Problem-solving with MRI in acute abdominopelvic conditions, part 1: gastrointestinal, hepatobiliary, and pancreatic diseases.
The purpose of this article is to review the benefit and added value and advantages of magnetic resonance imaging (MRI) compared with other cross-sectional imaging in patients presenting with abdominopelvic emergencies. During the past decade, there has been increased utilization of MRI in the emergency department with widespread availability of MR scanners, improvement in rapid imaging techniques, and methods to overcome motion-related artifacts. This has benefited patients at higher risk of radiation, particularly children and pregnant women, and patients with contraindications to iodinated contrast including allergy and renal dysfunction. Still the challenges are: on site MR scanner in the emergency department, after-hour services, as well as availability of time slot to rapidly scan emergency patient. MRI has additional advantages over other imaging modalities due to its high contrast resolution, which allows it to better characterize tissue and fluid collections, and may avoid the need for intravenous contrast. Radiologists must be familiar with the role and added value of MRI, spectrum of imaging findings, and problem-oriented modified MR protocols in abdominal and pelvic emergencies. In part 1, we will discuss the utility of MRI in gastrointestinal, hepatobiliary, and pancreatic diseases. In part 2, the authors will focus on the key MR imaging features of female pelvic gynecological diseases, pregnancy related complications, abdominal vascular complications, and renal diseases.


Academic Medicine's Fourth Mission: Building on Community-Oriented Primary Care to Achieve Community-Engaged Health Care.
A 2021 article, "Now is our time to act: Why academic medicine must embrace community collaboration as its fourth mission," by Association of American Medical Colleges (AAMC) authors, including AAMC president and CEO Dr. David J. Skorton, offers 2 aims that are highly related: community collaboration and health equity. The AAMC's call to prioritize community collaboration and health equity as pillars of the academic medicine mission echo earlier work on community-oriented primary care (COPC) and an even more robust model that builds on COPC, community-engaged health care (CEHC). COPC is a tested, systematic approach to health care by which a health clinic or system collaborates with a community to reshape priorities and services based on assessed health needs and determinants of health. COPC affirms health inequities' socioeconomic and political roots, emphasizing health care as a relationship, not a transaction or commodity. Communities where COPC is implemented often see reductions in health inequities, especially those related to socioeconomic, structural, and environmental factors. COPC was the foundation on which community health centers were built, and early models had demonstrable effects on community health and engagement. Several academic health centers build on COPC to achieve CEHC. In CEHC, primary care remains critical, but more of the academic health center's functions are pulled into community engagement and trust building. Thus, the AAMC has described and embraced a care and training model for which there are good, longitudinal examples among medical schools and teaching hospitals. Spreading CEHC and aligning the Community Health Needs Assessment requirements of academic health centers with the fourth mission could go a long way to improving equity, building trust, and repairing the social contract for health care.


Growth and stress response mechanisms underlying post-feeding regenerative organ growth in the Burmese python.
Previous studies examining post-feeding organ regeneration in the Burmese python (Python molurus bivittatus) have identified thousands of genes that are significantly differentially regulated during this process. However, substantial gaps remain in our understanding of coherent mechanisms and specific growth pathways that underlie these rapid and extensive shifts in organ form and function. Here we addressed these gaps by comparing gene expression in the Burmese python heart, liver, kidney, and small intestine across pre- and post-feeding time points (fasted, one day post-feeding, and four days post-feeding), and by conducting detailed analyses of molecular pathways and predictions of upstream regulatory molecules across these organ systems. Identified enriched canonical pathways and upstream regulators indicate that while downstream transcriptional responses are fairly tissue specific, a suite of core pathways and upstream regulator molecules are shared among responsive tissues. Pathways such as mTOR signaling, PPAR/LXR/RXR signaling, and NRF2-mediated oxidative stress response are significantly differentially regulated in multiple tissues, indicative of cell growth and proliferation along with coordinated cell-protective stress responses. Upstream regulatory molecule analyses identify multiple growth factors, kinase receptors, and transmembrane receptors, both within individual organs and across separate tissues. Downstream transcription factors MYC and SREBF are induced in all tissues. These results suggest that largely divergent patterns of post-feeding gene regulation across tissues are mediated by a core set of higher-level signaling molecules. Consistent enrichment of the NRF2-mediated oxidative stress response indicates this pathway may be particularly important in mediating cellular stress during such extreme regenerative growth.


Gene expression profile in pelvic organ prolapse.
It was hypothesized that the processes contributing to pelvic organ prolapse (POP) may be identified by transcriptional profiling of pelvic connective tissue in conjunction with light microscopy. In order to test this, we performed a frequency-matched case-control study of women undergoing hysterectomy for POP and controls. Total RNA, extracted from uterosacral and round ligament samples used to generate labeled cRNA, was hybridized to microarrays and analyzed for the expression of 32 878 genes. Significance Analysis of Microarrays (Stanford University, CA, USA) identified differentially expressed genes used for ontoanalysis. Quantitative PCR (qPCR) confirmed results. Light microscopy confirmed the tissue type and assessed inflammatory infiltration. The analysis of 34 arrays revealed 249 differentially expressed genes with fold changes (FC) larger than 1.5 and false discovery rates < or =5.2%. Immunity and defense was the most significant biological process differentially expressed in POP. qPCR confirmed the elevated steady-state mRNA levels for four genes: interleukin-6 (FC 9.8), thrombospondin 1 (FC 3.5) and prostaglandin-endoperoxide synthase 2 (FC 2.4) and activating transcription factor 3 (FC 2.6). Light microscopy showed all the samples were composed of fibromuscular connective tissue with no inflammatory infiltrates. In conclusion, genes enriched for 'immunity and defense' contribute to POP independent of inflammatory infiltrates.


A Remarkably Reduced Vascular Plant in the United States.
A clone-forming thallus lacking sex organs and propagating by gemmae occurs on rocks and tree trunks in the Appalachian region from Georgia to Virginia, Ohio, and Kentucky. Although bryophytic in appearance, the thallus is identified here for the first time as a greatly reduced variety of the vascular plant known as "shoestring fern," Vittaria lineata (L.) J. E. Smith, or a closely related species. The normally dominant sporophytic phase of the life cycle has been eliminated and the plant exists only as a vegetative prothallus.


Bimodal sensory discrimination is finer than dual single modality discrimination.
Here we show that discriminating between different signal modulation rates can be easier when stimuli are presented in two modalities (vision and audition) rather than just one. This was true even when the single modality signal was repeated. This facilitation did not require simultaneous presentations in both modalities and therefore cannot rely on sensory fusion. Signal detection threshold for bimodal signals and double single modality signals were found to be equivalent indicating that the double single modality signals were not intrinsically noisier. The lack of facilitation in double single modality conditions was not due to inaccessibility of the first sample because there is no performance difference when noise was added to either the first or second samples. We propose that the bimodal signal discrimination advantage arises from fluctuations in the magnitude of sensory noise over time and because observers select the most reliable modality on a trial by trial basis. Noise levels within repeated single modality trials are more likely to be similar than those within signals from different modalities. As a consequence, signal selection would be less effective in the former circumstances. Overall, our findings illustrate the advantage of using separate sensory channels to achieve reliable information processing.


MelaNostrum: a consensus questionnaire of standardized epidemiologic and clinical variables for melanoma risk assessment by the melanostrum consortium.
Many melanoma observational studies have been carried out across different countries and geographic areas using heterogeneous assessments of epidemiologic risk factors and clinical variables. To develop a consensus questionnaire to standardize epidemiologic and clinical data collection for melanoma risk assessment. We used a stepwise strategy that included: compilation of variables from case-control datasets collected at various centres of the MelaNostrum Consortium; integration of variables from published case-control studies; consensus discussion of the collected items by MelaNostrum members; revision by independent experts; addition of online tools and image-based charts; questionnaire testing across centres and generation of a final draft. We developed a core consensus questionnaire (MelanoQ) that includes four separate sections: A. general and demographic data; B. phenotypic and ultraviolet radiation exposure risk factors and lifestyle habits; C. clinical examination, medical and family history; and D. diagnostic data on melanoma (cases only). Accompanying online tools, informative tables, and image-based charts aid standardization. Different subsections of the questionnaire are designed for self-administration, patient interviews performed by a physician or study nurse, and data collection from medical records. The MelanoQ questionnaire is a useful tool for the collection and standardization of epidemiologic and clinical data across different studies, centres, cultures and languages. This will expedite ongoing efforts to compile high-quality data for pooled analyses or meta-analyses and offer a solid base for the design of clinical, epidemiologic and translational studies on melanoma.


Catheter and surgical treatment of cardiac arrhythmias.
Over the past decade, numerous impressive advances have been made using nonpharmacologic methods for control of cardiac arrhythmias. These methods include surgical or catheter ablation of abnormal foci. Current techniques involve catheter ablation of the atrioventricular junction to control supraventricular arrhythmias. In addition, surgical techniques have proved to be remarkably safe and effective for treatment of patients with accessory pathways and those with atrioventricular nodal reentrant tachycardia. Patients with drug-refractory ventricular tachycardia may benefit from surgical resection of the ventricular tachycardia focus. The use of these interventional methodologies has radically altered the approach to management of patients with drug-refractory cardiac arrhythmias.


New differentiation pathway for double-negative regulatory T cells that regulates the magnitude of immune responses.
Recent studies have demonstrated that in peripheral lymphoid tissues of normal mice and healthy humans, 1% to 5% of alphabeta T-cell receptor-positive (TCR(+)) T cells are CD4(-)CD8(-) (double-negative [DN]) T cells, capable of down-regulating immune responses. However, the origin and developmental pathway of DN T cells is still not clear. In this study, by monitoring CD4 expression during T-cell proliferation and differentiation, we identified a new differentiation pathway for the conversion of CD4(+) T cells to DN regulatory T cells. We showed that the converted DN T cells retained a stable phenotype after restimulation and that furthermore, the disappearance of cell-surface CD4 molecules on converted DN T cells was a result of CD4 gene silencing. The converted DN T cells were resistant to activation-induced cell death (AICD) and expressed a unique set of cell-surface markers and gene profiles. These cells were highly potent in suppressing alloimmune responses both in vitro and in vivo in an antigen-specific manner. Perforin was highly expressed by the converted DN regulatory T cells and played a role in DN T-cell-mediated suppression. Our findings thus identify a new differentiation pathway for DN regulatory T cells and uncover a new intrinsic homeostatic mechanism that regulates the magnitude of immune responses. This pathway provides a novel, cell-based, therapeutic approach for preventing allograft rejection.


The efficacy of 90cm-long peritoneal shunt catheters in newborns and infants.
Ventriculoperitoneal (VP) shunt is one of the options for the treatment of hydrocephalus. The aim of this study is to describe the efficacy and safety of a 90cm-long peritoneal catheter in newborns and infants treated for hydrocephalus. We analyzed the incidence of distal-related complications and the need of successive surgeries for malfunction or for lengthening of the peritoneal catheter. We reviewed medical records of neonates and infants treated with a VP shunt using a 90cm-long peritoneal catheter. Function and integrity of shunts were assessed through abdominal echographic studies, skull, neck, chest and abdomen X-rays. We compared shunt revision rates due to distal complications and insufficient length of the peritoneal catheter in the study group with an historical control group composed by newborns and infants treated with a standard VP shunt at our Institution during the last twenty years. Three neonates and 3 infants were treated with the insertion of the 90cm-long distal catheter into the peritoneal cavity for its total length. The mean follow-up was 7.6 years. As compared to controls, in the study group the revision rate for distal complications was not significantly increased (P=0.33), whereas revision surgeries due to insufficient peritoneal catheter length were significantly reduced (P=0.04). This study demonstrates for the first time that the use of 90cm-long peritoneal catheters in neonates and infants is a safe and effective procedure. It does not increase the incidence of abdominal complications, avoiding the need of revision for insufficient length of the peritoneal catheter.


Aliphatic polyketones as classic yet new molecular ropes for structural diversity in organic synthesis.
Polyketone compounds play an important role in organic chemistry as a prominent source of reactivity and functionality. Their chemical properties vary widely depending on the ketone sequence in carbon chains. Although vicinal and β-polyketones have been used for more than 150 years, the recent development of new ketone sequences composed of alternating 1,3- and 1,4-diketones has demonstrated the further potential of polyketones as structurally flexible molecular ropes capable of derivatization to π-conjugated chromophores and molecular assemblies. In this Feature Article, we review the synthetic strategies and reactivities of polyketones with respect to their ketone sequence. Furthermore, recent research on polyketones with hybrid ketone sequences is also discussed, focussing on their structural diversity in chemical transformations including intramolecular cyclization and stereoselective oxidation.


Ecological speciation in tropical reef fishes.
The high biodiversity in tropical seas provides a long-standing challenge to allopatric speciation models. Physical barriers are few in the ocean and larval dispersal is often extensive, a combination that should reduce opportunities for speciation. Yet coral reefs are among the most species-rich habitats in the world, indicating evolutionary processes beyond conventional allopatry. In a survey of mtDNA sequences of five congeneric west Atlantic reef fishes (wrasses, genus Halichoeres) with similar dispersal potential, we observed phylogeographical patterns that contradict expectations of geographical isolation, and instead indicate a role for ecological speciation. In Halichoeres bivittatus and the species pair Halichoeres radiatus/brasiliensis, we observed strong partitions (3.4% and 2.3% divergence, respectively) between adjacent and ecologically distinct habitats, but high genetic connectivity between similar habitats separated by thousands of kilometres. This habitat partitioning is maintained even at a local scale where H. bivittatus lineages are segregated between cold- and warm-water habitats in both Bermuda and Florida. The concordance of evolutionary partitions with habitat types, rather than conventional biogeographical barriers, indicates parapatric ecological speciation, in which adaptation to alternative environmental conditions in adjacent locations overwhelms the homogenizing effect of dispersal. This mechanism can explain the long-standing enigma of high biodiversity in coral reef faunas.


MicroRNA-182 promotes leptomeningeal spread of non-sonic hedgehog-medulloblastoma.
The contribution of microRNAs to the initiation, progression, and metastasis of medulloblastoma (MB) remains poorly understood. Metastatic dissemination at diagnosis is present in about 30% of MB patients, and is associated with a dismal prognosis. Using microRNA expression profiling, we demonstrate that the retinal miR-183-96-182 cluster on chromosome 7q32 is highly overexpressed in non-sonic hedgehog MBs (non-SHH-MBs). Expression of miR-182 and miR-183 is associated with cerebellar midline localization, and miR-182 is significantly overexpressed in metastatic MB as compared to non-metastatic tumors. Overexpression of miR-182 in non-SHH-MB increases and knockdown of miR-182 decreases cell migration in vitro. Xenografts overexpressing miR-182 invaded adjacent normal tissue and spread to the leptomeninges, phenotypically reminiscent of clinically highly aggressive large cell anaplastic MB. Hence, our study provides strong in vitro and in vivo evidence that miR-182 contributes to leptomeningeal metastatic dissemination in non-SHH-MB. We therefore reason that targeted inhibition of miR-182 may prevent leptomeningeal spread in patients with non-SHH-MB.


MicroRNAs in the atherosclerotic plaque.
MicroRNAs (miRNA, miR) are noncoding RNAs that regulate gene expression by hindering translation. miRNA expression profiles have been shown to differ in vivo and in vitro in many cellular processes associated with cardiovascular diseases (CVDs). The progression of CVDs has also been shown to alter the blood miRNA profile in humans. We summarize the results of animal and cell experiments concerning the miRNA profile in the atherosclerotic process and the changes which occur in the blood miRNA profile of individuals with CVD. We also survey the relationship of these CVD-related miRNAs and their expression in the human advanced atherosclerotic plaque, thereby providing more insight into miRNA function in human atherosclerotic lesions. The miRNAs miR-126, -134, -145, -146a, -198, -210, -340*, and -92a were found to be expressed differently in the blood of individuals affected and unaffected by CVD. These differences paralleled those seen in tissue comparisons of miRNA expression in advanced atherosclerotic plaques and healthy arteries. Furthermore, several miRNAs associated with atherosclerosis in in vitro studies (such as miR-10a, -126, -145, -146a/b, -185, -210, and -326) were expressed in plaques in a similar pattern as was predicted by the in vitro experiments. The clinical implications of miRNAs in atherosclerosis as biomarkers and as possible drug targets are also reviewed. miRNA profiles in in vitro and in vivo studies as well as in human peripheral blood are quite representative of the miRNA expression in human atherosclerotic plaques. miRNAs appear promising in terms of future clinical applications.


How skill expertise shapes the brain functional architecture: an fMRI study of visuo-spatial and motor processing in professional racing-car and naïve drivers.
The present study was designed to investigate the brain functional architecture that subserves visuo-spatial and motor processing in highly skilled individuals. By using functional magnetic resonance imaging (fMRI), we measured brain activity while eleven Formula racing-car drivers and eleven 'naïve' volunteers performed a motor reaction and a visuo-spatial task. Tasks were set at a relatively low level of difficulty such to ensure a similar performance in the two groups and thus avoid any potential confounding effects on brain activity due to discrepancies in task execution. The brain functional organization was analyzed in terms of regional brain response, inter-regional interactions and blood oxygen level dependent (BOLD) signal variability. While performance levels were equal in the two groups, as compared to naïve drivers, professional drivers showed a smaller volume recruitment of task-related regions, stronger connections among task-related areas, and an increased information integration as reflected by a higher signal temporal variability. In conclusion, our results demonstrate that, as compared to naïve subjects, the brain functional architecture sustaining visuo-motor processing in professional racing-car drivers, trained to perform at the highest levels under extremely demanding conditions, undergoes both 'quantitative' and 'qualitative' modifications that are evident even when the brain is engaged in relatively simple, non-demanding tasks. These results provide novel evidence in favor of an increased 'neural efficiency' in the brain of highly skilled individuals.


Severe arm-muscle wasting: sign of lethal malnutrition in sick elderly men.
During a 3-yr period, I detected 29 sick men with severe muscle wasting defined by corrected arm-muscle area less than or equal to 16.9 cm2. Almost invariably, these men had weight and body mass index below the 3rd percentile. All had marked depletion of total-body muscle and protein mass, as evidenced by low urinary creatinine-height ratio and total-body nitrogen from neutron-activation analysis. Median survival was only 1.2 mo. Subjects were divided according to survival at 3 mo. The 8 survivors differed from the 21 who died in that they had higher energy intake and a greater chance of restoring muscle mass (5/8 vs. 0/21, P less than 0.001). Treatment of this lethal wasting state remains unsatisfactory. Hence, the most sensible approach is prevention.


Innovative Approaches to Safe Surgery: A Narrative Synthesis of Best Practices.
By encompassing a wide range of best practices within the ever-changing realm of modern surgical care, this exhaustive narrative compendium attempts to unravel the complex tapestry of novel approaches to safe surgery. Within the context of a dynamic surgical environment, this research endeavors to illuminate and integrate state-of-the-art methods that collectively methodically improve patient safety. The narrative elucidates a diverse array of practices that seek to revolutionize the paradigm of safe surgery, emphasizing technological progress, patient-centric approaches, and global viewpoints. The combined effectiveness of these methods in fostering an all-encompassing culture of safety, improving surgical precision, and decreasing complications is revealed by the results obtained from their implementation. The recognition of the dynamic interplay among multiple components, including the active participation of patients, the integration of cutting-edge technologies, and the establishment of comprehensive quality improvement programs, is fundamental to this narrative. By their collective composition, these components support the notion that secure surgical practices are intricate and interrelated. The present synthesis functions as a fundamental resource for healthcare professionals, policymakers, and researchers, providing an enlightening examination of the current condition of secure surgical practices. By emphasizing the promotion of innovation, continuous development, and the utmost quality of patient care, it offers a strategic guide for navigating the complex terrain of safe surgery. In the ever-evolving landscape of surgical care, this narrative synthesis serves as a guiding principle for stakeholders striving to understand better and implement safe surgical procedures in various healthcare environments.


Measuring the universal synchronization properties of driven oscillators across a Hopf instability.
When a driven oscillator loses phase-locking to a master oscillator via a Hopf bifurcation, it enters a bounded-phase regime in which its average frequency is still equal to the master frequency, but its phase displays temporal oscillations. Here we characterize these two synchronization regimes in a laser experiment, by measuring the spectrum of the phase fluctuations across the bifurcation. We find experimentally, and confirm numerically, that the low frequency phase noise of the driven oscillator is strongly suppressed in both regimes in the same way. Thus the long-term phase stability of the master oscillator is transferred to the driven one, even in the absence of phase-locking. The numerical study of a generic, minimal model suggests that such behavior is universal for any periodically driven oscillator near a Hopf bifurcation point.


Adherence to follow-up after a positive fecal occult blood test in an organized colorectal cancer screening program in Korea, 2004-2008.
To investigate the participation rates, positivity rates, and follow-up rates from 2004 to 2008 in an organized colorectal cancer (CRC) screening program using a fecal occult blood test (FOBT) in Korea. The study population was men and women aged 50 years or older who were invited to participate in the National Cancer Screening Program for CRC between 1 January 2004 and 31 December 2008. We collected the FOBT results and follow-up information for the FOBT positives. Participation rates increased steadily each year from 10.5% in 2004 to 21.1% in 2008. Between 2004 and 2008, FOBT positivity rates declined from 8.0% to 6.8%. Among the FOBT-positives, 61.3% of participants underwent either colonoscopy or double contrast barium enema (DCBE) in 2004, and this rate decreased to 38.6% in 2008. Age, health insurance type, and screening history were associated with adherence to follow-up test after a positive FOBT. With regard to follow-up tests, colonoscopy rates increased from 17.9% in 2004 to 27.6% in 2008, while DCBE decreased from 43.4% in 2004 to 11.0% in 2008. Colonoscopy was significantly more likely to be chosen as a follow-up test by men, participants aged 50-59 years, and National Health Insurance beneficiaries. These findings suggest that targeting participants for follow-up, based on age and previous screening history, could be a good way to improve the follow-up rate.


Relationships among dopamine transporter affinities and cocaine-like discriminative-stimulus effects.
The discriminative-stimulus effects of cocaine have been reported to be mediated by indirect agonist actions initiated by the blockade of dopamine uptake, and the potencies of drugs that have discriminative-stimulus effects like cocaine are directly related to their dopamine transporter binding affinities. The binding to the dopamine transporter by cocaine and many of its analogs has been reported to fit better using a two-site model than a one-site model. The present study examined the relationship among binding affinities of dopamine uptake inhibitors at these two sites and their potencies to produce discriminative-stimulus effects. The inhibition constants (K(i) values) were derived for unlabeled dopamine uptake inhibitors for displacement of [(3)H]WIN 35,428 from rat caudate putamen membranes. These K(i) values were related to the ED(50) values obtained in rats trained to discriminate 10 mg/kg cocaine from saline injections under a fixed-ratio 20 schedule of food reinforcement. Among the dopamine uptake inhibitors studied, the binding data for eight compounds (WIN 35,428, nomifensine, WIN 35,981, WIN 35,065-2, methylphenidate, cocaine, cocaethylene, and bupropion) were better fit by a two-site model than a one-site model. The data for the remaining eleven compounds (RTI-31, RTI-55, RTI-121, RTI-32, LU19-005, BTCP, GBR12909, GBR12935, mazindol, LU17-133, and EXP561) were better fit by a one-site model. Of the drugs that were fit best by a two-site model, there was a higher correlation among the K(i) values for the high-affinity site and the ED(50) values (R(2)=0.655; P=0.015) than there was for the low-affinity site (R(2)=0.543; P=0. 037). Of the remaining drugs, there was a high correlation among the K(i) values and the ED(50) values for the discriminative-stimulus effects (R(2)=0.523; P=0.012). These data suggest that the discriminative-stimulus effects of cocaine are more closely related to actions mediated by high-affinity binding to the dopamine transporter than they are to actions mediated by the low-affinity site. The further assessment of the respective contributions of high- and low-affinity binding to the behavioral effects of cocaine will be greatly enhanced with the development of pharmacological tools that have a high degree of selectivity for one of these components.


Upper limb amputees can be induced to experience a rubber hand as their own.
We describe how upper limb amputees can be made to experience a rubber hand as part of their own body. This was accomplished by applying synchronous touches to the stump, which was out of view, and to the index finger of a rubber hand, placed in full view (26 cm medial to the stump). This elicited an illusion of sensing touch on the artificial hand, rather than on the stump and a feeling of ownership of the rubber hand developed. This effect was supported by quantitative subjective reports in the form of questionnaires, behavioural data in the form of misreaching in a pointing task when asked to localize the position of the touch, and physiological evidence obtained by skin conductance responses when threatening the hand prosthesis. Our findings outline a simple method for transferring tactile sensations from the stump to a prosthetic limb by tricking the brain, thereby making an important contribution to the field of neuroprosthetics where a major goal is to develop artificial limbs that feel like a real parts of the body.


From hiding out to coming out: empowering lesbian and gay educators.
The purposes of this participatory research project were to describe the experiences of thirteen lesbian and gay educators and to empower the participants through collective reflection and action. Each participant was interviewed and given a copy of her or his audio-tape and transcript. Using these materials, each participant developed a profile of themselves to share with the other participants. During a series of group meetings that spanned fifteen months, participants discussed their experiences, searched for common themes, and planned two collective actions. This chapter describes the professional experiences of these lesbian and gay educators and the process of empowerment that changed their lives.


Functional responses and apoptosis of CD25 (IL-2R alpha)-deficient T cells expressing a transgenic antigen receptor.
IL-2 was initially defined as a T lymphocyte growth factor, but recent studies have provided evidence that it may also play a role in regulating T cell differentiation, apoptosis, and tolerance. To examine the contribution of IL-2 to these processes, we have bred a class II-restricted TCR transgene into mice deficient in the alpha-chain of the IL-2R, CD25. We show that in response to Ag, T cells from these mice are unable to use IL-2 and, as a result, are less efficient at traversing the cell cycle, and proliferate less than wild-type cells. Furthermore, CD25 -/- T cells exhibit reduced survival in vitro, even in the presence of costimulatory signals. IL-4 and IL-15, a cytokine related to IL-2, enhance the survival and Ag-induced proliferation of CD25 -/- T cells. Activated CD25 -/- T cells are resistant to Fas-mediated activation-induced cell death (AICD), and this defect cannot be corrected by other cytokines. Therefore, IL-2 plays a unique role in regulating AICD, but has redundant roles in T cell survival and proliferation in vitro. The failure of AICD observed with CD25 -/- T cells may explain the unexpected observation that deficiency of IL-2 or of the alpha- or beta-chain of the IL-2R results not in immunodeficiency, but in autoimmune disease.


Identification of the Mg2+-binding site in the P-type ATPase and phosphatase members of the HAD (haloacid dehalogenase) superfamily by structural similarity to the response regulator protein CheY.
The large HAD (haloacid dehalogenase) superfamily of hydrolases comprises P-type ATPases, phosphatases, epoxide hydrolases and L-2-haloacid dehalogenases. A comparison of the three-dimensional structure of L-2-haloacid dehalogenase with that of the response regulator protein CheY allowed the assignment of a conserved pair of aspartate residues as the Mg2+-binding site in the P-type ATPase and phosphatase members of the superfamily. From the resulting model of the active site, a conserved serine/threonine residue is suggested to be involved in phosphate binding, and a mechanism comprising a phosphoaspartate intermediate is postulated.


Regulation of Bruton tyrosine kinase by the peptidylprolyl isomerase Pin1.
Bruton tyrosine kinase (Btk) is expressed in B-lymphocytes. Mutations in Btk cause X-linked agammaglobulinemia in humans. However, the mechanism of activation and signaling of this enzyme has not been fully investigated. We have here shown that the peptidylprolyl cis/trans isomerase (PPIase) Pin1 is a negative regulator of Btk, controlling its expression level by reducing its half-life, whereas the catalytic activity of Btk was unaffected. The negative regulatory effect of Pin1 was observed both in cell lines and in Pin(-/-) mice and was found to be dependent on a functionally intact Btk. This may constitute a feedback loop for the regulation of Btk. The target region in Btk was localized to the pleckstrin homology domain suggesting that interphase phosphorylation of serine 115 (Ser-115) in Btk is required, whereas mitosis phosphorylation of serine 21 (Ser-21) is critical. Accordingly, Pin 1 was shown to associate with Btk through binding to Ser-21 and -115, respectively, both of which lie in a classical Pin1-binding pocket. Using a phosphomitotic antibody, it was found that Btk harbors a bona fide MPM2 epitope corresponding to a phosphorylated serine or threonine residue followed by a proline. Our results indicate that the peptidylprolyl isomerase Pin1 interacts with Btk in a cell cycle-dependent manner, regulating the Btk expression level.


The Nucleocapsid Protein of Potato Yellow dwarf Virus: Protein Interactions and Nuclear Import Mediated by a Non-Canonical Nuclear Localization Signal.
Potato yellow dwarf virus (PYDV) is the type species of the genus Nucleorhabdovirus and, like all members of this genus, replication and morphogenesis occurs inside the nuclei of infected cells. Protein localization prediction algorithms failed to identify a nuclear localization signal (NLS) in PYDV nucleocapsid (N) protein, although PYDV-N has been shown to localize exclusively to the nucleus when expressed as a green fluorescent protein (GFP):N fusion in plant cells. Deletion analysis using fragments of PYDV-N identified a karyophilic region in the carboxy-terminal 122 amino acids. Alanine-scanning mutagenesis was performed across this region in the context of the full-length N protein. Mutants were assayed for their ability to nuclear localize using live-cell imaging and a yeast-based assay. Two amino acid motifs, (419)QKR(421) and (432)KR(433) were shown to be essential for nuclear import and interaction with importin-α. Additional bimolecular fluorescence complementation showed that the PYDV-N-NLS mutants cannot be ferried into the nucleus via interaction with PYDV-P or -M. In contrast, interaction with N-NLS mutants appeared to retard the nuclear import of PYDV-P. GFP fused to aa 419-434 established that the PYDV-N-NLS can function outside the context of this protein. Taken together, it was determined that PYDV-N contains the bipartite NLS (419)QKRANEEAPPAAQKR(433).


Lack of association of EGR2 variants with bipolar disorder in Japanese population.
The early growth response gene 2 (EGR2) has been recently reported to be associated with bipolar disorder in the Korean population. However replication studies in independent cohorts of same and different ethnicities are essential for establishing the credibility of a genotype-phenotype association. With this notion, in the present study we have performed a replication study of the reported association of SNPs in EGR2 in a case-control study comprising of 867 unrelated Japanese bipolar disorder patients and 895 age-, sex- and ethnicity-matched controls. Results showed no significant differences in allele and genotype frequencies of EGR2 SNPs between bipolar disorder patients and controls and also in a sex-stratified genetic analysis. The haplotype and meta-analyses also showed no significant association with bipolar disorder. In conclusion, this is the first replication study of the previously reported association of EGR2 with bipolar disorder in a larger sample set and the results showed that the EGR2 gene is unlikely to contribute to the susceptibility of bipolar disorder in a Japanese cohort.


Comparative efficacy of first-line ceritinib and crizotinib in advanced or metastatic anaplastic lymphoma kinase-positive non-small cell lung cancer: an adjusted indirect comparison with external controls.
Objective: In the absence of head-to-head trials, this study indirectly compared progression free survival (PFS) and overall survival (OS) between ceritinib and crizotinib among patients with previously untreated advanced anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC).Methods: A matching-adjusted indirect comparison method was implemented to adjust for cross-trial differences in patient characteristics between ASCEND-4 and PROFILE 1014 trials. Patient-level data from ASCEND-4 and published summary data from PROFILE 1014 were used. Patients in ASCEND-4 were reweighted to match average baseline characteristics (i.e. age, sex, race, tumor histology, ECOG score, smoking status, extent of disease, and presence of brain metastases) reported for PROFILE 1014 patients using propensity score weighting. PFS and OS were then compared between balanced populations.Results: ASCEND-4 included more current smokers (8.0% vs 4.4%) and fewer patients under the age of 65 years (78.5% vs 84.0%) compared to PROFILE 1014. After matching, these and all other patient characteristics were balanced between the two trial populations. Compared to crizotinib, ceritinib was associated with a significantly longer PFS (hazard ratio [95% confidence interval] (HR [CI]) = 0.64 [0.47-0.87]; median PFS: 25.2 vs 10.8 months, log-rank p-value = 0.003). OS did not differ significantly, with a HR of 0.82 [0.54-1.27] for ceritinib compared to crizotinib.Conclusions: In the adjusted indirect comparison with external controls, the second generation ALK inhibitor, ceritinib, was associated with a significantly prolonged PFS compared to crizotinib as first-line treatment for ALK-positive NSCLC.


DNA-damaging agents greatly increase the transduction of nondividing cells by adeno-associated virus vectors.
None of the vector systems currently available for gene therapy applications have been shown to be capable of both efficient gene transfer into nondividing cells and long-term expression through stable integration into host cell DNA. While integrating vectors based on adeno-associated virus are capable of mediating gene transfer into nondividing cells, this process is 200-fold less efficient than transduction of dividing cells. We demonstrate that the transduction efficiency of adeno-associated virus vectors can be increased by treatment with DNA-damaging agents. Nondividing cells are especially responsive, with increases in transduction efficiency of up to 750-fold. This finding has the potential to facilitate gene therapy applications requiring gene transfer to nondividing cells.


Seismic signature of active intrusions in mountain chains.
Intrusions are a ubiquitous component of mountain chains and testify to the emplacement of magma at depth. Understanding the emplacement and growth mechanisms of intrusions, such as diapiric or dike-like ascent, is critical to constrain the evolution and structure of the crust. Petrological and geological data allow us to reconstruct magma pathways and long-term magma differentiation and assembly processes. However, our ability to detect and reconstruct the short-term dynamics related to active intrusive episodes in mountain chains is embryonic, lacking recognized geophysical signals. We analyze an anomalously deep seismic sequence (maximum magnitude 5) characterized by low-frequency bursts of earthquakes that occurred in 2013 in the Apennine chain in Italy. We provide seismic evidences of fluid involvement in the earthquake nucleation process and identify a thermal anomaly in aquifers where CO2 of magmatic origin dissolves. We show that the intrusion of dike-like bodies in mountain chains may trigger earthquakes with magnitudes that may be relevant to seismic hazard assessment. These findings provide a new perspective on the emplacement mechanisms of intrusive bodies and the interpretation of the seismicity in mountain chains.


Using propensity scores to estimate the cost-effectiveness of medical therapies.
The cost-effectiveness ratio is a popular statistic that is used by policy makers to decide which programs are cost-effective in the public health sector. Recently, the net monetary benefit has been proposed as an alternative statistical summary measure to overcome the limitations associated with the cost-effectiveness ratio. Research on using the net monetary benefit to assess the cost-effectiveness of therapies in non-randomized studies has yet to be done. Propensity scores are useful in estimating adjusted effectiveness of programs that have non-randomized or quasi-experimental designs. This article introduces the use of propensity score adjustment in cost-effectiveness analyses to estimate net monetary benefits for non-randomized studies. The uncertainty associated with the net monetary benefit estimate is evaluated using cost-effectiveness acceptability curves. Our method is illustrated by applying it to SEER-Medicare data for muscle invasive bladder cancer to determine the most cost-effective treatment protocol.


Proton-transfer and H2-elimination reactions of trimethylamine alane: role of dihydrogen bonding and Lewis acid-base interactions.
Proton-transfer and H(2)-elimination reactions of aluminum hydride AlH(3)(NMe(3)) (TMAA) with XH acids were studied by means of IR and NMR spectroscopy and DFT calculations. The dihydrogen-bonded (DHB) intermediates in the interaction of the TMAA with XH acids (CH(3)OH, (i)PrOH, CF(3)CH(2)OH, adamantyl acetylene, indole, 2,3,4,5,6-pentafluoroaniline, and 2,3,5,6-tetrachloroaniline) were examined experimentally at low temperatures, and the spectroscopic characteristics, dihydrogen bond strength and structures, and the electronic and energetic characteristics of these complexes were determined by combining experimental and theoretical approaches. The possibility of two different types of DHB complexes with polydentate proton donors (typical monodentate and bidentate coordination with the formation of a symmetrical chelate structure) was shown by DFT calculations and was experimentally proven in solution. The DHB complexes are intermediates of proton-transfer and H(2)-elimination reactions. The extent of this reaction is very dependent on the acid strength and temperature. With temperature increases the elimination of H(2) was observed for OH and NH acids, yielding the reaction products with Al-O and Al-N bonds. The reaction mechanism was computationally studied. Besides the DHB pathway for proton transfer, another pathway starting from a Lewis complex was discovered. Preference for one of the pathways is related to the acid strength and the nucleophilicity of the proton donor. As a consequence of the dual Lewis acid-base nature of neutral aluminum hydride, participation of a second ROH molecule acting as a bifunctional catalyst forming a six-member cycle connecting aluminum and hydride sites notably reduces the reaction barrier. This mechanism could operate for proton transfer from weak OH acids to TMAA in the presence of an excess of proton donor.


True UV color vision in a female butterfly with two UV opsins.
In true color vision, animals discriminate between light wavelengths, regardless of intensity, using at least two photoreceptors with different spectral sensitivity peaks. Heliconius butterflies have duplicate UV opsin genes, which encode ultraviolet and violet photoreceptors, respectively. In Heliconius erato, only females express the ultraviolet photoreceptor, suggesting females (but not males) can discriminate between UV wavelengths. We tested the ability of H. erato, and two species lacking the violet receptor, Heliconius melpomene and Eueides isabella, to discriminate between 380 and 390 nm, and between 400 and 436 nm, after being trained to associate each stimulus with a sugar reward. We found that only H. erato females have color vision in the UV range. Across species, both sexes show color vision in the blue range. Models of H. erato color vision suggest that females have an advantage over males in discriminating the inner UV-yellow corollas of Psiguria flowers from their outer orange petals. Moreover, previous models ( McCulloch et al., 2017) suggested that H. erato males have an advantage over females in discriminating Heliconius 3-hydroxykynurenine (3-OHK) yellow wing coloration from non-3-OHK yellow wing coloration found in other heliconiines. These results provide some of the first behavioral evidence for female H. erato UV color discrimination in the context of foraging, lending support to the hypothesis ( Briscoe et al., 2010) that the duplicated UV opsin genes function together in UV color vision. Taken together, the sexually dimorphic visual system of H. erato appears to have been shaped by both sexual selection and sex-specific natural selection.


Newer Insights Into Fetal Growth and Body Composition.
Based on epidemiological and experimental evidence, the origins of childhood obesity and early onset metabolic syndrome can be extended back to developmental processes during intrauterine life. It is necessary to actively investigate antecedent conditions that affect fetal growth by developing reliable measures to identify variations in fetal fat deposition and body composition. Recently, the resolution of ultrasonography has remarkably improved, which enables better tissue characterization and quantification of fetal fat accumulation. In addition, fetal fractional limb volume has been introduced as a novel measure to quantify fetal soft tissue volume, including fat mass and lean mass. Detecting extreme variations in fetal fat deposition may provide further insights into the origins of altered fetal body composition in pathophysiological conditions (i.e., fetal growth restriction or fetal macrosomia), which are predisposed to the metabolic syndrome in later life. Further studies are warranted to determine the maternal or placental factors that affect fetal fat deposition and body composition. Elucidating these factors may help develop clinical interventions for altered fetal growth and body composition, which could potentially lead to primary prevention of the future risk of metabolic dysfunction.


Binge Eating in a Slovenian Population-based Sample of Adults.
Binge eating is the most common form of disordered eating associated with obesity, reduced quality of life, and medical and psychological comorbidities. It therefore affects the well-being of individuals. This underscores the fact that it is a serious public health problem. The study aimed to investigate binge eating and anxiety across gender, age and body mass index in a large population sample of adults in Slovenia. A total of 3,310 adult volunteers participated in this cross-sectional study. Questionnaires, including a binge eating and anxiety scale and an eating behaviour questionnaire, were completed by 1,487 subjects (90.9% female, ages 18 to 69). The frequency of reported binge eating was 29.9%, with 9.8% of participants reporting severe binge eating, and the presence of overweight and obesity was high (41.8%). BMI was associated with this problematic eating, and explained 5.4% of the variation in binge eating. Importantly, anxiety was the most important factor related to binge eating, with younger participants and women reporting significantly more anxiety. The high presence of binge eating, obesity and anxiety in the Slovenian population-based sample is worrying. Anxiety is clearly an important factor in understanding the relationship between negative affect and binge eating, as it accounts for a greater proportion of the variance in binge eating symptoms than BMI. Particularly concerning was the fact that the youngest participants showed the greatest anxiety. Targeting anxious adolescents and females is important from a health perspective because it can impact the physical and mental health of the population in the long term.


Sexual life and sexual frigidity among women developing acute myocardial infarction.
The various aspects of the sexual life of 100 female patients aged 40-60 with acute myocardial infarction were compared with those of a control group of 100 female patients of the same age, hospitalized for other diseases. Sexual frigidity and dissatisfaction were found among 65% of the coronary patients as compared with 24% of the controls. The commonest cause for sexual dissatisfaction was premature ejaculation or impotence in the husband. The incidence of premarital sexual relations was greater among the frigid patients when compared with those who achieved orgasm. The coronary patients had an earlier menopausal age than the controls. The number of coronary patients who underwent artificial abortions in the past was lower than in the control group. All these findings were statistically significant at a level of P less than 0.05. No connection was found between extramarital relations and sexual frigidity. There was no relation found between sexual frigidity and diabetes, essential hypertension, marital status, pathological gynecological findings, or localization of the infarction. Until now, sexual frigidity and dissatisfaction appear to have been a neglected aspect in the female coronary patient.


Germline and somatic c-met mutations in multifocal/bilateral and sporadic papillary renal carcinomas of selected patients.
Papillary renal carcinoma (PRC) comprises about 10% of all kidney epithelial tumors. Familiar/hereditary papillary renal carcinomas (HPRCs) have been described, but the majority of cases seem to be sporadic. HPRC is characterized by the predisposition to develop bilateral, multifocal renal tumors. Activating mutations in the tyrosine kinase domain (TK) of the hepatocyte growth factor (HGF) receptor, c-met, have been identified in both hereditary and sporadic PRC. The main aim of this study was to examine a family with no history of PRC in which the proband was a female patient affected by multiple and bilateral PRC at early onset. DNA mutation analysis has been performed by direct sequencing of exons 14-21 of c-met gene which include the TK domain. The proband displayed the germline c-met missense mutation g.3522G--> A in exon 16. Two other family members were found to carry the same mutation. The mutation analysis extended to 15 selected patients, allowed to identify the first case of an Italian patient affected by PRC displaying the somatic missense mutation g.3997 T-->C curved arrow C located in exon 19 of c-met. The mutation frequency of the selected-based population of PRC patients in this report was 12.5%. Furthermore, the phosphorylated c-met expression detected by immunohistochemistry in PRCs with germline/somatic or no c-met mutation, supports the concept that c-met activation may occur in PRC oncogenesis by c-met mutations and/or c-met over-expression.


Effect of external electric field on the bulk and interfacial properties of weakly dipolar fluid in slab-shaped and sphere-shaped systems.
The effect of a uniform electric field on the bulk and interfacial properties of a model dipolar fluid is investigated by using a modified mean-field density functional theory. Particular attention is given to the dependence of the vapor-liquid phase coexistence in a slab-shaped system on the direction of the electric field with respect to the slab surfaces, as well as in the sphere-shaped system on the surrounding dielectric permittivity. For planar vapor-liquid interfaces, the interfacial profiles of the orientation order parameters and components of the dielectric-permittivity tensor are calculated. Analytical expressions for these interfacial profiles and their dependence on the electric field are obtained. When the electric field is normal to the interface we find that the thermodynamic surface tension is lowered compared to that in zero field, and that when the electric field is parallel to the interface the surface tension is enhanced. In contrast, the mechanical surface tension at the equimolar dividing surface is always enhanced by the field regardless of the field direction, and it assumes its highest value when the field is parallel to the interface.


Conjugation of a GM3 lactone mimetic on carbon nanotubes enhances the related inhibition of melanoma-associated metastatic events.
GM3-ganglioside is known to be involved in melanoma proliferation. In order to modulate metastatic-related events, we have functionalized multi-walled carbon nanotubes (MWCNTs) with multiple copies of a GM3-lactone mimetic. The MWCNTs proved to guarantee the appropriate spatial arrangement of the mimetic allowing a stronger inhibition of migration and invasiveness of human melanoma (A375) cells compared to other multivalent constructs reported before. In addition, the effect of the multivalent tubular conjugate on the inhibition of specific tyrosine kinases, which are associated with the ganglioside complexes within the membrane domains, was demonstrated. Finally, the short-term fate of the conjugate was assessed, for the first time, by means of the 1H NMR relaxometry technique by exploiting the signal arising from the CNTs.


Stilbene analogs of resveratrol improve insulin resistance through activation of AMPK.
Resveratrol (RSV), 3,5,4'-trihydroxy-trans-stilbene, is known to have many beneficial physiological activities. We have synthesized several stilbene analogues and have reported that the hydroxyl group in the 4' position of RSV exhibited strong radical scavenging action. Using stilbene analogs, we investigated the structure of RSV to explain its protective effect against obesity and type 2 diabetes. All six analogs used in this study inhibited the differentiation of 3T3-L1 adipocytes. 3-Hydroxy-trans stilbene (3(OH)ST), and 3,4'-dihydroxy-trans stilbene (3,4'(OH)2ST) increased glucose uptake and induced adenosine monophosphate kinase (AMPK) phosphorylation in C2C12 myotubes independently of insulin. An in vivo study using mice fed high-fat diets indicated that 3(OH)ST was more effective than RSV in improving insulin resistance. In conclusion, RSV and its derivatives, particularly 3(OH)ST, inhibited adipocyte differentiation and enhanced glucose uptake in the myotubes, resulting in a reduction of obesity and an improvement in glucose tolerance in vivo.


[Effect of Rhizobium leguminosarum 252 agglutinins on the activity of some plant cell enzymes].
The incubation of pea seedling roots with the surface agglutinins R1 and R2 of Rhizobium leguminosarum 252 brought about an increase in the activity of proteases, beta-glucosidase, and, especially, succinate dehydrogenase in the roots. The data presented show that rhizobial agglutinins play an important part in the formation and functioning of legume-rhizobial associations.


Understanding Past Experiences of Suicidal Ideation and Behavior in the Life Narratives of Transgender Older Adults.
Transgender people (collectively referred to here as trans) experience disproportionate rates of suicidal ideation and behavior (plans and attempts) attributed to complex constellations of structural and individual factors. Interpretive methods in suicide research elucidate and contextualize intricate patterns of risk factors and strategies for recovery. The life narratives of trans older adults offer unique insights into past suicidal behavior and recovery after distress has diminished and perspective has been gained. This study aimed to illuminate the lived experiences of suicidal ideation and behavior in the biographical interviews of 14 trans older adults as part of the project To Survive on This Shore (N=88). Data analysis was conducted using a two-phase narrative analysis. Trans older adults contextualized suicide attempts, plans, ideation, and recovery as navigating impossible to possible paths. Impossible paths were seen as hopelessness in their life direction, often after a significant loss. Possible paths were described as pathways to recovery from crises. Transitions from impossible to possible paths were narrated as a turning point or moment of strength combined with outreach to family, friends, or mental health professionals. Narrative approaches hold the potential to illuminate pathways to well-being among trans persons with lived experiences of suicidal ideation and behavior. For social work practitioners, therapeutic narrative work around past suicidal ideation and behavior with trans older adults holds promise for suicidal prevention by identifying important supportive resources and previously used coping skills in crises.


Combined deletion of four Francisella novicida acid phosphatases attenuates virulence and macrophage vacuolar escape.
Francisella tularensis is a facultative intracellular pathogen and the etiologic agent of tularemia. It is capable of escape from macrophage phagosomes and replicates in the host cell cytosol. Bacterial acid phosphatases are thought to play a major role in the virulence and intracellular survival of a number of intracellular pathogens. The goal of this study was to delete the four primary acid phosphatases (Acps) from Francisella novicida and examine the interactions of mutant strains with macrophages, as well as the virulence of these strains in mice. We constructed F. novicida mutants with various combinations of acp deletions and showed that loss of the four Acps (AcpA, AcpB, AcpC, and histidine acid phosphatase [Hap]) in an F. novicida strain (DeltaABCH) resulted in a 90% reduction in acid phosphatase activity. The DeltaABCH mutant was defective for survival/growth within human and murine macrophage cell lines and was unable to escape from phagosome vacuoles. With accumulation of Acp deletions, a progressive loss of virulence in the mouse model was observed. The DeltaABCH strain was dramatically attenuated and was an effective single-dose vaccine against homologous challenge. Furthermore, both acpA and hap were induced when the bacteria were within host macrophages. Thus, the Francisella acid phosphatases cumulatively play an important role in intracellular trafficking and virulence.


Inhibitory effects of recombinant neurotoxin BmK IM on seizures induced by pentylenetetrazol in Rats.
To elucidate the inhibitory effects of recombinant Chinese scorpion neurotoxin BmK IM on seizures induced by pentylenetetrazol (PTZ) and the possible mechanism. After purifying recombinant BmK IM from an E. coli cell line, its toxicity (both LD50 and minimum lethal dose) on rats was determined. BmK IM was then microinjected into the CA3 region of the right hippocampus and its ability to inhibit the effects of an intraperitoneal injection of PTZ was assessed. The effects of BmK IM on the electrophysiological properties of isolated CA3 pyramidal neurons were then studied using whole-cell patch clamp techniques. BmK IM can significantly prolong the latent period of epileptic seizures, decrease the degree of seizures, and decrease the frequency of epileptiform discharges induced by PTZ. At the same time, 24h after injection of BmK IM into the hippocampal tissue, BmK IM significantly reduces the concentration of the neurotransmitter glutamate and alleviates PTZ-induced lesions in the hippocampus. Whole-cell patch clamp recordings indicate that BmK IM inhibits INa of rat hippocampal neurons in a dose-dependent manner. BmK IM significantly shifts the activation curve of INa in a positive direction, indicating that BmK IM enhances the threshold potential of INa. BmK IM has significant anti-epileptic properties, and may prove useful as a drug in the therapy of epilepsy. The inhibitory effects of BmK IM on seizures caused by pentylenetetrazol might depend on reductions in the release of presynaptic glutamate via the blocking of Na+ channels.


Activation of human Kupffer cells by thymostimulin (TP-1) to produce cytotoxicity against human hepatocellular cancer.
In a small pilot study, thymostimulin (TP-1) produced tumor regression in almost 50% of patients with hepatocellular cancer (HCC) who were treated with TP-1 alone. However, the mechanism of the TP-1-mediated antitumor effect against HCC is unknown. Human hepatocytes and Kupffer cells were isolated from liver biopsy specimens by collagenase infusion and counterflow elutriation. Hepatocytes and Kupffer cells were incubated in vitro with clinically relevant doses of TP-1. Cell-free supernatant levels for a panel of growth factors and monokines were determined by enzyme-linked immunosorbent assay. The cytotoxic activity of TP-1 alone of TP-1-stimulated hepatocyte and Kupffer cell supernatants against Hep G2 and Hep 3B human HCC cells in vitro was measured by MIT assay. Doses of TP-1 up to 100 micrograms/ml produced no cytotoxicity against Hep G2 or Hep 3B cells. Furthermore, supernatants from TP-1-treated hepatocytes produced no cytotoxicity against Hep G2 or Hep 3B cells, and TP-1 did not stimulate the release of transforming growth factor (TGF)-alpha, TGF-beta, or hepatocyte growth factor. TP-1-treated Kupffer cell supernatants produced significant cytotoxicity against Hep G2 cells but produced no cytotoxicity against Hep 3B cells. Kupffer cells stimulated by TP-1 released significant amounts of tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1 alpha, and IL-6 compared with control Kupffer cells (p < 0.01). The activity of TP-1-treated Kupffer cell supernatants against Hep G2 cells was blocked by anti-TNF-alpha antibodies, whereas neither anti-IL-1 alpha nor anti-IL-6 antibodies blocked cytotoxicity. These results demonstrate that TP-1 cytotoxicity against human HCC cells is not mediated directly or through hepatocytes, but occurs through activation of Kupffer cells and release of TNF-alpha. Understanding the mechanism of TP-1 cytotoxicity against human HCC has been used to plan a phase 1 trial of TP-1 combined with regional infusion of doxorubicin to treat unresectable HCC.


Angola's 2013 dengue outbreak: clinical, laboratory and molecular analyses of cases from four Portuguese institutions.
Dengue virus (DENV) is the arbovirus with the widest impact on human health. In Africa in general, and in Angola in particular, the epidemiology and public health impact of DENV is far from clear. However, rapid population growth, unplanned urbanization, increased international travel, and the presence of virus major vector (Aedes aegypti) in the country suggest that DENV transmission may occur. In parallel to the occurrence of a dengue outbreak affecting the capital of Angola, between March and July 2013 four Portuguese institutions diagnosed dengue infection in 146 individuals returning to Portugal. Clinical presentation, laboratory findings, and molecular analyses of partial viral genomic segments were performed. The mean age of the individuals included in this study was 42 years old, the majority being men of Portuguese nationality, reporting various lengths of stay in Angola. Fever was the most reported clinical sign, being frequently associated (61.0%) with myalgia and headache. Hematological values, including hematocrit, white-blood cell and platelets counts, correlated with the absence of severe or complicated cases, or coagulation disorders. No deaths were observed. Viral NS1 was detected in 56.2% of the samples, and all NS1 negative cases had anti-dengue IgM antibodies. RT-PCR indicated the presence of DENV1, which was confirmed by phylogenetic analysis of 25 partial NS5 viral sequences. The DENV cases analyzed conformed to classical and uncomplicated dengue, caused by the suggested exclusive circulation of a genetically homogeneous DENV1 of genotype III, apparently with a single origin.


Methotrexate and misoprostol vs misoprostol alone for early abortion. A randomized controlled trial.
To compare the safety and efficacy of early abortion by administration of methotrexate and misoprostol vs administration of misoprostol alone. Randomized controlled trial. San Francisco (Calif) General Hospital. Pregnant women at 56 days' gestation or less seeking elective abortion. Sixty-three women volunteered for the trial; 61 completed the study and are included in the analysis. Intramuscular administration of 50 mg of methotrexate per square meter of body surface area followed 3 days later by vaginal administration of 800 micrograms of misoprostol (group 1) or the same dose of misoprostol given alone (group 2). The misoprostol dose was repeated 24 hours later if abortion had not occurred. Successful abortion, duration of vaginal bleeding, side effects, and change in beta-human chorionic gonadotropin (beta-hCG) level. An abortion was considered successful if the pregnancy ended without requiring a surgical procedure. Complete abortion occurred in 28 (90%) of 31 patients in group 1 and 14 (47%) of 30 patients in group 2 (P < .001). Seventeen (61%) of the 28 women in group 1 who aborted did so the same day as misoprostol administration; vaginal bleeding lasted a mean (+/- SD) of 10 (+/- 4) days, and beta-hCG level was less than or equal to 10 IU/L by a mean of 31 (+/- 6) days after methotrexate administration. The 11 other women in group 1 who aborted did so after a mean delay of 29 (+/- 11) days; vaginal bleeding lasted 7 (+/- 4) days, and beta-hCG level was less than or equal to 10 IU/L by a mean of 24 (+/- 11) days after the abortion. There were three treatment failures in group 1: two ongoing pregnancies (6%) and one incomplete abortion (3%). For the 14 women with successful abortions in group 2, vaginal bleeding lasted a mean of 10 (+/- 6) days and beta-hCG level was less than or equal to 10 IU/L by mean of 39 (+/- 18) days after the misoprostol. There were 16 treatment failures in group 2: eight ongoing pregnancies (27%), and eight incomplete abortions (27%). Methotrexate side effects were minimal. Misoprostol side effects were diarrhea in 18% and nausea and vomiting in 5%. Methotrexate and vaginal misoprostol are more effective than misoprostol alone. Both drugs are available throughout the United States, and both drugs are inexpensive. This combination may offer an alternative to the use of antiprogestin and prostaglandin for medical abortion.


Cardioprotective Effects of Dietary Flaxseed Post-Infarction Are Associated with Changes in MicroRNA Expression.
MicroRNAs (miRNAs/miRs) such as miR-1, miR-133a, miR-133b, miR-135a, and miR-29b play a key role in many cardiac pathological remodeling processes, including apoptosis, fibrosis, and arrhythmias, after a myocardial infarction (MI). Dietary flaxseed has demonstrated a protective effect against an MI. The present study was carried out to test the hypothesis that dietary flaxseed supplementation before and after an MI regulates the expression of above-mentioned miRNAs to produce its cardioprotective effect. Animals were randomized after inducing MI by coronary artery ligation into: (a) sham MI with normal chow, (b) MI with normal chow, and (c-e) MI supplemented with either 10% milled flaxseed, or 4.4% flax oil enriched in alpha-linolenic acid (ALA), or 0.44% flax lignan secoisolariciresinol diglucoside. The feeding protocol consisted of 2 weeks before and 8 weeks after the surgery. Dietary flax oil supplementation selectively upregulated the cardiac expression of miR-133a, miR-135a, and miR-29b. The levels of collagen I expression were reduced in the flax oil group. We conclude that miR-133a, miR-135a, and miR-29b are sensitive to dietary flax oil, likely due to its rich ALA content. The cardioprotective effect of flaxseed in an MI could be due to modulation of these miRNAs.


An unexpected discovery of 1,4-benzoquinone as a lipophilic mediator for toxicity detection in water.
Since most toxicological risk assessments are based on individual single-species tests, there is uncertainty in extrapolating these results to ecosystem assessments. Herein, we successfully developed a mediated microbial electrochemical biosensor with mixed microorganisms for toxicity detection by microelectrode array (MEA). In order to fully mobilize all the mixed microorganisms to participate in electron transfer to amplify the current signal, 1,4-benzoquinone (BQ) was used as the lipophilic mediator to mediate the intracellular metabolic activities. Hydrophilic K3[Fe(CN)6] was employed as an extracellular electron acceptor to transport electrons from hydroquinone (HQ) to the working electrode. Under the optimal conditions of 50 mM phosphate buffer solution (PBS), 0.4 mM BQ, 10 mM K3[Fe(CN)6] and OD600 = 0.5 bacteria concentration, the half-maximal inhibitory concentration (IC50) values measured with the composite-mediated respiration (CM-RES) of BQ-K3[Fe(CN)6] for Cu2+, Cd2+ and Zn2+ were 5.95, 7.12 and 8.86 mg L-1, respectively. IC50 values obtained with the single mediator K3[Fe(CN)6] were 2.34, 5.88 and 2.42 mg L-1 for the same samples. The results indicate that the biosensor with the single mediator K3[Fe(CN)6] had higher sensitivity to heavy metal ions than the biosensor with composite mediators. After verification, we found that the addition of BQ cannot amplify the current. The IC50 value of 0.89 mg L-1 for BQ was obtained using K3[Fe(CN)6] as the single mediator. This suggests that BQ is highly toxic, which explained why the sensitivity of the biosensor with the combined mediator BQ-K3[Fe(CN)6] was lower than that of the biosensor with the single mediator K3[Fe(CN)6]. At the same time, this also implies that toxicity itself cannot be ignored when it is used as an electronic mediator in a mediated microbial electrochemical biosensor.


Enhanced carnosic acid levels in two rosemary accessions exposed to cold stress conditions.
Two rosemary accessions were subjected to chilling temperatures in control environmental cabins analyzing their variations in rosmarinic and carnosic acids together with their adaptability to these stress conditions. Cold stressed plants of both accessions showed increases in caffeic acid and carnosic acid concentration levels, while other secondary metabolites such as rosmarinic acid, naringin, cirsimaritin, hispidulin, and carnosol showed different responses in both accessions. In addition, cold stressed plants exhibited significant reductions in chlorophylls, beta-carotene, and violaxanthin levels as well as the maximum quantum yield of PSII in both accessions. Hydrogen peroxide and lipid peroxidation levels showed similar responses in both accessions, which were positively and negatively correlated with rosmarinic and carnosic acids. From these results it is therefore suggested that carnosic acid biosynthesis in rosemary plants is induced by chilling periods. On the other hand, we demonstrate that not all rosemary accessions are equally well adapted to chilling temperatures. In fact, for (one) accession cold treated plants severe losses in chlorophyll, beta-carotene, and even xanthophylls (including zeaxanthin and antheraxanthin) were observed, despite no visual symptoms of leaf injury. More research is needed to understand rosmarinic acid variations in rosemary plants under stress conditions.


Increased percentages of tumor necrosis factor-alpha+/interferon-gamma+ T [corrected] lymphocytes and calprotectin+/tumor necrosis factor-alpha+ monocytes in patients with acute Kawasaki disease.
In vivo exposure to microorganisms resident in the oral cavity is considered as a possible cause of Kawasaki disease (KD), and some epitopes derived from streptococci display homology with Factor H of Complement. Additionally, calprotectin, a major calcium binding protein released by neutrophils and activated monocytes, could be directly involved in endothelial damage occurring in KD. The aim of our study is to evaluate the percentages of IFN-gamma+ and/or TNF-alpha+ lymphocytes and double positive calprotectin/TNF-alpha monocytes (CD14+) after in vitro stimulation with streptococcal- and/or Factor H-derived peptides, in patients with acute KD. Peripheral Blood Mononuclear Cells (PBMCs) obtained from KD patients and febrile controls were stimulated in vitro with peptides. After culture, cells were collected, stained with fluorochrome-labelled monoclonal antibodies against CD3, CD14, calprotectin, IFN-gamma and TNF-alpha, and cytofluorimetric analyses were performed. Our results showed increased percentages of TNF-alpha+/IFN-gamma+ lymphocytes in KD patients in respect to controls when PBMCs were stimulated with streptococcal or Factor H-derived epitopes. In addition, also calprotectin+/TNF-alpha+ monocytes from KD patients were activated after PBMC in vitro stimulation. These findings lead us to speculate that some peptides, derived from oral streptococci and cross-reactive with the human Factor H of Complement, could induce lymphocyte and monocyte activation potentially involved in the pathogenesis of KD. Our results should be confirmed by further studies enrolling more patients and controls than those analyzed in our study.


Sequential Determination of Free Acidity and Plutonium Concentration in the Dissolver Solution of Fast-Breeder Reactor Spent Fuels in a Single Aliquot.
A simple potentiometric method for determining the free acidity without complexation in the presence of hydrolysable metal ions and sequentially determining the plutonium concentration by a direct spectrophotometric method using a single aliquot was developed. Interference from the major fission products, which are susceptible to hydrolysis at lower acidities, had been investigated in the free acidity measurement. This method is applicable for determining the free acidity over a wide range of nitric acid concentrations as well as the plutonium concentration in the irradiated fuel solution prior to solvent extraction. Since no complexing agent is introduced during the measurement of the free acidity, the purification step is eliminated during the plutonium estimation, and the resultant analytical waste is free from corrosive chemicals and any complexing agent. Hence, uranium and plutonium can be easily recovered from analytical waste by the conventional solvent extraction method. The error involved in determining the free acidity and plutonium is within ±1% and thus this method is superior to the complexation method for routine analysis of plant samples and is also amenable for remote analysis.


Prey, predators, parasites: intraguild predation or simpler community modules in disguise?
1. Competition and predation are at the heart of community ecology. The theoretical concept of intraguild predation (IGP) combines these key interactions in a single community module. Because IGP is believed to be ubiquitous in nature, it has been subject to extensive research, and there exists a well-developed theoretical framework. 2. We show that a general class of IGP models can be transformed to simpler, but equivalent community structures. This rather unexpected simplification depends critically on the property of 'indiscriminate predation', which we define broadly as the top-predator not distinguishing between its two different prey species. 3. In a broader context, the great importance of IGP and of the simplifying transformation we report here is enhanced by the recent insight that the basic IGP structure extends naturally to host-parasitoid and host-pathogen communities. We show that parasites infecting prey (predators) tend to render IGP effectively into exploitative competition (tritrophic food chain, respectively). 4. The equivalence between the original and simplified community module makes it possible to take advantage from already existing insights. We illustrate this by means of an eco-epidemiological IGP model that is strikingly similar to a classical exploitative competition model. 5. The change of perspective on certain community modules may contribute to a better understanding of food web dynamics. In particular, it may help explain the interactions in food webs that include parasites. Given the ubiquity of parasitism, food webs may appear in a different light when they are transformed to their simplified analogue.


Climate change and African trypanosomiasis vector populations in Zimbabwe's Zambezi Valley: A mathematical modelling study.
Quantifying the effects of climate change on the entomological and epidemiological components of vector-borne diseases is an essential part of climate change research, but evidence for such effects remains scant, and predictions rely largely on extrapolation of statistical correlations. We aimed to develop a mechanistic model to test whether recent increases in temperature in the Mana Pools National Park of the Zambezi Valley of Zimbabwe could account for the simultaneous decline of tsetse flies, the vectors of human and animal trypanosomiasis. The model we developed incorporates the effects of temperature on mortality, larviposition, and emergence rates and is fitted to a 27-year time series of tsetse caught from cattle. These catches declined from an average of c. 50 flies per animal per afternoon in 1990 to c. 0.1 in 2017. Since 1975, mean daily temperatures have risen by c. 0.9°C and temperatures in the hottest month of November by c. 2°C. Although our model provided a good fit to the data, it cannot predict whether or when extinction will occur. The model suggests that the increase in temperature may explain the observed collapse in tsetse abundance and provides a first step in linking temperature to trypanosomiasis risk. If the effect at Mana Pools extends across the whole of the Zambezi Valley, then transmission of trypanosomes is likely to have been greatly reduced in this warm low-lying region. Conversely, rising temperatures may have made some higher, cooler, parts of Zimbabwe more suitable for tsetse and led to the emergence of new disease foci.


Vascular malformations and arteriovenous fistulas of the kidney.
Vascular malformations of the kidney are disease processes that involve renal veins and arteries and include congenital arteriovenous malformations (AVMs) and arteriovenous fistulas. AVMs are congenital communications between arteries and veins with a vascular nidus that bypass the capillary bed. Congenital AVMs are rare and subclassified in cirsoid, angiomatous, and aneurysmal types. Congenital AVMs are different from iatrogenic or traumatic arteriovenous fistulas (AVF), which are characterized by a single direct communication between an artery and a vein without an intervening vascular nidus. These lesions may present with a wide range of signs and symptoms that vary from hypertension to renal masses. Imaging is valuable in the detection and characterization of AVM and AVF. The presence of arteriovenous shunting characterizes AVM and AVF. These lesions represent an important group of entities for diagnostic consideration, and understanding the vascular anatomy helps in guiding for proper treatment. This article describes the imaging features of each lesion that help to differentiate it from the others and the endovascular therapies to treat these vascular processes and their possible complications.


Inductions of histidine decarboxylase in mouse tissues following systemic antigen challenge: contributions made by mast cells, non-mast cells and IL-1.
Previous findings suggest that antigen challenge (AC) may induce histidine decarboxylase (HDC) in cells other than mast cells (MCs) via MC-derived IL-1. We examined this hypothesis. Mice were sensitized to ovalbumin. After the sensitization, an AC was delivered intravenously. In control mice, AC markedly induced HDC at a postanaphylactic time in the liver, lung, spleen, and ears. In MC-deficient W/W(v) mice, AC also induced HDC, although the effect was weaker than in control mice. AC increased IL-1 in the tissues, the pattern being similar in W/W(v) and control mice. AC induced HDC similarly in IL-1-deficient and control mice. In control mice, AC decreased histamine in the tissues (except the liver) for several hours. (1) AC induces HDC in both MC-dependent and MC-independent ways. (2) AC induces IL-1 mostly in non-MCs, but this IL-1 is not a prerequisite for the induction of HDC by AC. (3) HDC induction may contribute to the replenishment of the reduced pool of MC histamine in the anaphylactic period. (4) In the case of MC-dependent HDC induction, AC may stimulate MCs in such a way as to induce HDC within the MCs themselves, and/or AC-stimulated MCs may stimulate HDC induction in other cells, which will need to be directly identified in future studies.


A national study of the provision of oncology sperm banking services among Canadian fertility clinics.
The purpose of this study was to survey the current state of oncology sperm banking services provided by fertility clinics across Canada. A total of 78 Canadian fertility facilities were invited to complete a questionnaire related to the availability, accessibility, affordability and utilisation of sperm banking services for cancer patients. The total response rate was 59%, with 20 (69%) in vitro fertilisation clinics and 26 (53%) other fertility centres returning the survey. A total of 24 responding facilities accepted oncology sperm banking referrals. The time frame to book the first banking appointment for 19 (79%) facilities was within 2 days. Inconsistent practice was found regarding the consent process for cancer patients who are of minority age. Eight (33%) facilities did not provide any subsidy and charged a standard banking fee regardless of patients' financial situations. Overall, the utilisation of oncology sperm banking services was low despite its availability and established efficacy, suggesting that Canadian cancer patients are notably underserved. The study has highlighted some important issues for further consideration in improving access to sperm banking services for cancer patients, especially for adolescents. Better collaboration between oncology and reproductive medicine to target healthcare providers would help to improve sperm banking rates.


Early life factors and blood pressure at age 31 years in the 1966 northern Finland birth cohort.
Data on the birth weight-blood pressure relationship are inconsistent. Although an inverse association has been suggested in several large studies, interpretation is complicated by publication and other biases. Few data are available on the relationship between other early growth measures and blood pressure. We examined the shape and size of association between determinants of fetal growth, size at birth, growth in infancy, and adult systolic and diastolic blood pressure at 31 years in the prospective northern Finnish 1966 birth cohort of 5960 participants. Birth weight, birth length, gestational age, ponderal index, and birth weight relative to gestational age showed a significant inverse association with blood pressure at age 31. Rapid growth in infancy ("change-up") was positively associated with blood pressure. Adjusted regression coefficients for birth weight indicated systolic/diastolic blood pressure lower by -1.7 (95% confidence interval [CI], -2.5, -1.0)/-0.7 (95% CI, -1.4, -0.02) mm Hg for 1 kg higher birth weight. The significant inverse association between birth weight and systolic blood pressure persisted without adjustment for adult body mass index for males. Among females, gestational age showed a stronger association with blood pressure than birth weight: gestational age higher by 7 weeks (equivalent to an average of 1 kg higher birth weight) among singletons associated with -2.9 (95% CI, -4.7, -1.1) mm Hg lower systolic blood pressure. Our results support the concept that birth weight, other birth measures, and infant growth are important determinants of blood pressure and hence cardiovascular disease risk in later life.


Cystic fibrosis diagnosed after 2 months of age leads to worse outcomes and requires more therapy.
Newborn screening for cystic fibrosis remains controversial because improved pulmonary function has not been established. Studies to date have not accounted for differences in treatments delivered to clinically diagnosed children and newborn-screened controls. Here, we compare outcomes and treatment of patients clinically diagnosed within the newborn-screening reporting window (early-clinically diagnosed), those presenting after this period (late-clinically diagnosed), and patients diagnosed by newborn screening. In a cross-sectional analysis of cohorts retrospectively ascertained, patients who were homozygous deltaF508 with cystic fibrosis, attending specialist cystic fibrosis centers, and 1 to 10 years of age between 2000 and 2002 were identified from the United Kingdom Cystic Fibrosis Database and stratified into newborn-screened, early-clinically diagnosed, or late-clinically diagnosed cohorts. Two analyses were performed: (1) after restricting to the most recent year of data collection, early-clinically diagnosed and late-clinically diagnosed cohorts were matched to newborn-screened patients by patient age and year of data collection (133 patients per cohort were identified); and (2) for all years of data collection, annual sets of data for early-clinically diagnosed and late-clinically diagnosed patients were matched to newborn-screened patients by patient age and year of data collection (291 data sets per cohort were identified). Median height and weight z scores, proportion of patients with height and weight <10th percentile, prevalence of chronic Pseudomonas aeruginosa infection, Shwachman-Kulczyki morbidity scores, percent predicted forced expiratory volume in 1 second, and numbers of long-term therapies were compared. In both analyses, newborn screening was associated with higher height z score, higher Shwachman-Kulczyki score, lower likelihood of height <10th percentile, and fewer long-term therapies compared with late-clinically diagnosed patients. No other differences were found. Newborn screening was associated with improved growth, reduced morbidity, and reduced therapy, yet generated equivalent pulmonary outcome compared with late clinical diagnosis, suggesting that newborn screening may slow cystic fibrosis lung disease progression.


A murine cytomegalovirus-neutralizing monoclonal antibody exhibits autoreactivity and induces tissue damage in vivo.
The autoreactivity of murine cytomegalovirus (MCMV)-neutralizing monoclonal antibody (mAb) AC1 was examined in vitro and in vivo. Both mAb AC1 and a human antiserum reactive with U1-small nuclear ribonucleoprotein (U1-snRNP) stained uninfected mouse embryo fibroblasts (MEF) in a speckled nuclear pattern and reacted with 70,000 molecular weight (MW) MEF nuclear antigens by immunoblotting, suggesting that mAb AC1 cross-reacted with the 70,000 MW component of U1-snRNP. However, only mAb AC1 cross-reacted with an additional epithelial cytoplasmic autoantigen present in cultured HEp2 cells. On tissue sections from uninfected mice, mAb AC1 predominantly reacted with a component of central and peripheral nervous systems, although cross-reactivity with the stratum spinosum of the skin and the outer sheath of hair follicles was also observed. Immunoblotting revealed that mAb AC1 reacted with phosphorylated epitopes present on a 98,000 MW MCMV structural protein and the 200,000 MW mouse neurofilament protein (NFP). Treatment of uninfected mice with mAb AC1 resulted in a severe interstitial pneumonia with greatly thickened and congested alveolar septa. Severe oedema of the hypodermis and a mild mesangial proliferative glomerulonephritis were also observed. These results demonstrate that a mAb reacting with a MCMV structural phosphoprotein which can protect mice against the dissemination of MCMV, can also promote the development of autoimmune disease. Therefore, the production of such cross-reactive antibodies may be an important mechanism in the development of autoimmunity following viral infection.


[Enteral correction in gastroduodenal hemorrhage of peptic ulcer etiology].
Among 115 patients with gastroduodenal hemorrhage 60 received nonoperative treatment, 30 of them underwent enteral correction with a monomer electrolyte solution. Emergency operation was carried out on 55 patients, 35 of them were subjected to enteral correction in the postoperative period. Enteral administration of the monomer electrolyte solution in the early posthemorrhagic and postoperative periods promoted filling up of the blood circulation volume and its components and stabilization of the values of central hemodynamics. It was established on grounds of the clinical data, studies of the volemic indices and central hemodynamics that enteral correction does not yield to the traditional intravenous infusion-transfusion therapy in efficacy.


Human rhinovirus infections in symptomatic and asymptomatic subjects.
The role of rhinovirus asymptomatic infections in the transmission among close contacts subjects is unknown. We tested health care workers, a pair of one child and a family member and immunocompromised patients (n =191). HRV were detected on 22.9% symptomatic and 3.6% asymptomatic cases suggesting lower transmission among contacts.


Measurements of Functional Network Connectivity Using Resting State Arterial Spin Labeling During Neurosurgery.
In neurosurgery, an exact delineation of functional areas is of great interest to spare important regions to ensure the best possible outcome for the patient (i.e., maximum removal while maintaining the highest possible quality of life). Preoperative imaging is routinely performed, including the visualization of not only structural but also functional information. During surgery, however, brain shift can occur, leading to an offset between the previously defined and the real position. Real-time imaging during the procedure is therefore desired to obtain this information while performing surgery. In this study 15 patients suffering from glioblastoma multiforme were included. These patients underwent structural and perfusion imaging using arterial spin labeling during the procedure. The latter has been used for gathering information about tumor residual perfusion. However, special postprocessing of this data allows for additional mapping of resting state networks and is intended to be used to gather deeper insights to aid the surgeon in planning the procedure. The data of each patient could be successfully postprocessed and used to map different resting state networks alongside the default mode network. On the basis of this study, it is feasible to use the information obtained from perfusion imaging to visualize not only vascular signal but also functional activation of resting state networks without acquiring any additional data besides the already available information. This may help guide the neurosurgeon in real time to adjust the surgical plan.


RUTBC1 protein, a Rab9A effector that activates GTP hydrolysis by Rab32 and Rab33B proteins.
Rab GTPases regulate all steps of membrane trafficking. Their interconversion between active, GTP-bound states and inactive, GDP-bound states is regulated by guanine nucleotide exchange factors and GTPase-activating proteins. The substrates for most Rab GTPase-activating proteins (GAPs) are unknown. Rab9A and its effectors regulate transport of mannose 6-phosphate receptors from late endosomes to the trans-Golgi network. We show here that RUTBC1 is a Tre2/Bub2/Cdc16 domain-containing protein that binds to Rab9A-GTP both in vitro and in cultured cells, but is not a GTPase-activating protein for Rab9A. Biochemical screening of RUTBC1 Rab protein substrates revealed highest in vitro GTP hydrolysis-activating activity with Rab32 and Rab33B. Catalysis required Arg-803 of RUTBC1, and RUTBC1 could activate a catalytically inhibited Rab33B mutant (Q92A), in support of a dual finger mechanism for RUTBC1 action. Rab9A binding did not influence GAP activity of bead-bound RUTBC1 protein. In cells and cell extracts, RUTBC1 influenced the ability of Rab32 to bind its effector protein, Varp, consistent with a physiological role for RUTBC1 in regulating Rab32. In contrast, binding of Rab33B to its effector protein, Atg16L1, was not influenced by RUTBC1 in cells or extracts. The identification of a protein that binds Rab9A and inactivates Rab32 supports a model in which Rab9A and Rab32 act in adjacent pathways at the boundary between late endosomes and the biogenesis of lysosome-related organelles.


Antioxidant and Antisteatotic Activities of Fucoidan Fractions from Marine and Terrestrial Sources.
Fucoidan is a fucose-rich sulfated polysaccharide typically found in the cell wall of marine algae but also recently isolated from terrestrial sources. Due to a variety of biological activities, including antioxidant properties, fucoidan exhibits an attractive therapeutic potential against a wide array of metabolic diseases associated with oxidative stress. We used FTIR, 1H NMR and 13C NMR spectroscopy to investigate the structural features of a fucoidan fraction extracted from the brown alga Cystoseira compressa (CYS). The antioxidant potential of CYS was measured by DPPH, ABTS and FRAP assays, which revealed a radical scavenging capacity that was confirmed in in vitro cellular models of hepatic and endothelial cells. The same antioxidant effects were observed for another fucoidan fraction previously identified in the terrestrial tree Eucalyptus globulus (EUC). Moreover, in hepatic cells, CYS and EUC exhibited a significant antisteatotic action, being able to reduce intracellular triglyceride content through the regulation of key genes of hepatic lipid metabolism. EUC exerted stronger antioxidant and antisteatotic effects as compared to CYS, suggesting that both marine and terrestrial sources should be considered for fucoidan extraction and therapeutic applications.


Microplate hybridization of amplified viral DNA segment.
We have developed a simple hybridization method for a DNA segment which is amplified by the polymerase chain reaction: after heat denaturation, the amplified DNA segment with a length of more than 300 bases is adsorbed to microplate wells in the presence of 1.5 M NaCl or 0.5 M ammonium sulfate; the immobilized DNA is hybridized with a biotin-labeled DNA probe; then, the hybridization signal is detected by streptavidin-conjugated beta-galactosidase or peroxidase. This method has several advantages over the conventional dot blot hybridization method: (i) radioisotopes are not used, (ii) synthetic oligonucleotide for the probe is not needed, (iii) the time required for washing of the solid phase is greatly reduced, and (iv) the baking and prehybridization procedures are eliminated. By this method, we were able to detect viral genomes in vesicle specimens from patients infected with varicella-zoster virus.


Randomized treatment study of inosiplex versus combined inosiplex and intraventricular interferon-alpha in subacute sclerosing panencephalitis (SSPE): international multicenter study.
The efficacy of oral inosiplex alone (group A) versus combined treatment of inosiplex (Isoprinosine) and intraventricular interferon-alpha2b (Intron A) (group B) in patients with subacute sclerosing panencephalitis (SSPE) was compared. One hundred and twenty-one patients who met the diagnostic criteria for subacute sclerosing panencephalitis and presented at stage 2 or less were randomized into group A or B. Data were analyzable on 67 patients who met the inclusion criteria and adhered to the protocol. The inosiplex dosage was 100 mg/kg/day to a maximum of 3 g/day, taken orally in three divided doses for 6 months. Interferon-alpha2b started with 100,000 U/m2 and escalated to 1,000,000 U/m2 over 5 inpatient days and then 1,000,000 U/m2 twice a week for 6 months. Neurologic status was rated by the Neurological Disability Index, Brief Assessment Examination, and stages. Kaplan-Meier survival rates were not statistically significant between group A and group B (log-rank test chi2 = .1374, P = .7109). In longitudinal morbidity analyses, regression results were fitted to three outcome measures: the Neurological Disability Index, the Brief Assessment Examination, and stage. Group medians of the estimated regression slopes were then compared using the Wilcoxon rank-sum test. There was no statistically significant difference between the two groups on any of these three measures. Morbidity comparisons of clinical classification of outcomes (improvement, stabilization, worsening after treatment stopped, deterioration) also showed no statistically significant difference between groups. There were no statistically significant differences between the two treatment groups on any efficacy measure. However, the observed rates of satisfactory outcome (stabilization, improvement) of 34% in group A and 35% in group B were higher than the spontaneous remission rates of 5 to 10% reported in the literature, suggesting that treatment was superior to no treatment.