Exploring Differences between TTO and DCE in the Valuation of Health States.
There is recent interest in using discrete choice experiments (DCEs) to derive health state utility values, and results can differ from time tradeoff (TTO). Clearly, DCE is "choice based," whereas TTO is generally considered a "matching" task. We explore whether procedural adaptations to the TTO, which make the method more closely resemble a DCE, make TTO and choice converge. In particular, we test whether making the matching procedure in TTO less "transparent" to the respondent reduces disparities between TTO and DCE. We designed an interactive survey that was hosted on the Internet, and 2022 interviews were achieved in the United Kingdom in a representative sample of the population. We found a marked divergence between TTO and DCE, but this was not related to the "transparency" of the TTO procedure. We conclude that a difference in the error structure between TTO and choice and that factors other than differences in utility are affecting choices is driving the divergence. The latter has fundamental implications for the way choice data are analyzed and interpreted.


What percentage of the Cuban HIV-AIDS epidemic is known?
The data for the Cuban HIV-AIDS epidemic from 1986 to 2000 were presented. With the purpose of evaluating the efficiency of the HIV detection system, two methods were used to estimate the size of the HIV-infected population, backcalculation and a dynamical model. From these models it can be estimated that in the worst scenario 75% of the HIV-infected persons are known and in the best case 87% of the total number of persons that have been infected with HIV have been detected by the National Program. These estimates can be taken as a measure of the efficiency of the detection program for HIV-infected persons.


Evaluation of primary care midwifery in The Netherlands: design and rationale of a dynamic cohort study (DELIVER).
In the Netherlands, midwives are autonomous medical practitioners and 78% of pregnant women start their maternity care with a primary care midwife. Scientific research to support evidence-based practice in primary care midwifery in the Netherlands has been sparse. This paper describes the research design and methodology of the multicenter multidisciplinary prospective DELIVER study which is the first large-scale study evaluating the quality and provision of primary midwifery care. Between September 2009 and April 2011, data were collected from clients and their partners, midwives and other healthcare professionals across the Netherlands. Clients from twenty midwifery practices received up to three questionnaires to assess the expectations and experiences of clients (e.g. quality of care, prenatal screening, emotions, health, and lifestyle). These client data were linked to data from the Netherlands Perinatal Register and electronic client records kept by midwives. Midwives and practice assistants from the twenty participating practices recorded work-related activities in a diary for one week, to assess workload. Besides, the midwives were asked to complete a questionnaire, to gain insight into collaboration of midwives with other care providers, their tasks and attitude towards their job, and the quality of the care they provide. Another questionnaire was sent to all Dutch midwifery practices which reveals information regarding the organisation of midwifery practices, provision of preconception care, collaboration with other care providers, and provision of care to ethnic minorities. Data at client, midwife and practice level can be linked. Additionally, partners of pregnant women and other care providers were asked about their expectations and experiences regarding the care delivered by midwives and in six practices client consults were videotaped to objectively assess daily practice. In total, 7685 clients completed at least one questionnaire, 136 midwives and assistants completed a diary with work-related activities (response 100%), 99 midwives completed a questionnaire (92%), and 319 practices across the country completed a questionnaire (61%), 30 partners of clients participated in focus groups, 21 other care providers were interviewed and 305 consults at six midwifery practices were videotaped.The multicenter DELIVER study provides an extensive database with national representative data on the quality of primary care midwifery in the Netherlands. This study will support evidence-based practice in primary care midwifery in the Netherlands and contribute to a better understanding of the maternity care system.


Prevalence and Management of Sexually Transmitted Infections in Correctional Settings: A Systematic Review.
Admissions to jails and prisons in the United States number 10 million yearly; persons entering locked correctional facilities have high prevalence of sexually transmitted infections (STIs). These individuals come disproportionately from communities of color, with lower access to care and prevention, compared with the United States as a whole. Following PRISMA guidelines, the authors present results of a systematic review of literature published since 2012 on STIs in US jails, prisons, Immigration and Customs Enforcement detention centers, and juvenile facilities. This updates an earlier review of STIs in short-term facilities. This current review contributed to new recommendations in the Centers for Disease Control and Prevention 2021 treatment guidelines for STIs, advising screening for Trichomonas in women entering correctional facilities. The current review also synthesizes recommendations on screening: in particular, opt-out testing is superior to opt-in protocols. Carceral interventions-managing diagnosed cases and preventing new infections from occurring (eg, by initiating human immunodeficiency virus preexposure prophylaxis before release)-can counteract structural racism in healthcare.


On the calcium receptor that mediates depolarization-secretion coupling at cholinergic motor nerve terminals.
1 The behaviour of the divalent cations Ca and Sr as agonists for receptors that mediate the synchronous evoked secretion of acetylcholine (ACh) was studied in the hope of determining whether the relationship between Ca binding and ACh secretion is determined only by the law of mass action or by the mathematical framework of receptor theory. Experiments were designed to evaluate the assumption that maximum effect requires occupation of all receptors by testing for the presence of spare Ca receptors on presynaptic terminals. Frog cutaneous nerve-muscle preparations were employed in conjunction with conventional electrophysiological methods.2 Curves of log [Ca] or log [Sr] against the mean number of ACh quanta released (m) were constructed to saturation. The log [Sr]-m relationship was shifted to the right and had a smaller maximum than the log [Ca]-m curve. This suggests that Ca has a higher efficacy than Sr and raises the possibility that spare binding sites are present for Ca.3 As a qualitative test for spare Ca receptors, La(3+) (>/=0.5 mum) or 2-chloroadenosine (25 mum) was employed as an irreversible antagonist of the effects of extracellular Ca on evoked ACh release. Despite the irreversible blockade of a proportion of receptors, increases in the [Ca] overcame this antagonism and produced a parallel shift in the log [Ca]-m relation to the right. This suggests an apparent receptor reserve for Ca. Antagonism of Sr-mediated ACh release by either La(3+) or 2-chloroadenosine could not be overcome by increasing the [Sr].4 As a quantitative test for spare Ca binding sites, the equilibrium affinity constant for Sr(K(Sr)) as a competitive inhibitor of Ca was determined and compared with values for K(Sr) calculated by two other methods which invoke the spare receptor assumption. All three methods produced comparable results. (K(Sr) = 0.24-0.27 mm(-1)).5 The equilibrium affinity constant for Ca (K(Ca)) was calculated by comparing reciprocal plots of the concentrations of Ca that produce equal levels of ACh release in the presence and absence of La(3+) (0.5 mum-3 mum). K(Ca) was estimated to be between 0.02 and 0.06 mm(-1).6 Efficacy (e), which is thought to reflect the ability of Ca or Sr once bound to receptors to support ACh release, was determined by the modified occupation theory of Stephenson (1956). The e(Ca) was estimated to be 9-20 and e(Sr) was 0.2-0.5.7 The experimentally determined values for K(Ca), K(Sr), e(Ca), e(Sr) along with the assumptions that spare Ca binding sites exist and that the non-linearities in the log [Ca] or log [Sr]-m curves are introduced beyond the sites of binding and efficacy were used to generate theoretical log [Me]-m curves. The theoretical relationships were similar to the experimental results.8 The results suggest that spare Ca receptors are present at motor nerve endings and that receptor theory provides an accurate quantitative description of the lumped events between Ca binding and ACh secretion. The possible physical correlates of affinity and efficacy are discussed.


A multi-cohort phase 1b trial of rituximab in combination with immunotherapy doublets in relapsed/refractory follicular lymphoma.
Antibodies targeting PD-1 or 4-1BB achieve objective responses in follicular lymphoma (FL), but only in a minority of patients. We hypothesized that targeting multiple immune receptors could overcome immune resistance and increase response rates in patients with relapsed/refractory FL. We therefore conducted a phase 1b trial testing time-limited therapy with different immunotherapy doublets targeting 4-1BB (utomilumab), OX-40 (ivuxolimab), and PD-L1 (avelumab) in combination with rituximab among patients with relapsed/refractory grade 1-3A FL. Patients were enrolled onto 2 of 3 planned cohorts (cohort 1 - rituximab/utomilumab/avelumab; cohort 2 - rituximab/ivuxolimab/utomilumab). 3+3 dose escalation was followed by dose expansion at the recommended phase 2 dose (RP2D). Twenty-four patients were enrolled (16 in cohort 1 and 9 in cohort 2, with one treated in both cohorts). No patients discontinued treatment due to adverse events and the RP2D was the highest dose level tested in both cohorts. In cohort 1, the objective and complete response rates were 44% and 19%, respectively (50% and 30%, respectively, at RP2D). In cohort 2, no responses were observed. The median progression-free survivals in cohorts 1 and 2 were 6.9 and 3.2 months, respectively. In cohort 1, higher density of PD-1+ tumor-infiltrating T-cells on baseline biopsies and lower density of 4-1BB+ and TIGIT+ T-cells in on-treatment biopsies were associated with response. Abundance of Akkermansia in stool samples was also associated with response. Our results support a possible role for 4-1BB agonist therapy in FL and suggest that features of the tumor microenvironment and stool microbiome may be associated with clinical outcomes (NCT03636503).


Methyl sulfone manifests anticancer activity in a metastatic murine breast cancer cell line and in human breast cancer tissue--part 2: human breast cancer tissue.
Methyl sulfone is a small molecule that reverses cancerous phenotypes of a melanoma cell line. Here, we sought to determine whether methyl sulfone was effective against human breast cancer tissue. We studied normal and cancerous breast tissue obtained from 17 patients. Methyl sulfone introduced structural order, with cancer tissue taking on the morphology of normal in vivo breast tissue; this structural order was sustainable over long-term culture. Methyl sulfone promoted proper wound healing, including migration of cells into wounded areas and establishment of stable contact inhibition once wounds were covered. Methyl sulfone decreased expression of two breast stem cell marker proteins, HCAM and OCT3/4, which are associated with aberrantly rapid migration of metastatic cells. Finally, normal and cancerous primary breast cells remained viable and healthy in methyl sulfone culture for at least 90 days. Methyl sulfone reintroduced a normal structural phenotype to human breast cancer tissues.


Investigating the association between social interactions and personality states dynamics.
The recent personality psychology literature has coined the name of personality states to refer to states having the same behavioural, affective and cognitive content (described by adjectives) as the corresponding trait, but for a shorter duration. The variability in personality states may be the reaction to specific characteristics of situations. The aim of our study is to investigate whether specific situational factors, that is, different configurations of face-to-face interactions, are predictors of variability of personality states in a work environment. The obtained results provide evidence that within-person variability in personality is associated with variation in face-to-face interactions. Interestingly, the effects differ by type and level of the personality states: adaptation effects for Agreeableness and Emotional Stability, whereby the personality states of an individual trigger similar states in other people interacting with them and complementarity effects for Openness to Experience, whereby the personality states of an individual trigger opposite states in other people interacting with them. Overall, these findings encourage further research to characterize face-to-face and social interactions in terms of their relevance to personality states.


Newcastle Disease Virus: Potential Therapeutic Application for Human and Canine Lymphoma.
Research on oncolytic viruses has mostly been directed towards the treatment of solid tumors, which has yielded limited information regarding their activity in hematological cancer. It has also been directed towards the treatment of humans, yet veterinary medicine may also benefit. Several strains of the Newcastle disease virus (NDV) have been used as oncolytics in vitro and in a number of in vivo experiments. We studied the cytolytic effect of NDV-MLS, a low virulence attenuated lentogenic strain, on a human large B-cell lymphoma cell line (SU-DHL-4), as well as on primary canine-derived B-cell lymphoma cells, and compared them to healthy peripheral blood mononuclear cells (PBMC) from both humans and dogs. NDV-MLS reduced cell survival in both human (42% ± 5%) and dog (34% ± 12%) lymphoma cells as compared to untreated controls. No significant effect on PBMC was seen. Cell death involved apoptosis as documented by flow-cytometry. NDV-MLS infections of malignant lymphoma tumors in vivo in dogs were confirmed by electron microscopy. Early (24 h) biodistribution of intravenous injection of 1 × 10(12) TCID50 (tissue culture infective dose) in a dog with T-cell lymphoma showed viral localization only in the kidney, the salivary gland, the lung and the stomach by immunohistochemistry and/or endpoint PCR. We conclude that NDV-MLS may be a promising agent for the treatment of lymphomas. Future research is needed to elucidate the optimal therapeutic regimen and establish appropriate biosafety measures.


Risk Model-Based Lung Cancer Screening and Racial and Ethnic Disparities in the US.
The revised 2021 US Preventive Services Task Force (USPSTF) guidelines for lung cancer screening have been shown to reduce disparities in screening eligibility and performance between African American and White individuals vs the 2013 guidelines. However, potential disparities across other racial and ethnic groups in the US remain unknown. Risk model-based screening may reduce racial and ethnic disparities and improve screening performance, but neither validation of key risk prediction models nor their screening performance has been examined by race and ethnicity. To validate and recalibrate the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial 2012 (PLCOm2012) model-a well-established risk prediction model based on a predominantly White population-across races and ethnicities in the US and evaluate racial and ethnic disparities and screening performance through risk-based screening using PLCOm2012 vs the USPSTF 2021 criteria. In a population-based cohort design, the Multiethnic Cohort Study enrolled participants in 1993-1996, followed up through December 31, 2018. Data analysis was conducted from April 1, 2022, to May 19. 2023. A total of 105 261 adults with a smoking history were included. The 6-year lung cancer risk was calculated through recalibrated PLCOm2012 (ie, PLCOm2012-Update) and screening eligibility based on a 6-year risk threshold greater than or equal to 1.3%, yielding similar eligibility as the USPSTF 2021 guidelines. Predictive accuracy, screening eligibility-incidence (E-I) ratio (ie, ratio of the number of eligible to incident cases), and screening performance (sensitivity, specificity, and number needed to screen to detect 1 lung cancer). Of 105 261 participants (60 011 [57.0%] men; mean [SD] age, 59.8 [8.7] years), consisting of 19 258 (18.3%) African American, 27 227 (25.9%) Japanese American, 21 383 (20.3%) Latino, 8368 (7.9%) Native Hawaiian/Other Pacific Islander, and 29 025 (27.6%) White individuals, 1464 (1.4%) developed lung cancer within 6 years from enrollment. The PLCOm2012-Update showed good predictive accuracy across races and ethnicities (area under the curve, 0.72-0.82). The USPSTF 2021 criteria yielded a large disparity among African American individuals, whose E-I ratio was 53% lower vs White individuals (E-I ratio: 9.5 vs 20.3; P < .001). Under the risk-based screening (PLCOm2012-Update 6-year risk ≥1.3%), the disparity between African American and White individuals was substantially reduced (E-I ratio: 15.9 vs 18.4; P < .001), with minimal disparities observed in persons of other minoritized groups, including Japanese American, Latino, and Native Hawaiian/Other Pacific Islander. Risk-based screening yielded superior overall and race and ethnicity-specific performance to the USPSTF 2021 criteria, with higher overall sensitivity (67.2% vs 57.7%) and lower number needed to screen (26 vs 30) at similar specificity (76.6%). The findings of this cohort study suggest that risk-based lung cancer screening can reduce racial and ethnic disparities and improve screening performance across races and ethnicities vs the USPSTF 2021 criteria.


Binding of the antitumor drug nogalamycin and its derivatives to DNA: structural comparison.
The three-dimensional molecular structures of the complexes between a novel antitumor drug nogalamycin and its derivative U-58872 with a modified DNA hexamer d[m5CGT(pS)Am5CG] have been determined at 1.7- and 1.8-A resolution, respectively, by X-ray diffraction analyses. Both structures (in space group P6(1)) have been refined with constrained refinement procedure to final R factors of 0.208 (3386 reflections) and 0.196 (2143 reflections). In both complexes, two nogalamycins bind to the DNA hexamer double helix in a 2:1 ratio with the elongated aglycon chromophore intercalated between the CpG steps at both ends of the helix. The aglycon chromophore spans across the GC Watson-Crick base pairs with its nogalose lying in the minor groove and the aminoglucose lying in the major groove of the distorted B-DNA double helix. Most of the sugars remain in the C2'-endo pucker family, except three deoxycytidine residues (terminal C1, C7, and internal C5). All nucleotides are in the anti conformation. Specific hydrogen bonds are found in the complex between the drug and guanine-cytosine bases in both grooves of the helix. One hydroxyl group of the aminoglucose donates a hydrogen bond to the N7 of guanine, while the other receives a hydrogen bond from the N4 amino group of cytosine. The orientation of these two hydrogen bonds suggests that nogalamycin prefers a GC base pair with its aglycon chromophore intercalating at the 5'-side of a guanine (between NpG), or at the 3'-side of a cytosine (between CpN) with the sugars pointing toward the GC base pair. The binding of nogalamycin to DNA requires that the base pairs in DNA open up transiently to allow the bulky sugars to go through, suggesting that nogalamycin prefers GC sequences embedded in a stretch of AT sequences.


European cancer mortality predictions for the year 2015: does lung cancer have the highest death rate in EU women?
Cancer mortality statistics for 2015 were projected from the most recent available data for the European Union (EU) and its six more populous countries. Prostate cancer was analysed in detail. Population and death certification data from stomach, colorectum, pancreas, lung, breast, uterus, prostate, leukaemias and total cancers were obtained from the World Health Organisation database and Eurostat. Figures were derived for the EU, France, Germany, Italy, Poland, Spain and the UK. Projected 2015 numbers of deaths by age group were obtained by linear regression on estimated numbers of deaths over the most recent time period identified by a joinpoint regression model. A total of 1,359,100 cancer deaths are predicted in the EU in 2015 (766,200 men and 592,900 women), corresponding to standardised death rates of 138.4/100,000 men and 83.9/100,000 women, falling 7.5% and 6%, respectively, since 2009. In men, predicted rates for the three major cancers (lung, colorectum and prostate) are lower than in 2009, falling 9%, 5% and 12%. Prostate cancer showed predicted falls of 14%, 17% and 9% in the 35-64, 65-74 and 75+ age groups. In women, breast and colorectal cancers had favourable trends (-10% and -8%), but predicted lung cancer rates rise 9% to 14.24/100,000 becoming the cancer with the highest rate, reaching and possibly overtaking breast cancer rates--though the total number of deaths remain higher for breast (90 800) than lung (87 500). Pancreatic cancer has a negative outlook in both sexes, rising 4% in men and 5% in women between 2009 and 2015. Cancer mortality predictions for 2015 confirm the overall favourable cancer mortality trend in the EU, translating to an overall 26% fall in men since its peak in 1988, and 21% in women, and the avoidance of over 325,000 deaths in 2015 compared with the peak rate.


Mitochondrial cytopathies and cardiovascular disease.
The global epidemic of cardiovascular disease remains the leading cause of death in the USA and across the world. Functional and structural integrity of mitochondria are essential for the physiological function of the cardiovascular system. The metabolic adaptation observed in normal heart is lost in the failing myocardium, which becomes progressively energy depleted leading to impaired myocardial contraction and relaxation. Uncoupling of electron transfer from ATP synthesis leads to excess generation of reactive species, leading to widespread cellular injury and cardiovascular disease. Accumulation of mitochondrial DNA mutation has been linked to ischaemic heart disease, cardiomyopathy and atherosclerotic vascular disease. Mitochondria are known to regulate apoptotic and autophagic pathways that have been shown to play an important role in the development of cardiomyopathy and atherosclerosis. A number of pharmacological and non-pharmacological treatment options have been explored in the management of mitochondrial diseases with variable success.


Retrospective evaluation of prognosis and survival with various immunosuppressants in 82 dogs diagnosed with meningoencephalitis of unknown etiology (2010-2021).
Meningoencephalomyelitis of unknown etiology (MUE) is a comprehensive term for non-infectious inflammatory brain diseases of the central nervous system (CNS) caused by abnormal autoimmune responses. This study aims to compare the differences in survival and clinical response of MUE according to the adjuvant immunosuppressant use. Medical records of 82 dogs diagnosed with MUE were reviewed retrospectively. The overall survival time was 769 days (range 14-2687 days). The median survival time for each adjunctive was: leflunomide 1035 days (range 126-2163 days), mycophenolate mofetil 865 days (range 39-2191 days), cyclosporin 441 days (range 11-2176 days), cytosine arabinoside 754 days (range 6-1898 days) and a combination of mycophenolate mofetil and cytosine arabinoside 132 days (range 23-1227 days). There was no significant difference in the incidence rate of adverse events according to the immunosuppressants, but moderate to severe anemia was confirmed in 3 patients (18.7%) in the leflunomide group. The survival time and response rate of MUE dogs differed depending on which adjunctive immunosuppressants were used. Leflunomide showed a long survival time and a relatively good response rate in dogs with MUE. However, a large-scale further study with standardized doses of immunosuppressants and supportive treatment and constant monitoring interval is needed.


The effects of mesenchymal stromal cells and platelet-rich plasma treatments on cutaneous wound healing: ignoring the possibility of adverse events and side effects could compromise study results.
Common medical events may be associated with decreased immunologic activity and dysregulation of functional epithelial and neuronal tissues caused by growth factors and vesicle secretion by stem and somatic cells. Systemic injection of MSCs has been shown to reduce the immune response mainly through paracrine mechanisms, but some points related to the possibility of adverse events and side effects should be clarified. Flow cytometry for at least 20 cell markers is crucial to assess cell senescence and overall cell viability. Thus, adverse events and unreasonable expectations from cell therapy can be prevented. We believe that by using the precision cell phenotyping kits in clinical trials, many undesirable side effects related to misconceptions about the origin of the cells can be avoided.


A population study of prolonged grief in refugees.
Despite the frequency that refugees suffer bereavement, there is a dearth of research into the prevalence and predictors of problematic grief reactions in refugees. To address this gap, this study reports a nationally representative population-based study of refugees to determine the prevalence of probable prolonged grief disorder (PGD) and its associated problems. This study recruited participants from the Building a New Life in Australia (BNLA) prospective cohort study of refugees admitted to Australia between October 2013 and February 2014. The current data were collected in 2015-2016, and comprised 1767 adults, as well as 411 children of the adult respondents. Adult refugees were assessed for trauma history, post-migration difficulties, probable PGD, post-traumatic stress disorder (PTSD) and mental illness. Children were administered the Strengths and Difficulties Questionnaire. In this cohort, 38.1% of refugees reported bereavement, of whom 15.8% reported probable PGD; this represents 6.0% of the entire cohort. Probable PGD was associated with a greater likelihood of mental illness, probable PTSD, severe mental illness, currently unemployed and reported disability. Children of refugees with probable PGD reported more psychological difficulties than those whose parents did not have probable PGD. Probable PGD was also associated with the history of imprisonment, torture and separation from family. Only 56.3% of refugees with probable PGD had received psychological assistance. Bereavement and probable PGD appear highly prevalent in refugees, and PGD seems to be associated with disability in the refugees and psychological problems in their children. The low rate of access to mental health assistance for these refugees highlights that there is a need to address this issue in refugee populations.


Detection of drugs and poisons in postmortem tissues--determination of paraquat in tissues of rabbits buried underground.
The possibility of detecting paraquat in tissues of rabbits buried underground over a 2-year period was examined. Paraquat (1.2 g) was given orally to rabbits, which were sacrificed 1 h after administration. The animals were buried underground, and the skeletal muscles and the bones were collected 3 and 6 months after death, and 3, 6, 12, and 24 months after death, respectively. Paraquat was present in all bone marrow samples, showing a slight decrease in concentration until 12 months. Paraquat was also detected in all skeletal muscle samples, showing almost no change in concentration until 6 months. These results indicate that intoxication with paraquat as well as the degree of poisoning can both be determined from the skeletal muscles and bone marrow of cadavers which have been buried underground for a long period of time even in human cases.


Transcripts that associate with the RNA binding protein, DEAD-END (DND1), in embryonic stem (ES) cells.
The RNA binding protein, DEAD END (DND1), is essential for maintaining viable germ cells in vertebrates. It is also a testicular germ cell tumor susceptibility factor in mice. DND1 has been shown to interact with the 3'-untranslated region (3'-UTR) of mRNAs such as P27 and LATS2. Binding of DND1 to the 3'-UTRs of these transcripts blocks the inhibitory function of microRNAs (miRNA) from these transcripts and in this way DND1 helps maintain P27 and LATS2 protein expression. We found that DND1 is also expressed in embryonic stem (ES) cells. Because ES cells share similar gene expression patterns as germ cells, we utilized ES cells to identify additional candidate mRNAs that associate with DND1. ES cells are readily amenable to genetic modification and easier to culture in vitro compared to germ cells. Therefore, for the purpose of our study, we made a genetically modified, stable, human embryonic stem (hES) cell line that expresses hemagluttinin (HA)-tagged DND1 in a doxycycline (dox) regulatable manner. This line expresses modest levels of HA-DND1 and serves as a good system to study DND1 function in vitro. We used this stable cell line to identify the transcripts that physically interact with DND1. By performing ribonucleoprotein immunoprecipitation (RIP) followed by RT-PCR, we identified that transcripts encoding pluripotency factors (OCT4, SOX2, NANOG, LIN28), cell cycle regulators (TP53, LATS2) and apoptotic factors (BCLX, BAX) are specifically associated with the HA-DND1 ribonucleoprotein complex. Surprisingly, in many cases, bioinformatics analysis of the pulled-down transcripts did not reveal the presence of known DND1 interacting motifs. Our results indicate that the inducible ES cell line system serves as a suitable in vitro system to identify the mRNA targets of DND1. The RIP-RT results hint at the broad spectrum of mRNA targets that interact with DND1 in ES cells. Based on what is known about DND1 function, our results suggest that DND1 may impose another level of translational regulation to modulate expression of critical factors in ES cells.


Enhanced refractive index sensitivity of elevated short-range ordered nanohole arrays in optically thin plasmonic Au films.
A simple development of the colloidal lithography technique is demonstrated for fabrication of perforated plasmonic metal films elevated above the substrate surface. The bulk refractive index sensitivity of short-range ordered nanohole arrays in 20 nm thick Au films exhibits an increase of up to 37% due to reduction of substrate effect caused by lifting with a 40 nm silica layer. Analysis of the local electric field distribution suggests that the sensitivity increase is due to revealing of the enhanced field near the holes.


Intelligent control of the hierarchical agglomerative clustering process.
The basic process of Hierarchical Agglomerative (HAG) clustering is described as a merging of clusters based on their proximity. The importance of the selected cluster distance measure in the determination of resulting clusters is pointed out. We note a fundamental distinction between the nearest neighbor cluster distance measure, Min, and the furthest neighbor measure, Max. The first favors the merging of large clusters while the later favors the merging of smaller clusters. We introduce a number of families of intercluster distance measures each of which can be parameterized along a scale characterizing their preference for merging larger or smaller clusters. We then consider the use of this distinction between distance measures as a way of controlling the hierarchical clustering process. Combining this with the ability of fuzzy systems modeling to formalize linguistic specifications, we see the emergence of a tool to add human like intelligence to the clustering process.


An alkaloid from Menispermum dauricum, dauricine mediates Ca2+ influx and inhibits NF-κB pathway to protect chondrocytes from IL-1β-induced inflammation and catabolism.
Dauricine (DA) is a natural plant-derived alkaloid extracted from Menispermum dauricum. Menispermum dauricum has been used in traditional Chinese medicine as a classic remedy for rheumatoid arthropathy and is believed to be effective in alleviating swelling and pain in the limbs. Osteoarthritis (OA) is a classic degenerative disease involving chondrocyte death, and there is still a lack of effective therapeutic agents that can reverse the progression of the disease. Here we explored the therapeutic effects of DA against OA and further explored the mechanism. The effect of DA on cell viability was assessed by CCK-8. IL-1β-treated mouse chondrocytes were used as an in vitro model of OA, and apoptosis was detected by flow cytometry. QRT-PCR, western blotting, cell staining, and immunofluorescence were used to detect relevant inflammatory factors and cartilage-specific expression. RNA sequencing was used to identify pertinent signaling pathways. The therapeutic effect of DA was verified by micro-CT, histological analysis and immunohistochemical analysis in a mouse OA model. DA demonstrated a high safety profile on chondrocytes, significantly reversing the inflammatory response induced by IL-1β, and promoting factors associated with cartilage regeneration. Moreover, DA exhibited a significant protective effect on the knee joints of mice undergoing ACLT-DMM, effectively preventing cartilage degeneration and subchondral bone tissue destruction. These positive therapeutic effects were achieved through the modulation of the NF-κB pathway and the Ca2+ signaling pathway by DA. Being derived from a traditional herb, DA exhibits remarkable therapeutic potential and safety in OA treatment, presenting a promising option for patients dealing with osteoarthritis.


Bifidobacterium Species Colonization in Infancy: A Global Cross-Sectional Comparison by Population History of Breastfeeding.
Bifidobacterium species are beneficial and dominant members of the breastfed infant gut microbiome; however, their health benefits are partially species-dependent. Here, we characterize the species and subspecies of Bifidobacterium in breastfed infants around the world to consider the potential impact of a historic dietary shift on the disappearance of B. longum subsp. infantis in some populations. Across populations, three distinct patterns of Bifidobacterium colonization emerged: (1) The dominance of Bifidobacterium longum subspecies infantis, (2) prevalent Bifidobacterium of multiple species, and (3) the frequent absence of any Bifidobacterium. These patterns appear related to a country's history of breastfeeding, with infants in countries with historically high rates of long-duration breastfeeding more likely to be colonized by B. longum subspecies infantis compared with infants in countries with histories of shorter-duration breastfeeding. In addition, the timing of infant colonization with B. longum subsp. infantis is consistent with horizontal transmission of this subspecies, rather than the vertical transmission previously reported for other Bifidobacterium species. These findings highlight the need to consider historical and cultural influences on the prevalence of gut commensals and the need to understand epidemiological transmission patterns of Bifidobacterium and other major commensals.


Site-directed point mutation in the src gene oF rous sarcoma virus results in an inactive src gene product.
Site-directed mutagenesis techniques were used to construct defined point mutations within the src gene of the Prague A strain of Rous sarcoma virus. Bisulfite mutagenesis at a Bg/I restriction site in the src gene yielded three mutations which contained the same single base change, a guanine-to-adenine transition. The resulting genomes encoded an src protein containing a substitution of threonine for alanine at amino acid position 433. Transfection of chicken cells with mutagenized DNA did not result in cellular transformation even though the cells produced a pp60src. Immune complexes containing mutant pp60src did not phosphorylate immunoglobulin G heavy chain or casein.


NmDef02, a novel antimicrobial gene isolated from Nicotiana megalosiphon confers high-level pathogen resistance under greenhouse and field conditions.
Plant defensins are small cysteine-rich peptides that inhibit the growth of a broad range of microbes. In this article, we describe NmDef02, a novel cDNA encoding a putative defensin isolated from Nicotiana megalosiphon upon inoculation with the tobacco blue mould pathogen Peronospora hyoscyami f.sp. tabacina. NmDef02 was heterologously expressed in the yeast Pichia pastoris, and the purified recombinant protein was found to display antimicrobial activity in vitro against important plant pathogens. Constitutive expression of NmDef02 gene in transgenic tobacco and potato plants enhanced resistance against various plant microbial pathogens, including the oomycete Phytophthora infestans, causal agent of the economically important potato late blight disease, under greenhouse and field conditions.


Dynamic changes in the dendritic geometry of individual neurons visualized over periods of up to three months in the superior cervical ganglion of living mice.
We describe a means of visualizing the same neuron in the superior cervical ganglion of young adult mice over intervals of up to 3 months. The dendrites of these neurons change during this interval; some branches retract, others elongate, and still others appear to form de novo. Thus, neuronal dendrites in this part of the nervous system are subject to continual change beyond what is usually considered the developmental period. The remodeling of postsynaptic processes further implies that the synaptic connections made onto these cells undergo substantial rearrangement well into adulthood.


Optimization of Multiple Pathogen Detection Using the TaqMan Array Card: Application for a Population-Based Study of Neonatal Infection.
Identification of etiology remains a significant challenge in the diagnosis of infectious diseases, particularly in resource-poor settings. Viral, bacterial, and fungal pathogens, as well as parasites, play a role for many syndromes, and optimizing a single diagnostic system to detect a range of pathogens is challenging. The TaqMan Array Card (TAC) is a multiple-pathogen detection method that has previously been identified as a valuable technique for determining etiology of infections and holds promise for expanded use in clinical microbiology laboratories and surveillance studies. We selected TAC for use in the Aetiology of Neonatal Infection in South Asia (ANISA) study for identifying etiologies of severe disease in neonates in Bangladesh, India, and Pakistan. Here we report optimization of TAC to improve pathogen detection and overcome technical challenges associated with use of this technology in a large-scale surveillance study. Specifically, we increased the number of assay replicates, implemented a more robust RT-qPCR enzyme formulation, and adopted a more efficient method for extraction of total nucleic acid from blood specimens. We also report the development and analytical validation of ten new assays for use in the ANISA study. Based on these data, we revised the study-specific TACs for detection of 22 pathogens in NP/OP swabs and 12 pathogens in blood specimens as well as two control reactions (internal positive control and human nucleic acid control) for each specimen type. The cumulative improvements realized through these optimization studies will benefit ANISA and perhaps other studies utilizing multiple-pathogen detection approaches. These lessons may also contribute to the expansion of TAC technology to the clinical setting.


Binding of p23 and hsp90 during assembly with the progesterone receptor.
Upon incubation in rabbit reticulocyte lysate, the unactivated progesterone receptor (PR) associates with the heat shock proteins hsp90 and hsp70, the immunophilins FKBP52, FKBP54, and CyP-40, and another protein p23. We have previously described a protein complex between p23, hsp90, and the immunophilins that forms in rabbit reticulocyte lysate in the absence of the PR. Immunodepletion of p23 from lysate prevented the binding of hsp90 and CyP-40 to the PR, suggesting that hsp90, CyP-40, and p23 bind the receptor as a complex. We have further examined the properties of this p23 complex to determine how it is involved in receptor assembly in vitro. Use was made of three chemical probes, sodium molybdate, the nonhydrolyzable ATP analog, 5'-adenylylimidodiphosphate, and the hsp90-binding agent geldanamycin. Molybdate has previously been shown to stabilize the heat-induced dissociation of hsp90 and p23 from the PR. This stabilization is not mediated through the PR, as molybdate stabilizes the heat-induced dissociation of hsp90 from p23 even in the absence of the PR. Molybdate also stabilizes both p23 and PR complexes under conditions of low ATP and magnesium concentration. The ATP analog, 5'-adenylylimidodiphosphate, which does not support the assembly of PR complexes, promotes both the assembly and stabilization of p23 complexes. Geldanamycin disrupts p23 complexes, and when PR complexes are treated with this agent, p23, CyP-40, and some hsp90 are lost from the receptor. Thus, all three of these chemical agents appear to target the p23 complex, which is thought to enter at the last step in the assembly of the PR complex. A model is presented to relate these findings to previous models and another complex between hsp90, hsp70, and p60 that appears to be an intermediate in PR assembly.


Human Parvovirus Infection of Human Airway Epithelia Induces Pyroptotic Cell Death by Inhibiting Apoptosis.
Human bocavirus 1 (HBoV1) is a human parvovirus that causes acute respiratory tract infections in young children. In this study, we confirmed that, when polarized/well-differentiated human airway epithelia are infected with HBoV1 in vitro, they develop damage characterized by barrier function disruption and cell hypotrophy. Cell death mechanism analyses indicated that the infection induced pyroptotic cell death characterized by caspase-1 activation. Unlike infections with other parvoviruses, HBoV1 infection did not activate the apoptotic or necroptotic cell death pathway. When the NLRP3-ASC-caspase-1 inflammasome-induced pathway was inhibited by short hairpin RNA (shRNA), HBoV1-induced cell death dropped significantly; thus, NLRP3 mediated by ASC appears to be the pattern recognition receptor driving HBoV1 infection-induced pyroptosis. HBoV1 infection induced steady increases in the expression of interleukin 1α (IL-1α) and IL-18. HBoV1 infection was also associated with the marked expression of the antiapoptotic genes BIRC5 and IFI6 When the expression of BIRC5 and/or IFI6 was inhibited by shRNA, the infected cells underwent apoptosis rather than pyroptosis, as indicated by increased cleaved caspase-3 levels and the absence of caspase-1. BIRC5 and/or IFI6 gene inhibition also significantly reduced HBoV1 replication. Thus, HBoV1 infection of human airway epithelial cells activates antiapoptotic proteins that suppress apoptosis and promote pyroptosis. This response may have evolved to confer a replicative advantage, thus allowing HBoV1 to establish a persistent airway epithelial infection. This is the first report of pyroptosis in airway epithelia infected by a respiratory virus.IMPORTANCE Microbial infection of immune cells often induces pyroptosis, which is mediated by a cytosolic protein complex called the inflammasome that senses microbial pathogens and then activates the proinflammatory cytokines IL-1 and IL-18. While virus-infected airway epithelia often activate NLRP3 inflammasomes, studies to date suggest that these viruses kill the airway epithelial cells via the apoptotic or necrotic pathway; involvement of the pyroptosis pathway has not been reported previously. Here, we show for the first time that virus infection of human airway epithelia can also induce pyroptosis. Human bocavirus 1 (HBoV1), a human parvovirus, causes lower respiratory tract infections in young children. This study indicates that HBoV1 kills airway epithelial cells by activating genes that suppress apoptosis and thereby promote pyroptosis. This strategy appears to promote HBoV1 replication and may have evolved to allow HBoV1 to establish persistent infection of human airway epithelia.


Serological response to influenza vaccine after hematopoetic stem cell transplantation.
Vaccination is the best strategy to prevent influenza infection that is a potential cause of morbidity and mortality in immunosuppressed patients. Here, we evaluated the factors that may affect serological response to influenza vaccine in patients who have undergone hematopoetic stem cell transplantation (HSCT). Sixty-one HSCT recipients were included in the study during the 2007-2008 influenza season. Serum samples prior to vaccination and 6-10 weeks after vaccination were collected. Samples were assayed for antibodies to influenza virus A/H1N1, A/H3N2, and B strains by hemagglutination-inhibition assay. The patients were followed in terms of clinical symptoms up to the next influenza season and for adverse effects within a month after vaccination. Overall, pre-vaccine seroprotection rate against all vaccine antigens (A/H1N1, A/H3N2, and B antigens) was 45.1%, post-vaccine seroprotection rate 91% and seroconversion rate was 28.3%. Seroconversion rates were found to be low against B in patients who were vaccinated in the late influenza season (p = 0.018; respectively). Five patients (10.9%) had no immune response against H1N1. Adverse events were reported in 19.6% (n = 9/46) of the patients. In conclusion, the patients should be vaccinated as early as possible in the influenza season, before they are exposed to the virus.


Limulus rhodopsin: rapid return of transient intermediates to the thermally stable state.
Spectral transitions of rhodopsin in single cells of the Limulus ventral eye were observed both with flash photometry and by measuring the early receptor potential. Even with repetitive stimulus flashes the rhodopsin did not bleach; after each flash the spectral intermediates decayed rapidly to the initial thermally stable state. The pigment returns to the stable state in a time comparable with the duration of the late receptor potential.


Cloning of novel trinucleotide-repeat (CAG) containing genes in mouse brain.
CAG trinucleotide repeat (CTR) sequence often appears in mammalian genome including transcription-regulatory protein and homeobox genes. Its expansion is associated with six genetic disorders in human. To identify novel CTR-containing genes expressed in mouse brain, a brain cDNA library was screened using an oligonucleotide, (CTG)10. Eight clones were novel mouse genes and they were sequenced on both strands. The size of the cloned DNA ranged from 0.5 to 2.1 kb. The number of the CAG repeats in the clones ranged from 6 to 25. The inserts of the clones were analyzed for open reading frames and the peptide sequences were used for a GenBank homology search. Of the clones, one (CAG-6) shared 13 consecutive identical amino acid residues with the OB-cadherin gene, a member of cadherin family. CAG-14 showed high homology (657 nucleotides identity in 1022 nucleotides; 64%) with the 3'-untranslated region of rat leukocyte common antigen-related (LAR) tyrosine phosphatase receptor. All the 8 clones were originated from mouse DNA as judged by Southern blot analysis of mouse genomic DNA. The expression of the clones in mouse brain was addressed by RT-PCR and 4 clones showed specific expression.


Inhibition of human natural killer cell activity by a synthetic peptide homologous to a conserved region in the retroviral protein, p15E.
It has been shown previously that the retroviral envelope protein p15E suppresses certain monocyte and lymphocyte functions. In this paper, we describe the effects on natural killer (NK) activity of a synthetic peptide (CKS-17) with homology to a region of p15E conserved among numerous retroviruses. Enriched human NK cells were assayed against K562 tumor target cells in a 51Cr-release cytotoxicity assay. Pretreatment of NK cells with CKS-17 at concentrations as low as 1.5 microM, but not with equivalent concentrations of control materials, markedly and reproducibly suppressed NK lytic activity. Prior exposure of NK cells to interferon-alpha (IFN-alpha) at 1000 U/ml did not alter their sensitivity to CKS-17-induced inhibition. Pretreating NK cells with CKS-17 almost entirely diminished their responsiveness to IFN-alpha and IFN-gamma, but not to interleukin 2 (IL 2). Kinetics experiments demonstrated that CKS-17-mediated suppression of both endogenous and activated NK cells was reversible after 18 hr at 37 degrees C. Experiments designed to examine the CKS-17 mechanism of action revealed that the peptide bound to all Leu-11+ lymphocytes, as shown by two-color flow cytometry. CKS-17 did not, however, inhibit effector cell/target cell conjugate formation. These data suggest a new mechanism for immune suppression mediated by retroviruses; inhibition of NK function. They moreover imply that the CKS-17 peptide interferes with the lytic phase of NK cytolysis.


Compacting oblivious agents on dynamic rings.
In this paper we investigate dynamic networks populated by autonomous mobile agents. Dynamic networks are networks whose topology can change continuously, at unpredictable locations and at unpredictable times. These changes are not considered to be faults, but rather an integral part of the nature of the system. The agents can autonomously move on the network, with the goal of solving cooperatively an assigned common task. Here, we focus on a specific network: the unoriented ring. More specifically, we study 1-interval connected dynamic rings (i.e., at any time, at most one of the edges might be missing). The agents move according to the widely used Look-Compute-Move life cycle, and can be homogenous (thus identical) or heterogenous (agents are assigned colors from a set of c > 1 colors). For identical agents, their goal is to form a compact segment, where agents occupy a continuous part of the ring and no two agents occupy the same node: we call this the Compact Configuration Problem. In the case of agents with colors, called the Colored Compact Configuration Problem, the goal is to group agents such that each group is formed by all agents having the same color, it occupies a continuous segment of the network, and groups of agents having different colors occupy distinct areas of the network. In this paper we determine the necessary conditions to solve both proposed problems. For all solvable cases, we provide algorithms for both the monochromatic and the colored version of the compact configuration problem. All our algorithms work even for the simplest model where agents have no persistent memory, no communication capabilities and do not agree on a common orientation within the network. To the best of our knowledge this is the first work on the compaction problem in a dynamic network.


Temperature prediction using fuzzy time series.
A drawback of traditional forecasting methods is that they can not deal with forecasting problems in which the historical data are represented by linguistic values. Using fuzzy time series to deal with forecasting problems can overcome this drawback. In this paper, we propose a new fuzzy time series model called the two-factors time-variant fuzzy time series model to deal with forecasting problems. Based on the proposed model, we develop two algorithms for temperature prediction. Both algorithms have the advantage of obtaining good forecasting results.


Epidemiological evaluation of cat health at a first-response animal shelter in Fukushima, following the Great East Japan Earthquakes of 2011.
The Great East Japan Earthquakes of March 11, 2011 caused immense harm to the community and subsequent nuclear accident in Fukushima Prefecture extended the damage. Local residents were forced to evacuated without pets and the left behind animals were rescued from the restricted zone one month later. Unplanned animal rescue and unregulated sheltering caused secondary damage to animals such as disease epidemics at impounded animal shelter. The purpose of this study was to retrospectively evaluate the incidence of upper respiratory infection (URI) and diarrhea in cats at the first response animal shelter in Fukushima, and investigate factors affecting the duration of disease and determinants of treatments performed. Eighty percent and 59% of impounded cats developed URI, 71% and 54% of cats developed diarrhea, and 91% and 83% of cats had at least one disease in 2011 and 2012, respectively. Uses of multiple drug administration (more than five drugs) was associated with prolonged URI and diarrhea. Multiple antibiotics, antihistamines, interferon, and steroids were associated with relapse of and prolonged URI. Developing a standardized treatment protocol for commonly observed diseases at Japanese animal shelters to prevent and control diseases, to promote animal welfare, and protect public health in the face of future disasters is overdue.


[Intelligence and school success in 16-year-old risk children and in a control group].
Report about part--results of a longterm follow-up--study with 123 sixteenged risk--children, which were treated with an exchange transfusion because of hemolytic disease in newborn age. The control group was paralleled to social--demographic criteria. Before all biological and social factors of influence the parental education and qualification level was the most influential social determinant on the development of intelligence and school-achievement. 33,3% of the risk group and 15,5% of the control group did not reach the 10th form of the polytechnical school according to their age.


Spread of murine cytomegalovirus to inner ocular structures following disruption of the blood-retina barrier in immunosuppressed BALB/c mice.
The aims of this study were to determine whether disruption of the blood-retina barrier (BRB) increases spread of murine cytomegalovirus (MCMV) to the eye after intraperitoneal inoculation and whether systemic immunosuppression influences the location of MCMV in the ocular compartment. The BRB of the left eye of normal and immunosuppressed mice was disrupted by supraciliary inoculation of tissue culture medium followed 2 hours later by intraperitoneal injection of MCMV. Plaque assay of homogenized ocular tissue was used to determine the frequency of virus-positive eyes and the titer of virus in the eyes. Beta-galactosidase staining of frozen sections was used to locate virus in the eyes. In nonimmunosuppressed mice, the frequency of virus isolation, as well as the titer of virus, were significantly higher in eyes in which the BRB had been disrupted. Although the frequency of virus isolation was the same in both eyes of immunosuppressed mice, the titer of virus was significantly higher in the eye in which the BRB had been disrupted. The most striking result was that the location of virus was different in the nondisrupted eyes of immunosuppressed mice than it was in the disrupted eyes of immunosuppressed mice. In the former, virus was seen only in the outer ocular structures (conjunctiva, sclera, lacrimal gland), whereas in the latter, virus was observed in the retina and anterior segment (iris, ciliary body) as well as the outer ocular structures. The results of these studies suggest that ocular damage followed by increased spread of virus to and within the eye during systemic infection with CMV may be one mechanism by which development of CMV retinitis is facilitated in patients with acquired immune deficiency syndrome.


Embedded performance validity testing in neuropsychological assessment: Potential clinical tools.
The article aims to suggest clinically-useful tools in neuropsychological assessment for efficient use of embedded measures of performance validity. To accomplish this, we integrated available validity-related and statistical research from the literature, consensus statements, and survey-based data from practicing neuropsychologists. We provide recommendations for use of 1) Cutoffs for embedded performance validity tests including Reliable Digit Span, California Verbal Learning Test (Second Edition) Forced Choice Recognition, Rey-Osterrieth Complex Figure Test Combination Score, Wisconsin Card Sorting Test Failure to Maintain Set, and the Finger Tapping Test; 2) Selecting number of performance validity measures to administer in an assessment; and 3) Hypothetical clinical decision-making models for use of performance validity testing in a neuropsychological assessment collectively considering behavior, patient reporting, and data indicating invalid or noncredible performance. Performance validity testing helps inform the clinician about an individual's general approach to tasks: response to failure, task engagement and persistence, compliance with task demands. Data-driven clinical suggestions provide a resource to clinicians and to instigate conversation within the field to make more uniform, testable decisions to further the discussion, and guide future research in this area.


More than redox, biological organic ligands control iron isotope fractionation in the riparian wetland.
Although redox reactions are recognized to fractionate iron (Fe) isotopes, the dominant mechanisms controlling the Fe isotope fractionation and notably the role of organic matter (OM) are still debated. Here, we demonstrate how binding to organic ligands governs Fe isotope fractionation beyond that arising from redox reactions. The reductive biodissolution of soil Fe(III) enriched the solution in light Fe isotopes, whereas, with the extended reduction, the preferential binding of heavy Fe isotopes to large biological organic ligands enriched the solution in heavy Fe isotopes. Under oxic conditions, the aggregation/sedimentation of Fe(III) nano-oxides with OM resulted in an initial enrichment of the solution in light Fe isotopes. However, heavy Fe isotopes progressively dominate the solution composition in response to their binding with large biologically-derived organic ligands. Confronted with field data, these results demonstrate that Fe isotope systematics in wetlands are controlled by the OM flux, masking Fe isotope fractionation arising from redox reactions. This work sheds light on an overseen aspect of Fe isotopic fractionation and calls for a reevaluation of the parameters controlling the Fe isotopes fractionation to clarify the interpretation of the Fe isotopic signature.


Birth Control Sabotage Motivation and Measurement: A Mixed-Methods Analysis among Latina Women.
Reproductive coercion (RC) is a type of intimate partner violence that includes birth control sabotage (BCS). We explored the perceived intent behind BCS to refine RC measurement, using a mixed-methods design with a clinic-based sample of Latina women (13 interviews; 482 surveys). Women perceived partners used BCS for reasons beyond pregnancy promotion. Specifically, 16.8% of participants reported any past-year RC; this decreased to 9.5% when asked if their partner used BCS with the sole intent of getting them pregnant. RC measures and assessment should separate behavior from intent in BCS questions to not underestimate the prevalence and to guide clinical response.


Renal denervation in the management of resistant hypertension: current evidence and perspectives.
Catheter-based renal denervation has emerged as a novel treatment modality for resistant hypertension. This review summarizes the current evidence on this procedure in treatment of resistant hypertension, limitations of available evidence and questions to be answered. The SYMPLICITY studies showed that renal denervation is feasible in treating resistant hypertension, but failed to provide conclusive evidence on the size and durability of the antihypertensive, renal and sympatholytic effects, as well as the long-term safety. The definition of resistant hypertension was loose in the SYMPLICITY studies and the management of resistant hypertension was suboptimal. Future studies should have a randomized design and enroll truly resistant hypertension patients by excluding secondary hypertension, white-coat hypertension and nonadherent patients. Questions to be addressed by the ongoing and future trials include the long-term efficacy and safety of this procedure, identification of responders and uncovering of the underlying mechanisms. Only well-designed, randomized clinical trials addressing the limitations of the SYMPLICITY studies will be able to demonstrate whether renal denervation is an efficacious treatment modality in resistant hypertension and in which patients. For now, renal denervation remains an experimental procedure and should only be offered to truly resistant hypertensive patients in a research context after careful selection.


Roles of mental health professionals in multidisciplinary medically supervised treatment programs for obesity.
Excess weight is a major medical problem for more than one third of Americans and, after cigarette smoking, is the second largest cause of death. However, obesity treatments remain controversial, and only surgical therapies have patient volume and appropriate follow-up adequate to prove effectiveness. National Institutes of Health conferences on obesity treatments and the Institute of Medicine have suggested that all obesity treatment programs, including those which are medically supervised, should be multidisciplinary, involving professionals from the behavioral, nutritional, and exercise fields to facilitate delivery of a patient-treatment matching strategy. There are no models to suggest how these recommendations should be accomplished or whether they are financially feasible. We present a case management model that includes psychotherapists in a multidisciplinary obesity treatment program. More data are needed to show whether these suggestions improve cost-effectiveness of obesity treatments.


[Value of surgery in the palliative therapy for rectal cancer].
The treatment of advanced rectal cancer is a complicated task that can only poorly be reduced to the simple question "to operate or not to operate?" Instead the following factors must be taken into consideration: symptomatic versus non-symptomatic patients, emergency surgery versus elective surgery, proximal versus distal rectal cancer, local advanced versus metastatic disease, primary tumour versus recurrence, unresectable versus potentially resectable metastases, resection versus diversionary surgical procedures, etc. Also within the conservative group one must decide between interventional therapy (combined chemotherapy, stent placement, radiotherapy, etc.) and purely palliative therapy. Results from studies are not sufficient for the formulation of general recommendations. However, there are only few arguments against a surgical procedure in a symptomatic situation when the primary tumour dominates. In cases of metastasizing colorectal cancer modern chemotherapeutic procedures and new antibody therapies can markedly prolong survival. These results cannot be achieved by surgery alone. In this situation, it should be considered whether the longer life expectancy will be accompanied by the later occurrence of symptoms, which again justifies a surgical indication within the framework of multimodality therapy. The widely differing starting situations lead to different therapeutic approaches so that an individual indication can be made in the course of a tumour board discussion.


Modulation of Oxidative Status by Normoxia and Hypoxia on Cultures of Human Dermal Fibroblasts: How Does It Affect Cell Aging?
Reactive oxygen species (ROS) production in the skin is among the highest compared to other organs, and a clear correlation exists between ROS production and skin aging. Many attempts are underway to reduce oxidative stress in the skin by topical treatment or supplementation with antioxidants/cosmeceuticals, and cultures of human dermal fibroblasts (HDF) are widely used for these studies. Here, we examined the influence of oxygen tension on cell aging in HDF and how this impacted ROS production, the enzymatic and nonenzymatic antioxidant response system, and the efficacy of this defense system in limiting DNA damage and in modulating gene expression of proteins involved in the extracellular matrix, linked to skin aging. We investigated a selection of parameters that represent and reflect the behavior of cellular responses to aging and oxygen tension. Serial passaging of HDF under normoxia (21%) and hypoxia (5%) leads to cell aging as confirmed by β-galactosidase activity, p16 expression, and proliferation rate. However, in HDF under 21% O2, markers of aging were significantly increased compared to those under 5% O2 at matched cell passages despite having lower levels of intracellular ROS and higher levels of CoQ10, total GSH, SOD1, SOD3, and mitochondrial superoxide anion. miRNA-181a, which is known to be upregulated in HDF senescence, was also analyzed, and indeed, its expression was significantly increased in old cells at 21% O2 compared to those at 5% O2. Upregulation of MMP1 and downregulation of COL1A1 along with increased DNA damage were also observed under 21% O2 vs 5% O2. The data highlight that chronic exposure to atmospheric 21% O2 is able to trigger hormetic adaptive responses in HDF that however fail, in the long term, to prevent cellular aging. This information could be useful in further investigating molecular mechanisms involved in adaptation of skin fibroblasts to oxidative stress and may provide useful hints in addressing antiaging strategies.


Inhibition of platelet aggregation by combined therapy with aspirin and cilostazol after off-pump coronary artery bypass surgery.
Although off-pump coronary artery bypass (OPCAB) has become an increasingly common surgical procedure, recent concerns have been raised regarding the existence of a hypercoagulable or prothrombotic state associated with OPCAB. To determine the optimal antiplatelet regimen after OPCAB, we investigated the effects of aspirin alone and of combined therapy with aspirin + cilostazol on platelet aggregation in patients after OPCAB. Twenty patients scheduled to undergo OPCAB were randomized to one of two antiplatelet regimens: aspirin alone (n=10) and aspirin + cilostazol (n=10). Anti-platelet agents had not been received for at least 1 week before surgery and were initiated on the afternoon of postoperative day 1. Platelet aggregability and hemostatic parameters were evaluated at four time points: before and 3, 7, and 14 days after OPCAB. We measured agonist-and shear stress-induced platelet aggregation (SIPA) using a modified cone-plate viscometer. No complications resulting from postoperative antiplatelet therapy-related bleeding were seen in either group. Collagen-and arachidonate-induced platelet aggregation and SIPA were significantly inhibited in the aspirin + cilostazol group compared with the aspirin-alone group (collagen-and arachidonate-induced aggregation, p<0.0001; SIPA, p=0.0367). Adding cilostazol to aspirin augmented the inhibitory effects on platelet aggregation induced by collagen and arachidonate. adenosine diphosphate (ADP)-induced platelet aggregation tended to be inhibited in the aspirin + cilostazol group compared with the aspirin-alone group (p=0.0534). The results of this study suggest that combined therapy with aspirin + cilostazol is more effective than aspirin monotherapy in reducing platelet aggregation in patients after OPCAB. This combination therapy may represent a new therapeutic option for an anti-thrombotic regimen in patients after OPCAB.


Efficacy of oral irinotecan against neuroblastoma xenografts.
The efficacy of the topoisomerase I inhibitor, 7-ethyl-10-(4-[1-piperidino]-1-piperidino)-carbonyloxy-camptotheci n (irinotecan, CPT-11), administered by oral gavage has been examined against a panel of six independently derived neuroblastoma xenografts. Irinotecan was administered either daily for 5 days on 12 consecutive weeks ¿(d x 5)12¿ or for 5 days on two consecutive weeks repeated every 21 days for 4 cycles ¿[(d x 5)2]4¿. Given on the (d x 5)12 schedule the maximum tolerated dose (MTD) was 50 mg/kg. For intermittent scheduling ¿[(d x 5)2]4¿, the MTD was 75 mg/kg, resulting in the same total dose being administered (3 g/kg) over the period of treatment. At the MTD for the 12 consecutive week schedule there were two of 42 toxicity related deaths, whereas intermittent scheduling at the MTD resulted in none of 42 deaths. The intermittent schedule ¿[(d x 5)2]4¿ was less toxic than therapy given (d x 5)12, as at the end of treatment mice weighed 92 +/- 4% (SD; n = 6 experiments) and 81 +/- 4% (SD; n = 6 experiments) of their body weight at the start of therapy, respectively. The latter schedule was associated with loose feces starting around week 8 of therapy, broken teeth and a high incidence of swelling of the orbital conjunctiva that developed late in the course of therapy. Given (d x 5)12, irinotecan caused complete regressions of all six neuroblastoma xenograft lines. Because mice tolerate significantly greater systemic exposure to SN-38 lactone than do patients (as determined by plasma AUC at the respective MTD), we evaluated the intermittent schedule of administration, reducing the dose/administration to determine the lowest dose levels that produced objective regressions of these neuroblastoma xenografts and determined the daily systemic exposure associated with these dose levels. In four lines examined objective responses were obtained at dose levels of 12.5 or 6.25 mg/kg. The daily plasma AUC exposures associated with minimum dose achieving response in NB1691 (12.5 mg/kg), NB1643 (6.25 mg/kg) and NBEB (12.5 mg/kg) for irinotecan lactone were 219, 152 and 653 ng-h/ml, respectively; and for SN-38 lactone were 704, 418 and 987 ng-h/ml, respectively. These results indicate that childhood neuroblastoma xenografts are highly sensitive to irinotecan given by oral administration and therapeutic activity is similar to i.v. irinotecan administered on similar schedules.


Hyperactivity and impaired attention in Gamma aminobutyric acid transporter subtype 1 gene knockout mice.
Attention-deficit hyperactivity disorder (ADHD) is a common neurobehavioural disorder. It is conceivable that Gamma aminobutyric acid (GABA) neurotransmission is implicated in the pathophysiology of ADHD. This study investigated the effect of GABA transporter 1 (GAT-1) on the anxiety-like behaviours and cognitive function in knockout mice. In all, 20 adult male mice were divided into two groups: wild-type (WT) group and GAT-1-/- group. The open field test, elevated O-maze (EZM) and Morris water maze were used to evaluate behavioural traits relevant to ADHD. Compared with WT mice, the GAT-1-/- mice travelled longer and displayed an enhanced kinematic velocity with the significant reduction of rest time in the open field test (p<0.05). The EZM showed that GAT-1-/- mice displayed a significant increase in total entries into the open sectors and the closed sectors compared with the WT mice. The WT mice showed shorter latencies after the training session (p<0.01), whereas the GAT-1-/- mice made no difference during probe test, the GAT-1-/- mice spent less time in the target quadrant (p<0.01). Our results demonstrated that GAT-1-/- mice have phenotypes of hyperactivity, impaired sustained attention and learning deficiency, and the performance of GAT-1-/- mice is similar to ADHD symptoms. So, the study of the GAT-1-/- mice may provide new insights into the mechanisms and the discovery of novel therapeutics for the treatment of ADHD.


Primary lever masses in infants.
Sixteen primary liver masses in infants less than 2 years of age collected from four centers over 12 years included six hepatoblastomas, five benign vascular tumors, three amebic abscesses, a simple hepatic cyst and a calcified cystic hematoma. The diagnostic features of the various lesions are reviewed and the efficient use of the different imaging modalities is discussed. Modern ultrasound techniques offer a diagnostic short-cut in the investigation of primary liver masses in infants and should be done early.


Cholestasis and behavioral disorders.
Acute and chronic failure in liver function may give rise to cognitive and non-cognitive impairments in the brain, namely hepatic encephalopathy (HE). Liver diseases may cause cholestasis, which is defined as the impaired secretion of bile. It is characterized by the accumulation of substances in plasma that are normally excreted in bile such as bile acids. Cholestasis can lead to hepatic encephalopathy. Several investigations have indicated that HE induces several symptoms, such as the impairment of learning and memory, anxiolytic-like behaviors, alterations in sleep pattern, and tremors. It has been reported that after HE, all classical neurotransmitter systems such as opioidergic, dopaminergic, cholinergic, GABAergic, adrenergic, serotonergic, and glutamatergic systems can be altered. This review focuses on cholestasis, hepatic encephalopathy, and behavioral disorders.


An Enhancement-focused framework for developing high quality single best answer multiple choice questions.
The primary goal of any assessment of students is to provide valid and reliable evaluations of students' knowledge and skills as well as provision of accurate feedback to students about their performance. Contrary to best practice guidelines for development of multiple choice questions (MCQs), however, items used within medical schools are often flawed. This disappoints students and discourages examiners from using in-house MCQ databases. Vetting and reviewing items can improve the quality of MCQs. In this paper, we describe our approach to standardize the format used for MCQ assessment and provide recommendations for quality enhancement of high-stakes assessment. A collaborative enhancement-focused vetting and review approach to development of high quality single best answer MCQs has been described. Implementation of a collaborative strategy to blueprint, vet, review and standard set MCQ items for high stakes examinations can effectively contribute to assessment quality assurance. Similarly, shared responsibility for post examination analyses of items may reveal the psychometric properties of items in need of improvement and contribute to closure of the assessment outcomes feedback loop. Devolving responsibility for implementation of assessment processes as an integral part of educational practices and values can maximize reliability and standards of assessment processes. We contend that while logistics and time constraints are of concern to busy faculty members, judicious utilization of resources to develop well-written MCQ items are well worth the effort to produce reliable and valid examinee scores. An enhancement-focused approach can be institutionally rewarding and lead to improved quality of high stakes assessments.


Respiratory distress in heavier versus lighter twins.
We performed a retrospective study of twin pairs under 36 weeks gestation admitted to a regional neonatal unit over a three year period to determine if the larger twin of a twin pair is at increased risk of respiratory distress in the immediate postnatal period compared to the smaller twin. Gestation, gender, birth weight, mode and reason for delivery, birth order, and Apgar at 5 minutes were correlated with the need for added oxygen at 4 hours, the need for ventilation, oxygen requirement at 28 days and mortality. One hundred and twenty-four twin pairs were analyzed with a median gestation of 31 weeks (range 23-35). There were 47 female-female pairs, 40 male-male pairs and 37 mixed pairs. Multiple logistic regression revealed no significant increased risk for ventilation in male, heavier or second twins. The need for oxygen at 4 hours was strongly associated with being male and being the second twin, but not with being the heavier twin. However, on analysis of twins of 28 weeks gestation or above a significant association was found between a persisting oxygen requirement at 4 hours and being male (OR 2.2; 95% CI 1.15-4.16), being the heavier twin (OR 1.9; 95% CI 1.03-3.46), and being the second twin (OR 2.7; 95% CI 1.48-4.99). No association was found between mortality and being male, and being the second or smaller twins. Heavier twins above 28 weeks gestation are at increased risk of short term mild respiratory problems following delivery compared to lighter twins at the same gestation. This is not as strong a factor as birth order or male gender, but it is important to be aware of this in antenatal counselling of the parents as the smaller twin is usually perceived to be at greater risk of morbidity.


64Cu-TETA-octreotide as a PET imaging agent for patients with neuroendocrine tumors.
64Cu (half-life, 12.7 h; beta+, 0.653 MeV [17.4%]; beta-, 0.579 MeV [39%]) has shown potential as a radioisotope for PET imaging and radiotherapy. (111)In-diethylenetriaminepentaacetic acid (DTPA)-D-Phe1-octreotide (OC) was developed for imaging somatostatin-receptor-positive tumors using conventional scintigraphy. With the advantages of PET over conventional scintigraphy, an agent for PET imaging of these tumors is desirable. Here, we show that 64Cu-TETA-OC (where TETA is 1,4,8,11-tetraazacyclotetradecane-N,N',N'',N'''-tetraacetic acid) and PET can be used to detect somatostatin-receptor-positive tumors in humans. Eight patients with a history of neuroendocrine tumors (five patients with carcinoid tumors and three patients with islet cell tumors) were imaged by conventional scintigraphy with (111)In-DTPA-OC (204-233 MBq [5.5-6.3 mCi]) and by PET imaging with 64Cu-TETA-OC (111 MBq [3 mCi]). Blood and urine samples were collected for pharmacokinetic analysis. PET images were collected at times ranging from 0 to 36 h after injection, and the absorbed doses to normal organs were determined. In six of the eight patients, cancerous lesions were visible by both (111)In-DTPA-OC SPECT and 64Cu-TETA-OC PET. In one patient, (111)In-DTPA-OC showed mild uptake in a lung lesion that was not detected by 64Cu-TETA-OC PET. In one patient, no tumors were detected by either agent; however, pathologic follow-up indicated that the patient had no tumors. In two patients whose tumors were visualized with (111)In-DTPA-OC and 64Cu-TETA-OC, 64Cu-TETA-OC and PET showed more lesions than (111)In-DTPA-OC. Pharmacokinetic studies showed that 64Cu-TETA-OC was rapidly cleared from the blood and that 59.2% +/- 17.6% of the injected dose was excreted in the urine. Absorbed dose measurements indicated that the bladder wall was the dose-limiting organ. The high rate of lesion detection, sensitivity, and favorable dosimetry and pharmacokinetics of 64Cu-TETA-OC indicate that it is a promising radiopharmaceutical for PET imaging of patients with neuroendocrine tumors.


Monitoring activities of daily living of the elderly and the potential for its use in telecare and telehealth: a review.
This review was designed to determine whether telemonitoring activities of daily living (ADL) of elderly people can improve quality of life and be beneficial to their healthcare. Electronic databases were searched for studies that monitored ADL of elderly people and preferably measured some clinical outcomes such as ability to predict key events that require intervention and for studies that assessed perception of elderly people of such telemonitoring systems. The articles were reviewed and assessed independently by two reviewers. One hundred seventy-five unique studies were found. Sixty-seven of these were identified for potential inclusion, and 25 studies were finally included. Study characteristics, parameters monitored, outcomes, and problems encountered were summarized and discussed. The main focus was on the potential benefits of ADL monitoring on the care of elderly people. Although most studies reported on technical improvements in methods for detecting changes in ADL, few, if any, determined the benefits to the patient of telemonitoring for changes in ADL or correlation with any physiological changes. We propose sensor and system characteristics for improved user acceptance and deployment in a large-scale care plan. We present areas requiring further investigation.


Symbol Emergence as an Interpersonal Multimodal Categorization.
This study focuses on category formation for individual agents and the dynamics of symbol emergence in a multi-agent system through semiotic communication. In this study, the semiotic communication refers to exchanging signs composed of the signifier (i.e., words) and the signified (i.e., categories). We define the generation and interpretation of signs associated with the categories formed through the agent's own sensory experience or by exchanging signs with other agents as basic functions of the semiotic communication. From the viewpoint of language evolution and symbol emergence, organization of a symbol system in a multi-agent system (i.e., agent society) is considered as a bottom-up and dynamic process, where individual agents share the meaning of signs and categorize sensory experience. A constructive computational model can explain the mutual dependency of the two processes and has mathematical support that guarantees a symbol system's emergence and sharing within the multi-agent system. In this paper, we describe a new computational model that represents symbol emergence in a two-agent system based on a probabilistic generative model for multimodal categorization. It models semiotic communication via a probabilistic rejection based on the receiver's own belief. We have found that the dynamics by which cognitively independent agents create a symbol system through their semiotic communication can be regarded as the inference process of a hidden variable in an interpersonal multimodal categorizer, i.e., the complete system can be regarded as a single agent performing multimodal categorization using the sensors of all agents, if we define the rejection probability based on the Metropolis-Hastings algorithm. The validity of the proposed model and algorithm for symbol emergence, i.e., forming and sharing signs and categories, is also verified in an experiment with two agents observing daily objects in the real-world environment. In the experiment, we compared three communication algorithms: no communication, no rejection, and the proposed algorithm. The experimental results demonstrate that our model reproduces the phenomena of symbol emergence, which does not require a teacher who would know a pre-existing symbol system. Instead, the multi-agent system can form and use a symbol system without having pre-existing categories.


The gut and the skin.
Many disorders of the gastrointestinal tract have cutaneous manifestations. In this article the skin signs and diseases that are most commonly associated with gastrointestinal disease are described.


Maximal exercise and muscle oxygen extraction in acclimatizing lowlanders and high altitude natives.
The tight relation between arterial oxygen content and maximum oxygen uptake (Vv(o2max)within a given person at sea level is diminished with altitude acclimatization. An explanation often suggested for this mismatch is impairment of the muscle O(2) extraction capacity with chronic hypoxia, and is the focus of the present study. We have studied six lowlanders during maximal exercise at sea level (SL) and with acute (AH) exposure to 4,100 m altitude, and again after 2 (W2) and 8 weeks (W8) of altitude sojourn, where also eight high altitude native (Nat) Aymaras were studied. Fractional arterial muscle O(2) extraction at maximal exercise was 90.0+/-1.0% in the Danish lowlanders at sea level, and remained close to this value in all situations. In contrast to this, fractional arterial O(2) extraction was 83.2+/-2.8% in the high altitude natives, and did not change with the induction of normoxia. The capillary oxygen conductance of the lower extremity, a measure of oxygen diffusing capacity, was decreased in the Danish lowlanders after 8 weeks of acclimatization, but was still higher than the value obtained from the high altitude natives. The values were (in ml min(-1) mmHg(-1)) 55.2+/-3.7 (SL), 48.0+/-1.7 (W2), 37.8+/-0.4 (W8) and 27.7+/-1.5 (Nat). However, when correcting oxygen conductance for the observed reduction in maximal leg blood flow with acclimatization the effect diminished. When calculating a hypothetical leg V(o2max)at altitude using either the leg blood flow or the O(2) conductance values obtained at sea level, the former values were almost completely restored to sea level values. This would suggest that the major determinant V(o2max)for not to increase with acclimatization is the observed reduction in maximal leg blood flow and O(2) conductance.


Na+/H+ exchange activity and NHE-3 expression in renal tubules from the spontaneously hypertensive rat.
The NHE-3 isoform of the Na+/H+ antiporter, in the apical membrane of renal proximal tubule, is responsible for the bulk transport of Na+ and fluid reabsorption. Studies have reported that apical NHE-3 translocates to internal pools, thereby facilitating natriuresis when blood pressure increases abruptly. The present study examined Na+/H+ exchange activity and NHE-3 expression in renal cortical tubules from the spontaneously hypertensive rat (SHR) and WKY rats before and after the development of hypertension. SHR 4 to 6 weeks of age were pre-hypertensive, 6 to 7 weeks old had mild hypertension, and 8 to 13 weeks old had severe hypertension. Renal proximal tubules (PTs) were isolated and purified by Percoll gradient centrifugation. NHE-3 protein and mRNA levels were determined by Western and Northern blots, respectively. Apical brush border membrane vesicles (BBMV) were prepared using the MgSO4 aggregation method and Na+/H+ exchange activity assessed using the acridine orange method. Na+/H+ exchange activity, determined as the rate of Na+-dependent intracellular pH (pHi) recovery assessed using BCECF after an acute acid load, was significantly greater in PTs from SHR than in WKY rats at all age groups (4 to 6 weeks, 0.30 +/- 0.04 vs. 0.24 +/- 0.02 pH U/30 sec, P < 0.05; 6 to 7 weeks, 0.42 +/- 0.07 vs. 0.29 +/- 0.05 pH U/30 sec, P < 0.05; and 8 to 13 weeks, 0.48 +/- 0.07 vs. 0.40 +/- 0.07 pH U/30 sec, P < 0.05). The Na+-dependent recovery in BBMV was also greater in SHR than WKY rats (1464 +/- 62 vs. 1042 +/- 79 fluorescence. U/5 sec, P < 0.001) and was unaffected by cariporide, a specific NHE-1 inhibitor. NHE-3 protein levels also were significantly higher in SHR than age-matched WKY rats at all stages during the development of hypertension (pre-hypertensive 1.8-fold; early onset hypertension twofold; established hypertension 1.5-fold; each P < 0.05). By contrast, NHE-3 mRNA levels were not different between SHR and WKY rats at each age group. Na+/H+ exchange activity and NHE-3 protein abundance in renal proximal tubules from the SHR are increased while NHE-3 mRNA is not. A post-transcriptional event(s) best explains the increase in NHE-3 protein expression since mRNA levels were not increased. The alterations in the SHR antedate the development of hypertension and fail to decrease as blood pressure increases with age in the SHR, which likely results in inappropriate renal sodium retention in the face of a chronic rise in blood pressure.


Implementation of a bundle of quality indicators for the early management of severe sepsis and septic shock is associated with decreased mortality.
The purpose of this study was to examine the outcome implications of implementing a severe sepsis bundle in an emergency department as a quality indicator set with feedback to modify physician behavior related to the early management of severe sepsis and septic shock. Two-year prospective observational cohort. Academic tertiary care facility. Patients were 330 patients presenting to the emergency department who met criteria for severe sepsis or septic shock. Five quality indicators comprised the bundle for severe sepsis management in the emergency department: a) initiate central venous pressure (CVP)/central venous oxygen saturation (Scvo2) monitoring within 2 hrs; b) give broad-spectrum antibiotics within 4 hrs; c) complete early goal-directed therapy at 6 hrs; d) give corticosteroid if the patient is on vasopressor or if adrenal insufficiency is suspected; and e) monitor for lactate clearance. Patients had a mean age of 63.8 +/- 18.5 yrs, Acute Physiology and Chronic Health Evaluation II score 29.6 +/- 10.6, emergency department length of stay 8.5 +/- 4.4 hrs, hospital length of stay 11.3 +/- 12.9 days, and in-hospital mortality 35.2%. Bundle compliance increased from zero to 51.2% at the end of the study period. During the emergency department stay, patients with the bundle completed received more CVP/Scvo2 monitoring (100.0 vs. 64.8%, p < .01), more antibiotics (100.0 vs. 89.7%, p = .04), and more corticosteroid (29.9 vs. 16.2%, p = .01) compared with patients with the bundle not completed. In a multivariate regression analysis including the five quality indicators, completion of early goal-directed therapy was significantly associated with decreased mortality (odds ratio, 0.36; 95% confidence interval, 0.17-0.79; p = .01). In-hospital mortality was less in patients with the bundle completed compared with patients with the bundle not completed (20.8 vs. 39.5%, p < .01). Implementation of a severe sepsis bundle using a quality improvement feedback to modify physician behavior in the emergency department setting was feasible and was associated with decreased in-hospital mortality.


Emergence of a coherent and cohesive swarm based on mutual anticipation.
Collective behavior emerging out of self-organization is one of the most striking properties of an animal group. Typically, it is hypothesized that each individual in an animal group tends to align its direction of motion with those of its neighbors. Most previous models for collective behavior assume an explicit alignment rule, by which an agent matches its velocity with that of neighbors in a certain neighborhood, to reproduce a collective order pattern by simple interactions. Recent empirical studies, however, suggest that there is no evidence for explicit matching of velocity, and that collective polarization arises from interactions other than those that follow the explicit alignment rule. We here propose a new lattice-based computational model that does not incorporate the explicit alignment rule but is based instead on mutual anticipation and asynchronous updating. Moreover, we show that this model can realize densely collective motion with high polarity. Furthermore, we focus on the behavior of a pair of individuals, and find that the turning response is drastically changed depending on the distance between two individuals rather than the relative heading, and is consistent with the empirical observations. Therefore, the present results suggest that our approach provides an alternative model for collective behavior.


[Effects of induction of tubular epithelial-myofibroblast transition by monocyte chemoattractant protein-1 and mechanism thereof: an in vitro experiment].
To examine the effects of monocyte chemoattractant protein-1 (MCP-1) on epithelial-myofibroblast transition (EMT) of renal proximal tubular epithelial cells and the possible mechanism involved. Human renal proximal tubular epithelial cells of the line HK-2 were cultured and divided into three groups: negative control group; positive control group, treated with transforming growth factor (TGF)-beta1 5 microg/L, and MPC-1 group, treated with MCP-1 0.1, 1, 10, and 100 microg/L for 24 h, 36 h, 48 h, and 72 h respectively. The expressions of alpha-smooth muscle actin (alpha-SMA) mRNA and protein of cells were detected by s. Western blotting and RT-PCR were used to detect the expression of P-Erk1/2, Erk1/2, P-P38MAPK, P38MAPK, and RhoA protein levels of the HK-2 cells, and RT-PCR was used to detect the expression of RhoC and Snail mRNA. Specific inhibitors of the Erk, P38MAPK, and Rho signal transduction pathways PD98059, SB203580, and Y27632 were added into the culture fluid of HK-2 cells respectively, 1 h later MCP-1 microg/L was added for 48 h, and Western blotting was used to detect the protein expression of alpha-small muscle actin (SMA). The expression levels of alpha-SMA protein and mRNA significantly increased in the MCP-1 treated HK-2 cells,and these expression levels were the highest in the HK-2 cells treated with MCP-1 1 microg/L for 48 h. The ratios of (P-Erk1/2)/ (Erk1/2) and P-P38MAPK/P38MAPK were significantly increased (all P < 0.05) in the MCP-1 treated HK-2 cells with the highest ratios seen in the HK-2 cells treated by 100 microg/L of MCP-1. The expression levels of RhoA protein and RhoC mRNA of the HK-2 cells stimulated with MCP-1 of different concentrations were not significantly different (all P > 0.05). MCP-1 induced expression of a-SMA was only partly inhibited by PD98059 but not by SB203587 or Y27632. MCP-1 dose-dependently increased the expression of Snail mRNA of the HK-2 cells compared with those of the negative control cells. The level of Snail mRNA was the highest in the HK-2 cells treated with 100 microg/L MCP-1. MCP-1 may induce the EMT of renal proximal tubular epithelial cells in vitro, and this effect may involve upregulation of Erk1/2 Map kinase signal pathways and Snail mRNA expression. P38MAPK or Rho kinase signal pathways can not be proven to be involved in MCP-1 induced EMT.


Efficacy of oral sucralfate suspension in prevention and treatment of chemotherapy-induced mucositis.
The efficacy of orally administered sucralfate suspension in preventing and treating chemotherapy-induced mucositis was evaluated in a double-blind trial. Forty-eight children and adolescents with newly diagnosed acute nonlymphocytic leukemia were randomized to receive suspensions of either sucralfate or placebo orally every 6 hours during the first 10 weeks of intensive remission-induction chemotherapy. Patients given sucralfate suspension were less likely than subjects receiving placebo to acquire colonization with potentially pathogenic microorganisms: 14 (58%) of 24 versus 22 (92%) of 24, respectively (p = 0.008). However, no effect on preexisting colonization was noted. Subjective reporting of discomfort, objective scoring of the severity of mucositis, and the maximal percent of body weight lost during therapy were similar; 58% of patients receiving sucralfate reported no oral pain compared with 25% receiving placebo (p = 0.06). Ten episodes of gastrointestinal bleeding, 25 documented infections, and 886 days with fever were also equally distributed between sucralfate and placebo groups. We conclude that sucralfate suspension is of limited, if any efficacy, in the prevention and treatment of chemotherapy-induced mucositis. Sucralfate administration can, however, reduce acquisition of alimentary colonization with potential pathogens, perhaps by interfering with adherence to mucosal membranes.


[Aspects of solution of the postoperative infection problem in heart surgery].
The study of the incidence and etiological pattern of infectious complications included 376 patients operated for acquired valvular disease. 40,280 bacteriological tests of the materials from the patients obtained during the operations and during the postoperative period as well as 30,113 sanitary bacteriological tests of the specimens from the cardiological operation unit were conducted. The possible use of the results of bacteriological monitoring for prediction of septic complications and optimization of antibiotic prophylaxis and therapy as well as for development and operation of a system of sanitary and hygienic measures for infection prevention was shown and statistically confirmed.


Macrophage activation selectively enhances expression of Fc receptors for IgG2a.
After infection with bacillus Calmette-Guérin, peritoneal macrophages (Mø) display enhanced expression of FcR for both monomeric and complexed IgG2a, but not IgG2b. Isotype specificity of FcR can be reversed on nonactivated Mø by immune lymphokines, and IgG2a immune complexes are more effective triggers of the respiratory burst in activated Mø. Selective enhancement of IgG2a FcR by Mø activation could account for efficacy of homologous ab in mediating cytotoxicity in some systems.


The inner of the two Muc2 mucin-dependent mucus layers in colon is devoid of bacteria.
We normally live in symbiosis with approximately 10(13) bacteria present in the colon. Among the several mechanisms maintaining the bacteria/host balance, there is limited understanding of the structure, function, and properties of intestinal mucus. We now demonstrate that the mouse colonic mucus consists of two layers extending 150 mum above the epithelial cells. Proteomics revealed that both of these layers have similar protein composition, with the large gel-forming mucin Muc2 as the major structural component. The inner layer is densely packed, firmly attached to the epithelium, and devoid of bacteria. In contrast, the outer layer is movable, has an expanded volume due to proteolytic cleavages of the Muc2 mucin, and is colonized by bacteria. Muc2(-/-) mice have bacteria in direct contact with the epithelial cells and far down in the crypts, explaining the inflammation and cancer development observed in these animals. These findings show that the Muc2 mucin can build a mucus barrier that separates bacteria from the colon epithelia and suggest that defects in this mucus can cause colon inflammation.