Treatment Decision Regret Among Long-Term Survivors of Localized Prostate Cancer: Results From the Prostate Cancer Outcomes Study.
Purpose To determine the demographic, clinical, decision-making, and quality-of-life factors that are associated with treatment decision regret among long-term survivors of localized prostate cancer. Patients and Methods We evaluated men who were age ≤ 75 years when diagnosed with localized prostate cancer between October 1994 and October 1995 in one of six SEER tumor registries and who completed a 15-year follow-up survey. The survey obtained demographic, socioeconomic, and clinical data and measured treatment decision regret, informed decision making, general- and disease-specific quality of life, health worry, prostate-specific antigen (PSA) concern, and outlook on life. We used multivariable logistic regression analyses to identify factors associated with regret. Results We surveyed 934 participants, 69.3% of known survivors. Among the cohort, 59.1% had low-risk tumor characteristics (PSA < 10 ng/mL and Gleason score < 7), and 89.2% underwent active treatment. Overall, 14.6% expressed treatment decision regret: 8.2% of those whose disease was managed conservatively, 15.0% of those who received surgery, and 16.6% of those who underwent radiotherapy. Factors associated with regret on multivariable analysis included reporting moderate or big sexual function bother (reported by 39.0%; OR, 2.77; 95% CI, 1.51 to 5.0), moderate or big bowel function bother (reported by 7.7%; OR, 2.32; 95% CI, 1.04 to 5.15), and PSA concern (mean score 52.8; OR, 1.01 per point change; 95% CI, 1.00 to 1.02). Increasing age at diagnosis and report of having made an informed treatment decision were inversely associated with regret. Conclusion Regret was a relatively infrequently reported outcome among long-term survivors of localized prostate cancer; however, our results suggest that better informing men about treatment options, in particular, conservative treatment, might help mitigate long-term regret. These findings are timely for men with low-risk cancers who are being encouraged to consider active surveillance.


Piracetam: physiological disposition and mechanism of action.
Piracetam, the prototype of nootropic drugs, is claimed to have therapeutic value in some patients suffering from cognitive deficits, especially when hypoxia may be a factor in the deficits. The drug lacks sedative or stimulatory effects and apparently does not influence behavior in normal people. The site of action and the mechanism by which piracetam exerts its beneficial effects are not well established. This review has summarized experimental and clinical data on its absorption, distribution, and excretion, and described the biochemical data available that bear on its mechanism of action.


A novel picornavirus associated with gastroenteritis.
A novel picornavirus genome was sequenced, showing 42.6%, 35.2%, and 44.6% of deduced amino acid identities corresponding to the P1, P2, and P3 regions, respectively, of the Aichi virus. Divergent strains of this new virus, which we named salivirus, were detected in 18 stool samples from Nigeria, Tunisia, Nepal, and the United States. A statistical association was seen between virus shedding and unexplained cases of gastroenteritis in Nepal (P = 0.0056). Viruses with approximately 90% nucleotide similarity, named klassevirus, were also recently reported in three cases of unexplained diarrhea from the United States and Australia and in sewage from Spain, reflecting a global distribution and supporting a pathogenic role for this new group of picornaviruses.


Hematopoietic transplants for disease suppression and cure in type 1 diabetes.
Recent clinical studies have demonstrated the capacity of immunosuppressive therapy to delay progression of inflammatory insulitis in type 1 diabetes (T1D). The procedure includes depletion of pathogenic cells by immunosuppressive therapy and support of recovery by reinfusion of autologous hematopoietic progenitors. The short-term outcome of these clinical transplants is similar to the predictions drawn from NOD mice: debulking of diabetogenic cells is ineffectively achieved by immunosuppressive therapy, and resetting of immune homeostasis does not restrain autoimmunity. Murine models indicate that allogeneic transplants are potentially curative, through restored mechanisms of negative regulation that are effective in continuous and indefinite suppression of autoimmunity.


Effects of Athlete-Dependent Traits on Joint and System Countermovement-Jump Power.
To establish the influence of athlete-dependent characteristics on the generation and timing of system and individual joint powers during a countermovement jump (CMJ). Male national representative athletes from volleyball (n = 7), basketball (n = 6), and rugby (n = 7) performed a set of 3 CMJs at relative barbell loads of 0%, 10%, 20%, 30%, and 40% of absolute back-squat strength. Ground-reaction forces and joint kinematics were captured using a 16-camera motion-capture system integrated with 2 in-ground force plates. Limb lengths and cross-sectional areas were defined using 3-dimensional photonic scans. A repeated-measures analysis of variance determined the interaction between system and joint load-power profiles, whereas a multiregression analysis defined the explained variance of athlete-dependent characteristics on the load that maximized system power. System and isolated hip, knee, and ankle peak powers were maximized across a spectrum of loads between and within sports; power values were not significantly different across loads. A positive shift in the timing of hip and ankle peak powers corresponded to a significant (P < .05) positive shift in the timing of system peak power to occur closer to toe-off. An optimal 3-input combination of athlete-dependent characteristics accounted for 68% (P < .001) of the explained variance in the load that maximized system peak power. The load maximizing system power is athlete-dependent, with a mixture of training and heredity-related characteristics influencing CMJ load-power profiles. The authors recommend that a combination of relative loads be individually prescribed to maximize the generation and translation of system CMJ power.


Video compression for lossy packet networks with mode switching and a dual-frame buffer.
Video codecs that use motion compensation benefit greatly from the development of algorithms for near-optimal intra/inter mode switching within a rate-distortion framework. A separate development has involved the use of multiple-frame prediction, in which more than one past reference frame is available for motion estimation. In this paper, we show that using a dual-frame buffer (one short-term frame and one long-term frame available for prediction) together with intra/inter mode switching improves the compression performance of the coder. We improve the mode-switching algorithm with the use of half-pel motion vectors. In addition, we investigate the effect of feedback in making more informed and effective mode-switching decisions. Feedback information is used to limit drift errors due to packet losses by synchronizing the long-term frame buffers of both the encoder and the decoder.


Evaluating Adults With Idiopathic Pancreatitis for Genetic Predisposition: Higher Prevalence of Abnormal Results With Use of Complete Gene Sequencing.
In adults with unexplained pancreatitis, the yield of complete gene versus select exosome sequencing on mutation detection and distinguishing clinical characteristics associated with mutations requires clarification. We sought to (1) compare frequency of mutations identified using different techniques and (2) compare clinical characteristics between adults with and without mutations. This is a cohort study of adults with unexplained pancreatitis who underwent genetic testing between January 2008 and December 2012. We compare probabilities of having a positive mutation with complete gene sequencing versus alternatives and describe differences in characteristics among patients with and without mutations. Of the 370 patients, 67 (18%) had a genetic mutation; 24 (6%) were of high risk. Mutations were significantly more prevalent with use of complete sequencing (42%) versus other approaches (8%, P < 0.0001). Most (44/67, 66%) with a mutation had no family history. Those with high-risk mutations were more likely to have a family history of chronic pancreatitis (21% vs 4%, P = 0.002). Patients with pancreas divisum were more likely to have mutations (27% vs 14%, P = 0.0007). Among individuals with adult-onset pancreatic disease, the probability of finding any mutation, including high risk, is significantly higher using complete gene sequencing. The impact on patients and providers requires further investigation.


Hypothalamic suppression during adolescence varies by bone envelope.
The purposes of this study were to suppress estradiol levels in adolescent (postpubertal rats) using gonadotropin-releasing hormone antagonist (GnRH-a) injections and to determine the changes in bone structure and mechanical strength. In an Institutional Animal Care and Use Committee-approved study, female rats at 23 d of age were assigned to a baseline group (BL65; n = 10) sacrificed on day 65, a control group (Control; n = 15) sacrificed on day 90, or an experimental group (AMEN; n = 9) sacrificed on day 90 that received daily injections of GnRH-a for a 25-d period from 65 to 90 d of age (2.5 mg·kg(-1) per dose). Body weights were similar on day 65; however, the AMEN group was significantly heavier than the Control group (17%, P = 0.001) on day 90. In the AMEN rats relative to the Control group, plasma estradiol levels were reduced by 36% (P = 0.0001) and plasma insulin-like growth factor 1 levels were 24% higher (P = 0.003). In the femur, there was no change in periosteal bone apposition or total cross-sectional area. The marrow area increased by 13.7% (P = 0.05) resulting in a 7.8% decrease in relative cortical area (P = 0.012), and endocortical bone formation rate increased by 39.4% (P = 0.04). Trabecular volume and number decreased by 51.5% (P = 0.0003) and 49.5% (P = 0.0003), respectively. The absolute peak moments of the tibiae and femurs were unchanged in the AMEN group relative to the Control group, but these were reduced by 8.8% (P = 0.03) and 7.5% (P = 0.09), respectively, when normalized by body weight. Suppression of estradiol by 25 d of GnRH-a administration to 65-d-old (postpubertal) rats reduced trabecular volume and number by about 50%, increased endocortical bone turnover, and reduced relative cortical thickness without changing tibial and femoral total area. These changes in bone structure were associated with no change in absolute mechanical strength possibly because of increases in body weight or in insulin-like growth factor 1 concentrations.


Case report: A pulseless radial artery in a child under anesthesia for radiotherapy.
Treatment of cancer in children often requires a combination of chemotherapy, surgery, and/or radiotherapy. Radiotherapy and chemotherapy are not painful processes, but children undergoing these procedures must be made motionless through anesthesia or sedation. There are a few reports of complications during these procedures in relation to the procedures themselves or to the anesthesia given. This report describes an unexpected pulseless radial artery which was preliminarily and unduly attributed to anesthesia. A 2.5 year-old male pediatric patient with an acute lymphoblastic leukaemia was scheduled for radiotherapy. Anesthesia with intramuscular ketamine was induced before starting radiotherapy. About 5 minutes after injection of ketamine we found the right radial pulse undetectable. There was no other manifestation of hypoxia or hypo-perfusion. Carotid pulsation was normal. Examination of the left radial pulse and other peripheral pulses showed normal pulsation. The procedure was continued uneventfully. The next follow-up after radiotherapy, showed a scar and swelling on the right antecubital area, caused by extravasation of chemotherapeutic agent in the prior period of chemotherapy. Doppler ultrasonography of the antecubital vein confirmed the diagnosis. This case study therefore demonstrates that proper intravenous cannula establishment before chemotherapy is of great importance. Furthermore, accurate history and physical examination before induction of anesthesia or sedation may be useful in preventing mismanagement in pediatric cancer procedures.


A PC-based system for predicting movement from deep brain signals in Parkinson's disease.
There is much current interest in deep brain stimulation (DBS) of the subthalamic nucleus (STN) for the treatment of Parkinson's disease (PD). This type of surgery has enabled unprecedented access to deep brain signals in the awake human. In this paper we present an easy-to-use computer based system for recording, displaying, archiving, and processing electrophysiological signals from the STN. The system was developed for predicting self-paced hand-movements in real-time via the online processing of the electrophysiological activity of the STN. It is hoped that such a computerised system might have clinical and experimental applications. For example, those sites within the STN most relevant to the processing of voluntary movement could be identified through the predictive value of their activities with respect to the timing of future movement.


Identification and diversity of killer cell Ig-like receptors in Aotus vociferans, a New World monkey.
Previous BAC clone analysis of the Platyrrhini owl monkey KIRs have shown an unusual genetic structure in some loci. Therefore, cDNAs encoding KIR molecules from eleven Aotus vociferans monkeys were characterized here; ten putative KIR loci were found, some of which encoded atypical proteins such as KIR4DL and transcripts predicted to encode a D0+D1 configuration (AOTVOKIR2DL1*01v1) which appear to be unique in the Aotus genus. Furthermore, alternative splicing was found as a likely mechanism for producing activator receptors in A. vociferans species. KIR proteins from New World monkeys may be split into three new lineages according to domain by domain phylogenetic analysis. Although the A. vociferans KIR family displayed a high divergence among paralogous genes, individual loci were limited in their genetic polymorphism. Selection analysis showed that both constrained and rapid evolution may operate within the AvKIR family. The frequent alternative splicing (as a likely mechanism generating activator receptors), the presence of KIR4DL and KIR2DL1 (D0+D1) molecules and other data reported here suggest that the KIR family in Aotus has had a rapid evolution, independent from its Catarrhini counterparts.


Shared Decision Making in a Youth Mental Health Service Design and Research Project: Insights From the Pan-Canadian ACCESS Open Minds Network.
Shared decision making (SDM) is the process by which health care providers and patients collaborate to make health care decisions. This collaboration leads to informed decision making and improved outcomes. However, research on SDM specific to the field of youth mental health is scarce. ACCESS Open Minds (ACCESS OM) is a youth mental health research and evaluation project that implemented and evaluated SDM practices within its various activities and operations. The ACCESS OM network spans a diversity of youth mental health settings across Canada, and includes various stakeholders such as youth, family members and carers, clinicians, researchers, and policy makers. The project values all types of knowledge (specifically, experiential, cultural, clinical, and scientific knowledge) as necessary to lead to better health research, care delivery, and outcomes for patients and their communities. Similarly, it acknowledges the lived experience of patients and, family and carers as expertise. Through the integration of SDM practices, ACCESS OM has formulated valuable insights that can be applied to other health problems and settings. This paper, written by youth and family council members, operational staff, and researchers from the project, will share challenges and solutions that arose in the integration of SDM practices within ACCESS OM's knowledge translation strategy, governance structures, clinical contexts, and capacity-building initiatives. Shared Decision Making in a Youth Mental Health Service Design and Research Project: Insights From the Pan-Canadian ACCESS Open Minds Network (MP4 234838 kb).


The Effect of Vitamin D Supplementation on Adiposity, Blood Glycated Hemoglobin, Serum Leptin and Tumor Necrosis Factor-α in Type 2 Diabetic Patients.
Since tumor necrosis factor-α (TNF-α) could be one of the risk factors at the development of diabetes complications; as well as serum leptin deficiency is related to increased susceptibility to infections in diabetic patients, they are potential indices from the preventive medicine viewpoint. This study was conducted to represent the effect of supplemental vitamin D3 on serum leptin, TNF-α and adiposity in type 2 diabetic patients. In this randomized double-blind placebo-controlled trial, study sample was selected through type 2 diabetic patients (n = 51). A total of 26 patients were orally supplemented by vitamin D3 (400 IU/d) (vitamin D group) and 25 patients by placebo (placebo group) for 14 weeks. The blood glycated hemoglobin (HbA1c) and the serum ionized Ca, leptin, TNF-α, and serum 25-hydroxyvitamin D (25[OH] D) were measured at the two groups in the baseline and postintervention stages. It was shown that despite of theplacebo group, serum 25(OH) D and serum leptin was significantly increased (P = 0.001 and P = 0.002, respectively), while serum TNF-α was decreased significantly (P = 0.001) in vitamin D group. The remaining parameters, including body fat mass and HbA1c had no alterations between baseline and postintervention stages in vitamin D group. This study may advocate vitamin D supplementation among type 2 diabetic patients due to its beneficial effects on prevention of diabetes complications.


Challenges to the student nurse on clinical placement in the rural setting: a review of the literature.
Positive learning experiences for students on clinical placement in rural settings have the potential for supporting the recruitment of qualified nurses to these areas. Recruitment of such nurses is a global concern because current shortages have resulted in decreased healthcare quality for rural residents. By understanding the challenges faced by nursing students unfamiliar with rural settings, educational and organizational strategies can be developed to promote positive learning experiences and so enhance recruitment. A broad literature review was conducted to explore the question: 'What challenges do nursing students from urban communities experience while they are on clinical placements in rural areas, respecting that 'rural' is conceptualized differently by different stakeholders?' The review followed a 5 stage process: (1) identification of the problem and purpose of the review; (2) structured literature search; (3) data evaluation; (4) data analysis; and (5) presentation of findings. Thirteen studies were evaluated independently using tools from the Joanna Briggs Institute. The Ecological Model was the theoretical framework used for consideration of student challenges. This literature review revealed a paucity of studies that addressed the research question, with mostly Canadian and Australian studies meeting the inclusion criteria. Findings were organized according to Ecological Model levels and suggested that students face political, environmental, community-based, nursing-related, organizational, relational, and personal challenges on rural placement. Challenges vary according to the placement setting and available student supports. Policy, educational, and nursing practice recommendations include that students should be aware of the impact of limited resources in rural settings; that comprehensive orientation should be provided to clinical and community settings; and that an exploration of financial and distance education supports prior to the placement would be beneficial. Rural practice nurse educators also require support, and it is critical that they and those at the educational institution be receptive to student questions and learning needs.


Screening archaeological bone for palaeogenetic and palaeoproteomic studies.
The recovery and analysis of ancient DNA and protein from archaeological bone is time-consuming and expensive to carry out, while it involves the partial or complete destruction of valuable or rare specimens. The fields of palaeogenetic and palaeoproteomic research would benefit greatly from techniques that can assess the molecular quality prior to sampling. To be relevant, such screening methods should be effective, minimally-destructive, and rapid. This study reports results based on spectroscopic (Fourier-transform infrared spectroscopy in attenuated total reflectance [FTIR-ATR]; n = 266), palaeoproteomic (collagen content; n = 226), and palaeogenetic (endogenous DNA content; n = 88) techniques. We establish thresholds for three different FTIR indices, a) the infrared splitting factor [IRSF] that assesses relative changes in bioapatite crystals' size and homogeneity; b) the carbonate-to-phosphate [C/P] ratio as a relative measure of carbonate content in bioapatite crystals; and c) the amide-to-phosphate ratio [Am/P] for assessing the relative organic content preserved in bone. These thresholds are both extremely reliable and easy to apply for the successful and rapid distinction between well- and poorly-preserved specimens. This is a milestone for choosing appropriate samples prior to genomic and collagen analyses, with important implications for biomolecular archaeology and palaeontology.


Complementary and alternative medicine in multiple sclerosis: survey of licensed naturopaths.
This paper describes the treatments and treatment outcome measures used by licensed naturopathic physicians in the United States who treat people with multiple sclerosis (MS). A cross-sectional mail survey was used. The participants were licensed naturopaths who were members of the American Association of Naturopathic Physicians. Outcome measures included practitioner demographics; patient demographics by practitioner report; recommended therapies; perceived effectiveness of treatments for MS; methods for measuring treatment effectiveness. Forty three percent (43%) of the respondents (166/385) had treated at least one patient with MS while 56.9% (291/385) had never treated MS. 63.3% had treated 1-10 patients with MS, 19.9% had treated 11-20 patients with MS, and 16.8% had treated > or =20 patients with MS. Among the naturopaths, 68.1% communicated with an M.D. about their patient(s)' care and the majority of patients with MS were diagnosed by an M.D. (mean % = 96.3). The mean number of therapies recommended for M.S. was 3.91 (standard deviation [SD] =2.01, range 1-10). The most frequently recommended therapies included, diet (52.4%), essential fatty acid supplementation (44.6%), vitamin/mineral supplementation (33.7%), homeopathy (30.7%), botanicals (22.3%), and antioxidants (18.1%). Respondents perceived their treatments as "very effective" for the following stages of MS: early stage (57.2%); middle stage (25.3%); and late stage (3.0%). Respondents perceived their treatments as "very effective" for the following disease-related outcomes: improved quality of life (59.0%); decrease relapse rates (48.2%); decreased symptom severity (45.8%); prevention of disease progression (41.6%). The methods used "most often" for measuring treatment effectiveness included, patient report (88.0%); physical examination (27.1%); medical records/laboratory testing (13.3%). The mean estimated percentage of patients not taking conventional disease-modifying medication was 51.2% (SD = 42.7%). Naturopaths use both a broad range and multiple complementary and alternative medicine CAM therapies for treating MS and report treatment effectiveness on the following outcomes: quality of life; symptom severity; relapse rates; and disease progression. Further research on single CAM therapies and holistic CAM systems is warranted in MS.


The Economic Burden of Bladder Cancer Due to Occupational Exposure.
To estimate the economic burden of bladder cancer due to occupational exposures. Using a societal perspective, we estimate the lifetime costs of newly diagnosed cases of bladder cancer in Canada that is associated with occupational exposure for the calendar year 2011. The three major categories we consider are direct, indirect, and quality of life costs. There were 199 newly identified cases of bladder cancer. The estimated total cost of bladder cancer for new cases in 2011 was $131 million and an average per-case cost of $658,055 CAD (2011 dollars). Of the total costs, direct costs accounted for 6%, indirect costs 29%, and health-related quality of life costs 65%. The per-case economic burden of bladder cancer due to occupational exposure is substantial which suggests the importance and value of exposure reduction.


NGF gene expression in actively growing brain glia.
Previous work suggested that brain NGF acts locally on cells adjacent to sites of synthesis, in addition to any putative actions on distant, projecting perikarya. To define the basis of local action, we used a sensitive nuclease protection assay to identify cells expressing the NGF gene in vivo and in vitro. In addition to neurons, glia from a variety of developing brain areas synthesized NGF mRNA, suggesting that CNS glia exhibit a generalized capacity to express the gene. Expression was associated with active glial growth. Stimulation of growth with serum increased NGF message 2-fold in culture. Moreover, rapidly growing, low-density glial cultures exhibited 8-fold higher levels of NGF mRNA than quiescent, confluent cultures. The optic nerve, which contains all 3 major types of glia, expressed the message in vivo during neonatal development. In contrast, expression was barely detectable in the adult optic nerve. Transection, which induces glial proliferation, elicited de novo appearance of NGF mRNA in the adult nerve. Our observations suggest that active glial growth is associated with expression of the NGF gene and raise the possibility that actively growing glia in the developing or injured brain regulate neuronal growth through the elaboration of NGF.


Perspectives in diabetes. Islet transplantation with immunoisolation.
Immunoisolation is a potentially important approach to transplanting islets without need for immunosuppressive drugs. Immunoisolation systems have been conceived in which the transplanted tissue is separated from the immune system of the host by an artificial barrier. These systems offer a solution to the problem of human islet procurement by permitting use of islets isolated from animal pancreases. The devices used are referred to as biohybrid artificial organs because they combine synthetic, selectively permeable membranes that block immune rejection with living transplants. Three major types of biohybrid pancreas devices have been studied. These include devices anastomosed to the vascular system as AV shunts, diffusion chambers, and microcapsules. Results in diabetic rodents and dogs indicate that biohybrid pancreas devices significantly improve glucose homeostasis and can function for more than a year. Recent progress made with this approach is discussed, and some of the remaining problems that must be resolved to bring this technology to clinical reality are addressed.


Changing faces in virology: the dutch shift from oncogenic to oncolytic viruses.
Viruses have two opposing faces. On the one hand, they can cause harm and disease. A virus may manifest directly as a contagious disease with a clinical pathology of varying significance. A viral infection can also have delayed consequences, and in rare cases may cause cellular transformation and cancer. On the other hand, viruses may provide hope: hope for an efficacious treatment of serious disease. Examples of the latter are the use of viruses as a vaccine, as transfer vector for therapeutic genes in a gene therapy setting, or, more directly, as therapeutic anticancer agent in an oncolytic-virus therapy setting. Already there is evidence for antitumor activity of oncolytic viruses. The antitumor efficacy seems linked to their capacity to induce a tumor-directed immune response. Here, we will provide an overview on the development of oncolytic viruses and their clinical evaluation from the Dutch perspective.


Composite biomaterial repair strategy to restore biomechanical function and reduce herniation risk in an ex vivo large animal model of intervertebral disc herniation with varying injury severity.
Back pain commonly arises from intervertebral disc (IVD) damage including annulus fibrosus (AF) defects and nucleus pulposus (NP) loss. Poor IVD healing motivates developing tissue engineering repair strategies. This study evaluated a composite injectable IVD biomaterial repair strategy using carboxymethylcellulose-methylcellulose (CMC-MC) and genipin-crosslinked fibrin (FibGen) that mimic NP and AF properties, respectively. Bovine ex vivo caudal IVDs were evaluated in cyclic compression-tension, torsion, and compression-to-failure tests to determine IVD biomechanical properties, height loss, and herniation risk following experimentally-induced severe herniation injury and discectomy (4 mm biopsy defect with 20% NP removed). FibGen with and without CMC-MC had failure strength similar to discectomy injury suggesting no increased risk compared to surgical procedures, yet no biomaterials improved axial or torsional biomechanical properties suggesting they were incapable of adequately restoring AF tension. FibGen had the largest failure strength and was further evaluated in additional discectomy injury models with varying AF defect types (2 mm biopsy, 4 mm cruciate, 4 mm biopsy) and NP removal volume (0%, 20%). All simulated discectomy defects significantly compromised failure strength and biomechanical properties. The 0% NP removal group had mean values of axial biomechanical properties closer to intact levels than defects with 20% NP removed but they were not statistically different and 0% NP removal also decreased failure strength. FibGen with and without CMC-MC failed at super-physiological stress levels above simulated discectomy suggesting repair with these tissue engineered biomaterials may perform better than discectomy alone, although restored biomechanical function may require additional healing with the potential application of these biomaterials as sealants and cell/drug delivery carriers.


Viral hepatitis, HIV, human herpes virus and Treponema pallidum infection in haemodialysis patients from Kosovo, 2005.
The serological status of hepatitis viruses and other infectious diseases in the 66 dialysed patients of one haemodialysis unit in Kosovo were studied, comparing the data with a large group of blood donors and out-patients. All dialysed patients were hepatitis A virus (HAV) positive. Prevalence of hepatitis B surface antigen (HBsAg), hepatitis B surface antibodies (anti-HBs), and hepatitis B core antibodies (anti-HBc) was 14 of 66, 21% (95% confidence interval (CI): 12-33%), 5 of 66, 8% (95%CI: 5-22%), and 50 of 66, 76% (95%CI: 64-85%), respectively. Antibodies to hepatitis C virus (anti-HCV) prevalence was 57 of 66, 86% (95%CI: 76-94%). No human immunodeficiency virus (HIV) positive case was found. Prevalence of past herpes simplex virus type 2 (HSV-2) infection was 29% (95%CI: 18-41%). Two patients (3%, 95%CI: 0-10%) were positive for Treponema pallidum and 18% (95%CI: 10-30%) were human herpesvirus 8 (HHV-8) antibody positive. Four hundred and fifty-two subjects were recruited for comparison. Markers of past HAV infection was associated with haemodialysis (Fisher s exact test p-value=0.037). Dialysed patients were at a higher risk of being HBsAg positive than others: the sex- and age-adjusted odds ratio (OR) was 5.18 (95%CI: 1.87-14.32). Anti-HBc positivity was strongly associated with haemodialysis: the sex- and age-adjusted OR was 6.43 (95%CI: 3.22-12-85). Anti-HCV positivity was 86% and 1% in presence and absence of haemodialysis, respectively. The Fisher s exact test for association proved a strong association between haemodialysis and HCV (p-value<0.0001). The OR for association between haemodialysis and HSV-2 positivity was 3.20 (95%CI: 1.46-7.00). Significant associations were also observed between haemodialysis status and antibodies to Treponema pallidum (Fisher s exact test p-value=0.044). In Kosovo, the prevalence of viral hepatitis infection and other viral infections and Treponema pallidum among dialysed patients is high, indicating major ongoing nosocomial transmission.


Interdisciplinary Models for Research and Clinical Endeavors in Genomic Medicine: A Scientific Statement From the American Heart Association.
The completion of the Human Genome Project has unleashed a wealth of human genomics information, but it remains unclear how best to implement this information for the benefit of patients. The standard approach of biomedical research, with researchers pursuing advances in knowledge in the laboratory and, separately, clinicians translating research findings into the clinic as much as decades later, will need to give way to new interdisciplinary models for research in genomic medicine. These models should include scientists and clinicians actively working as teams to study patients and populations recruited in clinical settings and communities to make genomics discoveries-through the combined efforts of data scientists, clinical researchers, epidemiologists, and basic scientists-and to rapidly apply these discoveries in the clinic for the prediction, prevention, diagnosis, prognosis, and treatment of cardiovascular diseases and stroke. The highly publicized US Precision Medicine Initiative, also known as All of Us, is a large-scale program funded by the US National Institutes of Health that will energize these efforts, but several ongoing studies such as the UK Biobank Initiative; the Million Veteran Program; the Electronic Medical Records and Genomics Network; the Kaiser Permanente Research Program on Genes, Environment and Health; and the DiscovEHR collaboration are already providing exemplary models of this kind of interdisciplinary work. In this statement, we outline the opportunities and challenges in broadly implementing new interdisciplinary models in academic medical centers and community settings and bringing the promise of genomics to fruition.


Hepatic DNA damage in harbour porpoises (Phocoena phocoena) stranded along the English and Welsh coastlines.
One level at which persistent organic pollutants (POPs) and polycyclic aromatic hydrocarbons PAHs) can exert damage is by causing DNA strand-breaks or nucleotide base modifications, which, if unrepaired, can lead to embryonic mutations, abnormal development and cancer. In marine ecosystems, genotoxicity is expected to be particularly strong in long-lived apex predators due to pollutant bioaccumulation. We conducted 32 P-postlabeling analyses optimized for the detection and quantification of aromatic/hydrophobic DNA adducts in the livers of 40 sexually-mature North Atlantic harbour porpoises (Phocoena phocoena) stranded along the English and Welsh coastlines. We examined hepatic tissue to search for inflammatory and preneoplastic lesions and examine their association with adduct levels. Adducts were found in all porpoises (mean: 17.56 ± 11.95 per 108 nucleotides), and were higher than levels reported for marine vertebrates from polluted sites. The pollutants causing the induced DNA adducts could not be further characterized. Hepatic DNA damage did not correlate with levels of blubber POP concentrations (including total polychlorinated biphenyl [PCBs], dichlorodiphenyltrichloroethane [DDT] and dieldrin); PAH concentrations were not available for the present study. However, DNA damage predicted occurrence of inflammatory and preneoplastic lesions. Further, our data showed a reduction in hepatic DNA adduct levels with age in the 40 animals examined while POP concentrations, particularly PCBs, increased with age. Using a different dataset of 145 mature male harbour porpoises confirmed that higher contaminant levels (total PCBs, DDT and dieldrin) are found in older animals. The reduction in hepatic DNA adduct levels in older animals was in accordance with other studies which show that suppression of hepatic CYP1A enzyme activity at high PCB concentrations might impact on CYP1A-mediated DNA adduct formation of PAHs which are ubiquitous environmental pollutants and readily metabolized by CYP1A to species binding to DNA. In summary, our study shows that pollutant-induced DNA damage is prevalent in harbour porpoises from UK waters and may lead to detectable sub-lethal hepatic damage. Environ. Mol. Mutagen. 59:613-624, 2018. © 2018 The Authors Environmental and Molecular Mutagenesis published by Wiley Periodicals, Inc. on behalf of Environmental Mutagen Society.


Log (TG)/HDL-C ratio as a predictor of decreased islet beta cell function in patients with type 2 diabetes: 6-year cohort study.
The aim of the present study was to explore whether the triglyceride to high density lipoprotein cholesterol ratio [log (TG)/HDL-C] and peripheral blood leukocytes DNA telomere length could predict future islet beta cell function decreased in Chinese type 2 diabetes mellitus (T2DM) during a 6-year cohort. Sixty T2DM patients (without insulin treatment at baseline) were included in the 6-year cohort study. Peripheral blood leukocytes DNA telomere length, HbA1c, blood lipid profile, fatty fat acid, glucose, insulin and C peptide (3 h after a mixed meal) were determined. Delta C peptide area under curve (Delta CP AUC) was used to reflect change in beta cell secretion function (Delta CP AUC = baseline CP AUC - CP AUC after 6 years). Subjects were divided into slow decrease of beta cell function group (Delta CP AUCslow group) and fast decrease group (Delta CP AUCfast group) according to median of Delta CP AUC. Baseline demographic characteristics, clinical variables between two groups were compared. Correlations between baseline data and Delta CP AUC were analyzed. Baseline log (TG)/HDL-C was positively correlated with Delta CP AUC (r = 0.306, P = 0.027); log (TG)/HDL-C in Delta CP AUCfast group was higher than that in Delta CP AUCslow group (0.103 ± 0.033 vs 0.083 ± 0.030, P = 0.027). There was no significant difference in DNA telomere length between the two groups. Change in DNA telomere length over 6 years was not significantly correlated with baseline blood lipid. In Chinese T2DM patients, high baseline log (TG)/HDL-C ratio predicts fast progression of islet beta cell dysfunction. It may be a simple index to predict progression speed of islet beta cell dysfunction.


Activation of human respiratory muscles during different voluntary manoeuvres.
1. This study used three techniques (bilateral phrenic nerve stimulation, motor cortex stimulation and quantitative electromyography) to assess the degree of activation of the diaphragm, intercostal-accessory muscles and abdominal muscles during postural tasks and respiratory manoeuvres. They included maximal inspiratory and expulsive efforts. 2. Bilateral phrenic nerve stimuli at supramaximal levels produced an average change in transdiaphragmatic pressure (Pdi) of 28 cmH2O during relaxation. During maximal inspiratory or expulsive efforts, all subjects were able to activate the diaphragm fully at functional residual capacity as judged by the failure of stimuli delivered during the voluntary efforts to increase Pdi. Peak voluntary Pdi was about 30% less for inspiratory than expulsive manoeuvres. 3. By contrast, transcranial activation of motor cortical output to the diaphragm and abdominal muscles produced an increment in abdominal pressure of 25 +/- 7 cmH2O during maximal voluntary expulsive efforts. Given the lack of response to phrenic nerve stimulation at similar voluntary pressures, this suggests that abdominal muscles, and not the diaphragm, fail to generate their full contractile force during maximal voluntary expulsive manoeuvres. 4. Motor cortical stimulation during weak inspiratory efforts produced a small reduction in oesophageal pressure (i.e. increase in net inspiratory force) of 7-14 cmH2O. This response could not be extinguished during maximal voluntary inspiratory efforts in two of three subjects. This occurred despite the cortical co-activation of 'antagonist' muscles in the chest wall and abdomen, and passive transmission of pressure from the abdominal to thoracic compartments. 5. Integrated electromyographic activity (EMG) recorded from abdominal muscles (rectus abdominis, external oblique) was greater during trunk flexion than during maximal expulsive efforts. Similarly, integrated EMG of the intercostal-accessory muscles (sternomastoid, scalenes, parasternal intercostals) was greater during tasks requiring head and/or neck flexion than during the maximal inspiratory efforts. 6. These data show that the diaphragm can be fully activated by the central nervous system during voluntary respiratory tasks but that other agonist 'respiratory' muscles need not be activated fully. Given the complex actions of 'inseries' respiratory muscles revealed here, it is argued that differences in the transdiaphragmatic pressure during various postural and respiratory tasks do not necessarily imply variation in the level of diaphragmatic neural drive.


Outbreak analytics: a developing data science for informing the response to emerging pathogens.
Despite continued efforts to improve health systems worldwide, emerging pathogen epidemics remain a major public health concern. Effective response to such outbreaks relies on timely intervention, ideally informed by all available sources of data. The collection, visualization and analysis of outbreak data are becoming increasingly complex, owing to the diversity in types of data, questions and available methods to address them. Recent advances have led to the rise of outbreak analytics, an emerging data science focused on the technological and methodological aspects of the outbreak data pipeline, from collection to analysis, modelling and reporting to inform outbreak response. In this article, we assess the current state of the field. After laying out the context of outbreak response, we critically review the most common analytics components, their inter-dependencies, data requirements and the type of information they can provide to inform operations in real time. We discuss some challenges and opportunities and conclude on the potential role of outbreak analytics for improving our understanding of, and response to outbreaks of emerging pathogens. This article is part of the theme issue 'Modelling infectious disease outbreaks in humans, animals and plants: epidemic forecasting and control'. This theme issue is linked with the earlier issue 'Modelling infectious disease outbreaks in humans, animals and plants: approaches and important themes'.


Achieving long-term continuous blood naltrexone and 6-beta-naltrexol coverage following sequential naltrexone implants.
The aim of this study was to assess blood free naltrexone and 6-beta-naltrexol levels with time following treatment with sequential sustained-release naltrexone preparations. Data were collected from blood samples analysed independently for naltrexone and 6-beta-naltrexol and from clinical record review at a community heroin treatment clinic in Perth, Western Australia. Five patients received sequential 3.4 g (3.49+/-0.01 g and 3.36+/-0.05 g, respectively) naltrexone implants. The second implant was received on average within 131.2+/-15.67 days of the first implant. The mean length of follow-up was 307.2+/-18.28 days of the first implant. Blood naltrexone levels have the potential to remain above 2 and 1 ng/ml for a total of 390 and 524 days, respectively, and blood 6-beta-naltrexol was maintained above 10 ng/ml for a total of 222 days following insertion of these implants. No patient relapsed to dependent heroin use during the implant coverage period while blood naltrexone concentrations were above 2 ng/ml. Results indicate that blood naltrexone and 6-beta-naltrexol levels can be maintained above therapeutic levels for prolonged periods following use of sequential 3.4 g naltrexone implants. These extended periods of coverage will offer significant benefits for managing the heroin-dependent patient.


Design and fabrication of a supermirror with smooth and broad response for hard x-ray telescopes.
We present our design and fabrication scheme of a supermirror for hard x-ray telescopes to improve the performance of reflection. Supermirrors are designed to achieve target reflectivity profiles with small ripples in the interesting energy range with a limited number of layer pairs. Starting from conventional design methods, we optimized the thickness distribution of the structure using a numerical approach with the merit function established for this application. As an example, a platinum-carbon supermirror structure of 123 layer pairs with a varying d-space of 2-6 nm was designed to enhance the reflectivity in the energy range from 11 to 55 keV with a flat top at a grazing angle of 0.28 deg. The multilayer thus designed was deposited on a float glass by our DC magnetron sputtering system. The reflectivity profile was successfully measured to be ~20% with little oscillation in all energy band of interest.


Inhibition of focal adhesion kinase expression or activity disrupts epidermal growth factor-stimulated signaling promoting the migration of invasive human carcinoma cells.
Elevated focal adhesion kinase (FAK) expression in human tumor cells has been correlated with an increased cell invasion potential. In cell culture, studies with FAK-null fibroblasts have shown that FAK function is required for cell migration. To determine the role of elevated FAK expression in facilitating epidermal growth factor (EGF)-stimulated human adenocarcinoma (A549) cell motility, antisense oligonucleotides were used to reduce FAK protein expression >75%. Treatment of A549 cells with FAK antisense (ISIS 15421) but not a mismatched control (ISIS 17636) oligonucleotide resulted in reduced EGF-stimulated p130(Cas)-Src complex formation, c-Jun NH(2)-terminal kinase (JNK) activation, directed cell motility, and serum-stimulated cell invasion through Matrigel. Because residual FAK protein in ISIS 15421-treated A549 cells was highly phosphorylated at the Tyr-397/Src homology (SH)2 binding site, expression of the FAK COOH-terminal domain (FRNK) was also used as an inhibitor of FAK function. Adenoviral-mediated infection and expression of FRNK promoted FAK dephosphorylation at Tyr-397, resulted in reduced EGF-stimulated JNK as well as extracellular-regulated kinase 2 (ERK2) kinase activation, inhibited matrix metalloproteinase-9 (MMP-9) secretion, and potently blocked both random and EGF-stimulated A549 cell motility. Equivalent expression of a FRNK (S-1034) point-mutant that did not promote FAK dephosphorylation also did not affect EGF-stimulated signaling or cell motility. Dose-dependent reduction in EGF-stimulated A549 motility was observed with the PD98059 MEK1 inhibitor and the batimastat (BB-94) inhibitor of MMP activity, but not with the SB203580 inhibitor of p38 kinase. Finally, comparisons between normal, FAK-null, and FAK-reconstituted fibroblasts revealed that FAK enhanced EGF-stimulated JNK and ERK2 kinase activation that was required for cell motility. These data indicate that FAK functions as an important signaling platform to coordinate EGF-stimulated cell migration in human tumor cells and support a role for inhibitors of FAK expression or activity in the control of neoplastic cell invasion.


Glucocorticoid Receptor Transactivation Is Required for Glucocorticoid-Induced Ocular Hypertension and Glaucoma.
Glucocorticoid (GC)-induced ocular hypertension (GC-OHT) is a serious side effect of prolonged GC therapy that can lead to glaucoma and permanent vision loss. GCs cause a plethora of changes in the trabecular meshwork (TM), an ocular tissue that regulates intraocular pressure (IOP). GCs act through the glucocorticoid receptor (GR), and the GR regulates transcription both through transactivation and transrepression. Many of the anti-inflammatory properties of GCs are mediated by GR transrepression, while GR transactivation largely accounts for GC metabolic effects and side effects of GC therapy. There is no evidence showing which of the two mechanisms plays a role in GC-OHT. GRdim transgenic mice (which have active transrepression and impaired transactivation) and wild-type (WT) C57BL/6J mice received weekly periocular dexamethasone acetate (DEX-Ac) injections. IOP, outflow facilities, and biochemical changes to the TM were determined. GRdim mice did not develop GC-OHT after continued DEX treatment, while WT mice had significantly increased IOP and decreased outflow facilities. Both TM tissue in eyes of DEX-treated GRdim mice and cultured TM cells isolated from GRdim mice had reduced or no change in the expression of fibronectin, myocilin, collagen type I, and α-smooth muscle actin (α-SMA). GRdim mouse TM (MTM) cells also had a significant reduction in DEX-induced cytoskeletal changes, which was clearly seen in WT MTM cells. We provide the first evidence for the role of GR transactivation in regulating GC-mediated gene expression in the TM and in the development of GC-OHT. This discovery suggests a novel therapeutic approach for treating ocular inflammation without causing GC-OHT and glaucoma.


Effect of combination therapy of fatty acids, calcium, vitamin D and boron with regular physical activity on cardiovascular risk factors in rat.
The effect of consumption of fatty acids and selected nutrients, along with regular physical activity, on cardiovascular risk factors in rats was investigated.Male rats were divided into the seven groups: Group 1: regular food and drinking water, Group 2: same as Group. 1 + physical activity (whole body vibration; WBV), Group 3: same as Group. 2 + calcium, vitamin D, boron, Group 4: same as Group. 3 + canola oil, Group 5: same as Group. 3 + sunflower oil, Group 6: same as Group. 3 + mix of sunflower oil and canola oil, Group 7: same as Group. 3 + coconut oil. Rats were treated for 8 weeks, and analysis of the frozen plasmas was performed. A- Analysis between the treatment groups and control revealed that vibration training in Group 2 increased body weight (P = 0.04), plasma creatin kinase (CK), (P = 0.02), and estradiol (E2), (P = 0.03). Rats in Group 5 consumed less food and plasma levels of cholesterol and LDL-cholesterol (LDL-C) increased significantly (P = 0.02) in Group 6 and in Group 7 (p<0.05). B- Analysis of data among Group 4 - 7 (the oil consuming groups) and Group 3 revealed significant differences in cholesterol (Chol), LDL-C, HDL-cholesterol (HDL-C), triglycerides (TG), C- reactive protein (hs-CRP), estradiol (E2), atherogenic index (AI), and risk factor (RF), (p<0.05). In addition, plasma levels of testosterone (T) and free testosterone (FT) in Group 7 had a remarkable but non-significant increase. As a result of vibration training, a similar trend was observed for vitamin D in Group 2-7. The findings show that WBV is effective in improving health status by influencing cardiovascular disease (CVD) risk factors. Moreover, canola oil and sunflower oil, separately, showed beneficial impacts on CVD risk factors; whereas their combination had negative impacts on lipid profile. Coconut oil revealed to be efficient to provide health benefits in terms of CVD treatments.


Brain-specific autoantibodies in the plasma of subjects with autistic spectrum disorder.
Although autism spectrum disorder (ASD) is diagnosed on the basis of behavioral parameters, several studies have reported immune system abnormalities and suggest the possible role of autoimmunity in the pathogenesis of ASD. In this study we sought to assess the incidence of brain-specific autoantibodies in the plasma of children with autism (AU) compared to age-matched controls including, siblings without ASD, typically developing (TD) controls, and children with other developmental disabilities, but not autism (DD). Plasma from 172 individuals (AU, n = 63, median age: 43 months; TD controls, n = 63, median age: 48 months; siblings, n = 25, median age: 61 months; and DD controls, n = 21, median age: 38 months) was analyzed by Western blot for the presence of IgG antibodies against protein extracts from specific regions of the human adult brain including the hypothalamus and thalamus. The presence of a approximately 52 kDa MW band, in the plasma of subjects with AU, was detected with a significantly higher incidence when compared to plasma from TD controls (29% vs. 8%, P = 0.0027 and 30% vs. 11%, P = 0.01, in the thalamus and hypothalamus, respectively). Reactivity to three brain proteins (42-48 kDa MW), in particular in the hypothalamus, were observed with increased incidence in 37% of subjects with AU compared to 13% TD controls (P = 0.004). Multiple brain-specific autoantibodies are present at significantly higher frequency in children with AU. While the potential role of these autoantibodies in AU is currently unknown, their presence suggests a loss of self-tolerance to one or more neural antigens during early childhood.


Controlling ribozyme activity by metal ions.
The observed rates of ribozyme cleavage reactions are strongly dependent on the nature of the metal ion present. Metal ions can thereby exhibit a stronger inhibiting or accelerating effect compared to Mg(2+), which is usually considered the natural cofactor. Alkaline, alkaline earth, transition, d(10), and other metal ions are applied either to gain a spectroscopic handle on the metal center, and/or to elucidate the catalytic mechanism. Here we shortly review some of the most recent publications on the influence of different metal ions on catalysis of the hammerhead, hepatitis delta virus, and group II intron ribozymes. Comparison of the observed cleavage rates of hammerhead ribozymes with the metal ion affinities of different ligands reveals that these rates correlate perfectly with the intrinsic phosphate affinities of the metal ions involved.


Combined signaling through interleukin-7 receptors and flt3 but not c-kit potently and selectively promotes B-cell commitment and differentiation from uncommitted murine bone marrow progenitor cells.
Multiple cytokines can synergize to stimulate the in vitro proliferation and exclusive myeloid differentiation of multipotent bone marrow progenitor cells. The ligand for c-kit (stem cell factor [SCF]) plays a key role in stimulating myeloid and erythroid cell production of primitive hematopoietic progenitors. SCF in combination with interleukin-7 (IL-7) can also stimulate the combined myeloid and B-cell differentiation of uncommitted hematopoietic progenitor cells as well as the growth of early B-cell progenitor cells, although the involvement of c-kit in early B lymphopoiesis remains controversial. In the present study, the flt3-ligand (FL), which, in combination with other cytokines, has overlapping activities with SCF on myeloid cell production from uncommitted progenitors, was investigated for its ability to induce selective stroma-independent B-cell commitment from uncommitted Lin-Sca-1+ bone marrow progenitor cells. IL-7 alone did not induce any clonal growth and FL alone gave rise to a few clusters (< 50 cells) but no colonies (> 50 cells), whereas the combined stimulation with FL and IL-7 resulted in clonal growth of 10% of Lin-Sca-1+ bone marrow cells. After 12 days of incubation of Lin-Sca-1+ cells in FL + IL-7, an almost 400-fold increase in cell production was observed. Phenotyping showed that greater than 99% of the cells produced were of the B-cell lineage, in that they expressed B220, but not cell surface markers specific for myeloid, erythroid, or T-cell lineages. Furthermore, the cells did not express cytoplasmic mu-heavy chain (cmu) or surface IgM, but were positive for CD24 (heat stable antigen [HSA]) and CD43 (leukosialin), suggesting that the cells produced were blocked at a late pro-B-cell stage. Interestingly, although all FL + IL-7-responsive Lin-Sca-1+ progenitor cells and the resulting pro-B cells expressed c-kit, FL + IL-7 was much more potent (62-fold) than SCF + IL-7 in stimulating production of cells of the B-cell lineage. In addition, whereas FL + IL-7 selectively stimulated the production of pro-B cells, SCF + IL-7 predominantly stimulated the production of mature granulocytes. Replating studies showed that FL + IL-7-responsive Lin-Sca-1+ progenitors were not committed to the B-cell lineage, because after 2 days of incubation in FL + IL-7, 80% of the progenitors retained a myeloid potential. As much as 27% of the FL + IL-7-responsive progenitors remained uncommitted after 7 days of incubation, but all had committed to the B-cell lineage after 10 days of incubation in FL + IL-7. These results show that FL much more potently and selectively than SCF synergizes with IL-7 to enhance B-cell commitment and development from uncommitted progenitor cells.


Randomized study of lafutidine vs lansoprazole in patients with mild gastroesophageal reflux disease.
To compare the clinical efficacy of the second-generation H2RA lafutidine with that of lansoprazole in Japanese patients with mild gastroesophageal reflux disease (GERD). Patients with symptoms of GERD and a diagnosis of grade A reflux esophagitis (according to the Los Angeles classification) were randomized to receive lafutidine (10 mg, twice daily) or lansoprazole (30 mg, once daily) for an initial 8 wk, followed by maintenance treatment comprising half-doses of the assigned drug for 24 wk. The primary endpoint was the frequency and severity of heartburn during initial and maintenance treatment. The secondary endpoints were the sum score of questions 2 and 3 in the Gastrointestinal Symptom Rating Scale (GSRS), and the satisfaction score. Between April 2012 and March 2013, a total of 53 patients were enrolled, of whom 24 and 29 received lafutidine and lansoprazole, respectively. After 8 wk, the frequency and severity of heartburn was significantly reduced in both groups. However, lafutidine was significantly inferior to lansoprazole with regard to the severity of heartburn during initial and maintenance treatment (P = 0.016). The sum score of questions 2 and 3 in the GSRS, and satisfaction scores were also significantly worse in the lafutidine group than the lansoprazole group (P = 0.0068 and P = 0.0048, respectively). The clinical efficacy of lafutidine was inferior to that of lansoprazole, even in Japanese patients with mild GERD.


Thermodynamic stabilities of linear and crinkled tapes and cyclic rosettes in melamine--cyanurate assemblies: a model description.
In this paper we describe model calculations for the self-assembly of N,N-disubstituted melamines 1 and N-substituted cyanuric acid or 5,5-disubstituted barbituric acid derivatives 2 into linear or crinkled tapes and cyclic rosettes via cooperative hydrogen bond formation. The model description considers all possible stereoisomeric tape structures consisting of two to eight different components (270 different species in total) and one cyclic hexameric rosette structure. Furthermore, eight steric parameters (R(12)-R(28)) are included that represent the different types of steric interactions within the assemblies. Most importantly, the model calculations clearly show that the tape/rosette ratio is very sensitive to changes in parameters that directly affect the internal energy of the rosette structure. In this respect, three parameters have been characterized, i.e., the basic equilibrium constant K(0) for the bimolecular association of a melamine and cyanurate, the equilibrium constant K(r)/K(0) for the cyclization of a linear hexamer, and the parameter R(12)-a(Z)b, representing attractive or repulsive interactions between adjacent melamine and cyanurate moieties. For example, an increase in K(0) from 100 to 10,000 M(-1) ([A](0) = [B](0) = 10 mM, K(r) = 0.01 M) or in K(r) from 0.001 to 0.1 M ([A](0) = [B](0) = 10 mM, K(0) = 1000 M(-1)) raises the concentration of the rosette from <5 to approximately 90% or from approximately 10 to approximately 85%, respectively. Similarly, a change in R(12)-a(Z)b from 1.0 (no repulsive or attractive interactions) to 1.5 (slight attractive interaction) raises the rosette fraction of the mixture from 25% to 45%. In sharp contrast to this, the model calculations show that parameters that only affect the internal energy of the tapes (R(13)--R(28)) hardly change the tape/rosette ratio. For example, by changing R(13)-a(EE)a from 1.0 (no repulsive or attractive interactions) to 0.001 (maximum repulsion), the rosette fraction in the mixture changes by no more than 8%. Including all possible sterics that occur only in tapes (i.e., R(13)--R(28)), the maximum change in rosette fraction is no more than 16%. These predictions can be rationalized by considering that any change in the stability of the tapes only affects the rosette concentration by means of shifting the equilibrium between free 1 and 2 and the rosette. Since there are 270 different tapelike structures in equilibrium, this mixture represents the best buffer solution in the world. These model calculations seem to conflict with the concept of peripheral crowding as put forward by Whitesides et al., which states that bulky substituents on the periphery of the melamine (and cyanurate) components can be used to shift the tape/rosette equilibrium completely toward the rosette structure. Computer simulations (CHARMm 24.0) show that linear tapes with bulky substituents are severely distorted from planarity, while the corresponding rosette remains planar. Therefore, tapelike structures with bulky substituents are expected to have a much higher solubility than the corresponding rosettes, which can explain the observed crystal data.


Adult urinary bladder tumors with rhabdomyosarcomatous differentiation: clinical, pathological and immunohistochemical studies.
Adult rhabdomyosarcoma (RMS) in the urinary bladder is rare, and is the subject of case reports and small series. It consists of sheets of small round blue cells with high nuclear cytoplasmic ratio, brisk mitosis and apoptosis. In this study, we reported one case of pure rhabdomyosarcoma and two cases of urothelial carcinomas with extensive rhabdomyosarcomatous differentiation. In addition, their immunohistochemical profile was compared to that of small cell carcinoma of the bladder. Our study showed that sufficient sampling was critical for the diagnosis of urothelial carcinoma with extensive rhabdomyosarcomatous differentiation. As adult RMS in the bladder and urothelial carcinoma with rhabdomyosarcomatous differentiation shared morphological features with small cell carcinoma of the bladder, appropriate immunohistochemical stains were necessary in the differential diagnosis. We showed both rhabdomyosarcoma and rhabdomyosarcomatous areas of the urothelial carcinoma were positive for myogenin, negative for cytokeratin and chromogranin stains. In contrast, small cell carcinoma was positive for cytokeratin, and 7 out of 9 cases were also positive for chromogranin. Both rhabdomyosarcoma and small cell carcinoma could be positive for synaptophysin, a potential pitfall to avoid. In addition, all of the tumors with rhabdomyosarcomatous differentiation were negative for FKHR rearrangement.


Enhancement of laser performance using an intracavity deformable membrane mirror.
An intracavity deformable membrane mirror has been successfully used to optimise the brightness of solid-state lasers--a side-pumped Nd(3+):YAlO laser where the oscillation of a low-order transverse mode was obtained, and a grazing incidence Nd(3+):GdVO(4) laser where a brightness increase by an order of magnitude with negligible drop in power was achieved. Several search algorithms were also implemented in the system and compared with respect to intracavity optimisation.


Dynamic imaging of the effector immune response to listeria infection in vivo.
Host defense against the intracellular pathogen Listeria monocytogenes (Lm) requires innate and adaptive immunity. Here, we directly imaged immune cell dynamics at Lm foci established by dendritic cells in the subcapsular red pulp (scDC) using intravital microscopy. Blood borne Lm rapidly associated with scDC. Myelomonocytic cells (MMC) swarmed around non-motile scDC forming foci from which blood flow was excluded. The depletion of scDC after foci were established resulted in a 10-fold reduction in viable Lm, while graded depletion of MMC resulted in 30-1000 fold increase in viable Lm in foci with enhanced blood flow. Effector CD8+ T cells at sites of infection displayed a two-tiered reduction in motility with antigen independent and antigen dependent components, including stable interactions with infected and non-infected scDC. Thus, swarming MMC contribute to control of Lm prior to development of T cell immunity by direct killing and sequestration from blood flow, while scDC appear to promote Lm survival while preferentially interacting with CD8+ T cells in effector sites.


The preventable burden of productivity loss due to suboptimal asthma control: a population-based study.
Productivity loss is an overlooked aspect of the burden of chronic health conditions. While modern guidelines emphasize achieving clinical control in asthma management, few studies have reported on the relationship between asthma control and productivity loss. We calculated the productivity loss that can be avoided by achieving and maintaining clinical control in employed adults with asthma. We prospectively recruited a population-based random sample of adults with asthma in British Columbia, Canada. We measured productivity loss due to absenteeism and presenteeism using validated instruments, and ascertained asthma control according to the GINA (Global Initiative for Asthma) classification. We estimated the average gain in productivity for each individual if the individual's asthma was controlled in the past week, by fitting two-part regression models associating asthma control and productivity loss, controlling for potential confounding variables. The final sample included 300 employed adults (mean age, 47.9 years [SD 12.0]; 67.3% women). Of these, 49 (16.3%) reported absenteeism, and 137 (45.7%) reported presenteeism. Productivity loss due to presenteeism, but not absenteeism, was associated with asthma control. A person with uncontrolled asthma would avoid $184.80 (Canadian dollars [CAD]) in productivity loss by achieving clinical control during a week, CAD$167.50 (90.6%) of which would be due to presenteeism. The corresponding value was CAD$34.20 for partially controlled asthma and was not statistically significant. Our results indicate that substantial gain in productivity can be obtained by achieving asthma control. Presenteeism is more responsive than absenteeism to asthma control, and, thus, is a more important source of preventable burden.


The geography of hotspots of rarity-weighted richness of birds and their coverage by Natura 2000.
A major challenge for biogeographers and conservation planners is to identify where to best locate or distribute high-priority areas for conservation and to explore whether these areas are well represented by conservation actions such as protected areas (PAs). We aimed to identify high-priority areas for conservation, expressed as hotpots of rarity-weighted richness (HRR)-sites that efficiently represent species-for birds across EU countries, and to explore whether HRR are well represented by the Natura 2000 network. Natura 2000 is an evolving network of PAs that seeks to conserve biodiversity through the persistence of the most patrimonial species and habitats across Europe. This network includes Sites of Community Importance (SCI) and Special Areas of Conservation (SAC), where the latter regulated the designation of Special Protected Areas (SPA). Distribution maps for 416 bird species and complementarity-based approaches were used to map geographical patterns of rarity-weighted richness (RWR) and HRR for birds. We used species accumulation index to evaluate whether RWR was efficient surrogates to identify HRRs for birds. The results of our analysis support the proposition that prioritizing sites in order of RWR is a reliable way to identify sites that efficiently represent birds. HRRs were concentrated in the Mediterranean Basin and alpine and boreal biogeographical regions of northern Europe. The cells with high RWR values did not correspond to cells where Natura 2000 was present. We suggest that patterns of RWR could become a focus for conservation biogeography. Our analysis demonstrates that identifying HRR is a robust approach for prioritizing management actions, and reveals the need for more conservation actions, especially on HRR.


Recognition and management of bioterrorism infections.
Recent events have demonstrated that bioterrorists have the ability to disseminate biologic agents in the United States and cause widespread social panic. Family physicians would play a key role in the initial recognition of a potential bioterrorism attack. Familiarity with the infectious agents of highest priority can expedite diagnosis and initial management, and lead to a successful public health response to such an attack. High-priority infectious agents include anthrax, smallpox, plague, tularemia, botulism, and viral hemorrhagic fever. Anthrax and smallpox must be distinguished from such common infections as influenza and varicella. Anthrax treatment is stratified into postexposure prophylaxis and treatment of confirmed cutaneous, intestinal, or inhalation anthrax. Disease prevention by vaccination and isolation of affected persons is key in preventing widespread smallpox infection. Many resources are available to physicians when a bioterrorism attack is suspected, including local public health agencies and the Centers for Disease Control and Prevention.


The Corvids Literature Database--500 years of ornithological research from a crow's perspective.
Corvids (Corvidae) play a major role in ornithological research. Because of their worldwide distribution, diversity and adaptiveness, they have been studied extensively. The aim of the Corvids Literature Database (CLD, http://www.corvids.de/cld) is to record all publications (citation format) on all extant and extinct Crows, Ravens, Jays and Magpies worldwide and tag them with specific keywords making them available for researchers worldwide. The self-maintained project started in 2006 and today comprises 8000 articles, spanning almost 500 years. The CLD covers publications from 164 countries, written in 36 languages and published by 8026 authors in 1503 journals (plus books, theses and other publications). Forty-nine percent of all records are available online as full-text documents or deposited in the physical CLD archive. The CLD contains 442 original corvid descriptions. Here, we present a metadata assessment of articles recorded in the CLD including a gap analysis and prospects for future research. Database URL: http://www.corvids.de/cld.


Device-Associated Menstrual Toxic Shock Syndrome.
In the 1980s, menstrual toxic shock syndrome (mTSS) became a household topic, particularly among mothers and their daughters. The research performed at the time, and for the first time, exposed the American public as well as the biomedical community, in a major way, to understanding disease progression and investigation. Those studies led to the identification of the cause, Staphylococcus aureus and the pyrogenic toxin superantigen TSS toxin 1 (TSST-1), and many of the risk factors, for example, tampon use. Those studies in turn led to TSS warning labels on the outside and inside of tampon boxes and, as important, uniform standards worldwide of tampon absorbency labeling. This review addresses our understanding of the development and conclusions related to mTSS and risk factors. We leave the final message that even though mTSS is not commonly in the news today, cases continue to occur. Additionally, S. aureus strains cycle in human populations in roughly 10-year intervals, possibly dependent on immune status. TSST-1-producing S. aureus bacteria appear to be reemerging, suggesting that physician awareness of this emergence and mTSS history should be heightened.


Rates of undiagnosed attention deficit hyperactivity disorder in London drug and alcohol detoxification units.
ADHD is a common childhood onset mental health disorder that persists into adulthood in two-thirds of cases. One of the most prevalent and impairing comorbidities of ADHD in adults are substance use disorders. We estimate rates of ADHD in patients with substance abuse disorders and delineate impairment in the co-morbid group. Screening for ADHD followed by a research diagnostic interview in people attending in-patient drug and alcohol detoxification units. We estimated prevalence of undiagnosed ADHD within substance use disorder in-patients in South London around 12%. Those individuals with substance use disorders and ADHD had significantly higher self-rated impairments across several domains of daily life; and higher rates of substance abuse and alcohol consumption, suicide attempts, and depression recorded in their case records. This study demonstrates the high rates of untreated ADHD within substance use disorder populations and the association of ADHD in such patients with greater levels of impairment. These are likely to be a source of additional impairment to patients and represent an increased burden on clinical services.


Variant profiling of evolving prokaryotic populations.
Genomic heterogeneity of bacterial species is observed and studied in experimental evolution experiments and clinical diagnostics, and occurs as micro-diversity of natural habitats. The challenge for genome research is to accurately capture this heterogeneity with the currently used short sequencing reads. Recent advances in NGS technologies improved the speed and coverage and thus allowed for deep sequencing of bacterial populations. This facilitates the quantitative assessment of genomic heterogeneity, including low frequency alleles or haplotypes. However, false positive variant predictions due to sequencing errors and mapping artifacts of short reads need to be prevented. We therefore created VarCap, a workflow for the reliable prediction of different types of variants even at low frequencies. In order to predict SNPs, InDels and structural variations, we evaluated the sensitivity and accuracy of different software tools using synthetic read data. The results suggested that the best sensitivity could be reached by a union of different tools, however at the price of increased false positives. We identified possible reasons for false predictions and used this knowledge to improve the accuracy by post-filtering the predicted variants according to properties such as frequency, coverage, genomic environment/localization and co-localization with other variants. We observed that best precision was achieved by using an intersection of at least two tools per variant. This resulted in the reliable prediction of variants above a minimum relative abundance of 2%. VarCap is designed for being routinely used within experimental evolution experiments or for clinical diagnostics. The detected variants are reported as frequencies within a VCF file and as a graphical overview of the distribution of the different variant/allele/haplotype frequencies. The source code of VarCap is available at https://github.com/ma2o/VarCap. In order to provide this workflow to a broad community, we implemeted VarCap on a Galaxy webserver, which is accessible at http://galaxy.csb.univie.ac.at.


Zinc intake from supplements and diet and prostate cancer.
Laboratory and animal studies suggest a beneficial effect of zinc on prostate cancer. We evaluated the association between dietary and supplemental zinc and prostate cancer within the VITamins And Lifestyle (VITAL) cohort, a study specifically designed to evaluate the impact of dietary supplements and cancer risk. Of 35,242 men who completed the baseline dietary and supplemental questionnaire, 832 men developed invasive prostate cancers between October 2000 and December 2004. Ten-year average intake of supplemental zinc was not associated with a reduced prostate cancer risk overall (adjusted hazard ratio (HR) = 0.82 (95% confidence interval (CI) 0.58-1.14) for >15 mg/day vs. nonuse, P for trend = 0.44); however, risk of advanced prostate cancer (regionally invasive or distant metastatic, n = 123) decreased with greater intake of supplemental zinc (adjusted HR = 0.34, 95% CI = 0.13-1.09 for 10-yr average intake > 15 mg/day vs. nonuse, P for trend = 0.04). Dietary zinc was not associated with prostate cancer. In this prospective cohort, long-term supplemental zinc intake was associated with reduced risk of clinically relevant advanced disease. This study had limited ability to study early-stage disease because detection of early-stage disease is highly related to having a PSA test, and information on PSA was only available at baseline. Because few other epidemiologic studies have investigated the association between zinc and prostate cancer, and these have not yielded consistent findings, further research is needed.


Predicting alcohol consumption during the month before and after beginning college.
We sought to determine predictors of drinking the month before and after beginning college, as well as changes in drinking between these two periods among adjudicated students. We conducted these analyses to inform individual and university-wide approaches to addressing underage drinking, particularly among the heaviest drinkers. The sample consisted of 143 students entering college, adjudicated during their first semester, and interviewed during the same semester. The sample consisted of 43% women. Drinking data were collected through the Time-Line Follow-Back interview. The average number of drinking days (DD) during the first month of college was 7.0 (SD = 4.7), the average number of drinks per drinking day (DDD) was 7.4 (SD = 3.4), and the average volume of standard drink units consumed during this month was 56.3 (SD = 51.2). Students had volunteered for a two-year college facilitation study, and had been invited to participate after receiving a citation for violating university alcohol policies. Analyses consisted of nine backward elimination regression analyses with nine variables entered as predictors (one was a control variable). Age of first intoxication was related to every dependent measure. Men had a higher August DDD, September DDD, and September volume than women. Roommate drinking level was associated with September DDD and September volume. Out-of-state students had a lower August volume than in-state students. High school rank was inversely related to September drinking days. SAT score, declared major status, and fraternity/sorority status were not related to drinking according to these multivariate analyses. Results suggest that approaches to underage drinking for adjudicated students may need to be tailored according to age of first intoxication. Results also suggest the drinking level of the heaviest drinking roommate may moderate individual level interventions. Further, interventions applied to an entire dorm room may prove efficacious. Results also suggest that high school rank, rather than SAT scores, should be used as college entry criteria to yield a drier incoming class. Results may not generalize to non-adjudicated students.


The earliest pigeon fanciers.
Feral Pigeons have colonised all corners of the Earth, having developed a close association with humans and their activities. The wild ancestor of the Feral Pigeon, the Rock Dove, is a species of rocky habitats, nesting typically on cliff ledges and at the entrance to large caves. This habit would have brought them into close contact with cave-dwelling humans, a relationship usually linked to the development of dwellings in the Neolithic. We show that the association between humans and Rock Doves is an ancient one with its roots in the Palaeolithic and predates the arrival of modern humans into Europe. At Gorham's Cave, Gibraltar, the Neanderthals exploited Rock Doves for food for a period of over 40 thousand years, the earliest evidence dating to at least 67 thousand years ago. We show that the exploitation was not casual or sporadic, having found repeated evidence of the practice in different, widely spaced, temporal contexts within the cave. Our results point to hitherto unappreciated capacities of the Neanderthals to exploit birds as food resources on a regular basis. More so, they were practising it long before the arrival of modern humans and had therefore invented it independently.


Cyclic GMP-dependent protein kinase is required for thrombospondin and tenascin mediated focal adhesion disassembly.
Focal adhesions are specialized regions of cell membranes that are foci for the transmission of signals between the outside and the inside of the cell. Intracellular signaling events are important in the organization and stability of these structures. In previous work, we showed that the counter-adhesive extracellular matrix proteins, thrombospondin, tenascin, and SPARC, induce the disassembly of focal adhesion plaques and we identified the active regions of these proteins. In order to determine the mechanisms whereby the anti-adhesive matrix proteins modulate cytoskeletal organization and focal adhesion integrity, we examined the role of protein kinases in mediating the loss of focal adhesions by these proteins. Data from these studies show that cGMP-dependent protein kinase is necessary to mediate focal adhesion disassembly triggered by either thrombospondin or tenascin, but not by SPARC. In experiments using various protein kinase inhibitors, we observed that selective inhibitors of cyclic GMP-dependent protein kinase, KT5823 and Rp-8-Br-cGMPS, blocked the effects of both the active sequence of thrombospondin 1 (hep I) and the alternatively-spliced segment (TNfnA-D) of tenascin-C on focal adhesion disassembly. Moreover, early passage rat aortic smooth muscle cells which have high levels of cGMP-dependent protein kinase were sensitive to hep I treatment, in contrast to passaged cGMP-dependent protein kinase deficient cells which were refractory to hep I or TNfnA-D treatment, but were sensitive to SPARC. Transfection of passaged smooth muscle cells with the catalytic domain of PKG I alpha restored responsiveness to hep I and TNfnA-D. While these studies show that cGMP-dependent protein kinase activity is necessary for thrombospondin and tenascin-mediated focal adhesion disassembly, kinase activity alone is not sufficient to induce disassembly as transfection of the catalytic domain of the kinase in the absence of additional stimuli does not result in loss of focal adhesions.


Linking Antarctic krill larval supply and recruitment along the Antarctic Peninsula.
Antarctic krill (Euphausia superba) larval production and overwinter survival drive recruitment variability, which in turn determines abundance trends. The Antarctic Peninsula has been described as a recruitment hot spot and as a potentially important source region for larval and juvenile krill dispersal. However, there has been no analysis to spatially resolve regional-scale krill population dynamics across life stages. We assessed spatiotemporal patterns in krill demography using two decades of austral summer data collected along the North and West Antarctic Peninsula since 1993. We identified persistent spatial segregation in the summer distribution of euphausiid larvae (E. superba plus other species), which were concentrated in oceanic waters along the continental slope, and E. superba recruits, which were concentrated in shelf and coastal waters. Mature females of E. superba were more abundant over the continental shelf than the slope or coast. Euphausiid larval abundance was relatively localized and weakly correlated between the North and West Antarctic Peninsula, while E. superba recruitment was generally synchronized throughout the entire region. Euphausiid larval abundance along the West Antarctic Peninsula slope explained E. superba recruitment in shelf and coastal waters the next year. Given the localized nature of krill productivity, it is critical to evaluate the connectivity between upstream and downstream areas of the Antarctic Peninsula and beyond. Krill fishery catch distributions and population projections in the context of a changing climate should account for ontogenetic habitat partitioning, regional population connectivity, and highly variable recruitment.


Pharmacokinetics and pharmacodynamics of labetalol in the pregnant sheep.
The maternal-fetal disposition of labetalol, a combined alpha-1 and beta adrenergic blocker, and its pharmacodynamics in pregnancy are not well understood. This study describes the pharmacokinetics, cardiovascular and metabolic effects of labetalol in the mother and in utero fetus after a 100-mg maternal i.v. bolus administration, in the chronically instrumented pregnant sheep. Labetalol shows a triexponential decline in the mother with a total body clearance of 30.8 +/- 3.83 ml/min/kg, an apparent steady-state volume of distribution (nonparametric) of 3.02 +/- 0.18 liters/kg and terminal elimination half-life of 2.79 +/- 0.66 hr. These estimates are similar to the reported values in pregnant women. Labetalol rapidly crosses the sheep placenta. The peak fetal plasma concentration was 33.7 +/- 5.8 ng/ml, the fetal exposure to labetalol as calculated by the fetal to maternal area under the curve ratio was 14.37 +/- 1.54% and the apparent fetal elimination half-life was 3.71 +/- 0.5 hr. Labetalol persists in the amniotic and fetal tracheal fluids up to 24 hr with concentrations reaching 2- to 4 times the fetal plasma concentration. Whereas there were no significant maternal or fetal cardiovascular effects, some very significant metabolic effects were observed, including fetal and maternal lactic acidosis and hyperglycemia. Lactic acid accumulates in the fetal blood and amniotic fluid with peak concentrations (6.0 +/- 0.31 and 5.5 +/- 0.26 mM, respectively) showing a more than 300% increase over control values. The exact mechanism by which labetalol causes these metabolic effects is not clear, but it may involve its partial beta-2 agonist activity.


Use of alternative health care by family practice patients.
In recent years, the use of alternative medicine has become more acknowledged in the United States. Many different practices are encompassed by the terms alternative, unorthodox, or complementary medicine, and their use by the population is just now being defined. The number of established family practice patients also using alternative medicine is not yet known. To help answer this question, a survey of family practice patients concerning their use of alternative medicine was performed in 4 family practices in a large community in the western United States. Volunteers from the survey respondents attended a focus group to discuss more fully their use of alternative medicine. Questionnaires were completed by 113 family practice patients. Fifty percent (57/113) of patients had or were using some form of alternative medicine, but only 53% (30/57) had told their family physician about this use. No significant difference in the percentage who used alternative medicine or who told their physician about it was attributable to gender, educational level, age, race, or clinic attended. The main reason given for using alternative medicine, alone or in combination with care from a family physician, was a belief that it would work. Many of those who worked in combination with a family physician spoke of acceptance and control, but those who did not work with their physician mentioned traditional medicine's limitations and narrow-mindedness. Family physicians need to be aware that many of their patients may be using alternative health care. Open and nonjudgmental questioning of patients may help increase physician knowledge of this use and lead to improved patient care as physicians and patients work together toward health.


Using energy to go downhill - a genoprotective role for ATPase activity in DNA topoisomerase II.
Type II topoisomerases effect topological changes in DNA by cutting a single duplex, passing a second duplex through the break, and resealing the broken strand in an ATP-coupled reaction. Curiously, most type II topoisomerases (topos II, IV, and VI) catalyze DNA transformations that are energetically favorable, such as the removal of superhelical strain; why ATP is required for such reactions is unknown. Here, using human topoisomerase II β (hTOP2β) as a model, we show that the ATPase domains of the enzyme are not required for DNA strand passage, but that their loss leads to increased DNA nicking and double strand break formation by the enzyme. The unstructured C-terminal domains (CTDs) of hTOP2β strongly potentiate strand passage activity in the absence of the ATPase regions, as do cleavage-prone mutations that confer hypersensitivity to the chemotherapeutic agent etoposide. The presence of either the CTD or the mutations lead ATPase-less enzymes to promote even greater levels of DNA cleava in ge vitro , as well as in vivo . By contrast, the aberrant cleavage phenotypes of these topo II variants is significantly repressed when the ATPase domains are restored. Our findings are consistent with the proposal that type II topoisomerases acquired an ATPase function to maintain high levels of catalytic activity while minimizing inappropriate DNA damage.


Stimulus fear relevance and the speed, magnitude, and robustness of vicariously learned fear.
Superior learning for fear-relevant stimuli is typically indicated in the laboratory by faster acquisition of fear responses, greater learned fear, and enhanced resistance to extinction. Three experiments investigated the speed, magnitude, and robustness of UK children's (6-10 years; N = 290; 122 boys, 168 girls) vicariously learned fear responses for three types of stimuli. In two experiments, children were presented with pictures of novel animals (Australian marsupials) and flowers (fear-irrelevant stimuli) alone (control) or together with faces expressing fear or happiness. To determine learning speed the number of stimulus-face pairings seen by children was varied (1, 10, or 30 trials). Robustness of learning was examined via repeated extinction procedures over 3 weeks. A third experiment compared the magnitude and robustness of vicarious fear learning for snakes and marsupials. Significant increases in fear responses were found for snakes, marsupials and flowers. There was no indication that vicarious learning for marsupials was faster than for flowers. Moreover, vicariously learned fear was neither greater nor more robust for snakes compared to marsupials, or for marsupials compared to flowers. These findings suggest that for this age group stimulus fear relevance may have little influence on vicarious fear learning.


Renal damage in experimentally-induced cirrhosis in rats: Role of oxygen free radicals.
Cirrhosis with ascites is associated with impaired renal function accompanied by sodium and water retention. Although it has been suggested that mediators such as nitric oxide play a role in the development of renal failure in this situation, other mechanisms underlying the process are not well understood. This study examined the role of oxidative stress in mediating renal damage during the development of cirrhosis in order to understand mechanisms involved in the process. It was shown that carbon tetrachloride- or thioacetamide-induced cirrhosis in rats results in oxidative stress in the kidney as seen by increased lipid peroxidation and protein oxidation, accompanied by altered antioxidant status. Cirrhosis was also found to affect renal mitochondrial function, as assessed by measurement of the respiratory control ratio, the swelling of mitochondria, and calcium flux across mitochondrial membranes. Increased lipid peroxidation and changes in lipid composition were evident in the renal brush border membranes, with compromised transport of 14C glucose across these membranes. In conclusion, renal alterations produced as a result of cirrhosis in the rat are possibly mediated by oxidative stress.


Identification and tracking of problematic host cell proteins removed by a synthetic, highly functionalized nonwoven media in downstream bioprocessing of monoclonal antibodies.
The repertoire of complex proteins produced by the host cell during monoclonal antibody (mAb) production has generated a bottleneck in downstream bioprocessing. Low ppm levels of host cell proteins (HCPs) must be achieved at the downstream purification process stage to generate an end product suitable for use in humans. The increased demand for mAb drug products globally has driven research to focus on affordability of mAb production platforms. This has fuelled advancements in manufacturing R&D to deliver higher product titres with better economics without sacrificing product quality. This study highlights the beneficial effects of inclusion of the Emphaze™ AEX Hybrid Purifier, compared to a conventional clarification process, for removal problematic HCPs during downstream bioprocessing of mAbs. Advanced proteomic methods were used to track and identify known 'problematic' HCPs through a multi-cycle Protein A purification process. Removal of histone proteins was observed, along with an average total HCP reduction of 38-fold and an average reduction of 2.3 log in HCDNA concentration. Chromatographic clarification using the Emphaze™ AEX Hybrid Purifier in conjunction with Protein A chromatography resulted in the removal of problematic HCPs including 78 kD glucose-regulated protein, nidogen-1, heat shock proteins, actin, serine protease HTRA1 and matrix metalloproteinase-19. It is shown herein that the Emphaze™ AEX Hybrid Purifier, which is readily incorporated into a mAb purification process during the clarification stage, has the potential to increase Protein A resin lifetime and potentially reduce the number of subsequent polishing chromatographic steps needed to remove HCPs that have a tendency to co-purify with mAb products.


Violence, mental health, and physical symptoms in an academic internal medicine practice.
To assess how physical and/or sexual intimate partner violence (IPV), child abuse, and community violence relate to long-term mental and physical problems; to examine the overlap between different forms of violence and the impact of experiencing multiple forms of violence. Cross-sectional survey. Three general internal medicine practices affiliated with an academic medical center. English-speaking women aged 25 to 60. Telephone or in-person interview and chart review. One hundred seventy-four women completed interviews. A majority of participants experienced more than one form of violence. In separate multivariate analyses, each form of violence was associated with depressive symptoms or with at least 6 chronic physical symptoms, after adjustment for demographic factors and substance abuse. The degree of association with health outcomes was similar for each form of violence (odds ratio [OR], 2.4 to 3.9; P < .003). The association with chronic physical symptoms remained significant for IPV (OR, 3.3; P < .002) and community violence (OR, 3.4; P < .003), even after adjustment for depression and posttraumatic stress disorder. There were dose-response relationships between the number of forms of violence experienced and the odds of depressive symptoms and the odds of multiple chronic physical symptoms. Multiple types of victimizations may contribute to patients' current mental health and physical problems. Research or clinical protocols that only focus on one form of violence may underestimate the complexity of women's experiences and needs.


Thermodynamic properties of neutral and charged oxygen vacancies in BaZrO3 based on first principles phonon calculations.
The structural, electronic and thermodynamic properties of neutral and positively doubly charged oxygen vacancies in BaZrO3 are addressed by first principles phonon calculations. The calculations are performed using two complementary first principles approaches and functionals; the linear combination of atomic orbitals (LCAO) within the hybrid Hartree-Fock and density functional theory formalism (HF-DFT), and the projector augmented plane wave approach (PAW) within DFT. Phonons are shown to contribute significantly to the formation energy of the charged oxygen vacancy at high temperatures (∼1 eV at 1000 K), due to both its large distortion of the local structure, and its large negative formation volume. For the neutral vacancy, the resulting lattice distortions, and thus the contributions from phonons to the free formation energy, are significantly smaller. As a result, phonons affect the relative stability of the two defects at finite temperatures and the charge transition level for oxygen vacancies (+2/0) changes from 0.42 to 0.83 eV below the conduction band bottom from 0 K to 1000 K.


Cortical network dynamics during verbal working memory function.
This study is an exploratory investigation of the regional timing of cortical activity associated with verbal working memory function. ERP activity was obtained from a single subject using a 124-channel sensor array during a task requiring the monitoring of imageable words for occasional targets. Distributed cortical activity was estimated every 2.5 ms with high spatial resolution using real head, boundary element modelling of non-target activity. High-resolution structural MRI was used for segmentation of tissue boundaries and co-registration to the scalp electrode array. The inverse solution was constrained to the cortical surface. Cortical activity was observed in regions commonly associated with verbal working memory function. This included: the occipital pole (early visual processing); the superior temporal and inferior parietal gyrus bilaterally and the left angular gyrus (visual and phonological word processing); the dorsal lateral occipital gyrus (spatial processing); and aspects of the bilateral superior parietal lobe (imagery and episodic verbal memory). Activity was also observed in lateral and superior prefrontal regions associated with working memory control of sensorimotor processes. The pattern of cortical activity was relatively stable over time, with variations in the extent and amplitude of contributing local source activations. By contrast, the pattern of concomitant scalp topography varied considerably over time, reflecting the linear summation effects of volume conduction that often confound dipolar source modelling.