bacilliformis flagellin gene (fla) was cloned into pUB1 to generate pUB508, a fla-targeting suicide vector. Introduction of pUB508 into JB584 by electroporation generated eight Kan(r) clones of B. bacilliformis. Characterization of one of these strains, termed JB585, indicated that allelic exchange between pUB508 and fla had occurred. Analysis by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, immunoblotting, and electron microscopy showed that synthesis of flagellin encoded by fla and secretion/assembly of flagella were abolished. Complementation of fla in trans was accomplished with a pBBR1MCS recombinant containing the entire wild-type fla gene (pBBRFLAG). These data conclusively show that inactivation of fla results in a bald, nonmotile phenotype and that pMB1 and REP replicons make suitable B. bacilliformis suicide and shuttle vectors, respectively. When used in conjunction with the highly transformable strain JB584, this system for site-specific genetic manipulation and complementation provides a new venue for studying the molecular biology of B. bacilliformis.


Different SNP combinations in the GCH1 gene and use of labor analgesia.
The aim of this study was to investigate if there is an association between different SNP combinations in the guanosine triphosphate cyclohydrolase (GCH1) gene and a number of pain behavior related outcomes during labor. A population-based sample of pregnant women (n = 814) was recruited at gestational week 18. A plasma sample was collected from each subject. Genotyping was performed and three single nucleotide polymorphisms (SNP) previously defined as a pain-protective SNP combination of GCH1 were used. Homozygous carriers of the pain-protective SNP combination of GCH1 arrived to the delivery ward with a more advanced stage of cervical dilation compared to heterozygous carriers and non-carriers. However, homozygous carriers more often used second line labor analgesia compared to the others. The pain-protective SNP combination of GCH1 may be of importance in the limited number of homozygous carriers during the initial dilation of cervix but upon arrival at the delivery unit these women are more inclined to use second line labor analgesia.


Extracellular Matrix Structure and Composition in the Early Four-Chambered Embryonic Heart.
During embryonic development, the heart undergoes complex morphogenesis from a liner tube into the four chambers consisting of ventricles, atria and valves. At the same time, the cardiomyocytes compact into a dense, aligned, and highly vascularized myocardium. The extracellular matrix (ECM) is known to play an important role in this process but understanding of the expression and organization remains incomplete. Here, we performed 3D confocal imaging of ECM in the left ventricle and whole heart of embryonic chick from stages Hamburger-Hamilton 28-35 (days 5-9) as an accessible model of heart formation. First, we observed the formation of a fibronectin-rich, capillary-like networks in the myocardium between day 5 and day 9 of development. Then, we focused on day 5 prior to vascularization to determine the relative expression of fibronectin, laminin, and collagen type IV. Cardiomyocytes were found to uniaxially align prior to vascularization and, while the epicardium contained all ECM components, laminin was reduced, and collagen type IV was largely absent. Quantification of fibronectin revealed highly aligned fibers with a mean diameter of ~500 nm and interfiber spacing of ~3 µm. These structural parameters (volume, spacing, fiber diameter, length, and orientation) provide a quantitative framework to describe the organization of the embryonic ECM.


On-the-spot lung cancer differential diagnosis by label-free, molecular vibrational imaging and knowledge-based classification.
We report the development and application of a knowledge-based coherent anti-Stokes Raman scattering (CARS) microscopy system for label-free imaging, pattern recognition, and classification of cells and tissue structures for differentiating lung cancer from non-neoplastic lung tissues and identifying lung cancer subtypes. A total of 1014 CARS images were acquired from 92 fresh frozen lung tissue samples. The established pathological workup and diagnostic cellular were used as prior knowledge for establishment of a knowledge-based CARS system using a machine learning approach. This system functions to separate normal, non-neoplastic, and subtypes of lung cancer tissues based on extracted quantitative features describing fibrils and cell morphology. The knowledge-based CARS system showed the ability to distinguish lung cancer from normal and non-neoplastic lung tissue with 91% sensitivity and 92% specificity. Small cell carcinomas were distinguished from nonsmall cell carcinomas with 100% sensitivity and specificity. As an adjunct to submitting tissue samples to routine pathology, our novel system recognizes the patterns of fibril and cell morphology, enabling medical practitioners to perform differential diagnosis of lung lesions in mere minutes. The demonstration of the strategy is also a necessary step toward in vivo point-of-care diagnosis of precancerous and cancerous lung lesions with a fiber-based CARS microendoscope.


Survey of trainee attitudes to preparation for and participation in the FCEM examination.
In the UK, specialist trainees in emergency medicine are required to pass the Fellowship of the College of Emergency Medicine (FCEM). This examination assesses clinical knowledge, attitudes and skills, management principles, critical appraisal, and the ability to search medical literature and synthesise information. The aims of this study were to ascertain what resources trainees felt were most valuable in preparation for the FCEM and to obtain trainee feedback on the running of the FCEM. A questionnaire was developed in conjunction with the TSC into nine parts covering all aspects of preparation for and experience of sitting the FCEM. Email addresses of those trainees who had sat the FCEM examination in 2006 and 2007 were provided by the CEM and questionnaires were sent electronically to recipients. Responses were collated and analysed using Microsoft Excel. There was a response rate of 42% (86/203), of whom about three-quarters felt well prepared for the FCEM. The most highly valued resources for exam preparation were practice questions, private study and small group work. A yearly mock FCEM examination was felt to be important by those who had such access and local trainer involvement in exam preparation was perceived significant for success. Training programmes should make sure that facilities and expertise are available at a local level to allow trainees to have access to everything that is considered important in order to pass the FCEM.


Evaluation of the University of Minnesota Tri-plate and 3M Petrifilm for the isolation of Staphylococcus aureus and Streptococcus species from clinically mastitic milk samples.
The primary objective was to compare microbiological results of the University of Minnesota Tri-plate and the 3M Petrifilm Staph Express (STX) Count Plate to standard culture techniques for identification of clinical mastitis caused by Staphylococcus aureus. The secondary objective was to evaluate the Tri-plate's ability to differentiate Streptococcus spp. from other gram-positive organisms. The tests were evaluated using clinically positive mastitic milk samples (n = 282) to determine their ability to diagnose the pathogens of interest. A Tri-plate was classified positive for Staph. aureus when at least 1 colony exhibiting beta-hemolysis was present on the Factor media portion of the plate. When the plate was used in this manner and read by a trained laboratory technician, the sensitivity of the Tri-plate was 97.9% and the specificity was 81.8%. When the Tri-plate was evaluated by the laboratory technician for its ability to diagnose Streptococcus spp., both sensitivity and specificity of the test were very good (92.6 and 89.5%, respectively). Using the Petrifilm, samples were classified as positive for Staph. aureus if any red-violet colonies were present on the Petrifilm after an initial 24-h incubation. When used in this manner, the Petrifilm had a sensitivity of 97.4% and a specificity of 76.1%. Further evaluation of the Petrifilm was done using the STX disk, which was used to confirm the presence of Staph. aureus. When using the presence of 1 pink colony on the disk, the sensitivity of the Petrifilm was 92.1% and the specificity was 93.1%. Both the Tri-plate and the 3M STX Petrifilm successfully diagnosed Staph. aureus in clinical milk samples when used in a laboratory setting and the Tri-plate successfully differentiated Streptococcus spp. from other gram-positive organisms.


The influence of learning styles, enrollment status and gender on academic performance of optometry undergraduates.
This cross-sectional study was designed to determine whether the academic performance of optometry undergraduates is influenced by enrollment status, learning style or gender. Three hundred and sixty undergraduates in all 3 years of the optometry degree course at Aston University during 2008-2009 were asked for their informed consent to participate in this study. Enrollment status was known from admissions records. An Index of Learning Styles (http://www4.nscu.edu/unity/lockers/users/f/felder/public/Learning-Styles.html) determined learning style preference with respect to four different learning style axes; active-reflective, sensing-intuitive, visual-verbal and sequential-global. The influence of these factors on academic performance was investigated. Two hundred and seventy students agreed to take part (75% of the cohort). 63% of the sample was female. There were 213 home non-graduates (entrants from the UK or European Union without a bachelor's degree or higher), 14 home graduates (entrants from the UK or European Union with a bachelor's degree or higher), 28 international non-graduates (entrants from outside the UK or European Union without a bachelor's degree or higher) and 15 international graduates (entrants from outside the UK or European Union with a bachelor's degree or higher). The majority of students were balanced learners (between 48% and 64% across four learning style axes). Any preferences were towards active, sensing, visual and sequential learning styles. Of the factors investigated in this study, learning styles were influenced by gender; females expressed a disproportionate preference for the reflective and visual learning styles. Academic performance was influenced by enrollment status; international graduates (95% confidence limits: 64-72%) outperformed all other student groups (home non graduates, 60-62%; international non graduates, 55-63%) apart from home graduates (57-69%). Our research has shown that the majority of optometry students have balanced learning styles and, from the factors studied, academic performance is only influenced by enrollment status. Although learning style questionnaires offer suggestions on how to improve learning efficacy, our findings indicate that current teaching methods do not need to be altered to suit varying learning style preferences as balanced learning styles can easily adapt to any teaching style (Learning Styles and Pedagogy in Post-16 Learning: A Systematic and Critical Review. London, UK: Learning and Skills Research Centre, 2004).


Watervogels - Wintering waterbirds in Flanders, Belgium.
"Watervogels - Wintering waterbirds in Flanders, Belgium" is a sampling event dataset published by the Research Institute for Nature and Forest (INBO). It contains more than 94,000 sampling events (site counts), covering over 710,000 species observations (and zero counts when there is no associated occurrence) and 36 million individual birds for the period 1991-2016. The dataset includes information on 167 different species in nearly 1,100 wetland sites. The aim of these bird counts is to gather information on the size, distribution, and long-term trends of wintering waterbird populations in Flanders. These data are also used to assess the importance of individual sites for waterbirds, using quantitative criteria. Furthermore, the waterbird counts contribute to international monitoring programs, such as the International Waterbird Census (coordinated by Wetlands International) and fulfil some of the objectives of the European Bird Directive, the Ramsar Convention, and the Agreement on the Conservation of African-Eurasian Migratory Waterbirds (AEWA). Here the dataset is published as a standardized Darwin Core Archive and includes for each event: a stable event ID, date and location of observation and a short description of the sampling protocol, effort and conditions (in the event core), supplemented with specific information for each occurrence: a stable occurrence ID, the scientific name and higher classification of the observed species, the number of recorded individuals, and a reference to the observer of the record (in the occurrence extension). Issues with the dataset can be reported at https://github.com/inbo/data-publication/issues. The following information is not included in this dataset and available upon request: roost site counts, counts from historical (inactive) locations and counts from before 1991. We have released this dataset to the public domain under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication (https://creativecommons.org/publicdomain/zero/1.0/). We would appreciate it if you follow the INBO norms for data use (https://www.inbo.be/en/norms-data-use) when using the data. If you have any questions regarding this dataset, do not hesitate to contact us via the contact information provided in the metadata or via email@example.com.


Rectus Sheath Haematoma Secondary to Enoxaparin Injection- A Rare Case Report.
Rectus sheath haematoma is a well-documented condition with an elusive diagnosis. It is an uncommon complication of anti-coagulation therapy, which can have a mortality of upto 25%. The patient discussed here is a 40-year-old female who was on Inj. Enoxaparin, who developed severe abdominal pain and hypovolemia after three days of treatment. Ultrasonography and CT scan showed a large rectus sheath haematoma on the right side, which was crossing the midline towards the left side. Inj. Enoxaparin was stopped and the patient was posted for surgery. In surgery, all clots were evacuated and inferior epigastric vessels were ligated. Patient recovered well following surgery. Here, this report presents forward a case of rectus sheath haematoma secondary to enoxaparin injection, its presentation and its surgical management.


Investigation of an HIV transmission cluster centred in South Wales.
To describe an HIV transmission cluster centred in South Wales by the analysis of partner notification outcomes and demographic characteristics of individuals identified in the sexual network. After diagnosis of the index case, HIV testing and partner notification were undertaken by Cardiff Genitourinary Medicine Clinic in collaboration with the local Health Protection Team, National Public Health Service for Wales and Terrence Higgins Trust Cymru. Rapid test and standard venepuncture methods were used for HIV screening and the resulting clinical and behavioural data were analysed. Of the 123 individuals identified in the sexual network, all were men who had sex with men (MSM) except for seven men who self-identified as bisexual and five heterosexual women. Fifteen new cases of HIV were diagnosed; all were men. Partner notification outcomes are as follows: 104 provider referrals were made, 57 were successfully contacted with known outcomes, 14 were successfully contacted but with unknown outcomes and 33 were uncontactable. Fifteen patient referrals were made, 11 had known outcomes but four had unknown outcomes. Four patients self-referred. Eleven reported previous HIV diagnosis. The sexual network was distributed over South and West Wales extending into England, with high reported rates of unprotected anal intercourse, previous HIV tests and concurrent sexually transmitted infections. A one in four positive rate for those with a known HIV status outcome and a 68% provider referral success rate compares favourably with other studies. Partner notification revealed a relatively young, well-educated HIV network with high-risk behaviour and ongoing transmission despite previous knowledge and awareness of HIV. This analysis adds to the evidence supporting HIV partner notification in MSM.


Smart use of data, information and communication: the INFORM-ed Best Local Practice Project--Grafton Base Hospital.
This paper describes current progress for an information management project in a medium-sized rural hospital after the first four months of the one-year project. In particular, the article examines some of the project outcomes to date as these relate to the National Hospitals and Health Reform recommendations for the smart use of data, information and communication. The paper identifies a number of important challenges and issues that have been addressed by the project and proposes that the project findings may be used to inform similar projects in other settings. These findings relate to clinician requirements for reports, investment in human resources, development, and time for information management activities. An understanding of data collected, information systems, and presentation of clinician data are also important. The benefits of information sharing in assisting quality improvement activities are particularly relevant but, more importantly, they can engage and involve clinicians in the use of information. The importance of local data, information, and knowledge is described. Finally, issues for the health information management profession, such as working collegially and sharing knowledge and expertise, are outlined.


Home-based chlamydia testing of young people attending a music festival--who will pee and post?
Chlamydia is most common among young people, but only a small proportion of Australian young people are tested annually. Home-based chlamydia testing has been piloted in several countries to increase testing rates, but uptake has been low. We aimed to identify predictors of uptake of home-based chlamydia testing to inform future testing programs. We offered home-based chlamydia testing kits to participants in a sexual behaviour cross-sectional survey conducted at a music festival in Melbourne, Australia. Those who consented received a testing kit and were asked to return their urine or vaginal swab sample via post. Nine hundred and two sexually active music festival attendees aged 16-29 completed the survey; 313 (35%) opted to receive chlamydia testing kits, and 67 of 313 (21%) returned a specimen for testing. One participant was infected with chlamydia (1% prevalence). Independent predictors of consenting to receive a testing kit included older age, knowing that chlamydia can make women infertile, reporting more than three lifetime sexual partners and inconsistent condom use. Independent predictors of returning a sample to the laboratory included knowing that chlamydia can be asymptomatic, not having had an STI test in the past six months and not living with parents. A low proportion of participants returned their chlamydia test, suggesting that this model is not ideal for reaching young people. Home-based chlamydia testing is most attractive to those who report engaging in sexual risk behaviours and are aware of the often asymptomatic nature and potential sequelae of chlamydia infection.


Anti-inflammatory effects of gallic acid in human gestational tissues in vitro.
Spontaneous preterm birth is the leading cause of neonatal mortality and morbidity globally. Activation of the maternal immune system leads to a downstream cascade of proinflammatory events that culminate in the activation of spontaneous uterine contractions and the rupture of the foetal membranes. Anti-inflammatory agents may be a novel therapeutic approach to prevent inflammation-induced myometrial contractions and premature rupture of foetal membranes. The polyphenol gallic acid has been previously shown to exert potent anti-inflammatory effects. Thus, this study aimed to determine the effect of gallic acid on proinflammatory and pro-labour mediators in cytokine-stimulated gestational tissues in vitro. In primary human cells isolated from myometrium and foetal membranes (decidua, and amnion mesenchymal and epithelial cells), gallic acid treatment suppressed inflammation-induced expression of proinflammatory cytokines and chemokines and extracellular matrix-degrading and matrix-remodelling enzymes. Gallic acid also significantly inhibited inflammation-induced myometrial activation as evidenced by decreased expression of contraction-associated proteins, the uterotonic PGF2α and collagen cell contractility. Using a global proteomic approach, gallic acid may differentially regulate proteins associated with collagen synthesis, cell contractility and protein synthesis in primary myometrial and decidual cells. In summary, gallic acid inhibited inflammation-induced mediators involved in active labour in primary cells isolated from myometrium and foetal membranes. These in vitro studies suggest that the polyphenol gallic acid may be able to suppress the production of proinflammatory and pro-labour mediators involved in myometrial contractions and rupture of foetal membranes. Future preclinical studies may elucidate the efficacy of gallic acid in preventing inflammation-driven preterm birth.


Healthcare professionals' perspectives on development of assistive technology using the comprehensive assistive technology model.
The implementation of technology in healthcare shows promising results and provides new opportunities in rehabilitation. However, the adoption of technology into daily care is largely dependent on the acceptance rate of end-users. This study aims to gather information from healthcare professionals on the development of new assistive technology that match users' needs using the Comprehensive Assistive Technology model. In total 27 healthcare professionals (12 occupational therapists, 8 physiotherapists, 3 nurses, 2 allied health directors, a physician and a speech therapist) attended one of four online focus group discussions. These focus group discussions were structured using a question guide based on three predefined scenarios. Recordings were transcribed and data was analyzed using a thematic analysis (NVivo). Major themes identified in this study were safety, price and usability. Healthcare professionals focused on both functional capabilities of the user, as well as behavioral aspects of usability and attitude toward technology. Furthermore, the need for assistive technology that were catered toward the limitations in activity and user experience, was highlighted extensively. Based on information gathered from healthcare professionals a user-centered approach in development of safe, low-cost devices that maximize both functional outcomes and user acceptance, could potentially increase the adoption of new technology in rehabilitation.


Mosaic structure of plasmids from natural populations of Escherichia coli.
The distribution of plasmids related to the fertility factor F was examined in the ECOR reference collection of Escherichia coli. Probes specific for four F-related genes were isolated and used to survey the collection by DNA hybridization. To estimate the genetic diversity of genes in F-like plasmids, DNA sequences were obtained for four plasmid genes. The phylogenetic relationships among the plasmids in the ECOR strains is very different from that of the strains themselves. This finding supports the view that plasmid transfer has been frequent within and between the major groups of ECOR. Furthermore, the sequences indicate that recombination between genes in plasmids takes place at a considerably higher frequency than that observed for chromosomal genes. The plasmid genes, and by inference the plasmids themselves, are mosaic in structure with different regions acquired from different sources. Comparison of gene sequences from a variety of naturally occurring plasmids suggested a plausible donor of some of the recombinant regions as well as implicating a chi site in the mechanism of genetic exchange. The relatively high rate of recombination in F-plasmid genes suggests that conjugational gene transfer may play a greater role in bacterial population structure than previously appreciated.


Cardiac Energetics in Patients With Aortic Stenosis and Preserved Versus Reduced Ejection Fraction.
Why some but not all patients with severe aortic stenosis (SevAS) develop otherwise unexplained reduced systolic function is unclear. We investigate the hypothesis that reduced creatine kinase (CK) capacity and flux is associated with this transition. We recruited 102 participants to 5 groups: moderate aortic stenosis (ModAS) (n=13), SevAS, left ventricular (LV) ejection fraction ≥55% (SevAS-preserved ejection fraction, n=37), SevAS, LV ejection fraction <55% (SevAS-reduced ejection fraction, n=15), healthy volunteers with nonhypertrophied hearts with normal systolic function (normal healthy volunteer, n=30), and patients with nonhypertrophied, non-pressure-loaded hearts with normal systolic function undergoing cardiac surgery and donating LV biopsy (non-pressure-loaded heart biopsy, n=7). All underwent cardiac magnetic resonance imaging and 31P magnetic resonance spectroscopy for myocardial energetics. LV biopsies (AS and non-pressure-loaded heart biopsy) were analyzed for CK total activity, CK isoforms, citrate synthase activity, and total creatine. Mitochondria-sarcomere diffusion distances were calculated by using serial block-face scanning electron microscopy. In the absence of failure, CK flux was lower in the presence of AS (by 32%, P=0.04), driven primarily by reduction in phosphocreatine/ATP (by 17%, P<0.001), with CK kf unchanged (P=0.46). Although lowest in the SevAS-reduced ejection fraction group, CK flux was not different from the SevAS-preserved ejection fraction group (P>0.99). Accompanying the fall in CK flux, total CK and citrate synthase activities and the absolute activities of mitochondrial-type CK and CK-MM isoforms were also lower (P<0.02, all analyses). Median mitochondria-sarcomere diffusion distances correlated well with CK total activity (r=0.86, P=0.003). Total CK capacity is reduced in SevAS, with median values lowest in those with systolic failure, consistent with reduced energy supply reserve. Despite this, in vivo magnetic resonance spectroscopy measures of resting CK flux suggest that ATP delivery is reduced earlier, at the moderate AS stage, where LV function remains preserved. These findings show that significant energetic impairment is already established in moderate AS and suggest that a fall in CK flux is not by itself a necessary cause of transition to systolic failure. However, because ATP demands increase with AS severity, this could increase susceptibility to systolic failure. As such, targeting CK capacity and flux may be a therapeutic strategy to prevent and treat systolic failure in AS.


Implementation of marine spatial planning in shellfish aquaculture management: modeling studies in a Norwegian fjord.
Shellfish carrying capacity is determined by the interaction of a cultured species with its ecosystem, which is strongly influenced by hydrodynamics. Water circulation controls the exchange of matter between farms and the adjacent areas, which in turn establishes the nutrient supply that supports phytoplankton populations. The complexity of water circulation makes necessary the use of hydrodynamic models with detailed spatial resolution in carrying capacity estimations. This detailed spatial resolution also allows for the study of processes that depend on specific spatial arrangements, e.g., the most suitable location to place farms, which is crucial for marine spatial planning, and consequently for decision support systems. In the present study, a fully spatial physical-biogeochemical model has been combined with scenario building and optimization techniques as a proof of concept of the use of ecosystem modeling as an objective tool to inform marine spatial planning. The object of this exercise was to generate objective knowledge based on an ecosystem approach to establish new mussel aquaculture areas in a Norwegian fjord. Scenario building was used to determine the best location of a pump that can be used to bring nutrient-rich deep waters to the euphotic layer, increasing primary production, and consequently, carrying capacity for mussel cultivation. In addition, an optimization tool, parameter estimation (PEST), was applied to the optimal location and mussel standing stock biomass that maximize production, according to a preestablished carrying capacity criterion. Optimization tools allow us to make rational and transparent decisions to solve a well-defined question, decisions that are essential for policy makers. The outcomes of combining ecosystem models with scenario building and optimization facilitate planning based on an ecosystem approach, highlighting the capabilities of ecosystem modeling as a tool for marine spatial planning.


Food intake and neuronal activation after acute 2DG treatment are attenuated during lactation.
In the present study, we compared the ability of acute peripheral 2-deoxy--glucose (2DG) treatment to induce food intake and increase immediate early gene expression in lactating versus virgin female rats. In Experiment 1, virgin and lactating rats were treated intraperitoneally with either saline or 2DG (400 mg/kg) and their food intake was compared across the next 6 h. In Experiment 2, lactating and virgin rats were given saline or 2DG, sacrificed 1 h later, and their brains were processed for Fos-like immunocytochemistry (FLI). The average number of cells expressing Fos protein within different brain regions was compared among the different groups. Statistical analyses of the data from Experiment 1 show that 2DG produces an increase in food intake in virgin rats, but not in lactating rats. These data correlate with the results from Experiment 2, where 2DG treatment resulted in an increase in FLI within the caudal ventrolateral medulla (cVLM), the paraventricular nucleus of the hypothalamus (PVN), and the supraoptic nucleus of the hypothalamus (SON) of cycling females. In lactating rats, however, 2DG failed to increase FLI in these regions. Together, these results show that the 2DG-induced food intake response is attenuated during lactation and this attenuation is reflected in the activation of neuronal groups that are thought to participate specifically in the food intake response to glucoprivation. Processes mediating this differential response are discussed in terms of the hormonal and metabolic changes that are characteristic of lactation.


Morphology of a highly asymmetric double crystallizable poly(epsilon-caprolactone-b-ethylene oxide) block copolymer.
The morphology of a highly asymmetric double crystallizable poly(epsilon-caprolactone-b-ethylene oxide) (PCL-b-PEO) block copolymer has been studied with in situ simultaneously small and wide-angle x-ray scattering as well as atomic force microscopy. The molecular masses Mn of the PCL and PEO blocks are 24,000 and 5800, respectively. X-ray scattering and rheological measurements indicate that no microphase separation occurs in the melt. Decreasing the temperature simultaneously triggers off a crystallization of PCL and microphase separation between the PCL and PEO blocks. Coupling and competition between microphase separation and crystallization results in a morphology of PEO spheres surrounded by PCL partially crystallized in lamella. Further decreasing temperature induces the crystallization of PEO spheres, which have a preferred orientation due to the confinements from hard PCL crystalline lamella and from soft amorphous PCL segments in different sides. The final morphology of this highly asymmetric block copolymer is similar to the granular morphology reported for syndiotactic polypropylene and other (co-) polymers. This implies a similar underlying mechanism of coupling and competition of various phase transitions, which is worth further exploration.


Measurements of the force produced by the mitotic spindle in anaphase.
The force the spindle exerts on a single moving chromosome in anaphase was measured with a flexible glass needle calibrated in dynes per micron of tip deflection. The needle was used to produce a force on the chromosome, which opposed that produced by the spindle and was measurable from needle tip deflection. The measurements were made in intact grasshopper spermatocytes after proving that the presence of materials such as the cell surface did not interfere. The results from 12 experiments in seven cells are as follows: Chromosome velocity was not affected until the opposing force reached approximately 10(-5) dyn, and then fell rapidly with increasing force. The opposing force that caused chromosome velocity to fall to zero--the force that matched the maximum force the spindle could produce--was of order 7 X 10(-5) dyn. This directly measured maximum force potential is nearly 10,000 times greater than the calculated value of 10(-8) dyn for normal chromosome movement, in which only viscous resistance to movement must be overcome. The spindle's unexpectedly large force potential prompts a fresh look at molecular models for the mitotic motor, at velocity-limiting governors, and at the possibility that force may sometimes affect microtubule length and stability.


Efficacy and safety of sirolimus-eluting stents versus bare-metal stents in coronary artery disease patients with diabetes: a meta-analysis.
To compare by meta-analysis the efficacy and safety of sirolimus-eluting and bare-metal stents in coronary artery disease (CAD) patients with diabetes. PubMed, MEDLINE and EMBASE were searched from 1971 to 2012. Data on the efficacy and safety of sirolimus-eluting and bare-metal stents in patients with diabetes were collected. A meta-analysis was then performed on a total of 1 259 CAD patients with diabetes from six studies. The odds ratio (OR) was used for comparison. Subgroup analysis was performed according to the sample size, year of study, subjects' geographic area and study method. Compared with those in the bare-metal stent group (BMS), the subjects in the sirolimus-eluting stent (SES) group had a reduced risk for major cardiac events [OR 0.42, 95% confidence interval (CI): 024-0.74, p < 0.01] and target-lesion revascularisation (OR 0.26, 95% CI: 0.11 - 0.59, p < 0.01). There was no difference for myocardial infarction (OR 0.92, 95% CI: 0.61-1.40, p > 0.05) or mortality (OR 1.19, 95% CI: 0.74-1.92, p > 0.05). Subgroup analysis showed a significant difference for overall risk of major cardiac events between SES and BMS when the sample size was ≤ 90 (OR 0.28, 95% CI: 0.16-0.48, p < 0.01), when it was a randomised control trial (RCT) (OR 0.28, 95% CI: 0.19-0.42, p < 0.01), or when it was performed on European subjects (OR 0.45, 95% CI: 0.27-0.77, p < 0.01). The sensitivity was not different when one study was removed at a time. Our study confirmed that SES are safer and more effective than BMS in CAD patients with diabetes, as far as major cardiac events are concerned.


Selective suppression of pathologic, but not physiologic, retinal neovascularization by blocking the angiotensin II type 1 receptor.
To investigate the anti-inflammatory and anti-angiogenic effects of telmisartan, an angiotensin II type 1 receptor (AT1-R) antagonist, on ischemia-induced retinal neovascularization. C57BL/6 neonatal mice were reared in an 80% concentration of oxygen from postnatal day (P)7 to P12, followed by room-air breathing until P17, to induce ischemia-initiated retinal neovascularization (i.e., a murine model of ischemic retinopathy). Tissue localization of AT1-R was examined by immunohistochemistry for murine retinal wholemounts and human fibrovascular tissues excised at vitrectomy for proliferative diabetic retinopathy. Animals received intraperitoneal injection of telmisartan or vehicle. A concanavalin A lectin perfusion-labeling technique was used to evaluate the areas of physiological and pathologic retinal new vessels and the number of leukocytes adhering to the vasculature. Retinal mRNA and protein levels of intercellular adhesion molecule (ICAM)-1, vascular endothelial growth factor receptor (VEGFR)-1, and VEGFR-2 were examined by RT-PCR and ELISA. Vessels in human fibrovascular tissues and the murine retinas were positive for AT1-R. Pathologic (P < 0.01), but not physiologic (P > 0.05), retinal neovascularization was significantly suppressed in telmisartan-treated mice compared with vehicle-treated animals. The number of adherent leukocytes (P < 0.01) was also significantly reduced, together with retinal ICAM-1 levels (P < 0.01) in the telmisartan-treated group compared with the control group. No significant difference was detected in retinal VEGFR-2 levels between the two groups, whereas retinal VEGFR-1 levels in the telmisartan-treated group were significantly (P < 0.05) lower than in the vehicle-treated group. The present findings suggest that the AT1-R signaling blockade leads to the selective suppression of pathologic, but not physiological, retinal neovascularization through the inhibition of the inflammatory processes related to pathologic neovascularization.


Characterization of new ACADSB gene sequence mutations and clinical implications in patients with 2-methylbutyrylglycinuria identified by newborn screening.
Short/branched chain acyl-CoA dehydrogenase (SBCAD) deficiency, also known as 2-methylbutyryl-CoA dehydrogenase deficiency, is a recently described autosomal recessive disorder of isoleucine metabolism. Most patients reported thus far have originated from a founder mutation in the Hmong Chinese population. While the first reported patients had severe disease, most of the affected Hmong have remained asymptomatic. In this study, we describe 11 asymptomatic non-Hmong patients brought to medical attention by elevated C5-carnitine found by newborn screening and one discovered because of clinical symptoms. The diagnosis of SBCAD deficiency was determined by metabolite analysis of blood, urine, and fibroblast samples. PCR and bidirectional sequencing were performed on genomic DNA from five of the patients covering the entire SBCAD (ACADSB) gene sequence of 11 exons. Sequence analysis of genomic DNA from each patient identified variations in the SBCAD gene not previously reported. Escherichia coli expression studies revealed that the missense mutations identified lead to inactivation or instability of the mutant SBCAD enzymes. These findings confirm that SBCAD deficiency can be identified through newborn screening by acylcarnitine analysis. Our patients have been well without treatment and call for careful follow-up studies to learn the true clinical impact of this disorder.


Immunohistochemical detection of haem oxygenase in AA amyloidogenesis.
Haem oxygenase (HO)-1, a rate-limiting enzyme in the degradation of haem, is increased in Alzheimer's disease and in inflammations such as AA amyloidosis. However, the specific association of HO-1 is poorly understood in AA amyloidosis. In this study, we designed the experiment to reveal the contribution and association of HO-1 in the spleen during experimental murine AA amyloidosis. Experimental murine AA amyloidosis was induced with injection of an emulsion consisting of Freund's complete adjuvant and Mycobacterium butyricum. The serum amyloid A level was highest on day 3. The distribution of cells containing iron, indicating an increase of HO-1 in the red pulp, was detected with Berlin blue staining. AA amyloid formation was immunohistochemically detected as a marker by chondroitin sulphate proteoglycan (CSPG), one of the components of AA amyloid fibrils. Immunolocalizations of HO-1 and CSPG indicated a conspicuous increase and scattering of positive cells in the red pulp of the spleen. Double positive cells were not detected. On day 7, amyloid deposition was detected with Congo red staining in the extracellular spaces in the marginal zone of the white pulp in the spleen and HO-1-positive cells accumulated near the amyloid deposition area. CSPG was detected within the cells and also localized in the amyloid deposition area. CSPG was still not localized in the HO-1-positive cells. Double positive cells of HO-1 and CSPG were localized in the red pulp and in the amyloid deposition area on day 14. X-ray microanalysis indicated the existence of iron in the electron-dense bodies of fibroblasts in the amyloid deposition areas. The fibroblasts extended amyloid fibrils into the extracellular spaces of the marginal zone. These results suggest that HO-1-positive fibroblasts, but not HO-1-positive macrophages, are associated with the late stage of amyloid fibril formation.


Postmortem forensic toxicology of selective serotonin reuptake inhibitors: a review of pharmacology and report of 168 cases.
This paper reviews the complex pharmacology of the new class of antidepressant medications exhibiting selective inhibition of serotonin reuptake. The four selective serotonin reuptake inhibitors (SSRIs) considered--fluoxetine, fluvoxamine, sertraline and paroxetine--can result in toxicity and death through contributing to serotonergic excess resulting in serotonin syndrome, inhibiting the metabolism of other centrally acting drugs, leading to accumulation of toxic concentrations, and exerting complex vasoactive effects on the vascular smooth muscle. This latter feature is of particular concern in patients with preexisting heart disease. An analytical method involving isolation of the drugs by liquid/liquid extraction at alkaline pH into n-butyl chloride, and analysis by gas chromatography/mass spectrometry (GC/MS) is described, together with some of its limitations. Toxicologic and cause and manner of death data were examined in 60 deaths involving fluoxetine, 5 involving fluvoxamine, 75 involving sertraline, and 28 involving paroxetine. Deaths involving drug toxicity were generally a result of ingestion of multiple drugs, and in only a small number of the cases was death attributed principally to the SSRI involved. The potential for drug interactions between members of this class of drugs is discussed as well as their metabolites and a variety of other therapeutic and abused drugs which can contribute to their toxicity. In the absence of other risk factors, the lowest concentrations determined to have resulted in death were 0.63 mg/L for fluoxetine, 0.4 mg/L for paroxetine, and 1.5 mg/L for sertraline. We had insufficient data to make even this crude assessment for fluvoxamine. Drug-induced elevation of serotonin concentrations may be a significant risk factor for patients with atherosclerotic cardiovascular disease (ASCVD). Other factors including preexisting disease and the presence of other drugs and their pharmacology need to be carefully considered before determining the appropriate cause and manner of death in these cases.


Certification of null corrector by a single spherical lens.
In order to certify the accuracy of a null corrector, a method using a single spherical lens is proposed in this paper. An inversed optical path of the infinite conjugated null corrector is introduced, and the aberrations are compensated by using the certifying lens with a reflective inner surface. Initial configurations of the certifying lens are deduced from the aberration characteristics of the null test. A F1.33 ellipsoidal mirror's null corrector is taken for an example. Based on the calculated parameters of the certifying lens, the contribution of the surface's spherical aberration is set as a merit function in the optimization. The root-mean-square wavefront error of the optimized design is 0.0016λ (λ=632.8 nm). The method in this paper is simple and low-cost, compared with the existing methods.


Hemorrhage rate in patients with Spetzler-Martin grades IV and V arteriovenous malformations: is treatment justified?
We sought to examine the prospective annual risk of hemorrhage in patients harboring Spetzler-Martin grades IV and V arteriovenous malformations (AVMs) before and after initiation of treatment. Medical records of 61 consecutive patients presenting with Spetzler-Martin grades IV and V AVMs were retrospectively reviewed for demographics, angiographic features, presenting symptom(s), and time of all hemorrhage events, before or after treatment initiation. Pretreatment hemorrhage rates (excluding hemorrhages at presentation) and posttreatment rates were subsequently calculated. Modified Rankin Scale (mRS) scores before and after treatment were recorded. The annual pretreatment hemorrhage rate for all patients was 10.4% per year (95% CI, 2.2 to 15.4%), 13.9% (95% CI, 3.5 to 22.1%) in patients with hemorrhagic presentation and 7.3% (2.6 to 14.3%) in patients with nonhemorrhagic presentation. Posttreatment hemorrhage rates were 6.1% per year (95% CI, 2.5 to 13.2%) for all patients, 5.6% (95% CI, 2.1 to 11.8%) for patients presenting with hemorrhage and 6.4% (95% CI, 1.6 to 10.1%) in patients with nonhemorrhagic presentation. A noninferiority test showed that the posttreatment hemorrhage rate was less than or equal to the pretreatment hemorrhage rate (P<0.0001), with some indication that the reduction was greatest in patients with hemorrhagic presentation. Of the 62 patients, 51 (82%) had an mRS score of 0 to 2 before treatment, and 47 (76%) had an mRS score of 0 to 2 at the last follow-up after treatment. The annual rate of hemorrhage in grades IV and V AVMs is higher in this series than reported for all AVMs, which may reflect some referral bias in this single-center study. Nevertheless, initiation of treatment does not appear to increase the rate of subsequent hemorrhage. Treatment for these lesions may be warranted, given their poor natural history.


Morbidity among bystanders of bullying behavior at school: concepts, concerns, and clinical/research issues.
The role of the bystander is not one that is easily understood in the anti-bullying literature. Roles within the unofficial hierarchy of the school-yard and playground overlap considerably, and each role has its own social dynamic that brings with it a shifting behavioral landscape that affects every student. In this article, the mental health correlates of three categories of bystander are explored: the co-victim, the isolate, and the confederate. Each category of bystander has its own characterizations and mental health correlates. Reports of post-traumatic stress, internalized hostility, substance use, and suicide ideation are discussed with reference to studies involving witnesses of family abuse, community and school violence as well as bullying. It is argued that bystanders are the key to challenging bullying in schools, and their mental health and well-being is pivotal to the effectiveness of anti-bullying interventions.


Relation of Adiponectin to All-Cause Mortality, Cardiovascular Mortality, and Major Adverse Cardiovascular Events (from the Dallas Heart Study).
Adiponectin is a key component in multiple metabolic pathways. Studies evaluating associations of adiponectin with clinical outcomes in older adults have reported conflicting results. We investigated the association of adiponectin with mortality and cardiovascular disease (CVD) morbidity in a young, multiethnic adult population. We analyzed data from participants in the Dallas Heart Study without baseline CVD who underwent assessment of total adiponectin from 2000 to 2002. The primary outcome of all-cause mortality was assessed over median 10.4 years of follow-up using multivariable-adjusted Cox proportional hazards models. Secondary outcomes included CVD mortality, major adverse cardiovascular and cerebrovascular events (MACCE), and heart failure (HF). The study cohort included 3,263 participants, mean age 43.4 years, 44% women, and 50% black. There were 184 deaths (63 CVD), 207 MACCE, and 46 HF events. In multivariable models adjusted for age, gender, race, hypertension, diabetes, smoking, high-density lipoprotein cholesterol-C, hyperlipidemia, high-sensitivity C-reactive protein level, estimated glomerular filtration rate, and body mass index, increasing adiponectin quartiles were positively associated with all-cause mortality Q4 versus Q1 (hazard ratio [HR] = 2.27; 95% confidence interval [CI] 1.47, 3.50); CVD mortality Q4 versus Q1 (HR = 2.43; 95% CI 1.15, 5.15); MACCE Q4 versus Q1 (HR = 1.71; 95% CI 1.13, 2.60); and HF Q4 versus Q1 (HR = 2.95; 95% CI 1.14, 7.67). Findings were similar with adiponectin as a continuous variable and consistent across subgroups defined by age, gender, race, obesity, diabetes, metabolic syndrome, or elevated high-sensitivity C-reactive protein. In conclusion, higher adiponectin was associated with increased mortality and CVD morbidity in a young, multiethnic population. These findings may have implications for strategies aimed at lowering adiponectin to prevent adverse outcomes.


Prinzmetal angina: An unrecognized cause of recurrent ST elevation myocardial infarction.
Prinzmetal's angina is characterized by a transient reduction in luminal diameter of a coronary artery resulting in spontaneous and often recurrent episodes of angina with electrocardiography (ECG) findings consistent with ST elevation. A 67-year-old male presented with complaint of intermittent chest discomfort during the previous 2-3 weeks. ECG obtained at presentation was consistent with ST elevation in inferior leads. The patient underwent urgent cardiac catheterization with uncomplicated balloon angioplasty to proximal and distal right coronary artery (RCA). At two-week follow up, the patient continued to complain of recurrent chest discomfort with repeat ECG showing ST elevation in inferior leads. He was given nitroglycerin with symptomatic improvement and gradual resolution of ST elevation. Given concern for reocclusion, the patient again underwent urgent cardiac catheterization showing subtotal occlusion of the proximal RCA. During the procedure, intracoronary nitroglycerin was administered with visible resolution of the occlusion via angiography consistent with coronary vasospasm. The patient was therefore initiated on therapy with amlodipine and isosorbide mononitrate and remained symptom free at subsequent follow-up visits. Prinzmetal's angina is a well-documented but under-recognized etiology of recurrent ST elevation myocardial infarction which should be considered in those with both typical and atypical cardiovascular risk profiles.


Segregant-defective heterokaryons of Candida albicans.
Heterokaryons (hets) of the asexual, pathogenic yeast Candida albicans obtained by fusing protoplasts of complementing auxotrophic strains generate large numbers of parental-type auxotrophic monokaryons by random assortment of single nuclei into blastospores, and smaller numbers of monokaryons bearing hybrid nuclei formed through either karyogamy or the transfer of genetic material from one het nucleus to another. Het populations grown at 30 degrees C or 37 degrees C contain high frequencies (approx. 5%-10%) of two kinds of stable variants peculiar specifically for segregation of parental-type monokaryons: NS variants produce inviable auxotrophic monokaryons of one or both parental classes while AT variants yield parental-type monokaryons which grow very slowly. Variant frequencies are not affected by the wild-type strain background of hets, or the auxotrophies used to force heterokaryosis. However, both kinds of variants are induced by growth at 25 degrees C or by treatments with certain chemical or physical metabolic inhibitors. Evidence is presented that variant nuclei of independent origins carry different nutritionally irreparable recessive lethal (NS) or debilitating (AT) defects acquired in the course of actual or potential internuclear transfers of genetic material within het cells. The high incidence of variants, therefore, indicates considerable intrinsic genetic instability among het nuclei. Significances of these observations for parasexual genetic analyses of C. albicans and other yeasts through protoplast fusions are considered.


Transplantation of mesenchymal stem cells embedded in Atelocollagen gel to the intervertebral disc: a potential therapeutic model for disc degeneration.
Intervertebral disc degeneration is considered to be one of the major causes of low back pain. Despite this irreversible phenomenon, attempts to decelerate disc degeneration using various techniques have been reported. However, to date there has been no proven technique effective for broad clinical application. Based on previous studies, we hypothesize that maintenance of proteoglycan content in the disc is achieved by avoiding the depletion of nucleus pulposus and preserving the structure of the annulus is a primary factor in decelerating disc degeneration. One novel approach to solve the dilemma of intervertebral disc degeneration is found at the stem cell level. Mesenchymal stem cells (MSCs) are known to possess the ability to differentiate into various kinds of cells from mesenchymal origin. Although the majority of cells that contribute to disc formation are known to obtain chondrocyte-like phenotypes, no reported study has emphasized the correlation with mesenchymal stem cells. To evaluate the possible potential of MSCs in disc cell research and treatment of degenerative disc disease, autologous MSCs embedded in Atelocollagen gel were transplanted into the discs of rabbits which had undergone a procedure proven to induce degeneration. The results suggest that MSC transplantation is effective in decelerating disc degeneration in experimental models and provided new hopes for treatment of degenerative disc disease in humans. Atelocollagen gel served as an important carrier of MSCs in transplantation, permitting proliferation, matrix synthesis and differentiation of MSCs. This study strengthens the viable efficacy of practical application of MSCs in treatment of intervertebral disc disease.


Intake of Vegetables and Fruits Through Young Adulthood Is Associated with Better Cognitive Function in Midlife in the US General Population.
Vegetables and fruits (VF) may differentially affect cognitive functions, presumably due to their various nutrient contents, but evidence from epidemiologic studies is limited. The aim of this study was to examine the long-term association between VF intakes, including VF subgroups, in young adulthood and cognitive function in midlife. A biracial cohort of 3231 men and women aged 18-30 y at baseline in 1985-1986 were followed up for 25 y in the Coronary Artery Risk Development in Young Adults Study. Diet was measured at baseline, and in examination years 7 and 20. Cognitive function was assessed at examination year 25 through the use of 3 tests: the Rey Auditory Verbal Learning Test (RAVLT), the Digit Symbol Substitution Test (DSST), and the Stroop test. The mean differences (MDs) with 95% CIs in cognitive scores across intake categories were estimated through the use of the multivariable-adjusted general linear regression model. Excluding potatoes, intake of whole vegetables was significantly associated with a better cognitive performance after adjustment for potential confounders in all 3 cognitive tests (quintile 5 compared with quintile 1-RAVLT, MD: 0.33; 95% CI: 0.01, 0.64; P-trend = 0.08; DSST, MD: 2.84; 95% CI: 0.93, 4.75; P-trend < 0.01; Stroop test, MD: -2.87; 95% CI: -4.24, -1.50; P-trend < 0.01]. Similarly, intake of fruits, except fruit juices, was significantly related to a better cognitive performance (quintile 5 compared with quintile 1-DSST, MD: 2.41; 95% CI: 0.70, 4.12; P-trend = 0.03). This study supports the long-term benefits of VF consumption on cognitive performance, except those VF with relatively low fiber content such as potatoes and fruit juices, among the middle-aged US general population.


Intertidal epilithic bacteria diversity changes along a naturally occurring carbon dioxide and pH gradient.
Intertidal epilithic bacteria communities are important components of coastal ecosystems, yet few studies have assessed their diversity and how it may be affected by changing environmental parameters. Submarine CO2 seeps produce localised areas of CO2-enriched seawater with reduced pH levels. We utilised the seawater pH/CO2 gradient at Levante Bay (Italy) to test the hypothesis that epilithic bacteria communities are modified by exposure to seawater with the varying chemical parameters. Biofilms were sampled from three sites exposed to seawater with different pH/CO2 levels and diversity determined using high-throughput sequencing of 16S rRNA genes. Seawater pCO2 concentrations were increased from ambient at site 1 to 621 μatm at site 2 and 1654 μatm site 3, similar to the predicated future oceans beyond 2050 and 2150, respectively. Alpha diversity of total bacteria communities and Cyanobacteria communities was significantly different between sites (anova P < 0.05). Comparison between sites showed that bacteria communities and Cyanobacteria communities were significantly different (anosim P < 0.01; permanova P < 0.01). Proteobacteria, Bacteroidetes and Cyanobacteria dominated all communities; however, there were differences between sites in the relative abundance of specific orders. This study provides the most detailed assessment of intertidal epilithic bacteria diversity and shows that diversity is significantly different along a seawater pH/CO2 gradient. This information supports the evaluation of the impacts of future ocean acidification on coastal marine ecosystems.


Operation of a homeostatic sleep switch.
Sleep disconnects animals from the external world, at considerable risks and costs that must be offset by a vital benefit. Insight into this mysterious benefit will come from understanding sleep homeostasis: to monitor sleep need, an internal bookkeeper must track physiological changes that are linked to the core function of sleep. In Drosophila, a crucial component of the machinery for sleep homeostasis is a cluster of neurons innervating the dorsal fan-shaped body (dFB) of the central complex. Artificial activation of these cells induces sleep, whereas reductions in excitability cause insomnia. dFB neurons in sleep-deprived flies tend to be electrically active, with high input resistances and long membrane time constants, while neurons in rested flies tend to be electrically silent. Correlative evidence thus supports the simple view that homeostatic sleep control works by switching sleep-promoting neurons between active and quiescent states. Here we demonstrate state switching by dFB neurons, identify dopamine as a neuromodulator that operates the switch, and delineate the switching mechanism. Arousing dopamine caused transient hyperpolarization of dFB neurons within tens of milliseconds and lasting excitability suppression within minutes. Both effects were transduced by Dop1R2 receptors and mediated by potassium conductances. The switch to electrical silence involved the downregulation of voltage-gated A-type currents carried by Shaker and Shab, and the upregulation of voltage-independent leak currents through a two-pore-domain potassium channel that we term Sandman. Sandman is encoded by the CG8713 gene and translocates to the plasma membrane in response to dopamine. dFB-restricted interference with the expression of Shaker or Sandman decreased or increased sleep, respectively, by slowing the repetitive discharge of dFB neurons in the ON state or blocking their entry into the OFF state. Biophysical changes in a small population of neurons are thus linked to the control of sleep-wake state.


Coenzyme Q10 deficiency in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is related to fatigue, autonomic and neurocognitive symptoms and is another risk factor explaining the early mortality in ME/CFS due to cardiovascular disorder.
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a medical illness characterized by disorders in inflammatory and oxidative and nitrosative (IO&NS) pathways. This paper examines the role of Coenzyme Q10 (CoQ10), a mitochondrial nutrient which acts as an essential cofactor for the production of ATP in mitochondria and which displays significant antioxidant activities. Plasma CoQ10 has been assayed in 58 patients with ME/CFS and in 22 normal controls; the relationships between CoQ10 and the severity of ME/CFS as measured by means of the FibroFatigue (FF) scale were measured. Plasma CoQ10 was significantly (p=0.00001) lower in ME/CFS patients than in normal controls. Up to 44.8% of patients with ME/CFS had values beneath the lowest plasma CoQ10 value detected in the normal controls, i.e. 490 microg/L. In ME/CFS, there were significant and inverse relationships between CoQ10 and the total score on the FF scale, fatigue and autonomic symptoms. Patients with very low CoQ10 (<390 microg/L) suffered significantly more from concentration and memory disturbances. The results show that lowered levels of CoQ10 play a role in the pathophysiology of ME/CFS and that symptoms, such as fatigue, and autonomic and neurocognitive symptoms may be caused by CoQ10 depletion. Our results suggest that patients with ME/CFS would benefit from CoQ10 supplementation in order to normalize the low CoQ10 syndrome and the IO&NS disorders. The findings that lower CoQ10 is an independent predictor of chronic heart failure (CHF) and mortality due to CHF may explain previous reports that the mean age of ME/CFS patients dying from CHF is 25 years younger than the age of those dying from CHF in the general population. Since statins significantly decrease plasma CoQ10, ME/CFS should be regarded as a relative contraindication for treatment with statins without CoQ10 supplementation.


Melatonin: an ancient molecule that makes oxygen metabolically tolerable.
Melatonin is remarkably functionally diverse with actions as a free radical scavenger and antioxidant, circadian rhythm regulator, anti-inflammatory and immunoregulating molecule, and as an oncostatic agent. We hypothesize that the initial and primary function of melatonin in photosynthetic cyanobacteria, which appeared on Earth 3.5-3.2 billion years ago, was as an antioxidant. The evolution of melatonin as an antioxidant by this organism was necessary as photosynthesis is associated with the generation of toxic-free radicals. The other secondary functions of melatonin came about much later in evolution. We also surmise that mitochondria and chloroplasts may be primary sites of melatonin synthesis in all eukaryotic cells that possess these organelles. This prediction is made on the basis that mitochondria and chloroplasts of eukaryotes developed from purple nonsulfur bacteria (which also produce melatonin) and cyanobacteria when they were engulfed by early eukaryotes. Thus, we speculate that the melatonin-synthesizing actions of the engulfed bacteria were retained when these organelles became mitochondria and chloroplasts, respectively. That mitochondria are likely sites of melatonin formation is supported by the observation that this organelle contains high levels of melatonin that are not impacted by blood melatonin concentrations. Melatonin has a remarkable array of means by which it thwarts oxidative damage. It, as well as its metabolites, is differentially effective in scavenging a variety of reactive oxygen and reactive nitrogen species. Moreover, melatonin and its metabolites modulate a large number of antioxidative and pro-oxidative enzymes, leading to a reduction in oxidative damage. The actions of melatonin on radical metabolizing/producing enzymes may be mediated by the Keap1-Nrf2-ARE pathway. Beyond its direct free radical scavenging and indirect antioxidant effects, melatonin has a variety of physiological and metabolic advantages that may enhance its ability to limit oxidative stress.


Tryptic digestion coupled with ambient desorption electrospray ionization and liquid extraction surface analysis mass spectrometry enabling identification of skeletal muscle proteins in mixtures and distinguishing between beef, pork, horse, chicken, and turkey meat.
The use of ambient desorption electrospray ionization mass spectrometry (DESI-MS) and liquid extraction surface analysis mass spectrometry (LESA-MS) is explored for the first time to analyze skeletal muscle proteins obtained from a mixture of standard proteins and raw meat. Single proteins and mixtures of up to five proteins (myoglobin, troponin C, actin, bovine serum albumin (BSA), tropomyosin) were deposited onto a polymer surface, followed by in situ tryptic digestion and comparative analysis using DESI-MS and LESA-MS using tandem electrospray MS. Peptide peaks specific to individual proteins were readily distinguishable with good signal-to-noise ratio in the five-component mixture. LESA-MS gave a more stable analysis and greater sensitivity compared with DESI-MS. Meat tryptic digests were subjected to peptidomics analysis by DESI-MS and LESA-MS. Bovine, horse, pig, chicken, and turkey muscle digests were clearly discriminated using multivariate data analysis (MVA) of the peptidomic data sets. The most abundant skeletal muscle proteins were identified and correctly classified according to the species following MS/MS analysis. The study shows, for the first time, that ambient ionization techniques such as DESI-MS and LESA-MS have great potential for species-specific analysis and differentiation of skeletal muscle proteins by direct surface desorption.


Translational stalling at polyproline stretches is modulated by the sequence context upstream of the stall site.
The polymerization of amino acids into proteins occurs on ribosomes, with the rate influenced by the amino acids being polymerized. The imino acid proline is a poor donor and acceptor for peptide-bond formation, such that translational stalling occurs when three or more consecutive prolines (PPP) are encountered by the ribosome. In bacteria, stalling at PPP motifs is rescued by the elongation factor P (EF-P). Using SILAC mass spectrometry of Escherichia coli strains, we identified a subset of PPP-containing proteins for which the expression patterns remained unchanged or even appeared up-regulated in the absence of EF-P. Subsequent analysis using in vitro and in vivo reporter assays revealed that stalling at PPP motifs is influenced by the sequence context upstream of the stall site. Specifically, the presence of amino acids such as Cys and Thr preceding the stall site suppressed stalling at PPP motifs, whereas amino acids like Arg and His promoted stalling. In addition to providing fundamental insight into the mechanism of peptide-bond formation, our findings suggest how the sequence context of polyproline-containing proteins can be modulated to maximize the efficiency and yield of protein production.


Finite-element algorithm for radiative transfer in vertically inhomogeneous media: numerical scheme and applications.
The recently developed finite-element method for solution of the radiative transfer equation has been extended to compute the full azimuthal dependence of the radiance in a vertically inhomogeneous plane-parallel medium. The physical processes that are included in the algorithm are multiple scattering and bottom boundary bidirectional reflectivity. The incident radiation is a parallel flux on the top boundary that is characteristic for illumination of the atmosphere by the Sun in the UV, visible, and near-infrared regions of the electromagnetic spectrum. The theoretical basis is presented together with a number of applications to realistic atmospheres. The method is shown to be accurate even with a low number of grid points for most of the considered situations. The FORTRAN code for this algorithm is developed and is available for applications.


General practitioners' management of mental disorders: a rewarding practice with considerable obstacles.
Primary care improvement is the cornerstone of current reforms. Mental disorders (MDs) are a leading cause of morbidity worldwide and widespread in industrialised countries. MDs are treated mainly in primary care by general practitioners (GPs), even though the latter ability to detect, diagnose, and treat patients with MDs is often considered unsatisfactory. This article examines GPs' management of MDs in an effort to acquire more information regarding means by which GPs deal with MD cases, impact of such cases on their practices, factors that enable or hinder MD management, and patient-management strategies. This study employs a mixed-method approach with emphasis on qualitative investigation. Based on a previous survey of 398 GPs in Quebec, Canada, 60 GPs representing a variety of practice settings were selected for further study. A 10-minute-long questionnaire comprising 27 items was administered, and 70-minute-long interviews were conducted. Quantitative (SPSS) and qualitative (NVivo) analyses were performed. At least 20% of GP visits were MD-related. GPs were comfortable managing common MDs, but not serious MDs. GPs' based their treatment of MDs on pharmacotherapy, support therapy, and psycho-education. They used clinical intuition with few clinical tools, and closely followed their patients with MDs. Practice features (salary or hourly fees payment; psycho-social teams on-site; strong informal networks), and GPs' individual characteristics (continuing medical education; exposure and interest in MDs; traits like empathy) favoured MD management. Collaboration with psychologists and psychiatrists was considered key to good MD management. Limited access to specialists, system fragmentation, and underdeveloped group practice and shared-care models were impediments. MD management was seen as burdensome because it required more time, flexibility, and emotional investment. Strategies exist to reduce the burden (one-problem-per-visit rule; longer time slots). GPs found MD practice rewarding as patients were seen as grateful and more complying with medical recommendations compared to other patients, generally leading to positive outcomes. To improve MD management, this study highlights the importance of extending multidisciplinary GP practice settings with salary or hourly fee payment; access to psychotherapeutic and psychiatric expertise; and case-discussion training involving local networks of GPs and MD specialists that encourage both knowledge transfer and shared care.


Incidence, predictors and clinical characteristics of orolingual angio-oedema complicating thrombolysis with tissue plasminogen activator for ischaemic stroke.
Orolingual angio-oedema is a recognised complication of tissue plasminogen activator (tPA) for ischaemic stroke. We investigated its incidence, clinical characteristics and relationship with other factors in patients receiving tPA at a UK centre. 530 consecutive patients (median age 70 years) receiving tPA treatment for confirmed ischaemic stroke were included. Cases were defined as those developing angio-oedema within 24 h of initiation of tPA. Angio-oedema was retrospectively classified as mild, moderate or severe using predefined criteria. The primary analysis was the association between prior ACE inhibitor (ACE-I) treatment and angio-oedema. Orolingual angio-oedema was observed in 42 patients (7.9%; 95% CI 5.5% to 10.6%), ranging from 5 to 189 min after initiation of tPA (median 65 min). 12% of the angio-oedema cases were severe (1% of all patients treated with tPA), requiring urgent advanced airway management. 172 patients (33%) were taking ACE-I. In multifactorial analyses, only prior ACE-I treatment remained a significant independent predictor of angio-oedema (odds ratio (OR) 2.3; 95% CI 1.1 to 4.7). Angio-oedema occurs more frequently than previously reported and is associated with preceding ACE-I treatment. Angio-oedema may be delayed and progress to life-threatening airway compromise, which has implications for the assessment and delivery of thrombolysis.


Post-selection free, integrated optical source of non-degenerate, polarization entangled photon pairs.
We present an integrated source of polarization entangled photon pairs in the telecom regime, which is based on type II-phasematched parametric down-conversion (PDC) in a Ti-indiffused waveguide in periodically poled lithium niobate. The domain grating - consisting of an interlaced bi-periodic structure - is engineered to provide simultaneous phase-matching of two PDC processes, and enables the direct generation of non-degenerate, polarization entangled photon pairs with a brightness of B = 7 × 10(3) pairs/(s×mW×GHz). The spatial separation of the photon pairs is accomplished by a fiber-optical multiplexer facilitating a high compactness of the overall source. Visibilities exceeding 95 % and a violation of the Bell inequality with S = 2.57±0.06 could be demonstrated.


Data resource profile: Pathways to Health and Social Equity for Children (PATHS Equity for Children).
The PATHS Data Resource is a unique database comprising data that follow individuals from the prenatal period to adulthood. The PATHS Resource was developed for conducting longitudinal epidemiological research into child health and health equity. It contains individual-level data on health, socioeconomic status, social services and education. Individuals' data are linkable across these domains, allowing researchers to follow children through childhood and across a variety of sectors. PATHS includes nearly all individuals that were born between 1984 and 2012 and registered with Manitoba's universal health insurance programme at some point during childhood. All PATHS data are anonymized. Key concepts, definitions and algorithms necessary to work with the PATHS Resource are freely accessible online and an interactive forum is available to new researchers working with these data. The PATHS Resource is one of the richest and most complete databases assembled for conducting longitudinal epidemiological research, incorporating many variables that address the social determinants of health and health equity. Interested researchers are encouraged to contact [email@example.com] to obtain access to PATHS to use in their own programmes of research.


Rituximab, bendamustine and lenalidomide in patients with aggressive B-cell lymphoma not eligible for anthracycline-based therapy or intensive salvage chemotherapy - SAKK 38/08.
An increasing number of older patients are suffering from aggressive lymphoma. Effective and more tolerable treatment regimens are urgently needed for this growing patient population. Patients with aggressive lymphoma not eligible for anthracycline-based first-line therapy or intensive salvage regimens were treated with the rituximab-bendamustine-lenalidomide (R-BL) regimen (rituximab 375 mg/m(2) day 1, bendamustine 70 mg/m(2) d 1, 2, lenalidomide 10 mg d 1-21) for six cycles every 4 weeks. Forty-one patients with a median age of 75 (range 40-94) years were enrolled: 33 patients had substantial co-morbidities. 13 patients were not eligible for anthracycline-based first-line chemotherapy, 28 patients had relapsed/refractory disease. The primary endpoint, overall response, was achieved by 25 (61%) patients (95% confidence interval 45-76%). Grade ≥ 3 toxicity comprised haematological (59%), skin (15%), constitutional (15%) and neurological (12%) events. 9 patients died during trial treatment: 5 from lymphoma progression, 2 from toxicity, 2 with sudden death. After a median follow-up of 25·9 (interquartile range 20·4-31·6) months, 13 patients were still alive. Median overall survival was 14·5 months. In conclusion, R-BL can be considered a treatment option for elderly patients with treatment naïve or relapsed/refractory aggressive lymphoma not eligible for standard aggressive regimens.


Transient versus persistent fear of falling in community-dwelling older adults: incidence and risk factors.
To investigate the incidence of fear of falling (FOF) and the risk factors associated with transient versus persistent FOF in community-dwelling older adults. Prospective cohort study. Bronx County, New York. Three hundred eighty participants without FOF at baseline in the Einstein Aging Study aged 70 and older. FOF was assessed at baseline and during follow-up interviews at 2- to 3-month intervals for a minimum 2 years. Incident FOF was classified as transient or persistent FOF. Transient FOF was defined as new-onset FOF reported at only one interview, and persistent FOF was FOF reported at two or more interviews over a 2-year period. Twenty-four-month cumulative incidence of incident FOF was 45.4%, with 60.0% of FOF being persistent. Predictors of incident FOF included female sex (adjusted hazard ratio (aHR)=1.55, 95% confidence interval (CI)=1.08-2.23), depressive symptoms (aHR=1.16, 95% CI=1.07-1.26), falls (aHR=1.50, 95% CI=1.01-2.21), and clinical gait abnormality (aHR=2.07, 95% CI=1.42-3.01). The proportion of participants with incident FOF increased linearly with increasing number of risk factors. Predictors for transient and persistent FOF were depressive symptoms and clinical gait abnormality. Female sex and previous falls were predictors of persistent but not transient FOF. FOF status in older adults may change over time, with shared and distinct risk factors for persistent and transient FOF. Understanding the dynamic nature of FOF and these risk factors will help identify high-risk groups and design future intervention studies.


New management options for osteoporosis with emphasis on SERMs.
Albright was the first of many to show that loss of bone mass due to estrogen deficiency is an important part of the pathogenesis of postmenopausal osteoporosis. This led to the use of estrogen therapy which was shown to prevent bone loss at menopause and to reduce the risk of important fragility fractures. Selective estrogen receptor modulators (SERMs), with salutary estrogen-like skeletal effects and with protection from breast cancer, have important roles in the management of young postmenopausal women. New members of the SERM family may approach the effectiveness of estrogen in preventing bone loss and reducing fracture risk. When combined with estrogen, new SERMs prevent endometrial hyperplasia, and that combination reduces menopausal symptoms and prevents bone loss. Drugs that reduce bone turnover or stimulate bone formation by non-estrogen pathways have also been developed to treat osteoporosis. Emerging therapies, with unique mechanisms of action, may provide improved efficacy in treating women who already have osteoporosis.


Collective cell migration has distinct directionality and speed dynamics.
When a constraint is removed, confluent cells migrate directionally into the available space. How the migration directionality and speed increase are initiated at the leading edge and propagate into neighboring cells are not well understood. Using a quantitative visualization technique-Particle Image Velocimetry (PIV)-we revealed that migration directionality and speed had strikingly different dynamics. Migration directionality increases as a wave propagating from the leading edge into the cell sheet, while the increase in cell migration speed is maintained only at the leading edge. The overall directionality steadily increases with time as cells migrate into the cell-free space, but migration speed remains largely the same. A particle-based compass (PBC) model suggests cellular interplay (which depends on cell-cell distance) and migration speed are sufficient to capture the dynamics of migration directionality revealed experimentally. Extracellular Ca2+ regulated both migration speed and directionality, but in a significantly different way, suggested by the correlation between directionality and speed only in some dynamic ranges. Our experimental and modeling results reveal distinct directionality and speed dynamics in collective migration, and these factors can be regulated by extracellular Ca2+ through cellular interplay. Quantitative visualization using PIV and our PBC model thus provide a powerful approach to dissect the mechanisms of collective cell migration.


Dose-related effects of prostaglandin F2 alpha isopropylester on intraocular pressure, refraction, and pupil diameter in monkeys.
Topical application of Prostaglandin F2 alpha (PGF2 alpha) to the eye reduces intraocular pressure (IOP) in all mammalian species studied thus far, including humans. The L-isopropylester derivative is currently the one most commonly used in experimental and clinical studies. Dose-response relationships were determined between PGF2 alpha-IE and IOP, pupillary diameter, and refraction in ketamine-anesthetized ocular normotensive cynomolgus monkeys. Single doses of 10 and 30 micrograms had smaller and less consistent but longer lasting IOP-lowering effects than repeated doses (twice daily for 3 days) of 1-5 micrograms. For repeated dosing in this manner, the just-maximal dose is probably between 2-5 micrograms, producing a approximately 70% reduction in IOP to a final IOP of approximately 5 mm Hg. Continuing treatment for up to 18 days did not further enhance the efficacy of twice daily treatment with a submaximal 1-microgram dose. Partial reversal of anesthesia-induced tonic accommodation occurred with single 10- and 30-micrograms doses and with repeated 1-microgram doses, but additional myopia of 0.5-1.5 diopters was induced with repeated higher doses. These physiologic findings and previous morphologic data are consistent with a proposed dual PG action on the ciliary muscle, one involving a short-onset long-lasting direct effect on the muscle fibers (causing relaxation and narrowing of the muscle bundles) and the second involving a slowly developing but shorter duration dissolution of the intermuscular connective tissues.