Impact of an early-exposure geriatrics curriculum in an accelerated baccalaureate-MD program.
Current standard geriatric curricula and exposure of students to the elderly may be insufficient to influence students' interest in geriatric medicine. We developed an innovative curriculum to address this gap. This study aimed to identify knowledge, skill, and attitude changes of first-year students in an accelerated baccalaureate-MD program toward geriatrics after participation in an early-exposure geriatrics curriculum (GC). The GC consisted of fifteen 3-hr interactive teaching sessions facilitated by various health professionals. This was a single group, pre- and post-intervention study using a knowledge test and attitude survey. To assess the effectiveness of this curriculum, students also completed an Objective Structured Clinical Exam (OSCE) on falls, cognitive and functional assessment, and delivering bad news. Twenty-seven baccalaureate-MD students (mean age = 18.8 years) participated in the GC intervention between January and April 2015. The post-GC showed significant improvement in knowledge (P = 0.013), skills, and attitude (P < 0.01) toward older adults. Students as a group overall met the standard of 85% of possible points in all three OSCE cases. This study shows that an early-exposure geriatric education intervention is associated with an increase in students' knowledge, skills, and attitudes in caring for older adults.


Repair or Violation Detection? Pre-Attentive Processing Strategies of Phonotactic Illegality Demonstrated on the Constraint of g-Deletion in German.
Effects of categorical phonotactic knowledge on pre-attentive speech processing were investigated by presenting illegal speech input that violated a phonotactic constraint in German called "g-deletion." The present study aimed to extend previous findings of automatic processing of phonotactic violations and to investigate the role of stimulus context in triggering either an automatic phonotactic repair or a detection of the violation. The mismatch negativity event-related potential component was obtained in 2 identical cross-sectional experiments with speaker variation and 16 healthy adult participants each. Four pseudowords were used as stimuli, 3 of them phonotactically legal and 1 illegal. Stimuli were contrasted pairwise in passive oddball conditions and presented binaurally via headphones. Results were analyzed by means of mixed design analyses of variance. Phonotactically illegal stimuli were found to be processed differently compared to legal ones. Results indicate evidence for both automatic repair and detection of the phonotactic violation depending on the linguistic context the illegal stimulus was embedded in. These findings corroborate notions that categorical phonotactic knowledge is activated and applied even in the absence of attention. Thus, our findings contribute to the general understanding of sublexical phonological processing and may be of use for further developing speech recognition models.


Radiation exposure, socioeconomic status, and brain tumor risk in the US Air Force: a nested case-control study.
A nested case-control study was used to investigate the relation between a range of electromagnetic field exposures and brain tumor risk in the US Air Force. Cumulative extremely low frequency and radiofrequency/microwave electromagnetic field potential exposures were estimated from a job-exposure matrix developed for this study. Ionizing radiation exposures were obtained from personal dosimetry records. Men who were exposed to nonionizing electromagnetic fields had a small excess risk for developing brain tumors, with the extremely low frequency and radiofrequency/microwave age-race-senior military rank-adjusted odds ratios being 1.28 (95% confidence interval (Cl) 0.95-1.74) and 1.39 (95% Cl 1.01-1.90), respectively. By contrast, men who were exposed to ionizing radiation had an age-race-senior military rank-adjusted odds ratio of 0.58 (95% Cl 0.22-1.52). These results support a small association between extremely low frequency and radiofrequency/microwave electromagnetic field exposure and no association between ionizing radiation exposure and brain tumors in the US Air Force population. Military rank was consistently associated with brain tumor risk. Officers were more likely than enlisted men to develop brain tumors (age-race-adjusted odds ratio (OR) = 2.11, 95% Cl 1.48-3.01), and senior officers were at increased risk compared with all other US Air Force members (age-race-adjusted OR = 3.30, 95% Cl 1.99-5.45).


Holocene re-colonisation, central-marginal distribution and habitat specialisation shape population genetic patterns within an Atlantic European grass species.
Corynephorus canescens (L.) P.Beauv. is an outbreeding, short-lived and wind-dispersed grass species, highly specialised on scattered and disturbance-dependent habitats of open sandy sites. Its distribution ranges from the Iberian Peninsula over Atlantic regions of Western and Central Europe, but excludes the two other classical European glacial refuge regions on the Apennine and Balkan Peninsulas. To investigate genetic patterns of this uncommon combination of ecological and biogeographic species characteristics, we analysed AFLP variation among 49 populations throughout the European distribution range, expecting (i) patterns of SW European glacial refugia and post-glacial expansion to the NE; (ii) decreasing genetic diversity from central to marginal populations; and (iii) interacting effects of high gene flow and disturbance-driven genetic drift. Decreasing genetic diversity from SW to NE and distinct gene pool clustering imply refugia on the Iberian Peninsula and in western France, from where range expansion originated towards the NE. High genetic diversity within and moderate genetic differentiation among populations, and a significant pattern of isolation-by-distance indicate a gene flow drift equilibrium within C. canescens, probably due to its restriction to scattered and dynamic habitats and limited dispersal distances. These features, as well as the re-colonisation history, were found to affect genetic diversity gradients from central to marginal populations. Our study emphasises the need for including the specific ecology into analyses of species (re-)colonisation histories and range centre-margin analyses. To account for discontinuous distributions, new indices of marginality were tested for their suitability in studies of centre-periphery gradients.


Bottom-Up Proteomic Analysis of Polypeptide Venom Components of the Giant Ant Dinoponera Quadriceps.
Ant species have specialized venom systems developed to sting and inoculate a biological cocktail of organic compounds, including peptide and polypeptide toxins, for the purpose of predation and defense. The genus Dinoponera comprises predatory giant ants that inoculate venom capable of causing long-lasting local pain, involuntary shaking, lymphadenopathy, and cardiac arrhythmias, among other symptoms. To deepen our knowledge about venom composition with regard to protein toxins and their roles in the chemical-ecological relationship and human health, we performed a bottom-up proteomics analysis of the crude venom of the giant ant D. quadriceps, popularly known as the "false" tocandiras. For this purpose, we used two different analytical approaches: (i) gel-based proteomics approach, wherein the crude venom was resolved by denaturing sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and all protein bands were excised for analysis; (ii) solution-based proteomics approach, wherein the crude venom protein components were directly fragmented into tryptic peptides in solution for analysis. The proteomic data that resulted from these two methodologies were compared against a previously annotated transcriptomic database of D. quadriceps, and subsequently, a homology search was performed for all identified transcript products. The gel-based proteomics approach unequivocally identified nine toxins of high molecular mass in the venom, as for example, enzymes [hyaluronidase, phospholipase A1, dipeptidyl peptidase and glucose dehydrogenase/flavin adenine dinucleotide (FAD) quinone] and diverse venom allergens (homologous of the red fire ant Selenopsis invicta) and venom-related proteins (major royal jelly-like). Moreover, the solution-based proteomics revealed and confirmed the presence of several hydrolases, oxidoreductases, proteases, Kunitz-like polypeptides, and the less abundant inhibitor cysteine knot (ICK)-like (knottin) neurotoxins and insect defensin. Our results showed that the major components of the D. quadriceps venom are toxins that are highly likely to damage cell membranes and tissue, to cause neurotoxicity, and to induce allergic reactions, thus, expanding the knowledge about D. quadriceps venom composition and its potential biological effects on prey and victims.


Metals in the surface sediments of Istanbul Strait (Turkey).
Surface sediments from 17 stations in the Istanbul Strait and Marmara Sea were collected and analysed for major and trace elements by wavelength-dispersive X-ray fluorescence spectrometry (WDXRF). Metal concentrations in surface sediments varied from 1.3 to 7.2 % for Al, 4.8 to 18 mg kg(- 1) for As, 119 to 599 mg kg(- 1) for Ba, below detection limit (bdl) to 6.6 mg kg(- 1) for Cd, 18 to 222 mg kg(- 1) for Cr, 7.6 to 180 mg kg(- 1) for Cu, 1.0 to 5.5 % for Fe (10 000 to 55 000 mg kg(- 1)), 171 to 718 mg kg(- 1)for Mn, 3.3 to 64 mg kg(- 1) for Ni, 4.5 to 461 mg kg(- 1) for Pb, 1.3 to 68 mg kg(- 1) for Sn, 19 to 170 mg kg(- 1) for V and 16 to 859 mg kg(- 1) for Zn. Three tools have been applied in order to evaluate metal pollution in the sediments; Sediment quality guidelines (SQGs), enrichment factors (EFs) and geoaccumulation index (I(geo)). SQGs values indicate that Pb and Ni are the most likely contaminants to cause adverse biological effects. On the other hand, both metal enrichment factors and geoaccumulation index show that As, Zn, Pb and Cd contaminations exist in the entire study area and contamination of other metals is also present in some sites depending on the sources. Factor analysis (FA) receptor modelling technique was applied to investigate the sources affecting surface sediment samples at the Istanbul Strait.


Parental perspectives on evaluation and management of fever in young infants: an interview study.
Young febrile infants typically undergo meticulous evaluation to rule out serious bacterial infection. Parental perspectives on the process of evaluation and management of febrile infants can influence treatment satisfaction and outcomes. This study aimed to describe the perspectives of parents of young infants presenting to hospital with fever. We conducted semistructured, face-to-face interviews with parents of healthy, term infants aged less than 3 months, admitted to a tertiary children's hospital in Sydney, Australia, during the management of a febrile illness. The interview transcripts were thematically analysed. 36 parents of 27 infants participated. All infants underwent a complete sepsis work up, received empiric antibiotics and made a complete recovery. Parental empowerment was central to the three themes identified: expecting reassurance and support (overwhelming responsibility, heightened vulnerability), facilitators for parental empowerment (medical attentiveness, medical partnership, gaining closure and a sense of validation), and barriers to empowerment (unexpected medical seriousness, relinquished control, failed expectations of support and limited capacity for advocacy). Caring for a febrile infant is overwhelming for parents. When confronted by unexpected tests and hospitalisation, they fear the possibility of a severe illness, experience a sense of helplessness and loss of control as their infant undergoes painful tests, and doubt their own ability to meet their infant's needs. Family-centred care strategies that inform and support parents, acknowledging their concerns and distress, while involving them in the medical management, may promote parental empowerment and build better alliances between parents and healthcare providers.


Functional role of T-cell receptor nanoclusters in signal initiation and antigen discrimination.
Antigen recognition by the T-cell receptor (TCR) is a hallmark of the adaptive immune system. When the TCR engages a peptide bound to the restricting major histocompatibility complex molecule (pMHC), it transmits a signal via the associated CD3 complex. How the extracellular antigen recognition event leads to intracellular phosphorylation remains unclear. Here, we used single-molecule localization microscopy to quantify the organization of TCR-CD3 complexes into nanoscale clusters and to distinguish between triggered and nontriggered TCR-CD3 complexes. We found that only TCR-CD3 complexes in dense clusters were phosphorylated and associated with downstream signaling proteins, demonstrating that the molecular density within clusters dictates signal initiation. Moreover, both pMHC dose and TCR-pMHC affinity determined the density of TCR-CD3 clusters, which scaled with overall phosphorylation levels. Thus, TCR-CD3 clustering translates antigen recognition by the TCR into signal initiation by the CD3 complex, and the formation of dense signaling-competent clusters is a process of antigen discrimination.


[Bacillus anthracis: a molecular look at a famous pathogen].
Bacillus anthracis, a gram-positive rod belonging to the Bacillus cereus group, has an extremely monomorphic genome, and presents high structural and physiological similarity with B. cereus and Bacillus thuringiensis. In this work, the new molecular methods for the identification and typing of B. anthracis developed in the last years, based on variable number tandem repeats or on genetic differences detected through sequencing, are described. The molecular aspects of traditional virulence factors: capsule, protective antigen, lethal factor and edema factor are described in depth, together with virulence factors recently proposed, such as the siderophores petrobactin and bacillibactin, the S-layer adhesin and the MntA lipoprotein. It is detailed the molecular organization of megaplasmids pXO1 and pXO2, including the pathogenicity island of pXO1. The genetic skeleton of these plasmids has been observed in related species, and this could be attributed to lateral gene transfer. Finally, the two anthrax toxin protective antigen receptors, ANTXR1/TEM8 and ANTXR2/CMG2, essential for the interaction of the pathogen with the host, are presented. The molecular studies performed in recent years have greatly increased knowledge in different aspects of this microorganism and its relationship with the host, but at the same time they have raised new questions about this noted pathogen.


Pressurised metered-dose inhalers versus all other hand-held inhalers devices to deliver bronchodilators for chronic obstructive pulmonary disease.
Bronchodilator therapy for COPD may be delivered by a number of different inhaler devices. To determine the efficacy of pressurised metered dose inhalers (pMDI) compared to any other handheld inhaler device for the delivery of bronchodilators in non-acute COPD. The Cochrane Collaboration, Asthma and Wheeze Randomised Controlled Clinical Trials register was searched for studies. The UK pharmaceutical companies who manufacture inhaled COPD medication were also contacted. Two reviewers independently reviewed the results of computerised search and any potentially relevant articles were obtained in full. One reviewer extracted details of each trial and a second reviewer checked all extracted data. Dichotomous outcomes such as exacerbation rate were assessed using relative risk, with 95% confidence interval (CI). Fourteen studies appeared potentially relevant but only three studies (61 patients) met the entry criteria. Two studies compared a dry powder device (Turbuhaler or Rotahaler) with a pMDI for beta2-agonist delivery, and one (36 patients cross-over design) the Respimat (soft mist device for ipratropium) vs a pMDI. For the Turbuhaler and Rotahaler, none of the reported outcome measures were significantly different. The Rotahaler study used a high and low dose of medication with or without large volume spacer. The study using the Respimat showed significant increases in FEV1 when compared to a pMDI (difference in change from base line 70 ml, 95% CI 10, 130 ml). The effect on change in FVC was of similar size. There were no differences between these two devices for any other reported outcomes. Although none of the included studies required prior patient ability to use any of the inhalers (and no study mentioned device training), it was assumed that all patients randomised into the study would have undergone training in use of the study inhalers and were capable of using those devices. In patients with stable COPD, pMDI produced similar outcomes to a dry powder device for delivering beta2-agonists, but the very small number of studies and included patients does not permit firm conclusions to be drawn. The soft mist device for ipratropium was more effective than a pMDI, but the data come from one small study. There need to be further well designed randomised controlled trials to define the role of inhaler devices using bronchodilators in stable COPD.


Regulation of cardiac output in hypoxia.
This brief review addresses the regulation of cardiac output (Q) at rest and during submaximal exercise in acute and chronic hypoxia. To preserve systemic O2 delivery in acute hypoxia Q is increased by an acceleration of heart rate, whereas stroke volume (SV) remains unchanged. Tachycardia is governed by activation of carotid and aortic chemoreceptors and a concomitant reduction in arterial baroreflex activation, all balancing sympathovagal activity toward sympathetic dominance. As hypoxia extends over several days a combination of different adaptive processes restores arterial O2 content to or beyond sea level values and hence Q normalizes. The latter however occurs as a consequence of a decrease in SV whereas tachycardia persists. The diminished SV reflects a lower left ventricular end-diastolic volume which is primarily related to hypoxia-generated reduction in plasma volume. Hypoxic pulmonary vasoconstriction may contribute by increasing right ventricular afterload and thus decreasing its ejection fraction. In summary, the Q response to hypoxia is the result of a complex interplay between several physiological mechanisms. Future studies are encouraged to establish the individual contributions of the different components from an integrative perspective.


Enhanced ACh sensitivity is accompanied by changes in ACh receptor channel properties and segregation of ACh receptor subtypes on sympathetic neurons during innervation in vivo.
Although presynaptic input can influence the number and distribution of ACh receptors (AChRs) on muscle, the role of cellular interactions in the development of transmitter sensitivity in neurons is less clear. To determine whether presynaptic input modifies neuronal AChR channel function and distribution, we must first ascertain the profile of changes in receptor properties relative to the timing of synapse formation. We have examined the temporal aspects of synaptogenesis in the lumbar sympathetic ganglia of the embryonic chick in anatomical experiments with anterograde 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate labeling of presynaptic inputs and cytochrome oxidase histochemistry. Biophysical studies of sympathetic neurons, within hours of removal from animals at different stages relative to synapse formation, show that both the properties and distribution of AChR channels are modified concurrent with a significant increase in presynaptic input to the neurons. The most striking change in AChR channel distribution is revealed by patching multiple sites on the surface of individual neurons. Following innervation in vivo, many neurons express only one of the four AChR channel subtypes and the AChRs are clustered in discrete, high-activity patches. Furthermore, when neurons at this stage express more than one AChR channel subtype, the different classes are often spatially segregated from one another on the cell surface. This contrasts with patches from neurons removed earlier on, which have lower overall activity, often comprised of multiple channel subtypes. Comparison of the AChR properties of acutely dispersed neurons to those of neurons maintained in vitro indicates that most features of AChR channels are conserved despite their removal from presynaptic and other in vivo influences. These findings are consistent with inductive interactions between pre- and postsynaptic neurons playing an important regulatory role in transmitter receptor expression.


Physiological and therapeutic differences between vitamin D, its metabolites and analogues.
Since several metabolites and analogues of vitamin D have become available, their physiological and therapeutic potential have been studied in various disorders of mineral metabolism, particularly those classically termed vitamin D-resistant. In some instances this resistance appears to be due to defective metabolism of vitamin D or to defective target organ responses, but in others it is not. Although the precise effect of vitamin D or its metabolites on mineralization of bone is still unknown there is some evidence that the metabolites differ in their relative effects on intestine, bone, muscle and parathyroid glands. These differences may eventually have therapeutic value. At present the major advantage of 1alpha-hydroxylated derivatives of vitamin D over other compounds resides in their more rapid onset and reversal of action which makes them much easier and safer to use.


A new locus for split hand/foot malformation with long bone deficiency (SHFLD) at 2q14.2 identified from a chromosome translocation.
Split hand/foot malformation (SHFM) with long bone deficiency (SHFLD) is a distinct entity in the spectrum of ectrodactylous limb malformations characterised by associated tibial a/hypoplasia. Pedigrees with multiple individuals affected by SHFLD often include non-penetrant intermediate relatives, making genetic mapping difficult. Here we report a sporadic patient with SHFLD who carries a de novo chromosomal translocation t(2;18)(q14.2;p11.2). Characterisation of the breakpoints revealed that neither disrupts any known gene; however, the chromosome 2 breakpoint lies between GLI2 and INHBB, two genes known to be involved in limb development. To investigate whether mutation of a gene in proximity to the chromosome 2 breakpoint underlies the SHFLD, we sought independent evidence of mutations in GLI2, INHBB and two other genes (RALB and FLJ14816) in 44 unrelated patients with SHFM, SHFLD or isolated long bone deficiency. No convincing pathogenic mutations were found, raising the possibility that a long-range cis acting regulatory element may be disrupted by this translocation. The previous description of a translocation with a 2q14.2 breakpoint associated with ectrodactyly, and the mapping of the ectrodactylous Dominant hemimelia mouse mutation to a region of homologous synteny, suggests that 2q14.2 represents a novel locus for SHFLD.


The use of innovative cost-saving audience response system in orthodontic case-based learning: A potential approach in distance learning.
To provide a cost-saving innovative audience response system (ARS) that permits typing texts and compare its efficiency to the paper-based method in case-based learning (CBL). Orthodontic clinical cases were presented to 149 undergraduate dental students for discussion among teammates. Responses were collected using ARS-based and paper-based. ARS was constructed from an online survey platform (Google forms) then QR code was created for easy and fast access. Students used their cellphones to scan code, view questions, discuss, type, and submit answers within 10 minutes. Feedbacks were collected using a feedback survey. Outcome measures included the number of words, spelling mistakes, time required by the instructor to read submissions, and activity time compliance. The average number of words submitted by females in ARS-based 47 ± 8 was significantly higher than 35 ± 16 paper-based, and male ARS-based 36 ± 18 (P < 0.05). ARS-based submissions required significantly less time to read compared to paper-based among whole group, females, males (P < 0.001, P < 0.05, P < 0.001), respectively. Spelling mistakes were lower 1 ± 1 in ARS-based compared to paper-based 2 ± 2. The ARS-based first submission was (-4.28) minutes before the deadline, while paper-based last submission was (+2.19) minutes after (P < 0.05). ARS-based submissions were 12.5 seconds faster to read than paper-based (P < 0.001). Out of 56.4% of respondents, 63.1% preferred using ARS-based and 80% agreed that it provided immediate feedback, with high overall satisfaction. This innovated ARS was found to facilitate CBL. It is superior in time and cost-saving to paper-based and other ARSs. It could be useful in distance learning especially during the COVID-19 pandemic.


Management of acquired aplastic anemia in children.
The diagnosis of aplastic anemia in children requires exclusion of a variety of inherited or acquired BM failure syndromes with similar phenotypes. An efficient diagnostic plan is important because time from diagnosis to 'final' treatment is directly related to outcome regardless of the therapeutic option chosen. The gold standard of therapy remains hematopoietic SCT with a graft of BM cells for those children with matched sibling donors. Conversely for children without a sibling donor the high response and markedly improved overall survival rates of combined immunosuppressive therapy have proven robust, especially when horse derived anti-thymocyte globuline plus ciclosporine A are used. Incomplete response, relapse and progression to myelodysplasia/leukemia however have emerged as significant long-term issues. Improvements in outcome of alternative donor transplantation and the use of established and novel immunosuppressive agents provide multiple alternatives for treating refractory or relapsed patients. Regardless of the type of therapeutic approach, patients require centralized treatment in a center of excellence, ongoing monitoring for recurrence of disease and/or therapy-related immediate side effects and long-term effects.


The mosaic genome of warm-blooded vertebrates.
Most of the nuclear genome of warm-blooded vertebrates is a mosaic of very long (much greater than 200 kilobases) DNA segments, the isochores; these isochores are fairly homogeneous in base composition and belong to a small number of major classes distinguished by differences in guanine-cytosine (GC) content. The families of DNA molecules derived from such classes can be separated and used to study the genome distribution of any sequence which can be probed. This approach has revealed (i) that the distribution of genes, integrated viral sequences, and interspersed repeats is highly nonuniform in the genome, and (ii) that the base composition and ratio of CpG to GpC in both coding and noncoding sequences, as well as codon usage, mainly depend on the GC content of the isochores harboring the sequences. The compositional compartmentalization of the genome of warm-blooded vertebrates is discussed with respect to its evolutionary origin, its causes, and its effects on chromosome structure and function.


A large impact crater beneath Hiawatha Glacier in northwest Greenland.
We report the discovery of a large impact crater beneath Hiawatha Glacier in northwest Greenland. From airborne radar surveys, we identify a 31-kilometer-wide, circular bedrock depression beneath up to a kilometer of ice. This depression has an elevated rim that cross-cuts tributary subglacial channels and a subdued central uplift that appears to be actively eroding. From ground investigations of the deglaciated foreland, we identify overprinted structures within Precambrian bedrock along the ice margin that strike tangent to the subglacial rim. Glaciofluvial sediment from the largest river draining the crater contains shocked quartz and other impact-related grains. Geochemical analysis of this sediment indicates that the impactor was a fractionated iron asteroid, which must have been more than a kilometer wide to produce the identified crater. Radiostratigraphy of the ice in the crater shows that the Holocene ice is continuous and conformable, but all deeper and older ice appears to be debris rich or heavily disturbed. The age of this impact crater is presently unknown, but from our geological and geophysical evidence, we conclude that it is unlikely to predate the Pleistocene inception of the Greenland Ice Sheet.


Risk Factors for Transfusion-Related Acute Lung Injury.
Until now, transfusion-related acute lung injury (TRALI) has been considered the leading cause of blood transfusion-related diseases and death. In addition, there is no clinically effective treatment plan for TRALI. The aim of this study was to systematically summarize the literature on risk factors for TRALI in critical patients. Electronic searches (up to March 2020) were performed in the Cochrane Library, Web of Knowledge, Embase, and PubMed databases. We included studies reporting on the risk factors of TRALI for critical patients and extracted risk factors. A total of 13 studies met the inclusion criteria. We summarized and analyzed the potential risk factors of TRALI for critical patients in 13 existing studies. Host-related factors were age (odds ratio [OR] 1.16 [95% CI 1.08-1.24]), female sex (OR 1.26 [95% CI 1.16-1.38]), tobacco use status (OR 3.82 [95% CI 1.91-7.65]), chronic alcohol abuse (OR 3.82 [95% CI 2.97-26.83]), positive fluid balance (OR 1.24 [95% CI 1.08-1.42]), shock before transfusion (OR 4.41 [95% CI 2.38-8.20]), and American Society of Anesthesiologists (ASA) score of the recipients (OR 2.72 [95% CI 1.43-5.16]). The transfusion-related factors were the number of transfusions (OR 1.40 [95% CI 1.14-1.72]) and units of fresh frozen plasma (OR 1.21 [95% CI 1.01-1.46]). The device-related factor was mechanical ventilation (OR 4.13 [95% CI 2.20-7.76]). The risk factors that were positively correlated with TRALI in this study included number of transfusions and units of fresh frozen plasma. Age, female sex, tobacco use, chronic alcohol abuse, positive fluid balance, shock before transfusion, ASA score, and mechanical ventilation may be potential risk factors for TRALI. Our results suggest that host-related risk factors may play a more important role in the occurrence and development of TRALI than risk factors related to blood transfusions.


Community-oriented curriculum design for medical humanities.
Various recent surveys in Taiwan show physicians' decreasing satisfaction and increasing frustration with their working environment. Their major complaints are stress, long hours, salary, management's disrespect, and lack of trust from patients and society. To move towards restoration of social trust, this paper proposes incorporating the concept of "doctor as mediator in the changing relationship with patients" into the medical curriculum, as will be described in detail. This paper argues that structured community service for medical students facilitates self-learning, and will not only motivate them to develop good clinical and communication skills, but will also lead them to realize that the essence of medicine must be social trust. These effects have been seen after several years of an experimental curriculum involving more than 800 students. A program using methodology for community empowerment has been realized in a two-stage curriculum design. Students' self-assessment of achievements in these courses included further improvement in communication skills, courage to express own position, appropriate planning in advance, management of human resources, ability to deal with limited space and time, and experience of a profoundly moving learning process. In conclusion, community-based curriculum designs that facilitate self-learning for medical students should be the key element of reformed humanities education in Taiwan medical schools. Moreover, medical humanities continues to be a key element contributing to ongoing intellectual movements in Taiwan for building civil society and rooting democracy in the community.


Five-year Changes in Methamphetamine Use, Dependence, and Remission in a Community-recruited Cohort.
Investigate patterns of methamphetamine use over time, specifically factors associated with remission from dependent and harmful patterns of use; and examine drug treatment and health/support service utilization pathways among people who use methamphetamine. People who regularly use methamphetamine were recruited from nontreatment settings in Melbourne, Australia, in 2010, and followed up twice over 5 years. Trajectories of past-month methamphetamine use and methamphetamine dependence were mapped. Random-effects logistic regression modeling identified factors associated with these outcomes. Overall, past-month methamphetamine use and methamphetamine dependence decreased among the cohort over the study period. Variability in methamphetamine use and dependence trajectories was observed; 56% of participants achieved past-month abstinence; however, 14% subsequently relapsed and 44% reported past-month use at every time-point. During the study period, 27% of participants were never classified methamphetamine-dependent, 30% remitted from dependence, and 23% were consistently classified dependent. Factors independently associated with past-month methamphetamine use included male sex and poor physical health. Factors independently associated with methamphetamine dependence included poor physical health, low self-perceived social support, current mental health medication prescription, and current engagement with drug treatment services for methamphetamine use. Engagement with treatment and health/support services remained low (12%-22%) over the study period. Our findings indicate people who remit from methamphetamine dependence, reduce their frequency of use or cease entirely can maintain this over long periods. Initiatives addressing social determinants of health could be optimal for combating methamphetamine dependence. Community-based frontline service providers should be educated in relation to appropriately addressing methamphetamine use.


Validation of histone deacetylase 3 as a therapeutic target in castration-resistant prostate cancer.
Whereas the androgen receptor (AR) signaling axis remains a therapeutic target in castration-resistant prostate cancer (CRPC), the emergence of AR mutations and splice variants as mechanisms underlying resistance to contemporary inhibitors of this pathway highlights the need for new therapeutic approaches to target this disease. Of significance in this regard is the considerable preclinical data, indicating that histone deacetylase (HDAC) inhibitors may have utility in the treatment of CRPC. However, the results of clinical studies using HDAC inhibitors (directed against HDAC1, 2, 3, and 8) in CRPC are equivocal, a result that some have attributed to their ability to induce an epithelial to mesenchymal transition (EMT) and neuroendocrine differentiation. We posited that it might be possible to uncouple the beneficial effects of HDAC inhibitors on AR signaling from their undesired activities by targeting specific HDACs as opposed to using the pan-inhibitor strategy that has been employed to date. The relative abilities of pan- and selective-Class I HDAC inhibitors to attenuate AR-mediated target gene expression and proliferation were assessed in several prostate cancer cell lines. Small interfering RNA (siRNA)-mediated knockdown approaches were used to confirm the importance of of HDAC 1, 2, and 3 expression in these processes. Further, the ability of each HDAC inhibitor to induce the expression of EMT markers (RNA and protein) and EMT-like phenotype(s) (migration) were also assessed. The anti-tumor efficacy of a HDAC3-selective inhibitor, RGFP966, was compared to the pan-HDAC inhibitor Suberoylanilide Hydroxamic Acid (SAHA) in the 22Rv1 xenograft model. Using genetic and pharmacological approaches we demonstrated that a useful inhibition of AR transcriptional activity, absent the induction of EMT, could be achieved by specifically inhibiting HDAC3. Significantly, we also determined that HDAC3 inhibitors blocked the activity of the constitutively active AR V7-splice variant and inhibited the growth of xenograft tumors expressing this protein. Our studies provide strong rationale for the near-term development of specific HDAC3 inhibitors for the treatment of CRPC.


Does physical activity change predict functional recovery in low back pain? Protocol for a prospective cohort study.
Activity advice and prescription are commonly used in the management of low back pain (LBP). Although there is evidence for advising patients with LBP to remain active, facilitating both recovery and return to work, to date no research has assessed whether objective measurements of free living physical activity (PA) can predict outcome, recovery and course of LBP. An observational longitudinal study will investigate PA levels in a cohort of community-dwelling working age adults with acute and sub-acute LBP. Each participant's PA level, functional status, mood, fear avoidance behaviours, and levels of pain, psychological distress and occupational activity will be measured on three occasions during for 1 week periods at baseline, 3 months, and 1 year. Physical activity levels will be measured by self report, RT3 triaxial accelerometer, and activity recall questionnaires. The primary outcome measure of functional recovery will be the Roland Morris Disability Questionnaire (RMDQ). Free living PA levels and changes in functional status will be quantified in order to look at predictive relationships between levels and changes in free living PA and functional recovery in a LBP population. This research will investigate levels and changes in activity levels of an acute LBP cohort and the predictive relationship to LBP recovery. The results will assess whether occupational, psychological and behavioural factors affect the relationship between free living PA and LBP recovery. Results from this research will help to determine the strength of evidence supporting international guidelines that recommend restoration of normal activity in managing LBP. [Clinical Trial Registration Number, ACTRN12609000282280].


Dynamic simulation of water resources in an urban wetland based on coupled water quantity and water quality models.
Water quality in wetlands plays a huge role in maintaining the health of the wetland ecosystem. Water quality should be controlled by an appropriate water allocation policy for the protection of the wetlands. In this paper, models of rainfall/runoff, non-point source pollution load, water quantity/quality, and dynamic pollutant-carrying capacity were established to simulate the water quantity/quality of Xixi-wetland river network (in the Taihu basin, China). The simulation results showed a satisfactory agreement with field observations. Furthermore, a 'node-river-node' algorithm that adjusts to the 'Three Steps Method' was adopted to improve the dynamic pollutant-carrying capacity model and simulate the pollutant-carrying capacity in benchmark years. The simulation result shows that the water quality of the river network could reach class III stably all year round if the anthropogenic pollution is reduced to one-third of the current annual amount. Further investigation estimated the minimum amount of water diversion in benchmark years under the reasonable water quantity-regulating rule to keep water quality as class III. With comparison of the designed scale, the water diversion can be reduced by 184 million m3 for a dry year, 191 million m3 for a normal year, and 198 million m3 for a wet year.


Results of varicocelectomy in patients with isolated teratozoospermia.
Isolated teratozoospermia is rarely encountered in patients with clinically palpable varicocele, and the consequences of varicocelectomy remain unclear in these cases. In the current study, we assessed the effect of varicocelectomy on sperm morphology in a series of patients with infertility. The data obtained from 52 primary subfertile men with isolated teratozoospermia and clinical palpable varicocele were reviewed retrospectively. Varicocelectomy was performed on 29 patients, and the remaining 23 patients did not undergo any treatment (control group). The differences in sperm morphology assessed by using Kruger's strict criteria 3 months before and 12 months after varicocelectomy were taken into consideration for statistical analysis. One patient who underwent varicocelectomy was excluded from the study due to varicocele recurrence. Thus, data obtained from the remaining 28 patients were evaluated. Following varicocelectomy, significant improvement was detected in the ratio of normal sperm forms (p < 0.001). While there was significant improvement in the ratio of sperm cells with head defects, tail defects and immature forms (p < 0.001), the ratio of sperm with acrosome and mid-piece defects was not changed (p > 0.05). While an overall spontaneous pregnancy was achieved in 5 of the 28 (17.8%) couples in the varicocelectomy group within 12 months after operation, neither improvement in sperm morphology nor pregnancy in the patients' partners was detected in the control group. Varicocelectomy caused a significant improvement in sperm morphology, particularly in immature forms and forms with head and tail defects evaluated by Kruger's classification.


A team-based approach to autopsy education: integrating anatomic and clinical pathology at the rotation level.
Pathology residency training programs should aim to teach residents to think beyond the compartmentalized data of specific rotations and synthesize data in order to understand the whole clinical picture when interacting with clinicians. To test a collaborative autopsy procedure at Montefiore Medical Center (Bronx, New York), linking residents and attending physicians from anatomic and clinical pathology in the autopsy process from the initial chart review to the final report. Residents consult with clinical pathology colleagues regarding key clinical laboratory findings during the autopsy. This new procedure serves multiple functions: creating a team-based, mutually beneficial educational experience; actively teaching consultative skills; and facilitating more in-depth analysis of the clinical laboratory findings in autopsies. An initial trial of the team-based autopsy system was done from November 2010 to December 2012. Residents were then surveyed via questionnaire to evaluate the frequency and perceived usefulness of clinical pathology autopsy consultations. Senior residents were the most frequent users of clinical pathology autopsy consultation. The most frequently consulted services were microbiology and chemistry. Eighty-nine percent of the residents found the clinical pathology consultation to be useful in arriving at a final diagnosis and clinicopathologic correlation. The team-based autopsy is a novel approach to integration of anatomic and clinical pathology curricula at the rotation level. Residents using this approach develop a more holistic approach to pathology, better preparing them for meaningful consultative interaction with clinicians. This paradigm shift in training positions us to better serve in our increasing role as arbiters of outcomes measures in accountable care organizations.


Beyond reliability and validity: analysis of selected quality-of-life instruments for use in palliative care.
The purpose of this study was to review quality-of-life instruments for their potential usefulness in the palliative care setting. Conceptualizations of quality of life throughout history, and contemporary conceptualizations of quality of life were briefly discussed. The specific conceptualizations of six quality-of-life measurement tools (the Medical Outcomes Study Short-Form Health Survey [SF-36], the European Organization for Research and Treatment of Cancer [EORTC] QLQ-C30, the Quality of Life Index [QLI], the Hospice Quality of Life Index [HQLI], the McGill Quality of Life Questionnaire [MQOL], and the Missoula-VITAS Quality of Life Index [MVQOLI]) were evaluated. The origins, target populations, acceptability of individual items, completion time, number of questions, type of response format, and type of scoring of each instrument were discussed, and evidence of the instruments' reliability, validity, and responsiveness were reviewed. The researcher or clinician should consider all of these factors when choosing the quality-of-life instrument that best fits the purpose.


The genetics of vascular complications in autosomal dominant polycystic kidney disease (ADPKD).
The most important extra-renal manifestation of autosomal dominant polycystic kidney disease (ADPKD) in terms of debilitating injury and premature death is the development of intracranial aneurysms (IAs) and other vascular complications, resulting in subarachnoid hemorrhage (SAH). IAs are found at a rate approximately five times higher in ADPKD patients than in the general population and in patients with a family history of SAH/IAs the frequency is elevated further three to five times, indicating the importance of genetic factors in its etiology. Expression of the ADPKD gene products, polycystin-1 (PKD1) and polycystin-2 (PKD2), in vascular smooth muscle and the endothelium, and evidence that reduced levels of these proteins leads to IA development in mouse models, suggests a direct role of these proteins in the vascular disease. PKD1 and PKD2 patients seem equally likely to develop IAs, while patients with mutations to the 5' half of PKD1 may more likely have vascular complications. Genome wide association and candidate studies of multiplex families with IAs without ADPKD have identified a number of genes/proteins that may be risk factors for the development of IAs. These candidate proteins largely have roles in the maintenance and remodeling of the arterial wall of small brain arteries. The development of the genetic methodologies of massively parallel sequencing mean it is now possible to test these and other candidates in ADPKD families with multiplex and singleton IA cases. Identifying strong modifiers of this phenotype will be important for prioritizing patients for presymptomatic screening and interventions.


Biomechanical effect of medial advancement of the supraspinatus tendon. A study in cadavera.
During the repair of some rotator-cuff tears, the torn tendon cannot be freed up adequately to permit reattachment at its original anatomical site of insertion. An option is to advance the site of insertion medially and reattach the tendon to a trough in the sulcus or to the humeral head. The biomechanical effects of such medial advancement on the moment arm of the supraspinatus muscle during glenohumeral elevation were studied in ten fresh-frozen shoulders from cadavera. Medial advancement of the site of insertion of the supraspinatus tendon was simulated by the placement of suture anchors in the sulcus of the proximal part of the humerus at points three, ten, and seventeen millimeters medial to the junction of the supraspinatus tendon and the bone. These distances were chosen not because they represent clinical options but because the large range allowed biomechanical study of medial advancement. Nylon lines were attached to the suture anchors and were passed back through an eyehook at the midpoint of the supraspinatus muscle. The excursion of each line was measured as the humerus was elevated, and the moment arm was estimated from the joint angle and excursion data with use of the principle of virtual work. Three and ten millimeters of medial advancement of the tendon (attachment in the sulcus) had a minimum (non-significant) effect on the moment arm during elevation compared with the value determined for the intact condition. However, seventeen millimeters of medial advancement was found to reduce the moment arm significantly (p < 0.05).


Insulin knowledge and practice: a survey of district nurses in Northern Ireland.
Insulin is one of the top ten high-alert medications worldwide. Approximately 30% of people with diabetes in the UK use injectable therapies, most commonly insulin, to manage their condition. With an increasing number of people with diabetes being managed within the community, district nurses play an important role in the safe and effective use of insulin. This study surveyed a convenience sample of 164 district nurses working within one Health and Social Care Trust in Northern Ireland to ascertain their knowledge and practice regarding insulin. Study response rate was 38% (n=63). It was found that district nurses' knowledge and practice relating to insulin therapy was lacking as indicated by a total mean score of 53.1%. Total knowledge scores were slightly higher (58%) than total practice scores (46%). Nevertheless, 79.4% of district nurses felt secure and 6.3% felt very secure in managing diabetes. Deficits in district nurses' knowledge and practice were identified in areas relating to insulin action, dosage, storage, injection site technique and rotation, hypoglycaemic/hyperglycaemic management, pharmacological action and prescription format. These deficits highlight the need for workplacebased learning and development programmes, incorporating real time, point of care interventions, to enhance and maintain district nurses' insulin knowledge and practice.


Predicting survival for 1 year among different subtypes of stroke. Results from the Perth Community Stroke Study.
Few studies have evaluated the factors influencing or predicting long-term survival after stroke in an unselected series of patients in whom the underlying cerebrovascular pathology is clearly defined. Moreover, the relative importance of risk factors for stroke, including sociodemographic and premorbid variables, has not been described in detail. The study cohort consisted of 492 patients with stroke who were registered with a population-based study of acute cerebrovascular disease undertaken in Perth, Western Australia, during an 18-month period in 1989 and 1990. Objective evidence of the pathological basis of the stroke was obtained in 86% of cases, and all deaths among patients during a follow-up of 1 year were reviewed. One hundred twenty patients (24%) died within 28 days of the onset of stroke. Among the different subtypes of stroke, the 1-year case fatality (mean, 38%) varied from 6% and 16% for boundary zone infarction and lacunar infarction, respectively, to 42% and 46% for subarachnoid hemorrhage and primary intracerebral hemorrhage, respectively. Using Cox proportional-hazards analysis, a predictive model was developed on 321 patients with acute stroke (test sample). The best model contained five baseline variables that were independent predictors of death within 1 year: coma (relative risk [RR], 3.0; 95% confidence interval [CI], 1.1 to 8.4), urinary incontinence (RR, 3.9; 95% CI, 1.4 to 10.6), cardiac failure (RR, 6.5; 95% CI, 2.8 to 15.1), severe paresis (RR, 4.9; 95% CI, 1.6 to 15.5), and atrial fibrillation (RR, 2.0; 95% CI, 1.1 to 3.5). The sensitivity, specificity, and negative predictive value of this model for predicting death were 90%, 83%, and 95%, respectively. When applied to a second randomly selected validation sample of 171 events, sensitivity was 94%, specificity 62%, and negative predictive value 92%, indicating stability of the model. Although the case fatality, timing, and cause of death vary considerably among the different pathological subtypes of stroke, simple clinical measures that reflect the severity of the neurological deficit and associated cardiac disease at onset independently predict death by 1 year and may help to direct management.


Modulation of evoked contractions in rat arteries by ryanodine, thapsigargin, and cyclopiazonic acid.
The contribution of sarcoplasmic reticulum (SR) Ca2+ release to evoked tension in rat arterial rings was studied by comparing the effects of ryanodine (an SR Ca2+ channel opener) and thapsigargin and cyclopiazonic acid (CPA) (two Ca(2+)-ATPase inhibitors). Isometric tension was evoked by serotonin (5-HT), 30-50 mM external K+, and 10 mM caffeine in rings of aorta and a small (second-order) branch of the superior mesenteric artery (SMA). Resting tension was unaffected by 10 microM ryanodine or 1-5 microM thapsigargin, but 20 microM CPA raised resting tension in aortic rings and evoked spontaneous contractions in some SMA rings. Ryanodine (10 microM) or 1-5 microM thapsigargin partially depleted the SR Ca2+ stores (indicated by reduced caffeine-evoked contractions) and attenuated 5-HT- and high K(+)-evoked contractions in aortic rings but augmented 5-HT- and high K(+)-evoked contractions in SMA. Caffeine completely emptied the SR Ca2+ stores in the presence of ryanodine but not thapsigargin in both the aorta and SMA; thus, thapsigargin may selectively affect one component of a heterogeneous SR. When the aortic Ca2+ stores were empty (i.e., caffeine contractions were abolished), the 5-HT- and high K(+)-evoked contractions in the aorta were also augmented. CPA rapidly emptied the SR Ca2+ stores in both the aorta and SMA. CPA augmented the 5-HT-evoked contractions in the SMA and in five of nine aortic rings but attenuated evoked contractions in the remaining aortic rings. The attenuation or abolition of the caffeine contractions implies that ryanodine, thapsigargin, and CPA all deplete the SR Ca2+ stores. The attenuated responses to 5-HT and high K+ observed when the aortic SR Ca2+ stores were only partially depleted are consistent with the idea that evoked SR Ca2+ release is a large component of the Ca2+ transient in the aorta. The augmentation of 5-HT- and high K(+P)-evoked responses after partial (SMA) or complete (aorta) depletion of the SR Ca2+ stores suggests that evoked release of SR Ca2+ normally regulates Ca2+ entry by negative feedback and/or that the SR normally buffers the evoked rise in cytosolic Ca2+.


Alkaline manganese electrochemistry studied by in situ and operando spectroscopic methods - metal dissolution, oxide formation and oxygen evolution.
Manganese-based systems are considered as candidate electrocatalysts for the electrochemical oxygen evolution reaction (OER), because of their abundance in biochemical oxygen producing catalyst systems. In this work, the surface of metallic manganese was investigated in situ and operando in potentiodynamic cyclic voltammetry (CV) experiments and potentiostatic chronoamperometry (CA) experiments in NaOH. In both cases, the surfaces were initially reduced. At corresponding potentials, no oxide species can be detected by Raman spectroscopy, though electrochemical data and the absence of dissolution above the reversible potential for reactions of type Mn → MnII indicate that the material is passive. The CV shows anodic peaks at potentials in line with expectations on the basis of thermodynamic data for the oxidation to Mn3O4 and Mn2O3; the thickness of the surface layer increases by a few nm during these peaks, as evidenced by spectroscopic ellipsometry. Dissolution of Mn as evidenced by downstream electrolyte analysis by inductively coupled plasma mass spectrometry in a scanning flow cell (SFC-ICP-MS) of the electrolyte is negligible in the range of electrode potential vs. Ag|AgCl|3 M KCl, EAg|AgCl, up to 0.3 V. Remarkably, Raman spectra already show the occurrence of α-MnO2 at EAg|AgCl > -0.25 V, which is ca. 0.5 V below the potential at which oxidation to MnO2 is expected. This observation is attributed to disproportionation above a certain level of MnIII. For EAg|AgCl > 0.4 V, dissolution sets in, at a constant layer thickness. Above the onset potential of the OER, at EAg|AgCl≈ 0.6 V, SFC-ICP-MS analysis shows fast dissolution, and the oxide layer thickness is constant or increases. CA experiments during the OER show strong dissolution, and the re-formation of a strongly disordered, β-MnO2-like oxide, which exists in a quasi-stationary state at the interface. Several CV cycles increase the dissolution per cycle and the fraction of α-MnO2 on the surface which cannot be reduced. The high dissolution currents show that metallic Mn is hardly suitable as an OER catalyst, however, at least the MnIV oxides remain stationarily present in the system.


Mutations in endonuclease V that affect both protein-protein association and target site location.
A general mechanism by which proteins locate their target sites within large domains of DNA is a one-dimensional facilitated diffusion process in which the protein scans DNA in a nonspecifically bound state. An electrostatic contribution to this type of mechanism has been previously established. This study was designed to question whether other characteristics of a protein's structure might contribute to the scanning mechanism of target site location. In this regard, T4 endonuclease V was shown to establish an ionic strength dependent monomer-dimer equilibrium in solution. A protein dimer interaction site was postulated to exist along a putative alpha-helix containing amino acid residues 54-62. The conservative substitutions of Phe-60----Leu-60 and Phe-59, Phe-60----Leu-59, Leu-60 resulted in mutant enzymes which remained in the monomeric state independent of the ionic strength of the solution. The target site location mechanism of these mutants has also been altered. Under conditions where wild-type endonuclease V processively scans nontarget DNA, the target location mechanism of the monomeric mutant proteins was shifted toward a less processive search. This decrease in the processivity of the mutants was especially surprising because the nontarget DNA binding affinity was found to be significantly increased. Thus, an additional component of the endonuclease V DNA scanning mechanism appears to be the formation of a stable endonuclease V dimer complex.


Systematic review of uncalibrated arterial pressure waveform analysis to determine cardiac output and stroke volume variation.
The FloTrac/Vigileo™, introduced in 2005, uses arterial pressure waveform analysis to calculate cardiac output (CO) and stroke volume variation (SVV) without external calibration. The aim of this systematic review is to evaluate the performance of the system. Sixty-five full manuscripts on validation of CO measurements in humans, published in English, were retrieved; these included 2234 patients and 44,592 observations. have been analysed according to underlying patient conditions, that is, general critical illness and surgery as normodynamic conditions, cardiac and (post)cardiac surgery as hypodynamic conditions, and liver surgery and sepsis as hyperdynamic conditions, and subsequently released software versions. Eight studies compared SVV with other dynamic indices. CO, bias, precision, %error, correlation, and concordance differed among underlying conditions, subsequent software versions, and their interactions, suggesting increasing accuracy and precision, particularly in hypo- and normodynamic conditions. The bias and the trending capacity remain dependent on (changes in) vascular tone with most recent software. The SVV only moderately agreed with other dynamic indices, although it was helpful in predicting fluid responsiveness in 85% of studies addressing this. Since its introduction, the performance of uncalibrated FloTrac/Vigileo™ has improved particularly in hypo- and normodynamic conditions. A %error at or below 30% with most recent software allows sufficiently accurate and precise CO measurements and trending for routine clinical use in normo- and hypodynamic conditions, in the absence of large changes in vascular tone. The SVV may usefully supplement these measurements.


Control of asgE expression during growth and development of Myxococcus xanthus.
One of the earliest events in the Myxococcus xanthus developmental cycle is production of an extracellular cell density signal called A-signal (or A-factor). Previously, we showed that cells carrying an insertion in the asgE gene fail to produce normal levels of this cell-cell signal. In this study we found that expression of asgE is growth phase regulated and developmentally regulated. Several lines of evidence indicate that asgE is cotranscribed with an upstream gene during development. Using primer extension analyses, we identified two 5' ends for this developmental transcript. The DNA sequence upstream of one 5' end has similarity to the promoter regions of several genes that are A-signal dependent, whereas sequences located upstream of the second 5' end show similarity to promoter elements identified for genes that are C-signal dependent. Consistent with this result is our finding that mutants failing to produce A-signal or C-signal are defective for developmental expression of asgE. In contrast to developing cells, the large majority of the asgE transcript found in vegetative cells appears to be monocistronic. This finding suggests that asgE uses different promoters for expression during vegetative growth and development. Growth phase regulation of asgE is abolished in a relA mutant, indicating that this vegetative promoter is induced by starvation. The data presented here, in combination with our previous results, indicate that the level of AsgE in vegetative cells is sufficient for this protein to carry out its function during development.


Long-term follow-up of relapsing/refractory anti-neutrophil cytoplasm antibody associated vasculitis treated with the lymphocyte depleting antibody alemtuzumab (CAMPATH-1H).
Lymphocytes are a contributor to the pathogenesis of anti-neutrophil cytoplasm antibody (ANCA) associated vasculitis (AASV). Conventional immunosuppressive therapy is associated with high rates of relapse and toxicity. Humanised monoclonal anti-CD52 antibodies (alemtuzumab, CAMPATH-1H) selectively deplete lymphocytes. We present long-term follow-up results of patients with relapsing/refractory AASV treated with CAMPATH-1H. Between 1991 and 1999, 71 patients with refractory or relapsing AASV received CAMPATH-1H at Addenbrooke's Hospital, Cambridge, UK. Other immunosuppressive drugs were discontinued and prednisolone was tapered to 10 mg/day. The mean follow-up time was 5 years. In all, 79% had previously received cyclophosphamide (median dose 150 g). At the time of treatment, 42% had renal involvement (median creatinine for the cohort 101 micromol/litre excluding six patients who were dialysis dependent) and 18% were critically ill from AASV and required the intensive care unit. A total of 60 patients (85%) obtained a remission after treatment with CAMPATH-1H but 43 relapsed (median 9.2 months); 24 had a remission greater than 1 year, of which 10 had a remission of at least 3 years. A total of 31 patients died (median survival time of 106 months). Age >50 years, dialysis dependency and the development of a severe infection at the time of treatment were associated with an increased risk of death in multivariable analysis. Adverse events were common; 28 patients developed an infection, 3 malignancy and 8 thyroid disease. CAMPATH-1H induced remission in most patients with difficult to treat AASV. However, relapse and adverse events were common. Further study of CAMPATH-1H as an induction agent in AASV is warranted.


The mechanism of coronary collateral vasoconstriction in response to cyclooxygenase blockade.
The present study was performed to examine the mechanism by which cyclooxygenase blockade produces vasoconstriction in well-developed coronary collateral vessels. Eight dogs were studied 4 to 6 months after occlusion of the left anterior descending coronary artery (LAD) had been performed to stimulate collateral vessel growth. At the time of study, the LAD was cannulated at the site of occlusion for measurement of retrograde blood flow as an index of collateral blood flow. Levels of 6-ketoprostaglandin F1 alpha were 32 +/- 13% higher in blood diverted from the collateral-dependent LAD than in aortic blood (P < .05); the increase in this stable product of prostacyclin metabolism indicated production of prostacyclin across the coronary collateral system. Administration of arachidonic acid into the left main coronary artery to reach collateral vessels entering the LAD resulted in a 21 +/- 6% increase in retrograde flow (P < .01), demonstrating cyclooxygenase activity with production of vasodilator prostaglandins in the collateral system. Ibuprofen (10 mg/kg IV) caused a 55 +/- 7% decrease in retrograde flow (P < .03), suggesting that cyclooxygenase blockade inhibited tonic production of vasodilator prostaglandins in the collateral system. In contrast, neither thromboxane synthase inhibition with dazmegrel nor thromboxane receptor blockade with SQ 30741 caused a significant change in collateral flow, thus failing to support thromboxane-induced collateral constriction. After cyclooxygenase blockade, prostacyclin infused into the left main coronary artery was able to restore retrograde flow to the preibuprofen level.(ABSTRACT TRUNCATED AT 250 WORDS)


A monoclonal antibody reacting with distinct adhesion molecules defines a transition in the functional state of the receptor CD11b/CD18 (Mac-1).
CD11b/CD18 (Mac-1) is a member of the leukocyte integrin family, a group of receptors that have been implicated in various effector functions and cellular collaboration in the immune response. It has been shown previously that CD11b/CD18 on cells of monocyte and myeloid lineage appears to undergo rapid activation and acquire new functional receptor specificities after exposure to selected agonists such as adenosine diphosphate (ADP). We now show that ADP induces a reconformation of the CD11b/CD18 receptor with exposure of new epitopes characteristics of this activated state. By direct binding studies, flow cytometry, and immunoprecipitation experiments, it has been found that the mAb 7E3 reacts with CD11b/CD18 only after ADP-stimulation of the cell suspension. The activated state of CD11b/CD18 induced by ADP and recognized by 7E3 can also be recapitulated by agonists inducing transients in cytosolic Ca2+ such as the chemoattractant FMLP. Moreover, this process of receptor activation does not involve quantitative mobilization of the subcellular storage pool of CD11b/CD18 to the plasma membrane. Because 7E3 also recognizes a qualitative, ADP-mediated activated state of the platelet adhesion receptor GP IIb/IIIa, it is suggested that transients in cytosolic Ca2+ might represent early secondary events for a general pathway of rapid activation of integrin receptors and, as such, represent important signals for cellular interactions in the immune response.


Carbon nanotube decorated magnetic microspheres as an affinity matrix for biomolecules.
Carbon nanotube (CNT) decorated magnetic microspheres were fabricated to develop a multimodal platform that utilizes non-covalent molecular interactions of CNTs to magnetically separate biomolecules. Hybrid CNT-microspheres prepared by a feasible method reported herein had a well-defined structure as characterized by Raman spectroscopy and scanning electron microscopy. Binding interactions of resulting magnetic CNT-microspheres with DNA oligonucleotides were studied to demonstrate that single stranded DNA (ssDNA) in a solution can be effectively recovered by magnetic CNT-microspheres through strong physical wrapping of DNA around CNTs' walls. The magnetic character of these CNT-microspheres combined with their capability to bind other molecules including DNA allows their use as an affinity matrix that can be utilized in affinity separation of biomolecules, and also as a platform to monitor non-covalent binding interactions of CNTs with other biomolecules. As a proof of concept, we report on the use of these CNT-microspheres in in vitro selection of ssDNA aptamers against carcinoembryonic antigen (CEA), a cancer biomarker, by Systematic Evolution of Ligands by Exponential Enrichment (SELEX). ssDNA aptamer candidates that have strong affinity towards CEA were successfully separated magnetically from a pool of ssDNA (∼1014 molecules). Our results demonstrate that CNT-microspheres can serve as strong tools for affinity separation methodologies and can be utilized for various affinity pairs in solution.


Prenatal fluoride for growth and development: Part X.
Examinations of prenatal fluoride supplemented (PNF) teeth in an animal model and in a five-month human fetus find these teeth to be more developed than the non-supplemented controls. The fact that PNF allows teeth to develop to their full potential suggests that PNF could be an essential nutrient for the entire human and this could be demonstrated most easily during rapid fetal growth. A review of the recent literature, including trials by NIH and The World Health Organization, provide evidence that fluoride (F) does allow the fetus to grow and develop to its full potential. The authors conclude that PNF must be supplied in at least a 2 mg/day pulse dose, and then F must be given from shortly after birth in a daily amount appropriate for the weight of the child with some consideration for the amount of F water utilized.


Cystathionine-γ-lyase expression is associated with mitochondrial respiration during sepsis-induced acute kidney injury in swine with atherosclerosis.
Sepsis is associated with disturbed glucose metabolism and reduced mitochondrial activity and biogenesis, ultimately leading to multiple organ dysfunction, e.g., acute kidney injury (AKI). Cystathionine-γ-lyase (CSE), the major cardiovascular source of endogenous H2S release, is implicated in the regulation of glucose metabolism and mitochondrial activity through a PGC1α-dependent mechanism, and critical for kidney function. Atherosclerosis is associated with mitochondrial dysfunction and reduced CSE expression. Thus, the aim of this post hoc study was to test the hypothesis whether there is an interplay between CSE expression and kidney dysfunction, mitochondrial activity, and oxidative/nitrosative stress in porcine septic AKI with underlying coronary artery disease. This study is a post hoc analysis of material from anesthetized and instrumented swine with a high fat diet-induced hypercholesterolemia and atherosclerosis undergoing faecal peritonitis-induced septic shock or sham procedure and intensive care (comprising fluid resuscitation and continuous i.v. noradrenaline (NoA) infusion) for 24 h. Glucose metabolism was quantified from blood 13C6-glucose and expiratory 13CO2/12CO2 isotope enrichment during 13C6-glucose infusion. Mitochondrial activity was determined by high-resolution respirometry. CSE and PGC1α expression, as well as nitrotyrosine formation and albumin extravasation, were quantified by immunohistochemistry of formalin-fixed kidney paraffin sections. Sepsis was associated with lactic acidosis (p = 0.004) and AKI (50% fall of creatinine clearance (CrCl), p = 0.019). While both whole-body glucose production (p = 0.004) and oxidation (p = 0.006) were increased, kidney tissue mitochondrial respiration was reduced (p = 0.028), coinciding with decreased CSE (p = 0.003) and PGC1α (p = 0.003) expression. Albumin extravasation (p = 0.011) and nitrotyrosine formation (p = 0.008) were increased in septic kidneys. Sepsis-induced AKI is associated with disturbed mitochondrial respiration and biogenesis, which may be aggravated by oxidative and nitrosative stress. Our results confirm previous data in murine septic shock and porcine hemorrhage and resuscitation on the crucial role of CSE for barrier integrity and kidney function.


Association of neighborhood socioeconomic status with physical fitness in healthy young adults: the Coronary Artery Risk Development in Young Adults (CARDIA) study.
Impaired physical fitness, a contributor to obesity and cardiovascular disease, has been associated with both an individual's socioeconomic status (SES) and with residence in disadvantaged neighborhoods. The aim of the study was to examine the extent to which neighborhood socioeconomic status (SES) is associated with impaired fitness, independent of clinical characteristics and individual-level SES. Two thousand five hundred five participants 25 to 42 years old examined in the CARDIA study from 1992 to 1993 underwent symptom-limited exercise stress testing. Physical fitness was considered impaired if metabolic equivalents were in the lowest sex-specific quintile. Neighborhood SES was determined for each census tract using 1990 census data. Generalized estimating equations assessed the association between neighborhood SES and physical fitness, before and after adjustments for individual SES, sociodemographic, and clinical characteristics, and accounted for clustering within census tracts. Individuals in disadvantaged neighborhoods had lower educational attainment and income, and were more likely unemployed, black, and uninsured. The odds ratio (95% CI) for impaired physical fitness in the lowest vs highest tertile of neighborhood SES was 5.8 (3.7-7.3). These became 3.9 (2.7-5.7) after adjusting for individuals' educational attainment, personal income, employment status, and ability to pay for basic needs; and 1.9 (1.2-2.9) after additional adjustment for other sociodemographic and clinical factors. Features of one's neighborhood of residence are relevant to cardiovascular health. A health policy perspective that looks beyond an individual's characteristics may therefore be useful in identifying more effective interventions to reduce the prevalence of low physical fitness and its consequences in young adults.


Colorectal cancer in patients with inflammatory bowel disease: can we predict risk?
The inflammatory bowel diseases (IBD), Crohn's disease (CD) and ulcerative colitis (UC), may be complicated by colorectal cancer (CRC). In a recent population-based cohort study of 47 347 Danish patients with IBD by Tine Jess and colleagues 268 patients with UC and 70 patients with CD developed CRC during 30 years of observation. The overall risk of CRC among patients with UC and CD was comparable with that of the general population. However, patients diagnosed with UC during childhood or as adolescents, patients with long duration of disease and those with concomitant primary sclerosing cholangitis were at increased risk. In this commentary, we discuss the mechanisms underlying carcinogenesis in IBD and current investigations of genetic susceptibility in IBD patients. Further advances will depend on the cooperative work by epidemiologist and molecular geneticists in order to identify genetic polymorphisms involved in IBD-associated CRC. The ultimate goal is to incorporate genotypes and clinical parameters into a predictive model that will refine the prediction of risk for CRC in colonic IBD. The challenge will be to translate these new findings into clinical practice and to determine appropriate preventive strategies in order to avoid CRC in IBD patients. The achieved knowledge may also be relevant for other inflammation-associated cancers.


Return to high school- and college-level football after anterior cruciate ligament reconstruction: a Multicenter Orthopaedic Outcomes Network (MOON) cohort study.
There is a relative paucity of data regarding the effect of anterior cruciate ligament (ACL) reconstruction on the ability of American high school and collegiate football players to return to play at the same level of competition as before their injury or to progress to play at the next level of competition. (1) To identify the percentage of high school and collegiate American football players who successfully returned to play at their previous level of competition, (2) to investigate self-reported performance for those players able to return to play or reason(s) for not returning to play, and (3) to elucidate risk factors responsible for players not being able to return to play or not returning to the same level of performance. Cohort study; Level of evidence, 3. This study was a retrospective analysis of prospective patients taken from the Multicenter Orthopaedic Outcomes Network (MOON) cohort who identified football as their primary or secondary sport. Identified patients were then questioned in a structured interview regarding their ACL injury, participation in football before their injury, and factors associated with returning to play. Data were analyzed for player position, concurrent meniscal/ligamentous/chondral injury, surgical technique and graft used for ACL reconstruction, and issues pertaining to timing and ability to return to play. One hundred forty-seven players (including 68 high school and 26 collegiate) met our criteria and were contacted from the 2002 and 2003 MOON cohorts. Return to play rates for all high school and collegiate athletes were similar (63% and 69%, respectively). Based on player perception, 43% of the players were able to return to play at the same self-described performance level. Approximately 27% felt they did not perform at a level attained before their ACL tear, and 30% were unable to return to play at all. Although two thirds of players reported some "other interest" contributing to their decision not to return, at both levels of competition, fear of reinjury or further damage was cited by approximately 50% of the players who did not return to play. Analysis of patient-reported outcome scores at a minimum of 2 years after surgery between patients who returned to play and those who did not demonstrated clinically and statistically significant differences in the International Knee Documentation Committee form, Marx Activity Scale, and Knee injury and Osteoarthritis Outcome Score knee-related quality of life subscale in the collegiate players. Similar clinical differences were not statistically significant in the high school students. Player position did not have a statistically significant effect on the ability to return to play for high school players, and 41% of "skilled" position players and 50% of "nonskilled" position players were able to return to play at the same performance level. Return to play percentages for amateur American football players after ACL reconstruction are not as high as would be expected. While technical aspects of ACL reconstruction and the ensuing rehabilitation have been studied extensively, the psychological factors (primarily a fear of reinjury) influencing the ability to return to play after ACL surgery may be underestimated as a critical factor responsible for athletes not returning to play at any level of competition.


Genetic rescue persists beyond first-generation outbreeding in small populations of a rare plant.
Habitat fragmentation commonly causes genetic problems and reduced fitness when populations become small. Stocking small populations with individuals from other populations may enrich genetic variation and alleviate inbreeding, but such artificial gene flow is not commonly used in conservation owing to potential outbreeding depression. We addressed the role of long-term population size, genetic distance between populations and test environment for the performance of two generations of offspring from between-population crosses of the locally rare plant Ranunculus reptans L. Interpopulation outbreeding positively affected an aggregate measure of fitness, and the fitness superiority of interpopulation hybrids was maintained in the second offspring (F2) generation. Small populations benefited more strongly from interpopulation outbreeding. Genetic distance between crossed populations in neutral markers or quantitative characters was not important. These results were consistent under near-natural competition-free and competitive conditions. We conclude that the benefits of interpopulation outbreeding are likely to outweigh potential drawbacks, especially for populations that suffer from inbreeding.


Chemical pretreatment of combined sewer overflows for improved UV disinfection.
The aim of this research was to better understand chemical pre-treatment of combined sewer overflows (CSOs) for subsequent ultraviolet (UV) disinfection. Approximately 200 jar tests were completed. Alum (Al2(S04)3·12H2O) resulted in a higher UV light transmission (UVT), and equivalent total suspended solids (TSS) removal, than ferric chloride (FeCl3). An alum dose of 20 mg/L increased the UVT of the raw CSO from 30 to 60% after settling. The addition of 100 mg/L of alum maximized UVT reaching approximately 85%. Flocculation did not increase UVT. However, it did improve the removal of TSS. Cationic polymers worked quickly compared with metal coagulants, but only reached a UVT of 60%. A high positive charge density on the polymer improved the removal of turbidity when compared with low charge, but did not affect UVT. If the goal is to maximise UVT, a very high alum dose may be preferred. If the goal is to minimize coagulant dose with moderate UV performance, cationic polymer at approximately 3 mg/L is recommended.


Ambiguous participation in older hospitalized patients: gaining influence through active and passive approaches-a qualitative study.
Patient participation is required by law in Norway and in several western countries. Current participation ideology is based on individualism, which may conflict with the older generation's commonly held values of solidarity and community. Hence, different values and ideologies may come in conflict when older patients receive treatment and rehabilitation in geriatric wards. Participation is a guiding principle in rehabilitation. Criteria for admission of older patients to geriatric wards are complex health problems, acute illness and/or acute physical and/or cognitive functional failure. The ideal is an active and engaged patient. The aim of the study was to describe the difficulties experienced by older patients on acute geriatric wards when involving themselves with their own treatment and care. In this qualitative study older patients were interviewed during hospitalization in geriatric wards and asked to tell about their experiences with participation. Data analysis was conducted using a phenomenological hermeneutic method. The patients experienced difficulties in participating in decisions and care. They linked their difficulties to their own diminishing capabilities, and cited the ward's busy schedule as a reason for abstaining from participation. However, despite their reservations, they did participate in decisions in different ways. Their participatory practices appeared ambiguous and they employed various strategies to put themselves in a position of influence. The most important of these involved their relatives. The patients delegated to family the tasks of seeking, receiving and giving information to the nurses and the staff, and, to some extent, for the dialogues with hospital staff about their needs and plan of care. The family appeared to accept the responsibility willingly. The patients addressed their difficulties by authorizing family members to act and participate on their behalf. This underlines the family's important role in patient participation and the role that nurses and other staff must play in collaborating with the patient and their family to facilitate participation independently of the patients' performances of participation.


Distinct and Shared Determinants of Cardiomyocyte Contractility in Multi-Lineage Competent Ethnically Diverse Human iPSCs.
The realization of personalized medicine through human induced pluripotent stem cell (iPSC) technology can be advanced by transcriptomics, epigenomics, and bioinformatics that inform on genetic pathways directing tissue development and function. When possible, population diversity should be included in new studies as resources become available. Previously we derived replicate iPSC lines of African American, Hispanic-Latino and Asian self-designated ethnically diverse (ED) origins with normal karyotype, verified teratoma formation, pluripotency biomarkers, and tri-lineage in vitro commitment. Here we perform bioinformatics of RNA-Seq and ChIP-seq pluripotency data sets for two replicate Asian and Hispanic-Latino ED-iPSC lines that reveal differences in generation of contractile cardiomyocytes but similar and robust differentiation to multiple neural, pancreatic, and smooth muscle cell types. We identify shared and distinct genes and contributing pathways in the replicate ED-iPSC lines to enhance our ability to understand how reprogramming to iPSC impacts genes and pathways contributing to cardiomyocyte contractility potential.


Intermediate outcomes of a chronic disease self-management program for Spanish-speaking older adults in South Florida, 2008-2010.
The prevalence and negative health effects of chronic diseases are disproportionately high among Hispanics, the largest minority group in the United States. Self-management of chronic conditions by older adults is a public health priority. The objective of this study was to examine 6-week differences in self-efficacy, time spent performing physical activity, and perceived social and role activities limitations for participants in a chronic disease self-management program for Spanish-speaking older adults, Tomando Control de su Salud (TCDS). Through the Healthy Aging Regional Collaborative, 8 area agencies delivered 82 workshops in 62 locations throughout South Florida. Spanish-speaking participants who attended workshops from October 1, 2008, through December 31, 2010, were aged 55 years or older, had at least 1 chronic condition, and completed baseline and post-test surveys were included in analysis (N=682). Workshops consisted of six, 2.5-hour sessions offered once per week for 6 weeks. A self-report survey was administered at baseline and again at the end of program instruction. To assess differences in outcomes, a repeated measures general linear model was used, controlling for agency and baseline general health. All outcomes showed improvement at 6 weeks. Outcomes that improved significantly were self-efficacy to manage disease, perceived social and role activities limitations, time spent walking, and time spent performing other aerobic activities. Implementation of TCDS significantly improved 4 of 8 health promotion skills and behaviors of Spanish-speaking older adults in South Florida. A community-based implementation of TCDS has the potential to improve health outcomes for a diverse, Spanish-speaking, older adult population.


Behavioural effects of subthalamic nucleus lesions in the hemiparkinsonian marmoset (Callithrix jacchus).
Recent studies in non-human primates support a role for the subthalamic nucleus in the expression of parkinsonian symptomatology, and it has been proposed that subthalamic lesions may provide a surgical treatment for the symptoms of Parkinson's disease in humans. We have applied a broad range of behavioural tests to characterize the effects of lesions of the subthalamic nucleus on parkinsonian symptoms in the unilateral 6-hydroxydopamine (6-OHDA) lesioned marmoset (Callithrix jacchus). Thirteen marmosets were trained on a battery of behavioural tasks that were conducted at regular intervals before and after surgery. All received unilateral 6-OHDA lesions to the medial forebrain bundle. Seven animals were then given an additional N-methyl-D-aspartate lesion of the ipsilateral subthalamic nucleus, whereas the remaining six animals received a variety of control or sham lesions to the nucleus. The 6-OHDA lesions induced a strong ipsilateral bias in head position; mild-moderate ipsilateral rotation spontaneously and after injection of saline or amphetamine; and contralateral rotation after injection of apomorphine. Hemineglect was evident as delayed initiation of reaches on the contralateral side on the staircase reaching task. Additional subthalamic lesions significantly reversed the bias in head position from ipsilateral to contralateral and decreased neglect as evidenced by improved latencies to initiate reaching on the contralateral side at the staircase. However, deficits in skilled movements persisted in the subthalamic nucleus lesion group in that they did not complete the staircase task any faster than the control group and remained impaired on another task which required reaching into tubes. These behavioural effects demonstrate that excitotoxic lesioning of the subthalamic nucleus can ameliorate some, but not all, parkinsonian-like deficits in the unilateral 6-OHDA lesioned marmoset.


Bimodal Interventional Instrument Markers for Magnetic Particle Imaging and Magnetic Resonance Imaging-A Proof-of-Concept Study.
The purpose of this work was to develop instrument markers that are visible in both magnetic particle imaging (MPI) and magnetic resonance imaging (MRI). The instrument markers were based on two different magnetic nanoparticle types (synthesized in-house KLB and commercial Bayoxide E8706). Coatings containing one of both particle types were fabricated and measured with a magnetic particle spectrometer (MPS) to estimate their MPI performance. Coatings based on both particle types were then applied on a segment of a nonmetallic guidewire. Imaging experiments were conducted using a commercial, preclinical MPI scanner and a preclinical 1 tesla MRI system. MPI image reconstruction was performed based on system matrices measured with dried KLB and Bayoxide E8706 coatings. The bimodal markers were clearly visible in both methods. They caused circular signal voids in MRI and areas of high signal intensity in MPI. Both the signal voids as well as the areas of high signal intensity were larger than the real marker size. Images that were reconstructed with a Bayoxide E8706 system matrix did not show sufficient MPI signal. Instrument markers with bimodal visibility are essential for the perspective of monitoring cardiovascular interventions with MPI/MRI hybrid systems.


Improvement in prognosis of myocardial infarction by long-term beta-adrenoreceptor blockade using practolol. A multicentre international study.
In a large-scale double-blind controlled trial of practolol (200 mg twice daily) in the long-term prophylactic treatment of 3038 patients recovering from acute myocardial infarction treatment was started one to four weeks after the acute attack. The trial was originally planned to include 4000 patients treated for at least a year but had to be terminated prematurely because of the serious oculocutaneous and peritoneal reactions reported elsewhere. Nevertheless, important findings, probably applicable to other beta-adrenoreceptor antagonists, have emerged in relation to mortality and morbidity. (1) The practolol-treated group showed a significant reduction in overall mortality and in sudden deaths; (2) there was a highly significant reduction in "all cardiac events"; (3) the reduction in overall mortality was virtually confined to patients whose original pre-entry infarcts were sited anteriorly; (4) the protective effect of practolol was most evident in those patients with pre-entry anterior infarcts whose blood pressures at entry were below the mean for the trial as a whole; (5) there were highly significant group differences in favour of the drug relating to the incidence of angina pectoris and cardiac arrhythmias, and to the numbers of patients who had to be withdrawn from the trial because of these conditions; (6) significantly more patients were withdrawn from the treatment group because of suspected adverse reactions. It is concluded that practolol used in the long-term treatment of patients who have survived the acute phase of myocardial infarction reduces the death rate when the original infarct is sited anteriorly. It is postulated that the favourable results of the trial were due to beta-adrenoreceptor blockade rather than to some other property specific to practolol itself. Since practolol produces severe side effects in long-term use it is recommended that an alternative beta-adrenoreceptor blocking agent should be used.


Introduction: chronic kidney disease: a burgeoning health epidemic.
The kidneys function as excretory, biosynthetic, and metabolic organs, vital for maintaining normal physiology. Although dialysis can replace some kidney functions, it cannot replicate the biosynthetic and metabolic activities of the normal kidney. Chronic kidney disease (CKD) and its terminal complication, end-stage renal disease (ESRD), may progress undetected until immediately before symptomatic kidney failure develops. At this point in the disease process, few opportunities exist to prevent adverse outcomes. To (1) review the incidence, prevalence, and staging of CKD and ESRD and (2) elucidate that the management of CKD is suboptimal and costly. CKD is defined according to the presence or absence of kidney damage and level of kidney function. The Kidney Disease Outcomes Quality Initiative designates 5 stages of CKD, with stage 5 being ESRD -- the point at which patients' loss of kidney function precipitates a need for dialysis or kidney transplant. The United States Renal Data System has documented monumental growth of the ESRD population and its significant impact on Medicare and its budget. In 2005, approximately 1.2% of Medicare's 31 million beneficiaries who had ESRD generated 6.4% of Medicare's total costs. One of the most important aspects of CKD diagnosis and treatment is early detection and aggressive management of underlying causes. However, care for CKD patients is fragmented. Primary care physicians, cardiovascular specialists, endocrinologists, dietitians, and pharmacists may be engaged in the patient's care early but the nephrologist may not be approached until late, if at all. CKD is costly. Preventing progression to ESRD may improve quality of life and help save health care dollars. A concerted approach to manage CKD patients effectively starts with early detection and integrated management by multiple specialties. Delaying disease progression is crucial and must include patient education and aggressive treatment and management of CKD and its comorbidities. Interdisciplinary care models in which pharmacists are integrally involved should be replicated.


Improved sleep MRI at 3 tesla in patients with obstructive sleep apnea.
To describe a real-time MR imaging platform for synchronous, multi-planar visualization of upper airway collapse in obstructive sleep apnea at 3 Tesla (T) to promote natural sleep with an emphasis on lateral wall visualization. A real-time imaging platform was configured for sleep MR imaging which used a cartesian, partial k-space gradient-echo sequence with an inherent temporal resolution of 3 independent slices every 2 s. Combinations of axial, mid-sagittal, and coronal scan planes were acquired. The system was tested in five subjects with polysomnography-proven obstructive sleep apnea during sleep, with synchronous acquisition of respiratory effort and combined oral-nasal airflow data. Sleep was initiated and maintained to allow demonstration of sleep-induced, upper airway collapse as illustrated in two subjects when using a real-time, sleep MR imaging platform at 3T. Lateral wall collapse could not be visualized on mid-sagittal imaging alone and was best characterized on multiplanar coronal and axial imaging planes. Our dedicated sleep MR imaging platform permitted an acoustic environment of constant "white noise" which was conducive to sleep onset and sleep maintenance in obstructive sleep apnea patients at 3T. Apneic episodes, specifically the lateral walls, were more accurately characterized with synchronous, multiplanar acquisitions.


Objective motion sensor assessment highly correlated with scores of global levodopa-induced dyskinesia in Parkinson's disease.
Chronic use of medication for treating Parkinson's disease (PD) can give rise to peak-dose dyskinesia. Adjustments in medication often sacrifice control of motor symptoms, and thus balancing this trade-off poses a significant challenge for disease management. To determine whether a wrist-worn motion sensor unit could be used to ascertain global dyskinesia severity over a levodopa dose cycle and to develop a severity scoring algorithm highly correlated with clinician ratings. Fifteen individuals with PD were instrumented with a wrist-worn motion sensor unit, and data were collected with arms in resting and extended positions once every hour for three hours after taking a levodopa dose. Two neurologists blinded to treatment status viewed subject videos and rated global and upper extremity dyskinesia severity based on the modified Abnormal Involuntary Movement Scale (mAIMS). Linear regression models were developed using kinematic features extracted from motion sensor data and extremity, global, or combined (average of extremity and global) mAIMS scores. Dyskinesia occurring during a levodopa dose cycle was successfully measured using a wrist-worn sensor. The logarithm of the power spectrum area between 0.3-3 Hz and the combined clinician scores resulted in the best model performance, with a correlation coefficient between clinician and model scores of 0.81 and root mean square error of 0.55, both averaged across the arms resting and extended postures. One sensor unit worn on either hand can effectively predict global dyskinesia severity during the arms resting or extended positions.


Ceftriaxone or HIV associated angio-oedema? Case report.
Angio-oedema may be hereditary or acquired and is characterised by episodes of potentially life threatening localised tissue oedema and swelling resulting from deficiency of compliment pathway C1 esterase inhibitor. Acquired angio-oedema is about ten times less frequent than the hereditary type and has been associated with immune-deficiency disorders, malignancies and exposure to specific medications and food substances. We present a case of seven year old, human immune-deficiency virus positive girl, who developed gross swelling of the tongue and neck while on treatment for pneumococcal meningitis with ceftriaxone. Difficulties in arriving at a definitive diagnosis of angio-oedema in a resource poor country are discussed and alternative diagnostic options proposed.