Feasibility, Acceptability, and Design of a Mobile Ecological Momentary Assessment for High-Risk Men Who Have Sex With Men in Hanoi, Vietnam: Qualitative Study.
Men who have sex with men (MSM) are at a disproportionate risk for HIV infection and common mental disorders worldwide. In the context of HIV, common mental disorders are important and are frequent drivers of suboptimal prevention and treatment outcomes. Mobile ecological momentary assessments (EMAs), or the repeated sampling of people's behaviors and psychological states in their daily lives using mobile phones, can clarify the triggers and HIV-related sequelae of depressive-anxious symptoms and contribute toward the design of ecological momentary interventions (EMIs) that cater to the contextually varying needs of individuals to optimize prevention and treatment outcomes. This study aims to characterize the feasibility and acceptability of mobile EMA among high-risk MSM in Hanoi, Vietnam. It aims to evaluate the perceived relevance, usability, and concerns of this group with regard to the content and delivery of mobile EMA and the potential of leveraging such platforms in the future to deliver EMIs. Between January and April 2018, a total of 46 participants were recruited. The participants completed 6 to 8 mobile EMA surveys daily for 7 days. Surveys occurred once upon waking, 4 to 6 times throughout the day, and once before sleeping. All surveys queried participants' perceived safety, social interactions, psychological state, and mental health symptoms. The morning survey further queried on sleep and medication use within the past 24 hours, whereas the night survey queried on sexual activity and substance use and allowed participants to share an audio recording of a stressful experience they had that day. At the end of the week, participants were interviewed about their experiences with using the app. Participants completed an average of 21.7 (SD 12.7) prompts over the 7-day period. Excluding nonresponders, the average compliance rate was 61.8% (SD 26.6%). A thematic analysis of qualitative interviews suggested an overall positive reception of the app and 5 recurring themes, which were centered on the relevance of psychological and behavioral items to daily experiences (eg, mental health symptoms and audio recording), benefits of using the app (eg, increased self-understanding), worries and concerns (eg, privacy), usability (eg, confusion about the interface), and recommendations for future design (eg, integrating more open-ended questions). Mobile EMA is feasible and acceptable among young MSM in Vietnam; however, more research is needed to adapt EMA protocols to this context and enhance compliance. Most participants eagerly provided information about their mental health status and daily activities. As several participants looked toward the app for further mental health and psychosocial support, EMIs have the potential to reduce HIV and mental health comorbidity among MSM.


[Research funding in German ophthalmology].
Since 2004 applications for research funding in ophthalmology have been evaluated together with those from neurosurgery, neuropathology, psychiatry, psychotherapy, psychosomatics, otolaryngology and neurology by a joint review board of the German Research Council (DFG). Facing a decreasing number of applications--in contrast to the need and importance of widespread ocular diseases--the working group "young academics" of the Deutsche Ophthalmologische Gesellschaft (DOG) assessed the perception of funding programmes and grants available. Young ophthalmologists think that they have poor prospects to receive funding by a DFG proposal. In comparison, specialist funding quotas show a stable development within the neurosciences over the last years. The sum of requested funding has a strong correlation with the total amount actually paid. By clarifying the number of funded proposals, the better transparency and communication for the existing programmes should improve the cooperativeness, the funding rate and number of applications in future. This inventory explicitly includes a motivational guidance for young researchers to take the initiative to do more proposals.


A vasopressin/oxytocin-related conopeptide with gamma-carboxyglutamate at position 8.
Vasopressins and oxytocins are homologous, ubiquitous and multifunctional peptides present in animals. Conopressins are vasopressin/oxytocin-related peptides that have been found in the venom of cone snails, a genus of marine predatory molluscs that envenom their prey with a complex mixture of neuroactive peptides. In the present paper, we report the purification and characterization of a unique conopressin isolated from the venom of Conus villepinii, a vermivorous cone snail species from the western Atlantic Ocean. This novel peptide, designated gamma-conopressin-vil, has the sequence CLIQDCPgammaG* (gamma is gamma-carboxyglutamate and * is C-terminal amidation). The unique feature of this vasopressin/oxytocin-like peptide is that the eighth residue is gamma-carboxyglutamate instead of a neutral or basic residue; therefore it could not be directly classified into either the vasopressin or the oxytocin peptide families. Nano-NMR spectroscopy of the peptide isolated directly from the cone snails revealed that the native gamma-conopressin-vil undergoes structural changes in the presence of calcium. This suggests that the peptide binds calcium, and the calcium-binding process is mediated by the gamma-carboxyglutamate residue. However, the negatively charged residues in the sequence of gamma-conopressin-vil may mediate calcium binding by a novel mechanism not observed in other peptides of this family.


Development of mouse preantral follicle after in vitro culture in a medium containing melatonin.
Improvements in cancer treatment have allowed more young women to survive. However, many cancer patients suffer from ovarian failure. Cryopreservation is one of the solutions for fertility restoration in these patients. The cryopreservation of isolated follicles is a more attractive approach in the long term. Many endocrine and paracrine factors can stimulate the granulosa cells of preantral follicles to proliferate. Melatonin acts as direct free radical scavenger and indirect antioxidant. In this study, we investigated the direct effects of melatonin on follicle development and oocyte maturation by exposing in vitro cultured mouse vitrified-warmed ovarian follicles to melatonin. In an experimental study, preantral follicles with diameter of 150-180 µm were isolated from prepubertal mouse ovaries. Follicles were vitrified and thawed using cryolock method. They were then cultured individually for 7 days in droplets supplemented with 0, 10 and 100 pM melatonin, while ovulation was induced using epidermal growth factor (EGF) and human chorionic gonadotropin (hCG). The survival rate of follicles and nuclear maturation of ovulated oocytes were determined. At the end of culture, significant increases in follicle survival (p<0.001) and in diameter (p<0.05) were noticed in 10 pM melatonin group compared to control group. In the 100 pM group, survival rate was not affected by melatonin. It was revealed that after induction of ovulation, total number of metaphase II oocytes in treatment groups were not influenced by melatonin (p>0.05). Culture of mouse vitrified-warmed preantral follicles in a medium supplemented with 10 pM melatonin increased the number of surviving follicles.


Modulation of surface T11 molecules induced by monoclonal antibodies: analysis of the functional relationship between antigen-dependent and antigen-independent pathways of human T cell activation.
Previous data indicated that T lymphocyte activation can be achieved by using a combination of anti-T11 monoclonal antibodies (mAb) directed to the "T11(2)" and the "T11(3)" epitopes, respectively. Unlike the T cell activation induced by antibodies directed to the T3-T cell receptor (Ti) complex or to T44 molecules, the anti-T11 mAb-induced cell activation was not accompanied by surface modulation of the T11 antigen. In the present study we show that appropriate stimulatory combinations of anti-T11 mAb are able to induce T11 antigen modulation in a variety of T cells including polyclonal peripheral blood populations, normal as well as leukemic (JA3) T cell clones. The first anti-T11 mAb combination leading to both cell activation and T11 antigen modulation was given by a mAb directed to the T11(2) epitope and by another mAb recognizing an epitope belonging to the T11(1) group. The second combination was given by two mAb directed against two different determinants of the T11(1) group. The ability to induce T11 antigen modulation allowed a more precise analysis of the pathway of T cell activation initiated by T11 molecules and its physical and functional relationship with the other known pathways of T cell activation. T cells following T11 antigen modulation failed to respond to subsequent stimulation with anti-T11 mAb. The refractory period lasted for 48-72 h and the restoration of the responsiveness to anti-T11 mAb coincided with the re-expression of T11 molecules at the cell surface. Modulation of T11 antigen did not affect the surface expression of T3, Ti or T44 molecules, in addition, "modulated" cells maintained their ability to respond to mAb directed against T3, Ti or T44 molecules. On the contrary, antibody-induced modulation of the T3-Ti receptor complex abrogated both T11- and T44-dependent T cell activation. Finally, antibody-induced modulation of T44 antigen did not inhibit either the T11- or the T3-Ti-dependent pathway of T cell activation. These data indicate that down-regulation of the pathway of T cell activation initiated by T11 molecules can be induced not only by modulation of the antigen receptor complex but also by appropriate mAb to T11 molecules and, presumably, by the natural ligand binding to T11 molecules.


Operational Modal Analysis of Near-Infrared Spectroscopy Measure of 2-Month Exercise Intervention Effects in Sedentary Older Adults with Diabetes and Cognitive Impairment.
The Global Burden of Disease Study (GBD 2019 Diseases and Injuries Collaborators) found that diabetes significantly increases the overall burden of disease, leading to a 24.4% increase in disability-adjusted life years. Persistently high glucose levels in diabetes can cause structural and functional changes in proteins throughout the body, and the accumulation of protein aggregates in the brain that can be associated with the progression of Alzheimer's Disease (AD). To address this burden in type 2 diabetes mellitus (T2DM), a combined aerobic and resistance exercise program was developed based on the recommendations of the American College of Sports Medicine. The prospectively registered clinical trials (NCT04626453, NCT04812288) involved two groups: an Intervention group of older sedentary adults with T2DM and a Control group of healthy older adults who could be either active or sedentary. The completion rate for the 2-month exercise program was high, with participants completing on an average of 89.14% of the exercise sessions. This indicated that the program was practical, feasible, and well tolerated, even during the COVID-19 pandemic. It was also safe, requiring minimal equipment and no supervision. Our paper presents portable near-infrared spectroscopy (NIRS) based measures that showed muscle oxygen saturation (SmO2), i.e., the balance between oxygen delivery and oxygen consumption in muscle, drop during bilateral heel rise task (BHR) and the 6 min walk task (6MWT) significantly (p < 0.05) changed at the post-intervention follow-up from the pre-intervention baseline in the T2DM Intervention group participants. Moreover, post-intervention changes from pre-intervention baseline for the prefrontal activation (both oxyhemoglobin and deoxyhemoglobin) showed statistically significant (p < 0.05, q < 0.05) effect at the right superior frontal gyrus, dorsolateral, during the Mini-Cog task. Here, operational modal analysis provided further insights into the 2-month exercise intervention effects on the very-low-frequency oscillations (<0.05 Hz) during the Mini-Cog task that improved post-intervention in the sedentary T2DM Intervention group from their pre-intervention baseline when compared to active healthy Control group. Then, the 6MWT distance significantly (p < 0.01) improved in the T2DM Intervention group at post-intervention follow-up from pre-intervention baseline that showed improved aerobic capacity and endurance. Our portable NIRS based measures have practical implications at the point of care for the therapists as they can monitor muscle and brain oxygenation changes during physical and cognitive tests to prescribe personalized physical exercise doses without triggering individual stress response, thereby, enhancing vascular health in T2DM.


The effect of limited MR field of view in MR/PET attenuation correction.
A critical question in the development of combined MR/PET scanners is whether MR can provide the tissue attenuation data required for PET reconstruction. Unfortunately, MR images are often unable to encompass the entire patient. The resulting truncation in the transverse plane leads to incomplete attenuation maps, causing artifacts in the reconstructed PET image. This article describes the experiments performed to quantify these artifacts. A method to compensate the missing data was evaluated to determine whether software correction is possible or whether additional transmission hardware has to be included in the scanner. Three studies were made. First, simulated PET data were used to quantify the bias due to an incomplete attenuation map. A set of spherical lesions was simulated in the lungs and mediastinum of a patient. The data were reconstructed with complete and partial attenuation maps and the uptake differences were evaluated. Second, clinical data from PET/CT oncology patients were used. To reproduce the expected conditions in an MR/PET scanner, only patients scanned with the arms resting along the body were considered. These scans were then used to create maps of the reconstruction bias due to field of view (FOV) limitations. Lastly, a PET reconstruction with incomplete attenuation data was evaluated as a means to obtain attenuation information beyond the MR FOV. The patient outline was automatically segmented with a three-dimensional snake algorithm and used to fill the truncated data in the attenuation map. Average bias up to 15% and local biases up to 50% were estimated when PET data were reconstructed with incomplete attenuation information. Completing the attenuation map with data extracted from a PET prereconstruction globally reduced these biases to below 10%. This correction proved to be tolerant to inaccuracies in positioning and attenuation values. However, local artifacts up to 20% could still be found near the edges of the MR FOV. MR FOV restrictions can indeed make the reconstructed PET data unacceptable for diagnostic purposes. Biases can be globally compensated by automatic preprocessing of the attenuation map. However, inaccuracies in the correction will result in small artifacts near the periphery of the image that could lead to false-positive findings.


Delivery of optimized anticoagulant therapy: consensus statement from the Anticoagulation Forum.
To provide recommendations, policies, and procedures pertaining to the provision of optimized anticoagulation therapy designed to achieve desired clinical endpoints while minimizing the risk of anticoagulant-related adverse outcomes (principally bleeding and thrombosis). Due to this document's scope, the medical literature was searched using a variety of strategies. When possible, recommendations are supported by available evidence; however, because this paper deals with processes and systems of care, high-quality evidence (eg, controlled trials) is unavailable. In these cases, recommendations represent the consensus opinion of all authors who constitute the Board of Directors of The Anticoagulation Forum, an organization dedicated to optimizing anticoagulation care. The Board is composed of physicians, pharmacists, and nurses with demonstrated expertise and significant collective experience in the management of patients receiving anticoagulation therapy. Recommendations for delivering optimized anticoagulation therapy were developed collaboratively by the authors and are summarized in 9 key areas: (I) Qualifications of Personnel, (II) Supervision, (III) Care Management and Coordination, (IV) Documentation, (V) Patient Education, (VI) Patient Selection and Assessment, (VII) Laboratory Monitoring, (VIII) Initiation and Stabilization of Warfarin Therapy, and (IX) Maintenance of Therapy. Recommendations are intended to inform the development of care systems containing elements with demonstrated benefit in improvement of anticoagulation therapy outcomes. Recommendations for delivering optimized anticoagulation therapy are intended to apply to all clinicians involved in the care of outpatients receiving anticoagulation therapy, regardless of the structure and setting in which that care is delivered. Anticoagulation therapy, although potentially life-saving, has inherent risks. Whether a patient is managed in a solo practice or a specialized anticoagulation management service, a systematic approach to the key elements outlined herein will reduce the likelihood of adverse events. The need for continued research to validate optimal practices for managing anticoagulation therapy is acknowledged.


Perspectives, controversies and directives on pulpal-periodontal relationships.
While established clinical, radiographic and histologic criteria exist to explain the intimate relationship of the pulp and periodontium during pathological states, the recognition, diagnosis and treatment of this perplexing interplay remains a challenge for the practitioner. This dynamic interrelationship is investigated with a focus on simplicity and succinctness to enhance diagnostic probabilities, clarify treatment modalities and provide realistic prognoses in management.


Exploration of the nucleotide binding sites of the isolated ADP/ATP carrier protein from beef heart mitochondria. 1. Probing of the nucleotide sites by Naphthoyl-ATP, a fluorescent nontransportable analogue of ATP.
The ADP/ATP carrier protein was extracted and purified from beef heart mitochondria, and its binding parameters with respect to 3'-O-naphthoyladenosine 5'-triphosphate (N-ATP), a fluorescent nontransportable analogue of ATP, were studied. The binding of N-ATP to the isolated carrier protein was accompanied by a decrease in fluorescence. Conversely, the release of bound N-ATP upon addition of carboxyatractyloside (CATR) or ATP resulted in a fluorescence increase. The bound N-ATP that was released upon addition of an excess of CATR or ATP was referred to as specifically bound N-ATP, i.e., N-ATP bound to the nucleotide sites of the carrier protein. Two classes of binding sites for N-ATP could be identified; the number of high-affinity sites (Kd less than 10 nM) was equal to the number of low-affinity sites (Kd = 0.45 microM). CATR behaved apparently as a noncompetitive inhibitor of the binding of N-ATP. The amount of N-ATP released increased linearly with the amount of CATR added, indicating an extremely high affinity of the carrier protein for CATR. The number of CATR binding sites was equal to half the total number of N-ATP binding sites (high- and low-affinity sites); at saturating concentrations of N-ATP, the binding of 1 mol of CATR resulted in the release of 2 mol of bound N-ATP, one from the high-affinity site and the other from the low-affinity site, showing unambiguously that each CATR site is interacting with a pair of probably interdependent N-ATP sites. A clear competition between N-ATP and ATP for binding to the carrier protein was demonstrated. The Kd values of the high- and low-affinity sites for ATP were less than 50 nM and 5 microM, respectively. In the presence of high concentrations of ATP, the two classes of N-ATP binding sites became indistinguishable, suggesting interconversion. It is proposed that the asymmetry in affinity for N-ATP binding is induced by the binding step itself, the carrier protein exhibiting a negative cooperativity for N-ATP binding.


Respiratory care warrants studies for cost-effectiveness.
The need for careful cost-effectiveness studies in the field of RCS is apparent. Salaries consume most of the cost, and overtrained and expensive personnel may be saturating the work force. Costs for consumable and nonconsumable supplies have not risen out of proportion to general economic inflationary indixes. Close examination is needed of therapeutic modalities that are expensive and that stand on shaky scientific ground. However, the short-term experience of the medical center's multidisciplinary respiratory rehabilitation program has demonstrated that such programs can be worth the costs involved.


Performance evaluation of fusing protected fingerprint minutiae templates on the decision level.
In a biometric authentication system using protected templates, a pseudonymous identifier is the part of a protected template that can be directly compared. Each compared pair of pseudonymous identifiers results in a decision testing whether both identifiers are derived from the same biometric characteristic. Compared to an unprotected system, most existing biometric template protection methods cause to a certain extent degradation in biometric performance. Fusion is therefore a promising way to enhance the biometric performance in template-protected biometric systems. Compared to feature level fusion and score level fusion, decision level fusion has not only the least fusion complexity, but also the maximum interoperability across different biometric features, template protection and recognition algorithms, templates formats, and comparison score rules. However, performance improvement via decision level fusion is not obvious. It is influenced by both the dependency and the performance gap among the conducted tests for fusion. We investigate in this paper several fusion scenarios (multi-sample, multi-instance, multi-sensor, multi-algorithm, and their combinations) on the binary decision level, and evaluate their biometric performance and fusion efficiency on a multi-sensor fingerprint database with 71,994 samples.


Local adaptation to temperature conserves top-down control in a grassland food web.
A fundamental limitation in many climate change experiments is that tests represent relatively short-term 'shock' experiments and so do not incorporate the phenotypic plasticity or evolutionary change that may occur during the gradual process of climate change. However, capturing this aspect of climate change effects in an experimental design is a difficult challenge that few studies have accomplished. I examined the effect of temperature and predator climate history in food webs composed of herbaceous plants, generalist grasshopper herbivores and spider predators across a natural 4.8°C temperature gradient spanning 500 km in northeastern USA. In these grasslands, the effects of rising temperatures on the plant community are indirect and arise via altered predator-herbivore interactions. Experimental warming had no direct effect on grasshoppers, but reduced predation risk effects by causing spiders from all study sites to seek thermal refuge lower in the plant canopy. However, spider thermal tolerance corresponded to spider origin such that spiders from warmer study sites tolerated higher temperatures than spiders from cooler study sites. As a consequence, the magnitude of the indirect effect of spiders on plants did not differ along the temperature gradient, although a reciprocal transplant experiment revealed significantly different effects of spider origin on the magnitude of top-down control. These results suggest that variation in predator response to warming may maintain species interactions and associated food web processes when faced with long term, chronic climate warming.


Nanoporous Alumina Support Covered by Imidazole Moiety-Based Ionic Liquids: Optical Characterization and Application.
This work analyzes chemical surface and optical characteristics of a commercial nanoporous alumina structure (NPAS) as a result of surface coverage by different imidazolium-based ionic liquids (1-butyl-3-metylimidazolium hexafluorophosphate, 3-methyl-1-octylimidazolium hexafluorophosphate, or 1-ethyl-3-methylimidazolium tetrafluoroborate). Optical characteristics of the IL/NPAS samples were determined by photoluminescence (at different excitation wavelengths (from 300 nm to 400 nm), ellipsometry spectroscopy, and light transmittance/reflectance measurements for a range of wavelengths that provide information on modifications related to both visible and near-infrared regions. Chemical surface characterization of the three IL/NPAS samples was performed by X-ray photoelectron spectroscopy (XPS), which indicates almost total support coverage by the ILs. The IL/NPAS analyzed samples exhibit different photoluminescence behavior, high transparency (<85%), and a reflection maximum at wavelength ~380 nm, with slight differences depending on the IL, while the refractive index values are rather similar to those shown by the ILs. Moreover, the illuminated I−V curves (under standard conditions) of the IL/NPAS samples were also measured for determining the efficiency energy conversion to estimate their possible application as solar cells. On the other hand, a computational quantum mechanical modeling method (DFT) was used to establish the most stable bond between the ILs and the NPAS support.


Age nine is possible: Improving age 9 HPV initiation through a national quality improvement initiative during the COVID-19 pandemic.
The American Cancer Society collaborated with a range of healthcare partners in 2020-2022 to implement quality improvement clinical interventions with the goal of improving HPV vaccination rates among adolescents' ages 9-13. 2020 was the first cohort for which partners had been asked to submit HPV rate data for patients' ages 9-12. At least 80% of the partners across all reported project years were able and willing to report HPV rates for these ages. Partners submitted HPV initiation rates at the beginning and end of the 12-month project year along with project activities, including evidence-based interventions (EBIs) implemented. Mean initiation rates for ages 9-10 significantly increased 4.1% during 2020 compared to non-significant rate increases of 2.6% and 2.0% for ages 11-12 and age 13, respectively. In 2021, ages 9-10 initiation saw a non-significant increase of 2.2%, whereas ages 11-12 and age 13 decreased non-significantly by 0.3% and 0.1%, respectively. The 2022 cohort saw significant initiation rate increases of at least 4% across all ages, potentially a promising result of the myriad back on track HPV vaccination campaigns designed to reverse the damage of the COVID-19 pandemic on adolescent immunizations. These findings demonstrate an effective adaptation of quality improvement in increasing HPV vaccination coverage among younger ages even during a national pandemic.


Student Nurses Undertaking Acute Hospital Paid Placements during COVID-19: Rationale for Opting-In? A Qualitative Inquiry.
The research aim was to evaluate the rationale of undergraduate final-year student nurses to undertake paid clinical placements during COVID-19 (Wave 1). The nursing profession reacted innovatively to meet demands placed on the National Health Service during COVID-19. Temporary changes to professional regulation enabled final-year United Kingdom nursing students to voluntarily undertake paid placements in the National Health Service. Neither full-time employees nor full-time students, volunteers undertook a unique hybrid role bolstering the front-line health workforce. Using reflective qualitative inquiry, 17 volunteers evaluated reasoning for entering practice in acute hospitals. Online surveys based around the UK Nursing and Midwifery Council Competency Framework (NMC 2012) were completed weekly for 6 weeks. Data were thematically analysed. Six themes were identified, including sense of duty, and opting-in or out. These highlighted the importance of collaboration and the tripartite relationship between University, host and student during placement, and the influence of these on the learning experience. Several significant insights emerged for nurse education and curricula during pandemics related to patient safety, safety climate and governance. The insights were used to develop a "Student Nurses Placement Framework" with recommendations for Pre-During-Post placement, offering a guide for future nursing workforce recruitment and retention.


Model cell membranes: discerning lipid and protein contributions in shaping the cell.
The high complexity of biological membranes has motivated the development and application of a wide range of model membrane systems to study biochemical and biophysical aspects of membranes in situ under well defined conditions. The aim is to provide fundamental understanding of processes controlled by membrane structure, permeability and curvature as well as membrane proteins by using a wide range of biochemical, biophysical and microscopic techniques. This review gives an overview of some currently used model biomembrane systems. We will also discuss some key membrane protein properties that are relevant for protein-membrane interactions in terms of protein structure and how it is affected by membrane composition, phase behavior and curvature.


Antioxidant effects of water extracts from barley (Hordeum vulgare L.) prepared under different roasting temperatures.
The antioxidant effects of water extracts of roasted barley (WERB) were investigated under different roasting temperatures and compared with those of the water extracts of unroasted barley (WEUB). It was found that the Maillard reaction products increased upon increasing the roasting temperatures. Both WERB and WEUB exhibited significant antioxidant activities in linoleic acid and liposome model systems. Although WERB and WEUB afforded considerable protection against the damage of deoxyribose and proteins, the antioxidant efficiency of roasted samples was weaker than that of unroasted samples because of the reduction of antioxidant components (catechin, tocopherol, and lutein) with increasing roasting temperature. Unroasted samples were more effective in reducing power, quenching free radical, hydroxyl radical, and chelating iron than the roasted samples. The different antioxidant activity among roasted and unroasted barley samples may be partly attributed to the changes in catechin, tocopherol, and lutein contents.


[Helicobacter pylori and gastric cancer: relationship with histological subtype and tumor location].
Helicobacter pylori (HP) has been implicated in the pathogenesis of gastric adenocarcinoma. Published data on HP infection and its association with both histological subtype and tumor localization are contradictory and few data are available on this topic in Spain. The aim of the present study was to evaluate the association of HP infection with histological subtype and tumor localization in a series of patients with gastric adenocarcinoma. We retrospectively reviewed all the patients diagnosed with gastric neoplasms in Hospital del Mar in Barcelona between 1995 and 2001. The histological subtype was established using Lauren's classification. Tissue samples were obtained from the surgical specimen or from endoscopic biopsies. HP infection was histologically determined through hematoxylin-eosin, Masson's trichromic, and Giemsa staining. During the study period, 304 gastric neoplasms, 275 (90.4%) adenocarcinomas, 22 (7.2%) lymphomas, 3 (1.0%) leiomyosarcomas, 2 (0.7%) degenerated gastrointestinal stromal tumors (GIST) and 2 (0.7%) Kaposi's sarcomas were diagnosed. In patients with adenocarcinoma, the mean age at diagnosis was 69 years and most patients were male (62%). A total of 48.1% of the neoplasms were located in the gastric antrum, 23.7% in the body and 19.1% in the fundus (13.6% in the period 1994-1997 and 25.4% in the period 1998-2001, p = 0.018). Intestinal-type gastric carcinoma was observed in 56% of the patients, diffuse-type in 28% and indeterminate-type in 16%. HP infection was confirmed in 69% of the patients (68% in intestinal subtype, 69% in diffuse subtype, and 69% in indeterminate subtype, p = 0.84), and was significantly associated with distal adenocarcinomas vs. proximal adenocarcinomas (73.6% vs 48.6%, p < 0.05). No differences were observed between the histological type of adenocarcinoma and HP infection. In the last few years, the incidence of fundic adenocarcinomas has increased. These tumors show a lower association with HP infection.


Rashba-like spin splitting along three momentum directions in trigonal layered PtBi2.
Spin-orbit coupling (SOC) has gained much attention for its rich physical phenomena and highly promising applications in spintronic devices. The Rashba-type SOC in systems with inversion symmetry breaking is particularly attractive for spintronics applications since it allows for flexible manipulation of spin current by external electric fields. Here, we report the discovery of a giant anisotropic Rashba-like spin splitting along three momentum directions (3D Rashba-like spin splitting) with a helical spin polarization around the M points in the Brillouin zone of trigonal layered PtBi2. Due to its inversion asymmetry and reduced symmetry at the M point, Rashba-type as well as Dresselhaus-type SOC cooperatively yield a 3D spin splitting with αR ≈ 4.36 eV Å in PtBi2. The experimental realization of 3D Rashba-like spin splitting not only has fundamental interests but also paves the way to the future exploration of a new class of material with unprecedented functionalities for spintronics applications.


Boundary-spanning actors in complex adaptive governance systems: The case of multisectoral nutrition.
A growing literature highlights complexity of policy implementation and governance in global health and argues that the processes and outcomes of policies could be improved by explicitly taking this complexity into account. Yet there is a paucity of studies exploring how this can be achieved in everyday practice. This study documents the strategies, tactics, and challenges of boundary-spanning actors working in 4 Sub-Saharan Africa countries who supported the implementation of multisectoral nutrition as part of the African Nutrition Security Partnership in Burkina Faso, Mali, Ethiopia, and Uganda. Three action researchers were posted to these countries during the final 2 years of the project to help the government and its partners implement multisectoral nutrition and document the lessons. Prospective data were collected through participant observation, end-line semistructured interviews, and document analysis. All 4 countries made significant progress despite a wide range of challenges at the individual, organizational, and system levels. The boundary-spanning actors and their collaborators deployed a wide range of strategies but faced significant challenges in playing these unconventional roles. The study concludes that, under the right conditions, intentional boundary spanning can be a feasible and acceptable practice within a multisectoral, complex adaptive system in low- and middle-income countries.


[Long-term venous access].
The authors summarize the technique of placement of long term venous access systems. The complications encountered are described. As an example, the experience of the Institut Jules Bordet in this field is presented.


17beta-oestradiol increases intracellular Ca2+ concentration in rat enterocytes. Potential role of phospholipase C-dependent store-operated Ca2+ influx.
The involvement of the phospholipase C (PLC) pathway in the non-genomic regulation of duodenal cell Ca2+ concentration by 17beta-oestradiol was investigated. The PLC inhibitors neomycin (0.5 mM) and U-73122 (2 microM) suppressed the stimulatory effect of 0.1 nM 17beta-oestradiol on the 45Ca2+ influx into enterocytes isolated from rat duodenum. The hormone (1 pM to 10 nM) increased the formation of 1,2-diacylglycerol in a biphasic pattern, characterized by an early peak at 45 s (+82%) and a later peak at 5 min (+46%). Both PLC inhibitors suppressed the first peak but were unable to block the 17beta-oestradiol effect at 5 min. 17beta-Oestradiol also increased the generation of inositol 1,4,5-trisphosphate within 15 s, with maximal stimulation at 30 s. 17beta-Oestradiol induced a rapid (30 s) and sustained (up to 5 min) increase in the intracellular Ca2+ concentration ([Ca2+]i) of fura 2-loaded enterocytes. The fast rise in [Ca2+]i was specific because other sex steroid hormones were without effect and could be blocked to a great extent by U-73122 (by 86% at 1 min). The effects of 17beta-oestradiol on enterocyte [Ca2+]i were decreased significantly (by 75%) in a Ca2+-free extracellular medium but a pronounced increase in [Ca2+]i was obtained after readmission of Ca2+ to the medium. The latter change was suppressed by 10 microM La3+, whereas nitrendipine (1 microM) and verapamil (10 microM) separately were without effect. The permeability of the 17beta-oestradiol-induced Ca2+ influx pathway to Mn2+ was increased 2.8-fold by treatment with oestrogen. These results suggest the operation of a PLC-dependent store-operated Ca2+ channel mechanism in 17beta-oestradiol regulation of enterocyte extracellular Ca2+ influx.


Prevalence of domestic violence on pregnant women and maternal and neonatal outcomes in Bandar Abbas, Iran.
Pregnancy by itself, imposes great physical and psychological pressures on a person and consequently, coupled with other stressors such as violence, can have adverse effects on the fetus and mother. To assess the prevalence of domestic violence in pregnant women and maternal and infants' outcomes. This is a descriptive study using a questionnaire. Data were collected from 725 women who delivered their babies at Shariati Hospital in Bandar Abbas in the summer and autumn of 2013. The questionnaire consisted of four parts: demographic characteristics, factors affecting violence, areas of violence (physical, emotional, sexual) and maternal and fetal outcomes. Data analysis was performed by SPSS 18 using descriptive statistics, t-test, Chi-square, and logistic regression. The prevalence of physical, sexual and psychological violence were 6.5, 14.8 and 9.9 %, respectively. The variables of age, duration of marriage, previous marriage experience and the husband's addiction, had a significant relationship with applying physical violence of the husband. There was significant correlation between physical violence and maternal outcomes (p<0.000). There was a statistically significant association between physical violence and low birth weight and growth delay in the uterus (p=0.033). Due to the relatively high violence in pregnancy, and its impact on maternal and neonatal outcomes, it is suggested that violence screening programs in the health system and educating health professionals and women at risk and also the implementation of programs to protect these women, can be effective in reducing the cycle of violence and its negative consequences.


Intensifying postfire weather and biological invasion drive species loss in a Mediterranean-type biodiversity hotspot.
Prolonged periods of extreme heat or drought in the first year after fire affect the resilience and diversity of fire-dependent ecosystems by inhibiting seed germination or increasing mortality of seedlings and resprouting individuals. This interaction between weather and fire is of growing concern as climate changes, particularly in systems subject to stand-replacing crown fires, such as most Mediterranean-type ecosystems. We examined the longest running set of permanent vegetation plots in the Fynbos of South Africa (44 y), finding a significant decline in the diversity of plots driven by increasingly severe postfire summer weather events (number of consecutive days with high temperatures and no rain) and legacy effects of historical woody alien plant densities 30 y after clearing. Species that resprout after fire and/or have graminoid or herb growth forms were particularly affected by postfire weather, whereas all species were sensitive to invasive plants. Observed differences in the response of functional types to extreme postfire weather could drive major shifts in ecosystem structure and function such as altered fire behavior, hydrology, and carbon storage. An estimated 0.5 °C increase in maximum temperature tolerance of the species sets unique to each survey further suggests selection for species adapted to hotter conditions. Taken together, our results show climate change impacts on biodiversity in the hyperdiverse Cape Floristic Region and demonstrate an important interaction between extreme weather and disturbance by fire that may make flammable ecosystems particularly sensitive to climate change.


[Mycotic dacryocystitis related to naso-lacrimal stent. Case report].
A nasolacrimal stent was placed in a diabetic woman with a ten-year history of epiphora. Three months later the non-functional stent was removed and taken for histological study. A presumed diagnosis of fungical dacryocystitis was then established. An external dacryocystorhinostomy was performed and the obtained cultures confirmed Candida albicans as the infective agent. Only 1.2% of all dacryocystitis are due to fungal agents. This possibility must be considered when evaluating a routine chronic dacryocystitis. Cultures should be obtained when removing a nasolacrimal stent in order to rule out different causes of nasolacrymal obstruction.


Gene mutations and molecularly targeted therapies in acute myeloid leukemia.
Acute myelogenous leukemia (AML) can progress quickly and without treatment can become fatal in a short period of time. However, over the last 30 years fine-tuning of therapeutics have increased the rates of remission and cure. Cytogenetics and mutational gene profiling, combined with the option of allogeneic hematopoietic stem cell transplantation offered in selected patients have further optimized AML treatment on a risk stratification basis in younger adults. However there is still an unmet medical need for effective therapies in AML since disease relapses in almost half of adult patients becoming refractory to salvage therapy. Improvements in the understanding of molecular biology of cancer and identification of recurrent mutations in AML provide opportunities to develop targeted therapies and improve the clinical outcome. In the spectrum of identified gene mutations, primarily targetable lesions are gain of function mutations of tyrosine kinases FLT3, JAK2 and cKIT for which specific, dual and multi-targeted small molecule inhibitors have been developed. A number of targeted compounds such as sorafenib, quizartinib, lestaurtinib, midostaurin, pacritinib, PLX3397 and CCT137690 are in clinical development. For loss-of-function gene mutations, which are mostly biomarkers of favorable prognosis, combined therapeutic approaches can maximize the therapeutic efficacy of conventional therapy. Apart from mutated gene products, proteins aberrantly overexpressed in AML appear to be clinically significant therapeutic targets. Such a molecule for which targeted inhibitors are currently in clinical development is PLK1. We review characteristic gene mutations, discuss their biological functions and clinical significance and present small molecule compounds in clinical development, which are expected to have a role in treating AML subtypes with characteristic molecular alterations.


Induction of S.cerevisiae MAG 3-methyladenine DNA glycosylase transcript levels in response to DNA damage.
We previously showed that the expression of the Saccharomyces cerevisiae MAG 3-methyladenine (3MeA) DNA glycosylase gene, like that of the E. coli alkA 3MeA DNA glycosylase gene, is induced by alkylating agents. Here we show that the MAG induction mechanism differs from that of alkA, at least in part, because MAG mRNA levels are not only induced by alkylating agents but also by UV light and the UV-mimetic agent 4-nitroquinoline-1-oxide. Unlike some other yeast DNA-damage-inducible genes, MAG expression is not induced by heat shock. The S. cerevisiae MGT1 O6-methylguanine DNA methyltransferase is not involved in regulating MAG gene expression since MAG is efficiently induced in a methyltransferase deficient strain; similarly, MAG glycosylase deficient strains and four other methylmethane sulfonate sensitive strains were normal for alkylation-induced MAG gene expression. However, de novo protein synthesis is required to elevate MAG mRNA levels because MAG induction was abolished in the presence of cycloheximide. MAG mRNA levels were equally well induced in cycling and G1-arrested cells, suggesting that MAG induction is not simply due to a redistribution of cells into a part of the cell cycle which happens to express MAG at high levels, and that the inhibition of DNA synthesis does not act as the inducing signal.


EEG-based Brain-Computer Interface to support post-stroke motor rehabilitation of the upper limb.
Brain-Computer Interfaces (BCIs) process brain activity in real time, and mediate non-muscular interaction between and individual and the environment. The subserving algorithms can be used to provide a quantitative measurement of physiological or pathological cognitive processes - such as Motor Imagery (MI) - and feed it back the user. In this paper we propose the clinical application of a BCI-based rehabilitation device, to promote motor recovery after stroke. The BCI-based device and the therapy exploiting its use follow the same principles that drive classical neuromotor rehabilitation, and (i) provides the physical therapist with a monitoring instrument, to assess the patient's participation in the rehabilitative cognitive exercise; (ii) assists the patient in the practice of MI. The device was installed in the ward of a rehabilitation hospital and a group of 29 patients were involved in its testing. Among them, eight have already undergone a one-month training with the device, as an add-on to the regular therapy. An improved system, which includes analysis of Electromyographic (EMG) patterns and Functional Electrical Stimulation (FES) of the arm muscles, is also under clinical evaluation. We found that the rehabilitation exercise based on BCI-mediated neurofeedback mechanisms enables a better engagement of motor areas with respect to motor imagery alone and thus it can promote neuroplasticity in brain regions affected by a cerebrovascular accident. Preliminary results also suggest that the functional outcome of motor rehabilitation may be improved by the use of the proposed device.


Medroxyprogesterone acetate antagonizes estrogen up-regulation of brain mitochondrial function.
The impact of clinical progestins used in contraception and hormone therapies on the metabolic capacity of the brain has long-term implications for neurological health in pre- and postmenopausal women. Previous analyses indicated that progesterone and 17β-estradiol (E2) sustain and enhance brain mitochondrial energy-transducing capacity. Herein we determined the impact of the clinical progestin, medroxyprogesterone acetate (MPA), on glycolysis, oxidative stress, and mitochondrial function in brain. Ovariectomized female rats were treated with MPA, E2, E2+MPA, or vehicle with ovary-intact rats serving as a positive control. MPA alone and MPA plus E2 resulted in diminished mitochondrial protein levels for pyruvate dehydrogenase, cytochrome oxidase, ATP synthase, manganese-superoxide dismutase, and peroxiredoxin V. MPA alone did not rescue the ovariectomy-induced decrease in mitochondrial bioenergetic function, whereas the coadministration of E2 and MPA exhibited moderate efficacy. However, the coadministration of MPA was detrimental to antioxidant defense, including manganese-superoxide dismutase activity/expression and peroxiredoxin V expression. Accumulated lipid peroxides were cleared by E2 treatment alone but not in combination with MPA. Furthermore, MPA abolished E2-induced enhancement of mitochondrial respiration in primary cultures of the hippocampal neurons and glia. Collectively these findings indicate that the effects of MPA differ significantly from the bioenergetic profile induced by progesterone and that, overall, MPA induced a decline in glycolytic and oxidative phosphorylation protein and activity. These preclinical findings on the basis of acute exposure to MPA raise concerns regarding neurological health after chronic use of MPA in contraceptive and hormone therapy.


Synthesis of modular dipeptide mimetics on the basis of diazabicycloalkanes and derivatives thereof with sulphur containing side chains.
We present the synthesis of new modular dipeptide mimetics based on diazabicycloalkane backbones. These diazabicycloalkanes are ligands for the prostate specific membrane antigen (PSMA), a well known tumor marker. Our previously described synthetic route to enantiomerically pure diazabicycloalkanes is extended to yield polyfunctional diazabicycloalkanes with a modular character using a new ring closing methodology. This, finally, allows us to attach linker moieties to different positions of the diazabicycloalkane scaffold providing conjugation sites to other functional molecules such as markers or cytostatic compounds. Furthermore, successful synthesis of sulphur-containing dipeptide analogues as for example CysX(AA)- or HCysX(AA)-mimetics on the basis of diazabicycloalkanes is described.


Measuring methotrexate polyglutamates in red blood cells: a new LC-MS/MS-based method.
The folate antagonist methotrexate (MTX) is the anchor drug in the treatment of rheumatoid arthritis. The therapeutic effects of MTX are attributed to the intracellular levels of MTX, present in the cell as polyglutamates (MTXPGn). We developed a new liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS)-based assay to separately quantitate MTXPGn in red blood cells using stable-isotope-labelled internal standards. Samples were analyzed by LC-ESI-MS/MS using a Waters Acquity UPLC BEH C18 column with a 5-100% organic gradient of 10 mM ammonium bicarbonate (pH 10) and methanol. The analysis consisted of simple sample preparation and a 6-min run time. Detection was done using a Waters Acquity UPLC coupled to a Waters Quattro Premier XE with electrospray ionization operating in the positive ionization mode. Assay validation was performed following recent Food and Drug Administration guidelines. The method was linear from 1-1,000 nM for all MTXPGn (R(2) > 0.99). The coefficient of variation ranged from 1-4% for intraday precision and 6-15% for interday precision. Samples were stable for at least 1 month at -80 °C. Recovery ranged from 98-100%, and the relative matrix-effect varied from 95-99%. The lower limit of quantitation was 1 nM for each MTXPGn. Fifty patient samples from the tREACH study were analyzed. The MTXPGn concentration and distribution of these samples were comparable with values reported in literature. The developed LC-ESI-MS/MS method for the quantitative measurement of MTXPGn in red blood cells is both sensitive and precise within the clinically relevant range. The method can be easily applied in clinical laboratories due to the combination of simple pre-treatment with robust LC-ESI-MS/MS.


ISAR-REACT 3A: a study of reduced dose of unfractionated heparin in biomarker negative patients undergoing percutaneous coronary intervention.
Although a 140 U/kg dose of unfractionated heparin (UFH) was comparable with bivalirudin in terms of net clinical outcome in the Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment (ISAR-REACT) 3 trial, it was associated with a higher risk of bleeding. We designed this study to assess whether a reduction in the UFH dose from 140 to 100 U/kg is associated with improved net clinical outcome. A total of 2505 biomarker negative patients undergoing percutaneous coronary intervention (PCI) after clopidogrel pre-treatment received a single bolus of 100 U/kg UFH. The primary endpoint was net clinical outcome-a quadruple endpoint of death, myocardial infarction, urgent target-vessel revascularization within 30 days, or in-hospital REPLACE 2 defined major bleeding. The primary comparison was with the historical UFH group of ISAR-REACT 3 (2281 patients). In a second analysis, we checked for non-inferiority against the historical bivalirudin arm of ISAR-REACT 3 (2289 patients). The incidence of the primary endpoint was 7.3% in the lower UFH dose group compared with 8.7% in the higher UFH dose group [hazard ratio (HR) 0.81; 95% confidence interval (CI) 0.67-1.00; P = 0.045]. The incidence of major bleeding was 3.6% in the lower UFH dose group and 4.6% in the higher UFH dose group (HR 0.79; 95% CI 0.59-1.05; P = 0.11). The lower UFH dose met the criterion of non-inferiority compared with bivalirudin (P < 0.001). In biomarker negative patients undergoing PCI after clopidogrel loading, a reduced dose of 100 U/kg UFH provided net clinical benefit compared with the historical control of 140 U/kg UFH in the ISAR-REACT 3 trial. The benefit was mostly driven by reduction in bleeding. URL www.clinicaltrials.gov; Unique identifier NCT00735280.


Novel homo- and heterobinuclear ball-type phthalocyanines: synthesis and electrochemical, electrical, EPR and MCD spectral properties.
The mononuclear Fe(II) phthalocyanine 2 and ball-type homobinuclear Fe(II)-Fe(II) and Cu(II)-Cu(II) phthalocyanines, 3 and 4 respectively, were synthesized from the corresponding 4,4'-[1,1'-methylenebis-(naphthalene-2,1-diyl)]bis(oxy)diphthalonitrile 1, and then ball-type heterobinuclear Fe(II)-Cu(II) phthalocyanine 5 was synthesized from 2. The novel compounds 4 and 5 have been characterized by elemental analysis, UV/vis, IR and MALDI-TOF mass spectroscopies. Electron paramagnetic resonance and magnetic circular dichroism measurements of 3, 4 and 5 were also examined. The voltammetric measurements of the complexes showed the formation of various electrochemically stable ligand- and metal-based mixed-valence species, due to the intramolecular interactions between the two MPc units, especially in ball-type binuclear iron(II) phthalocyanine. Impedance spectroscopy and d.c. conductivity measurements of 4 and 5 were performed as a function of temperature (295-523 K) and frequency (40-10(5) Hz). While room temperature impedance spectra consist of a curved line, a transformation into a full semicircle with increasing temperature was observed for both compounds.


[Sequential sampling plans to Orthezia praelonga Douglas (Hemiptera: Sternorrhyncha, Ortheziidae) in citrus].
The sequential sampling is characterized by using samples of variable sizes, and has the advantage of reducing sampling time and costs if compared to fixed-size sampling. To introduce an adequate management for orthezia, sequential sampling plans were developed for orchards under low and high infestation. Data were collected in Matão, SP, in commercial stands of the orange variety 'Pêra Rio', at five, nine and 15 years of age. Twenty samplings were performed in the whole area of each stand by observing the presence or absence of scales on plants, being plots comprised of ten plants. After observing that in all of the three stands the scale population was distributed according to the contagious model, fitting the Negative Binomial Distribution in most samplings, two sequential sampling plans were constructed according to the Sequential Likelihood Ratio Test (SLRT). To construct these plans an economic threshold of 2% was adopted and the type I and II error probabilities were fixed in alpha = beta = 0.10. Results showed that the maximum numbers of samples expected to determine control need were 172 and 76 samples for stands with low and high infestation, respectively.


Nonsynonymous Variants in PAX4 and GLP1R Are Associated With Type 2 Diabetes in an East Asian Population.
We investigated ethnicity-specific exonic variants of type 2 diabetes (T2D) and its related clinical phenotypes in an East Asian population. We performed whole-exome sequencing in 917 T2D case and control subjects, and the findings were validated by exome array genotyping in 3,026 participants. In silico replication was conducted for seven nonsynonymous variants in an additional 13,122 participants. Single-variant and gene-based association tests for T2D were analyzed. A total of 728,838 variants were identified by whole-exome sequencing. Among nonsynonymous variants, PAX4 Arg192His increased risk of T2D and GLP1R Arg131Gln decreased risk of T2D in genome-wide significance (odds ratio [OR] 1.48, P = 4.47 × 10-16 and OR 0.84, P = 3.55 × 10-8, respectively). Another variant at PAX4 192 codon Arg192Ser was nominally associated with T2D (OR 1.62, P = 5.18 × 10-4). In T2D patients, PAX4 Arg192His was associated with earlier age at diagnosis, and GLP1R Arg131Gln was associated with decreased risk of cardiovascular disease. In control subjects without diabetes, the PAX4 Arg192His was associated with higher fasting glucose and GLP1R Arg131Gln was associated with lower fasting glucose and HbA1c level. Gene-based analysis revealed that SLC30A8 was most significantly associated with decreased risk of T2D (P = 1.0 × 10-4). In summary, we have identified nonsynonymous variants associated with risk of T2D and related phenotypes in Koreans.


The inhibition of mevalonate pathway induces upregulation of NALP3 expression: new insight in the pathogenesis of mevalonate kinase deficiency.
Mevalonate kinase deficiency (MKD) is a rare hereditary auto-inflammatory syndrome due to mutations in mevalonate kinase, the second enzyme of mevalonate pathway of cholesterol, and nonsterol-isoprenoids biosynthesis. The shortage of mevalonate-derived intermediates, and in particular of geranylgeranyl pyrophosphate (GGPP), has been linked with the activation of caspase-1 and thereby with the production of IL-1beta, but the true concatenation of these two events has not been clarified yet. We hypothesized that inflammasomes could mediate the activation of caspase-1 due to the shortage of GGPP. We monitored the expression of the principal proteins (NALP1, NALP3 and IPAF) of the three known inflammasomes, first in a cellular model of MKD and then in two MKD patients, after bacterial lipopolysaccharide (LPS) stimulation. In healthy subjects, alendronate alone induced the expression of NALP1 and NALP3, and then together with LPS it induced a dramatic increase in NALP3 expression. In MKD patients, NALP3 expression was higher than in untreated healthy controls. Our results, although preliminary, showed that the inhibition of the mevalonate pathway led to a hyper-expression of NALP3, suggesting a possible involvement of NALP3-inflammasome in the activation of caspase-1 consequent to GGPP decrement. This is the first time that the involvement of the inflammasome complexes was shown in MKD pathogenesis.


Dreamlike effects of LSD on waking imagery in humans depend on serotonin 2A receptor activation.
Accumulating evidence indicates that the mixed serotonin and dopamine receptor agonist lysergic acid diethylamide (LSD) induces an altered state of consciousness that resembles dreaming. This study aimed to test the hypotheses that LSD produces dreamlike waking imagery and that this imagery depends on 5-HT2A receptor activation and is related to subjective drug effects. Twenty-five healthy subjects performed an audiorecorded guided mental imagery task 7 h after drug administration during three drug conditions: placebo, LSD (100 mcg orally) and LSD together with the 5-HT2A receptor antagonist ketanserin (40 mg orally). Cognitive bizarreness of guided mental imagery reports was quantified as a standardised formal measure of dream mentation. State of consciousness was evaluated using the Altered State of Consciousness (5D-ASC) questionnaire. LSD, compared with placebo, significantly increased cognitive bizarreness (p < 0.001). The LSD-induced increase in cognitive bizarreness was positively correlated with the LSD-induced loss of self-boundaries and cognitive control (p < 0.05). Both LSD-induced increases in cognitive bizarreness and changes in state of consciousness were fully blocked by ketanserin. LSD produced mental imagery similar to dreaming, primarily via activation of the 5-HT2A receptor and in relation to loss of self-boundaries and cognitive control. Future psychopharmacological studies should assess the differential contribution of the D2/D1 and 5-HT1A receptors to cognitive bizarreness.


Solar Ultraviolet Radiation Exposure among Outdoor Workers in Three Canadian Provinces.
Solar ultraviolet radiation (UVR) exposure places outdoor workers at risk of skin cancer and exposure is difficult to control. In response, the Sun Safety at Work Canada (SSAWC) project was undertaken (2014-2016). The purpose of this substudy was to characterize the UVR exposure levels of outdoor workers in the SSAWC project. Thirteen workplaces in the provinces of British Columbia, Ontario, and Nova Scotia participated in an exposure monitoring campaign (late summer/early fall 2016). Study participants were workers from power utilities and municipalities. Participants wore a UVR measurement badge (light-sensitive polysulfone plastic) on their wrist, shoulder, or hardhat. Badge calibration and absorbance measurements were performed in the AusSun Research Lab. Personal UVR doses are presented as standard erythemal doses (SED) and compared with the internationally recommended exposure limit (1.3 SED), as well as to the total available UVR by date. Generalized linear models were used to examine determinants of solar UVR for personal UVR dose (for both SED and percent of ambient UVR). Models considered badge placement, date, province, industry, main job task, and the hours spent outdoors. Mean personal UVR dose of participating workers was 6.1 SED (nearly 5× the recommended limit). Just 14% of workers experienced 'acceptable' levels of solar radiation; 10% were exposed at >10 times the limit. In univariate analyses, workers in Ontario had the highest levels (mean 7.3 SED), but even in the lowest exposed province (British Columbia), the mean personal UVR dose was 4.5 SED. Utility workers had double the exposure of municipal workers (10.4 and 5.5 SED, respectively). In the determinants of exposure models, the differences by province were muted, but utility line workers and those in general maintenance had higher predicted exposures. Those who wore their badge on their hardhat also had higher values of SED in the fully adjusted determinants models. Solar ultraviolet overexposure among outdoor workers is a concern, even in a country like Canada with relatively low ambient UVR. Implementation of sun safety programs should be supported in an effort to reduce exposure in this vulnerable group of workers.


Correlates of Support Utilization After Experiencing a Sexual Assault Among College Women and Men.
Though previous research has examined survivors' use of formal and informal services, less research has looked at whether sexual orientation, race, and different sexual assault types (e.g., coercive) are associated with seeking support services. The purpose of this study is to examine factors associated with utilizing services or support from informal sources (e.g., telling a friend) and formal sources (e.g., psychological counseling) following a sexual assault. Data were gathered in Fall and Spring of 2019-2020 from undergraduate students at a Midwestern university. Logistic regression results showed that heterosexual students had 56% lower odds of using informal supports, while females were 2.05 times more likely to have used informal supports compared to their counterparts. Students who reported more heavy drinking had 37% lower odds of using informal supports compared to their counterparts. Those who experienced physical and incapacitated sexual assault were 2.09 times and 3.60 times more likely to have used informal supports, respectively. Additionally, older students were 1.35 times more likely to have used formal supports compared to younger students, whereas heterosexual students had 67% lower odds of using formal supports compared to sexual minority students. Those with greater PTSD symptoms were 1.07 times more likely to access formal services. Finally, students with greater depressive symptoms had 8% lower odds of using formal supports. Identifying college students who are less likely to access support services following a sexual assault has important implications for targeted prevention and intervention.


Addressing medical needs of adolescents and adults with autism spectrum disorders in a primary care setting.
Little has been reported about how to improve health care access and delivery for adolescents and adults with autism spectrum disorder. To understand the contributions to the health disparities in the autism spectrum disorder population, we conducted two independent research approaches to learn about current medical needs. A retrospective chart review was performed to evaluate medical comorbidities and medication use. A focus group was also created to address barriers faced in providing medical care. Of 126 charts reviewed, 49% (n = 62) had intellectual disability, 49% (n = 62) had attention-deficit hyperactivity disorder, 52% (n = 65) had anxiety, 41% (n = 52) had obesity, 31% (n = 39) with a history of aggressive behavior, 31% (n = 31) had depression, 22% (n = 28) had seizures, and 9% (n = 11) had hypertension. A Medical Regimen Complexity Index score was determined to examine medication use trends in the autism spectrum disorder population. Medical Regimen Complexity Index scores were significantly higher for patients with intellectual disability, patients with seizures, and patients with a history of aggressive behavior. Both the focus group and our pre-visit assessment identified the waiting room and waiting time as barriers to care. Understanding the comorbidities, polypharmacy, and medical barriers should provide a better understanding of the current health care access and delivery needs of adolescents and adults with autism spectrum disorder.


A case of recurrent bleeding stomal varix controlled using embolization with a liquid copolymer: an effective therapy for palliation.
Bleeding stomal varices (BSV) is a common problem in patients undergoing an ileostomy or colostomy. The diagnosis is often delayed as blood loss occurs in small amounts over a period of time, usually from minor anastamosing blood vessels at the ostomy site making it hard to diagnose. Treatment options can be limited in terms of modalities and efficacy. We describe a case of recurrent bleeding from a superior mesenteric vein (SMV) that was inadvertently sewn into the ileostomy site during surgery. Bleeding was initially controlled with percutaneous SMV coil embolization, but the bleeding persisted, only to be controlled finally by embolization using a liquid copolymer. Though the patient was terminally ill, his quality of life significantly improved thereafter, he did not have any further bleeding episodes during 10 months of follow-up. Embolization of a recurrent bleeding stomal varix with a liquid copolymer may be an effective therapeutic option.


T Cell Lymphoma and Leukemia in Severe Combined Immunodeficiency Pigs following Bone Marrow Transplantation: A Case Report.
After the discovery of naturally occurring severe combined immunodeficiency (SCID) within a selection line of pigs at Iowa State University, we found two causative mutations in the Artemis gene: haplotype 12 (ART12) and haplotype 16 (ART16). Bone marrow transplants (BMTs) were performed to create genetically SCID and phenotypically immunocompetent breeding animals to establish a SCID colony for further characterization and research utilization. Of nine original BMT transfer recipients, only four achieved successful engraftment. At approximately 11 months of age, both animals homozygous for the ART16 mutation were diagnosed with T cell lymphoma. One of these ART16/ART16 recipients was a male who received a transplant from a female sibling; the tumors in this recipient consist primarily of Y chromosome-positive cells. The other ART16/ART16 animal also presented with leukemia in addition to T cell lymphoma, while one of the ART12/ART16 compound heterozygote recipients presented with a nephroblastoma at a similar age. Human Artemis SCID patients have reported cases of lymphoma associated with a "leaky" Artemis phenotype. The naturally occurring Artemis SCID pig offers a large animal model more similar to human SCID patients and may offer a naturally occurring cancer model and provides a valuable platform for therapy development.


Association of diabetes and perineural invasion in pancreatic cancer.
Diabetes and perineural invasion are frequently observed in pancreatic cancer. In this study, we tested possible relations between diabetes and perineural invasion in patients with resected pancreatic cancer. We conducted a retrospective study in 544 cases of resected pancreatic adenocarcinoma seen at the University of Texas MD Anderson Cancer Center during 1996-2011. Information on tumor characteristics, diabetes history, and survival time was collected by personal interview and medical record review. Patients with diabetes before or at the time of the pancreatic cancer diagnosis were considered diabetes only. Pearson χ(2) test was used to compare categorical variables in diabetic and nondiabetic groups. Kaplan-Meier plot, log-rank test, and Cox proportional regression models were applied in survival analysis. The prevalence of diabetes and perineural invasion was 26.5% and 86.9%, respectively, in this study population. Patients with diabetes had a significantly higher prevalence of perineural invasion (92.4%) than those without diabetes (85%) (P = 0.025, χ(2) test). Diabetes was not associated with other pathological characteristics of the tumor, such as tumor size, lymphovascular invasion, tumor grade, lymph node metastasis, and resection margin status. Diabetic patients had a significantly lower frequency of abdominal pain (P = 0.01), but a slightly higher frequency of weight loss (P = 0.078) as early symptoms of their cancer. Both diabetes and perineural invasion were related to worse survival and increased risk of death after adjusting for tumor grade and margin and node status (P = 0.036 and 0.019, respectively). The observed associations of diabetes and perineural invasion as well as reduced frequency of pain as early symptom of pancreatic cancer support the hypothesis that diabetes may contribute to pancreatic progression via the mechanism of nerve damage.


Neopterin, a marker of cell-mediated immune activation in human pregnancy.
High neopterin excretion is closely associated with activation of cell-mediated immunity. We studied urine and serum neopterin concentrations and serum interferon-gamma concentrations in normal pregnant women. In our study population, neopterin concentrations exceeded the normal range in 663 of 840 samples (79%). Neopterin levels increased with the time of pregnancy. Serum samples drawn from women in the third trimester of pregnancy also showed high neopterin concentrations in almost all cases; however, no circulating interferon-gamma was detected. Whereas neopterin is able to penetrate into the blood stream because of its small size (M = 253 D), diffusion of interferon-gamma is limited. Raised neopterin levels provide evidence for activated cell-mediated immunity during pregnancy.


MicroRNA-378 Suppressed Osteogenesis of MSCs and Impaired Bone Formation via Inactivating Wnt/β-Catenin Signaling.
MicroRNAs (miRNAs) have been reported to serve as silencers to repress gene expression at post-transcriptional levels. Multiple miRNAs have been demonstrated to play important roles in osteogenesis. MicroRNA (miR)-378, a conserved miRNA, was reported to mediate bone metabolism and influence bone development, but the detailed function and underlying mechanism remain obscure. In this study, the miR-378 transgenic (TG) mouse was developed to study the role of miR-378 in osteogenic differentiation as well as bone formation. The abnormal bone tissues and impaired bone quality were displayed in the miR-378 TG mice, and a delayed healing effect was observed during bone fracture of the miR-378 TG mice. The osteogenic differentiation of mesenchymal stem cells (MSCs) derived from this TG mouse was also inhibited. We also found that miR-378 mimics suppressed, whereas anti-miR-378 promoted osteogenesis of human MSCs. Two Wnt family members, Wnt6 and Wnt10a, were identified as bona fide targets of miR-378, and their expression was decreased by this miRNA, which eventually induced the inactivation of Wnt/β-catenin signaling. Finally, the short hairpin (sh)-miR-378-modified MSCs were locally injected into the fracture sites in an established mouse fracture model. The results indicated that miR-378 inhibitor therapy could promote bone formation and stimulate the healing process in vivo. In conclusion, miR-378 suppressed osteogenesis and bone formation via inactivating Wnt/β-catenin signaling, suggesting that miR-378 may be a potential therapeutic target for bone diseases.


Stability analysis of a quantum cascade laser subject to phase-conjugate feedback.
We investigate the stability boundaries of a quantum cascade laser subject to phase-conjugate optical feedback. From a three-level model, we reduce our set of equations to the usual modified Lang-Kobayashi equations describing a semiconductor laser subject to phase-conjugate feedback. We then determine the Hopf bifurcation conditions, which we explore by using asymptotic methods. In the limit of large delays, we find approximations of the first Hopf bifurcation that is responsible for the destabilization of the system. We obtain an expression that depends only on three parameters: the feedback strength, the line-width enhancement factor, and the pump current. From this expression, we study the stability boundaries of our system. We compare our results with the initial three-level model using a continuation method. We find qualitative and quantitative agreements of the stability boundaries with the two methods. Finally, we compare our findings with the ones obtained for a quantum cascade laser subject to conventional optical feedback.


Long term home parenteral nutrition using a subcutaneous venous access.
Home parenteral nutrition (HPN) utilising a subcutaneous venous access (SVA) infusion system (port-a-cath((R)) (PAC)), allows patients with a nonfunctioning bowel to lead a relatively normal life with full nutritional support. A patient with pseudo-obstruction of the bowel due to scleroderma was treated with HPN for 1192 consecutive days. During this time the patient underwent 6 catheter or port changes due to occlusion of the infusion system. The infusion regime was modified several times in an attempt to prevent occlusion. Infusing carbohydrate and protein daily, with a lipid infusion twice weekly increased the patency of the infusion system. In 2 other patients, rinsing the infusion system with 2ml of a 45% alcohol solution after use increased the patency of the infusion system further. This regime has now been in use for 924 consecutive days with no occlusions.


Evidence to support common application switching behaviour on smartphones.
We find evidence to support common behaviour in smartphone usage based on analysis of application (app) switching. This is an overlooked aspect of smartphone usage that gives additional insight beyond screen time and the particular apps that are accessed. Using a dataset of usage behaviour from 53 participants over a six-week period, we find strong similarity in the structure of networks built from app switching, despite diversity in the apps used, and the volume of app switching. App switch networks exhibit small-world, broad-scale network features, with a rapid popularity decay, suggesting that preferential attachment may drive next-app decision-making.


Effects of molybdate, tungstate, and selenium compounds on formate dehydrogenase and other enzyme systems in Escherichia coli.
The role of selenium and molybdenum in the metabolism of Escherichia coli was explored by growing cells in a simple salts medium and examining the metabolic consequences of altering the concentration of molybdenum and selenium compounds in the medium. The addition of tungstate increased the molybdate deficiency of this medium, as reflected by lowered levels of enzyme systems previously recognized to require compounds of molybdenum and selenium for their formation [formate-dependent oxygen reduction, formate dehydrogenase (FDH) (EC 220.127.116.11), and nitrate reductase (EC 22.214.171.124)]. The requirement for selenium and molybdenum appears to be unique to the enzymes of formate and nitrate metabolism since molybdate- and selenite-deficient medium had no effect on the level of several dehydrogenase and oxidase systems, for which the electron donors were reduced nicotinamide adenine dinucleotide, succinate, d- or l-lactate, and glycerol. In addition, no effect was observed on the growth rate or cell yield with any carbon source tested (glucose, glycerol, dl-lactate, acetate, succinate, and l-malate) when the medium was deficient in molybdenum and selenium. dl-Selenocystine was about as effective as selenite in stimulating the formation of formate dehydrogenase, whereas dl-selenomethionine was only 1% as effective. In aerobic cells, an amount of FDH was formed such that 3,200 or 3,800 moles of formate were oxidized per min per mole of added selenium (added as dl-selenocystine or selenite, respectively).


Penetrant shape effects on activated dynamics and selectivity in polymer melts and networks based on self-consistent cooperative hopping theory.
We generalize and apply the microscopic self-consistent cooperative hopping theory for activated penetrant dynamics in polymer melts and crosslinked networks to address the role of highly variable non-spherical molecular shape. The focus is on vastly different shaped penetrants that have identical space filling volume in order to isolate how non-spherical shape explicitly modifies dynamics over a wide range of temperature down to the kinetic glass transition temperature. The theory relates intramolecular and intermolecular structure and kinetic constraints, and reveals how different solvation packing of polymer monomers around variable shaped penetrants impact penetrant hopping. A highly shape-dependent penetrant activated relaxation, including alpha time decoupling and trajectory level cooperativity of the hopping process, is predicted in the deeply supercooled regime for relatively larger penetrants which is sensitive to whether the polymer matrix is a melt or heavily crosslinked network. In contrast, for smaller size penetrants or at high/medium temperatures the effect of isochoric penetrant shape is relatively weak. We propose an aspect ratio variable that organizes how penetrant shape influences the activated relaxation times, leading to a (near) collapse or master curve. The relative absolute values of the penetrant relaxation time (inverse hopping rate) in polymer melts versus in crosslinked networks are found to be opposite when compared at a common absolute temperature versus when they are compared at a fixed value of distance from the glass transition based on the variable Tg/T with Tg the glass transition temperature. Quantitative comparison with recent diffusion experiments on chemically complex molecular penetrants of variable shape but fixed volume in crosslinked networks reveals good agreement, and testable new predictions are made. Extension of the theoretical approach to more complex systems of high experimental interest are discussed, including applications to realize selective transport in membrane separation applications.


Treatment of arteriovenous malformation of the brain--preliminary experience.
With the availability of new techniques, such as intravascular embolisation and radiosurgery, the therapeutic approach to arteriovenous malformations (AVMs) of the brain has recently been modified. The present study reports the authors, experiences in treating AVMs over the past 13 years. Spetzler-Martin grading of AVMs was I and II in 19 cases, III in 12, IV in 5 and V in 1 case. Four therapeutic regimens were utilised: surgical resection alone, embolisation and resection, and radiosurgery alone or after surgical resection. Generally, for low-grade AVMs (Spetzler-Martin grades I, II and III), the therapeutic choice was surgical resection in 27 cases, in combination with pre-operative embolisation in two of these patients. Two cases received radiotherapy only and one case received radiosurgery after embolisation, while one case was treated conservatively. Of the five cases of grade IV, four required surgical treatment, whereas the fifth case was treated conservatively. Favourable results (good recovery and moderate disability) were obtained in 96% of the low-grade AVMs as compared with the high-grade AVMs (66%) that had a poor outcome (due to primary brain damage resulting from haemorrhage at the onset in three cases and due to postoperative re-bleeding in one case). This report summarises preliminary experience in treating intracranial AVMs by surgical resection, intravascular embolisation and radiotherapy. Good therapeutic results can be expected by combining these therapeutic modalities.


Increased CO2 emissions surpass reductions of non-CO2 emissions more under higher experimental warming in an alpine meadow.
It is well documented that warming can accelerate greenhouse gas (GHG) emissions, further inducing a positive feedback and reinforcing future climate warming. However, how different kinds of GHGs respond to various warming magnitudes remains largely unclear, especially in the cold regions that are more sensitive to climate warming. Here, we concurrently measured carbon dioxide (CO2), methane (CH4), and nitrous oxide (N2O) fluxes and their total balance in an alpine meadow in response to three levels of warming (ambient, +1.5 °C, +3.0 °C). We found warming-induced increases in CH4 uptake, decreases in N2O emissions and increases in CO2 emissions at the annual basis. Expressed as CO2-equivalents with a global warming potential of 100 years (GWP100), the enhancement of CH4 uptake and reduction of N2O emissions offset only 9% of the warming-induced increase in CO2 emissions for 1.5 °C warming, and only 7% for 3.0 °C warming. CO2 emissions were strongly stimulated, leading to a significantly positive feedback to climate system, for 3.0 °C warming but less for 1.5 °C warming. The warming with 3.0 °C altered the total GHG balance mainly by stimulating CO2 emissions in the non-growing season due to warmer soil temperatures, longer unfrozen period, and increased soil water content. The findings provide an empirical evidence that warming beyond global 2 °C target can trigger a positive GHG-climate feedback and highlight the contribution from non-growing season to this positive feedback loop in cold ecosystems.


Evaluation of familial Mediterranean fever patients concomitant with juvenile spondyloarthropathy.
Familial Mediterranean fever (FMF) may present with various concomitant diseases. This study aims to evaluate the clinical characteristics of patients with FMF with Juvenile Spondyloarthropathy (jSpA). Thirty-two patients diagnosed with FMF/jSpA, sixty-four with FMF, and fifty-four with jSpA were included in this retrospective study. Three patient groups were compared in terms of clinical and laboratory features. The mean ages of patients in the FMF/jSpA, FMF and jSpA groups were 15.75(11.50-19.83), 15,41(6.83-21.50), and 16(9-22) years, respectively. Chronic arthritis (OR: 0.11, p = .049), erythrocyte sedimentation rate values (OR:1.07, p = .011), and C-reactive protein values (OR:1,08, p: .039) of the patients in remission period were found higher, the international severity scores for FMF (ISSF) before and after colchicine treatment (OR: 1.16, p: .021, OR: 2,21, p: .012) were higher in the FMF/jSpA group compared to FMF. Plantar fasciitis was more common and HLA-B27 positivity rate was lower in the FMF/jSpA group (OR:0.08, p = .024), (OR:4.71, p = .002) compared to jSpA. FMF/jSpA patients were divided as previous diagnosed FMF and jSpA.The diagnosis of jSpA was at a younger age(p = .002), Juvenile arthritis damage index-articular(p = 0.022) and extraarticular(p = .026), and the rate of biologic drug usage(p = .015) were higher in the previous jSpA group. The number of FMF attacks before colchicine was lower in the previous jSpA group(p = .02). Our findings suggest that both classical FMF and jSpA findings were lower in patients with FMF/jSpA. Patients who were diagnosed with jSpA at an early age and who had enthesitis and plantar fasciitis should also be evaluated in terms of FMF.


The pharmacology of voltage-gated sodium channel activators.
Toxins and venom components that target voltage-gated sodium (NaV) channels have evolved numerous times due to the importance of this class of ion channels in the normal physiological function of peripheral and central neurons as well as cardiac and skeletal muscle. NaV channel activators in particular have been isolated from the venom of spiders, wasps, snakes, scorpions, cone snails and sea anemone and are also produced by plants, bacteria and algae. These compounds have provided key insight into the molecular structure, function and pathophysiological roles of NaV channels and are important tools due to their at times exquisite subtype-selectivity. We review the pharmacology of NaV channel activators with particular emphasis on mammalian isoforms and discuss putative applications for these compounds. This article is part of the Special Issue entitled 'Venom-derived Peptides as Pharmacological Tools.'


PD-1 Expression in Pre-Treatment Follicular Lymphoma Predicts the Risk of Subsequent High-Grade Transformation.
Follicular lymphoma (FL) is an indolent, yet generally incurable neoplasia with a median survival exceeding 10 years. However, a subset of FL patients experiences histological transformation (HT) to a more aggressive lymphoma, in the majority of cases to diffuse large B-cell lymphoma (DLBCL). This affects both the clinical course and the prognostic outcome, resulting in a markedly reduced survival after transformation. Thus, early risk stratification and prediction of patients at risk of HT would be highly valuable in the clinical setting. Here, we investigated the potential of the immune inhibitory programmed death 1 (PD-1) receptor as a biomarker predictive of HT. Immunohistochemical staining and quantification by digital image analysis of PD-1 was performed on diagnostic tumor-tissue samples from FL patients with and without subsequent transformation (n=34 and n=46, respectively), and on paired samples from the transformed lymphoma (n=34). At the time of initial FL diagnosis, samples from patients with subsequent HT had significantly higher tumor-tissue expression of PD-1 compared with diagnostic FL samples from patients without subsequent HT (p=0.010). At the time of transformation, PD-1 expression was significantly reduced (p<0.001). No difference was observed in intra-follicular PD-1 expression at FL diagnosis between samples from patients with or without HT; however, high intra-follicular levels of PD-1 were associated with significantly shorter transformation-free survival times (p<0.043). Our data suggest that pre-treatment tumor-tissue PD-1 expression already predicts the risk of subsequent transformation to DLBCL, as early as the time of FL diagnosis.


Gas chromatographic determination of methoxyacetic and ethoxyacetic acid in urine.
Methoxyacetic acid (MAA) and ethoxyacetic acid (EAA), the major metabolites of, respectively, ethylene glycol monomethyl ether and ethylene glycol monoethyl ether and their acetates, are determined by gas chromatography after extraction from urine and methylation using 2-furoic acid (2-FA) as an internal standard. The mean recoveries (n = 30) from urine of MAA, EAA, and 2-FA are 31.4 +/- 7.0%, 62.5 +/- 13.4%, and 58.4 +/- 8.7%, respectively. The recoveries decreased (p less than 0.001), however, as the total amount of acids increased. Standard curves for MAA and EAA in urine are presented. The detection limits of MAA and EAA are 0.15 and 0.07 mg/l. Intra-assay variation for MAA and EAA was 6.0 +/- 2.5% and 6.4 +/- 2.8% and inter-assay variation was 6.2 +/- 2.2% and 8.9 +/- 2.4%. When volunteers were exposed to air containing ethylene glycol monoethyl ether (20 mg/m3), urinary concentration of EAA rose significantly one hour after the exposure period (2.39 +/- 1.03 v less than or equal to 0.07 mg/l, t = 5.2, p less than 0.005).


A phase I dose escalation study of the matrix metalloproteinase inhibitor BAY 12-9566 administered orally in patients with advanced solid tumours.
This phase I study was performed to evaluate the safety, tolerability, and efficacy of the oral matrix metalloproteinase inhibitor BAY 12-9566 in patients with advanced solid tumours, and to identify the maximum tolerated dose and dose for use in subsequent studies. BAY 12-9566 was administered to 29 patients at doses ranging from 100 mg o.d. to 1600 mg (given either 400 mg q.i.d. or 800 mg b.i.d.). Blood samples for pharmacokinetic analyses were drawn on days 1-5, day 15 and days 29 and 30. Patients were continued on daily oral treatment of BAY 12-9566 until a dose limiting toxicity or tumour progression occurred. A maximum tolerated dose was not defined because plasma levels of BAY 12-9566 could not be sufficiently increased, even with escalating doses of drug. Pharmacokinetic analysis suggested that absorption was saturable at higher doses. The predominant toxicities related to drug were asymptomatic reversible effects on platelets and transaminases and mild anemia. There were no significant musculoskeletal toxicities. No objective responses were seen at the doses tested, but stable disease was observed in some patients based on tumour measurements. The recommended dose of BAY 12-9566 for further studies is 800 mg b.i.d. as this dose provides maximal plasma levels that can be achieved with a convenient dosing schedule for a chronically administered oral agent.


[Cytokine regulation of immune response in patients with chronic hepatitis C].
To evaluate content of interleukines (IL-1, IL-2, IL-4 and IL-6) and tumor necrosis factor (TNF) in patients with chronic hepatitis C (CHC), 72 CHC patients (37 males and 35 females, mean age 37.2 +/- 4.8 years) were examined. The control group consisted of 20 healthy donors (mean age 25.5 +/- 2.3 years). It was found that low levels of IL-1, IL-2, IL-6, TNF evidence for weak immune response which means long-term virus circulation and active replication. The highest concentrations of the above cytokines correspond to low replicative activity while high IL-4 levels point to active virus replication. IL-1, IL-2, IL-4, IL-6, TNF were high in patients with high cytolysis. Cytokine regulation of immune response can be used for assessment of the effectiveness of antiviral and immunocorrective therapy.


In-vitro pulsatile flow visualization studies in a pulmonary artery model.
In-vitro pulsatile flow visualization studies were conducted in an adult-sized pulmonary artery model to observe the effects of valvular pulmonic stenosis on the flow fields of the main, left and right pulmonary arteries. The flow patterns revealed that as the degree of stenosis increased, the jet-type flow created by the valve became narrower, and it impinged on the far (distal) wall of the left pulmonary artery further downstream from the junction of the bifurcation. This in turn led to larger regions of disturbed turbulent flow, as well as helical-type secondary flow motions in the left pulmonary artery, compared to the right pulmonary artery. The flow field in the main pulmonary artery also became more disturbed and turbulent, especially during peak systole and the deceleration phase. The flow visualization observations have been valuable in helping to conduct further quantitative studies such as pressure and velocity field mapping. Such studies are important to understanding the fluid mechanics characteristics of the main pulmonary artery and its two major branches.


Selective immunoglobulin M deficiency in an adult with Streptococcus pneumoniae sepsis and invasive aspergillosis.
Primary selective immunoglobulin (Ig) M deficiency usually presents early in life with recurrent or severe infections caused by encapsulated and gram-negative organisms. Primary selective IgM deficiency in adults is rare and is usually associated with autoimmune diseases or malignant neoplasm. We performed an extensive immunological analysis of innate and adaptive immunity in an adult patient with possible primary selective IgM deficiency who presented with life-threatening Streptococcus pneumoniae septic shock and invasive Aspergillus fumigatus infection. The patient had no evidence of autoimmune disease or malignant neoplasm. Serum IgG, IgA, and IgE were normal; however, serum IgM levels and specific antibody titers against all 14 pneumococcal polysaccharide serotypes were consistently low. Complement CH50, C3, C4, and neutrophil phagocytosis and oxidative burst were normal. Toll-like receptor expression on monocytes was also normal. Therefore, adult patients with serious life-threatening and unusual infections should be investigated for possible selective primary IgM deficiency.


Preliminary Study on the Host Response to Bivalent and Monovalent Autogenous Vaccines against Mycoplasma agalactiae in Dairy Sheep.
In Italy, dairy sheep farming represents a vital agro-industry sector, but it is still challenged by contagious agalactia (CA), which is endemic there, and vaccination is the most economical and sustainable tool for control. This study aimed to evaluate the combined Mycoplasma agalactiae (Ma)-Staphylococcus aureus (Sa) vaccine (Ma-Sa) against the Ma monovalent vaccine in ewes. Twelve primiparous Ma-free ewes were randomly grouped into three equal groups: first, the control group injected with placebo, second, the group vaccinated with the Ma monovalent vaccine, and third, the group vaccinated with Ma-Sa combined vaccine, with two S/C doses at 45-day intervals. The animals were examined for serological, hematological, and somatic cell count (SCC) changes for 17 successive weeks. A significant increase in anti-Ma antibody mean titers, leukocytes, and platelets was observed in the vaccinated animals, with the highest values in those who received the combined vaccine. Neutrophils were high only in the animals who received the combined vaccine. SCC was lower in the vaccinated animals during the first six weeks. This study concludes that the combined Ma-Sa vaccines enhance immune response and potentiate its efficacy against Ma. This improvement might be attributed to the sensitization/activation effect of S. aureus on platelets, which are recoded to act as a key regulator for the coordination of all components of the innate immune system. Even though this study included a small number of animals, its findings about the potentialities of this inactivated vaccine in the control of CA are strongly encouraging. Further confirmation might be needed through additional replicates and a challenge study is needed before proceeding with widespread use.


The stem region of the sulfotransferase GlcNAc6ST-1 is a determinant of substrate specificity.
The GlcNAc-6-sulfotransferases are a family of Golgi-resident enzymes that modulate glycan function. Two members of this family, GlcNAc6ST-1 and -2, collaborate in the biosynthesis of ligands for the leukocyte adhesion molecule L-selectin. Although their biochemical properties are similar in vitro, the enzymes have distinct glycoprotein substrate preferences in vivo. The sulfotransferases share similar overall architecture with the exception of an extended stem region in GlcNAc6ST-1 that is absent in GlcNAc6ST-2. In this study we probed the importance of the stem region with respect to substrate preference, localization, and oligomerization. Analysis of truncation mutants demonstrated that perturbation of the stem region of GlcNAc6ST-1 affects the cellular substrate preference of the enzyme without altering its retention within the Golgi. A chimeric enzyme comprising the stem region of GlcNAc6ST-1 inserted between the catalytic and transmembrane domains of GlcNAc6ST-2 had the same substrate preference as native GlcNAc6ST-1. In cells, GlcNAc6ST-1 exists as a dimer; two cysteine residues within the stem and transmembrane domain were found to be critical for dimerization. However, disruption of the dimer by mutagenesis did not affect either localization or substrate preference. Collectively, these results indicate that the stem region of GlcNAc6ST-1 influences substrate specificity, independent of its role in dimerization or Golgi retention.