A scalable implementation of the recursive least-squares algorithm for training spiking neural networks.
Training spiking recurrent neural networks on neuronal recordings or behavioral tasks has become a popular way to study computations performed by the nervous system. As the size and complexity of neural recordings increase, there is a need for efficient algorithms that can train models in a short period of time using minimal resources. We present optimized CPU and GPU implementations of the recursive least-squares algorithm in spiking neural networks. The GPU implementation can train networks of one million neurons, with 100 million plastic synapses and a billion static synapses, about 1,000 times faster than an unoptimized reference CPU implementation. We demonstrate the code's utility by training a network, in less than an hour, to reproduce the activity of > 66, 000 recorded neurons of a mouse performing a decision-making task. The fast implementation enables a more interactive in-silico study of the dynamics and connectivity underlying multi-area computations. It also admits the possibility to train models as in-vivo experiments are being conducted, thus closing the loop between modeling and experiments.


Neural inference at the frontier of energy, space, and time.
Computing, since its inception, has been processor-centric, with memory separated from compute. Inspired by the organic brain and optimized for inorganic silicon, NorthPole is a neural inference architecture that blurs this boundary by eliminating off-chip memory, intertwining compute with memory on-chip, and appearing externally as an active memory chip. NorthPole is a low-precision, massively parallel, densely interconnected, energy-efficient, and spatial computing architecture with a co-optimized, high-utilization programming model. On the ResNet50 benchmark image classification network, relative to a graphics processing unit (GPU) that uses a comparable 12-nanometer technology process, NorthPole achieves a 25 times higher energy metric of frames per second (FPS) per watt, a 5 times higher space metric of FPS per transistor, and a 22 times lower time metric of latency. Similar results are reported for the Yolo-v4 detection network. NorthPole outperforms all prevalent architectures, even those that use more-advanced technology processes.


Physical and functional interactions between STAT3 and ZIP kinase.
Signal transducer and activator of transcription 3 (STAT3) is a latent cytoplasmic transcription factor that can be activated by cytokines and growth factors. It plays important roles in cell growth, apoptosis and cell transformation, and is constitutively active in a variety of tumor cells. In this study, we provide evidence that zipper-interacting protein kinase (ZIPK) interacts physically with STAT3. ZIPK specifically interacted with STAT3, and did not bind to STAT1, STAT4, STAT5a, STAT5b or STAT6. ZIPK phosphorylated STAT3 on serine 727 (Ser727) and enhanced STAT3 transcriptional activity. Small interfering RNA-mediated reduction of ZIPK expression decreased leukemia inhibitory factor (LIF)- and IL-6-induced STAT3-dependent transcription. Furthermore, LIF- and IL-6-mediated STAT3 activation stimulated ZIPK activity. Taken together, our data suggest that ZIPK interacts with STAT3 within the nucleus to regulate the transcriptional activity of STAT3 via phosphorylation of Ser727.


Asymptomatic urinary tract infection caused by Shigella sonnei.
The first case of asymptomatic urinary tract infection caused by Shigella sonnei in a patient, a 74-yr-old man, who was not a faecal carrier and had no history of dysentery is reported. Treatment with pivmecillinam 400 mg 3 times daily for 14 days was instituted and the bacteria were eradicated. The time and source of infection is unknown.


[Prognostic factors in elderly patient meningioma].
Frequently, therapeutic decisions must be made in order to manage meningioma in geriatric patients. This study analyzes the prognostic factors, as well as the Clinical Radiological Grading Score (CRGS) as a complement to make therapeutic decisions. A retrospective study was conducted between 2009 and 2010. The study population consisted of 28 patients over 65 years of age. We analyzed clinical, imaging and histopathological factors. We used the chi-squared test and the Fisher exact test for quantitative variables, as well as the Mann-Whitney U for qualitative variables. Overall mortality at 3, 6 and 12 months of follow-up was 7.14, 10.71 and 14.28 %, respectively. The analysis revealed that performance status with Karnofsky scale (p = 0.02), the location of the lesion (p = 0.002), histopathological malignancy grade (p = 0.038), and a score lower than 10 on the CRGS (p = 0.003) were associated with poor prognosis. The neurosurgical management of geriatric patients is a therapeutic option with a favorable prognosis in patients with a score equal to or greater than 10 and those with adequate functional status.


Molecular characterization of a cytosolic manganese superoxide dismutase from the Chinese mitten crab, Eriocheir sinensis.
A cytosolic manganese superoxide dismutase gene (Es-cMnSOD) was cloned from the Chinese mitten crab Eriocheir sinensis, using reverse transcription-polymerase chain reaction and the rapid amplification of cDNA ends. The open reading frame of Es-cMnSOD is 867 bp in length and encodes a 288-amino acid protein without a signal peptide. The calculated molecular mass of the translated protein of Es-cMnSOD is 31.43 kDa, with an estimated isoelectric point of 6.30. The deduced amino acid sequence of Es-cMnSOD has similarities of 90, 89, 84, 87, and 81% to those of white shrimp Litopenaeus vannamei MnSOD, black tiger shrimp Penaeus monodon MnSOD, giant freshwater prawn Macrobrachium rosenbergii MnSOD, blue crab Callinectes sapidus MnSOD, and red swamp crayfish Procambarus clarkii MnSOD, respectively. Es-cMnSOD contains a manganese superoxide dismutase domain (DVWEHAYY) and 4 conserved amino acids responsible for binding manganese. Es-cMnSOD was expressed in the hemocytes, eyestalk, muscle, intestine, gill, and hepatopancreas. Es-cMnSOD transcripts in hemocytes of E. sinensis increased at 1.5 and 48 h after injection of Aeromonas hydrophila, indicating that the induction of the SOD system response occurred within a short period of time. This study suggests that MnSOD may play a critical role in crab immunity, allowing efficient activation of an early innate immune response in the crab.


Age and Influenza-Specific Pre-Vaccination Antibodies Strongly Affect Influenza Vaccine Responses in the Icelandic Population whereas Disease and Medication Have Small Effects.
Influenza vaccination remains the best strategy for the prevention of influenza virus-related disease and reduction of disease severity and mortality. However, there is large individual variation in influenza vaccine responses. In this study, we investigated the effects of gender, age, underlying diseases, and medication on vaccine responses in 1,852 Icelanders of broad age range who received trivalent inactivated influenza virus vaccination in 2012, 2013, or 2015. Hemagglutination inhibition (HAI) and microneutralization (MN) titers were measured in pre- and post-vaccination sera. Of the variables tested, the strongest association was with level of pre-vaccination titer that explained a major part of the variance observed in post-vaccination titers, ranging from 19 to 29%, and from 7 to 21% in fold change (FC), depending on the strain and serological (HAI or MN) analysis performed. Thus, increasing pre-vaccination titer associated with decreasing FC (P = 1.1 × 10-99-8.6 × 10-30) and increasing post-vaccination titer (P = 2.1 × 10-159-1.1 × 10-123). Questionnaires completed by 87% of the participants revealed that post-vaccination HAI titer showed association with repeated previous influenza vaccinations. Gender had no effect on vaccine response whereas age had a strong effect and explained 1.6-3.1% of HAI post-vaccination titer variance and 3.1% of H1N1 MN titer variance. Vaccine response, both fold increase and seroprotection rate (percentage of individuals reaching HAI ≥ 40 or MN ≥ 20), was higher in vaccinees ≤37 years of age (YoA) than all other age groups. Furthermore, a reduction was observed in the H1N1 MN titer in people ≥63 YoA, demonstrating a decreased neutralizing functionality of vaccine-induced antibodies at older age. We tested the effects of underlying autoimmune diseases, asthma and allergic diseases and did not observe significant associations with vaccine responses. Intake of immune modulating medication did not show any association. Taken together, our results show that previous encounter of influenza vaccination or infection, reflected in high HAI and MN pre-vaccination titer has the strongest negative effect on vaccine responses measured as FC and the strongest positive effect on post-vaccination titer. Increasing age had also an effect but not gender, underlying disease or medication.


Half a Century of Research on Membrane-Containing Bacteriophages: Bringing New Concepts to Modern Virology.
Half a century of research on membrane-containing phages has had a major impact on virology, providing new insights into virus diversity, evolution and ecological importance. The recent revolutionary technical advances in imaging, sequencing and lipid analysis have significantly boosted the depth and volume of knowledge on these viruses. This has resulted in new concepts of virus assembly, understanding of virion stability and dynamics, and the description of novel processes for viral genome packaging and membrane-driven genome delivery to the host. The detailed analyses of such processes have given novel insights into DNA transport across the protein-rich lipid bilayer and the transformation of spherical membrane structures into tubular nanotubes, resulting in the description of unexpectedly dynamic functions of the membrane structures. Membrane-containing phages have provided a framework for understanding virus evolution. The original observation on membrane-containing bacteriophage PRD1 and human pathogenic adenovirus has been fundamental in delineating the concept of "viral lineages", postulating that the fold of the major capsid protein can be used as an evolutionary fingerprint to trace long-distance evolutionary relationships that are unrecognizable from the primary sequences. This has brought the early evolutionary paths of certain eukaryotic, bacterial, and archaeal viruses together, and potentially enables the reorganization of the nearly immeasurable virus population (~1 × 1031) on Earth into a reasonably low number of groups representing different architectural principles. In addition, the research on membrane-containing phages can support the development of novel tools and strategies for human therapy and crop protection.


Cationic Iridium-Catalyzed Decarboxylation of Aromatic Carboxylic Acids.
Practical synthetic applications of catalytic decarboxylation in producing useful molecules are limited. We report herein the cationic Ir-catalyzed decarboxylations of various electron-rich and -poor aromatic carboxylic acids to produce hydrocarbons in good yield (up to >99%). Additionally, this reaction is applicable in decarboxylative hydroarylation of bicyclic alkenes and decarboxylative fluorination, indicating the potential utility of this catalytic decarboxylation in synthetic chemistry.


Molecular genetic considerations in osteosarcoma.
Osteosarcoma tumorigenesis is consistent with a model by which tumorigenesis results if both alleles at the retinoblastoma susceptibility locus (RBI) are altered. Additional genetic evidence strongly suggests that another obligate event in osteosarcoma tumorigenesis is the homozygous alteration of another gene, p53. Both the RB1 gene and p53 have been proposed to act as tumor-suppressor genes, suggesting that, in this instance, tumorigenesis is the result of the loss of gene function of these two genes, rather than a gain of function.


The role of cognitions, trait anxiety and disgust sensitivity in generating faintness around blood-injury phobic stimuli.
The effects on blood-injury fear and fainting of scripts concerning pain, nausea, and anger and individual differences in trait anxiety and disgust sensitivity were investigated. Eighteen participants were high in disgust sensitivity and trait anxiety, 11 were low in disgust sensitivity but high in trait anxiety, 10 were high in disgust sensitivity but low in trait anxiety, and 16 were low in disgust sensitivity and trait anxiety. Participants were exposed to pain, nausea, and anger scripts during presentation of blood-injury slides. The ability of the scripts to increase symptoms of fear and faintness, on a state version of the Blood-Injection Symptom Scale (BISS; Page, A. C., Bennett, K. S., Carter, O., Smith, J., & Woodmore, K. (1997). Blood-Injection Symptom Scale (BISS): Assessing the structure of phobic symptomatology elicited by blood and injections. Behaviour Research and Therapy, 35, 457-464) were examined. Analyses indicated that individual differences in trait anxiety and disgust sensitivity interact to generate symptoms of faintness when the pain script was read. That is, disgust sensitive and trait anxious participants reported greater faintness relative to other conditions. The implications for theory and treatment of blood-injury-injection phobia are discussed.


Prevalence and populations of Listeria monocytogenes in meat products retailed in Sao Paulo, Brazil.
This study evaluated the prevalence of the populations and serotypes of Listeria monocytogenes in 552 refrigerated samples of ground beef, chicken leg, hot dog, and pork sausage collected in supermarkets in the city of Sao Paulo, SP, Brazil, between May 2008 and July 2009. The supermarkets were selected after stratification by geographical region and by random draw. Tests for presence and enumeration of L. monocytogenes were based on ISO 11290-1:1996/Amd.1:2004 and ISO 11290-2:1998 methods, respectively. Listeria spp. were detected in 469 (85.0%) of the studied meat products. The most frequently isolated species was L. innocua (64.1%), followed by L. monocytogenes (48.7%), L. welshimeri (13.4%), L. seeligeri (7.1%), L. ivanovii (0.2%), and L. grayi subspecies murrayi (0.2%). L. monocytogenes was detected in 269 (48.7%) samples, with highest prevalence in ground beef (59.4%) followed by chicken legs (58.0%), pork sausages (39.8%), and hot dogs (37.7%). The populations were <10(2) colony-forming units/g in the majority of samples (62.5%). Prevalence of serotypes varied according to the type of meat product. These data are relevant for estimating the risks of listeriosis associated with consumption of meat products in Sao Paulo, and for establishing science-based intervention strategies aimed at reducing these risks, especially for pregnant women and immunocompromised individuals.


The Adequate Use of Limited Information in Dispersal Decisions.
Several theoretical studies predict that informed (e.g., density-dependent) dispersal should generally result in lower emigration probabilities than uninformed (random) dispersal. In a 2012 publication, Bocedi et al. surprisingly come to the opposite conclusion. For most scenarios investigated, they found that noninformed and, particularly, less precisely informed dispersers evolve lower dispersal propensity than dispersers following "fully informed" strategies. Further, they observed that fully informed individuals evolved a steplike dispersal response-a response to local density that contradicts theoretical predictions for organisms with nonoverlapping generations. Replicating the individual-based simulations of Bocedi et al. we find that these conclusions are not justified and are based on a misinterpretation of simulation results: their controversial findings result from (i) a misleading use of the term "population density," (ii) a misconception concerning the true informative value of the different decision criteria they compared, and (iii) arbitrary constraints on the evolution of the dispersal response that prevented the evolution of strategies that allow for a fitness-enhancing utilization of available information.


Women's retention on the continuum of maternal care pathway in west Gojjam zone, Ethiopia: multilevel analysis.
The continuum of maternal care has been one of the effective approaches for improving the health of mothers and newborns. Although large numbers of Ethiopian women do not use maternal health services, points of drop out along the continuum are not understood well. Understanding of a particular point of maternal care dropout on the continuum, however, helps governments make effective interventions. This study aimed to assess the extent of women's service utilization and the factors affecting retention on the continuum of care in West Gojjam Zone, Ethiopia. A community-based study linked to health facility data was conducted in June 2018. Data were obtained from 1281 mothers who gave birth to their last baby within the preceding 12 months from a two-stage cluster sampling. Data were collected via face-to-face interviews using a pretested questionnaire. Multilevel logistic regression models were used to examine the effects of individual and cluster-level factors on key elements of the continuum of care. The measure of fixed effects was expressed as Odds Ratio with 95% confidence interval. The study revealed that only 12.1% of women completed the continuum of maternal care services (ANC4+, SBA, and PNC within 2 days after birth); while 25.1% of them did not receive any care during their recent births. There were commonalities and differences in the predictors of the three indicators of maternal health service utilization. Variables related to services received during antenatal care such as early initiation of ANC (AOR = 7.53, 95%CI, 2.94, 19.29) and receiving proper contents (AOR = 3.31, 95%CI, 1.08, 10.16) were among the predictors significantly associated with the completion of the continuum of care. The continuum of maternal care completion rate was extremely low, indicating that women were not getting the maximum possible health benefit from existing health services. The results also revealed that maternal health service utilization was influenced by factors operating at various levels-individual, household, community, and health facility. Since antenatal care is considered an entry point for the subsequent use of maternal services, strategies that aimed to improve maternal health service utilization should target early initiation and antenatal care quality.


Autoimmune bullous dermatoses: a review.
Bullous dermatoses can be debilitating and possibly fatal. A selection of autoimmune blistering diseases, including pemphigus vulgaris, paraneoplastic pemphigus, bullous pemphigoid, cicatricial pemphigoid, dermatitis herpetiformis and linear IgA dermatosis are reviewed. Pemphigus vulgaris usually starts in the oral mucosa followed by blistering of the skin, which is often painful. Paraneoplastic pemphigus is associated with neoplasms, most commonly of lymphoid tissue, but also Waldenström's macroglobulinemia, sarcomas, thymomas and Castleman's disease. Bullous pemphigoid is characterized by large, tense bullae, but may begin as an urticarial eruption. Cicatricial (scarring) pemphigoid presents with severe, erosive lesions of the mucous membranes with skin involvement in one third of patients focused around the head and upper trunk. Dermatitis herpetiformis is intensely pruritic and chronic, characterized by papulovesicles and urticarial wheals on the extensor surfaces in a grouped or herpetiform, symmetric distribution. Linear IgA dermatosis is clinically similar to dermatitis herpetiformis, but it is not associated with gluten-sensitive enteropathy as is dermatitis herpetiformis.


HLA DQA1-DQB1 genotypes in Bedouin families with celiac disease.
Celiac disease (CD) has a strong genetic association with human leukocyte antigens (HLA). The primary susceptibility for CD is HLA-DQA1*05 DQB1*02 (also known as DQ2), with the remainder of cases primarily HLA-DQA1*03 DQB1*03 (also known as DQ8). In a set of nine Bedouin multiplex celiac disease families and one simplex, we genotyped DNA samples at HLA DQA1 and DQB1. Nineteen celiac disease patients had at least one DQA1*05 DQB1*02 genotype (= DQ2), 4 affecteds had the second most common genotype of DQA1*03 DQB1*0302 (= DQ8), 9 were DQ2 and DQ8, and 4 had at least one copy of DQB1*02 without the DQA1*05 genotype. Using transmission disequilibrium testing, we observed a significant over-representation in affecteds of the DQA1*05 DQB1*02 genotype (p = 0.0089), as well as over-representation of the DQA1*03 DQB1*0302 genotype (p = 0.078). The HLA DQA1 DQB1 high-risk genotypes associated with celiac disease are similar in these Bedouin families with CD to what is observed in Northern and Southern Europeans.


Accelerating polarization structures in vectorial fields.
We generate optical fields whose polarization structures not only rotate about their propagation axis but also can be controlled to accelerate independently from their spatial profile. We show that by combining accelerated intensity transport with orthogonal polarization states, we can produce a vector beam that displays optical activity with periodical acceleration and deceleration of the Stokes vector during propagation. We achieve this with orthogonal, scalar fields, represented by weighted superpositions of oppositely charged Bessel beams. In addition to their creation, we show that the Stokes vector can be made to accelerate or decelerate at specific locations along the Poincaré sphere by tailoring the generating basis. We also witness an optical current, or intensity transport, between local positions in the field that corresponds with the occurrence of the state-of-polarization accelerating or decelerating.


Comparative Proteomic Analysis of Two Differently Extracted Coptis chinensis in the Treatment of Type 2 Diabetic Rats.
Coptis chinensis (CC) is widely used to treat diabetes in traditional Chinese medicine due to its significant hypoglycemic and hypolipidemic effects. It was reported that CC powders are more effective than CC decoctions. In this study, a rat model of type 2 diabetes was established and treated with supercritical-extracted CC and gastric juice extracted CC, respectively. Body weight, fasting plasma insulin, insulin resistance index, and lipid profiles were measured along with oral glucose tolerance tests (OGTTs). In addition, the levels of plasma proteins were compared between type 2 diabetic rats and CC-treated rats using an iTRAQ-based quantitative proteomic analysis. The results showed that the plasma levels of triglyceride (TC), total cholesterol (TG), and low-density lipoprotein (LDL) in rats of both CC-treated groups were significantly decreased. In addition, the proteomic analysis identified 929 proteins, while 15 proteins were selected from these 929 proteins based on their expression levels and bioinformatic results. Among these 15 proteins, 9 proteins (IGF-1, Igfbp4, Igfbp-6, Igfals, C2, C4, Cfi, Prdx-2, and Prdx-3) were upregulated in the two CC-treated groups, while 6 proteins (Pla2g7, Pcyox1, ApoC-1, ApoC-3, ApoB-100, and ApoE) were downregulated. The functions of these proteins are associated with glucose metabolism, insulin action, immunity, inflammation, lipid metabolism, oxidation, and antioxidation. The two differently extracted CC did not show significant differences in terms of their treatment efficacy. This research expanded our understanding on the therapeutic effects and mechanisms of CC in the treatment of type 2 diabetes.


Evaluation of free radical production in an ischaemia-reperfusion model in the rabbit using a tourniquet.
Use of a tourniquet on a limb to stem blood flow is frequent in surgery. However, this results in an ischaemia-reperfusion effect that causes damage through the production of free radicals. The aim of this work was to evaluate this production of free radicals in an ischaemia-reperfusion model in the rabbit after placement of a tourniquet. Plasma lipoperoxides were measured by high-performance liquid chromatography using the malondialdehyde assay method. We found significant (P < 0.01) production of free radicals 1 min after release of the tourniquet compared with controls; no variation in levels of free radicals was observed during the ischaemia phase.


Comparison of multi-mode Hong-Ou-Mandel interference and multi-slit interference.
Hong-Ou-Mandel (HOM) interference of multi-mode frequency entangled states plays a crucial role in quantum metrology. However, as the number of modes increases, the HOM interference pattern becomes increasingly complex, making it challenging to comprehend intuitively. To overcome this problem, we present the theory and simulation of multi-mode-HOM interference (MM-HOMI) and compare it to multi-slit interference (MSI). We find that these two interferences have a strong mapping relationship and are determined by two factors: the envelope factor and the details factor. The envelope factor is contributed by the single-mode HOM interference (single-slit diffraction) for MM-HOMI (MSI). The details factor is given by sin (Nx)/sin (x) ([sin (Nv)/sin (v)]2) for MM-HOMI (MSI), where N is the mode (slit) number and x (v) is the phase spacing of two adjacent spectral modes (slits). As a potential application, we demonstrate that the square root of the maximal Fisher information in MM-HOMI increases linearly with the number of modes, indicating that MM-HOMI is a powerful tool for enhancing precision in time estimation. We also discuss multi-mode Mach-Zehnder interference, multi-mode NOON-state interference, and the extended Wiener-Khinchin theorem. This work may provide an intuitive understanding of MM-HOMI patterns and promote the application of MM-HOMI in quantum metrology.


Reduced risk of reoperation after treatment of femoral neck fractures with total hip arthroplasty.
Background and purpose - Femoral neck fractures (FNFs) are commonly treated with some kind of arthroplasty, but evidence on whether to use hemiarthroplasty (HA) or total hip arthroplasty (THA) is lacking. HA reduces the risk of dislocation, but may lead to acetabular erosion. THA implies longer surgery and increased bleeding. THA may result in better function and health-related quality of life, but evidence is contradictory. We compared HA and THA and in terms of revision, reoperation and death. Patients and methods - Data were extracted from the Swedish Hip Arthroplasty Register for 11,253 patients with acute FNF receiving cemented HA or THA during 2008-2012. 2,902 patients with THA were matched by propensity score matching with as many patients with HA based on age, sex, BMI, and ASA classification. We used competing risks survival regression with reoperation or death and revision or death as endpoints. Results - THA patients had significantly reduced risk of revision (absolute risk reduction 0.51; 95% CI 0.39-0.67) and reoperation (0.58; 0.46-0.74). THA was associated with an almost 50% reduced mortality (risk ratio as competing risk for reoperation 0.51; 0.46-0.57). Interpretation - In our national register study of femoral neck fractures, THA had a lower risk than HA for further surgical procedures related to the hip. The reasons for lower mortality after THA are not known. Despite matching, there might be a selection of more healthy patients for this procedure, and other factors unknown to us, with or without relation to the choice of implant.


Using Creative Activities to Improve Treatment Perceptions of Patients on Hemodialysis.
Hemodialysis (HD) has a significant impact on health-related quality of life (HRQoL). We performed an observational study to assess the mental and physical status of 41 patients on chronic HD treatment. We planned and launched a program of recreational and therapeutic intradialysis activities to reduce patients' boredom due to inactivity. Patients' mental and physical status was reassessed at 12 months. Our initial attempt to introduce these recreational activities as intradialysis therapy has been rated positively by all patients. After one year, anxiety decreased (without statistical significance) and willingness to participate in activities increased from 50.00% to 85.71% (p=0.019). No improvement was observed on the remaining studied variables. This preliminary initiative is promising. We plan to maintain these successful therapies and include others to help consolidate this program.


Twelve tips for medical teaching in low-resource settings.
Teaching in a low-resource setting comes with its own challenges and pitfalls. Many concepts, ideas and strategies can be transferred but need to be adapted to the different environment. This article highlights some of the challenges and obstacles that healthcare professionals working in this setting might encounter when setting up an educational intervention. The following twelve specific tips are aimed toward individual healthcare workers, independent charities, and smaller non-governmental organizations (NGOs) who wish to initiate small-scale teaching projects or larger educational ventures. The article covers general matters to consider prior to embarking on this journey and includes cultural, educational, linguistic, and social aspects.


The viral death effector Apoptin reveals tumor-specific processes.
Several natural proteins, including the cellular protein TRAIL and the viral proteins E4orf4 and Apoptin, have been found to exert a tumor-preferential apoptotic activity. These molecules are potential anti-cancer agents with direct clinical applications. Also very intriguing is their possible utility as sensors of the tumorigenic phenotype. Here, we focus on Apoptin, discussing recent research that has greatly increased our understanding of its tumor-specific processes. Apoptin, which kills tumor cells in a p53- and Bcl-2-independent, caspase-dependent manner, is biologically active as a highly stable, multimeric complex consisting of 30 to 40 monomers that form distinct superstructures upon binding cooperatively to DNA. In tumor cells, Apoptin is imported into the nucleus prior to the induction of apoptosis; this contrasts with the situation in primary or low-passage normal cell cultures where nuclear translocation of Apoptin is rare and inefficient. Apoptin contains two autonomous death-inducing domains, both of which exhibit a strong correlation between nuclear localization and killing activity. Nevertheless, forced nuclear localization of Apoptin in normal cells is insufficient to allow induction of apoptosis, indicating that another activation step particular to the tumor or transformed state is required. Indeed, a kinase activity present in cancer cells but negligible in normal cells was recently found to regulate the activity of Apoptin by phosphorylation. However, in normal cells, Apoptin can be activated by transient transforming signals conferred by ectopically expressed SV40 LT antigen, which rapidly induces Apoptin's phosphorylation, nuclear accumulation and the ability to induce apoptosis. The region on LT responsible for conferring this effect has been mapped to the N-terminal J domain. In normal cells that do not receive such signals, Apoptin becomes aggregated, epitope-shielded and is eventually degraded in the cytoplasm. Finally, Apoptin interacts with various partners of the human proteome including DEDAF, Nmi and Hippi, which may help to regulate either Apoptin's activation or execution processes. Taken together, these recent advances illustrate that elucidating the mechanism of Apoptin-induced apoptosis can lead to the discovery of novel tumor-specific pathways that may be exploitable as anti-cancer drug targets.


Antiplatelet Therapy Combinations and Thrombogenicity in Patients with Non-Valvular Atrial Fibrillation.
Combination antiplatelet therapy reduces the risk of ischemic stroke compared with aspirin monotherapy in non-valvular atrial fibrillation (NVAF) patients. The underlying mechanism, however, remains unclear. In addition, the association between platelet inhibition and thrombogenicity in NVAF has not been evaluated. We randomized 60 patients with NVAF that were taking 100 mg of aspirin daily (>1 month) to adding 75 mg of clopidogrel daily (CLPD group), 100 mg of cilostazol twice daily (CILO group), or 1000 mg of omega-3 polyunsaturated fatty acid twice daily (PUFA group). Biomarkers (von Willebrand factor antigen [vWF:Ag], fibrinogen, D-dimer, and high-sensitivity C-reactive protein [hs-CRP]) and platelet reactivity (PR), which were the levels stimulated by adenosine diphosphate (ADP), thrombin-receptor agonist peptide, collagen, and arachidonic acid, were measured at baseline and 30-day follow-up. Combination antiplatelet therapy significantly reduced vWF:Ag and fibrinogen levels (7.7 IU/dL, p=0.015 and 15.7 mg/dL, p=0.005, respectively), but no changes were found in D-dimer and hs-CRP levels. The CLPD and CILO groups showed fibrinogen and vWF:Ag level reductions (24.9 mg/dL, p=0.015 and 9.3 IU/dL, p=0.044, respectively), whereas the PUFA group did not show any differences in biomarkers. Irrespective of regimen, the changes in fibrinogen and vWF:Ag levels were mainly associated with the change in ADP-mediated PR (r=0.339, p=0.008 and r=0.322, p=0.012, respectively). In patients with NVAF, combination antiplatelet therapy showed reductions for vWF:Ag and fibrinogen levels, which may be associated with the inhibitory levels of ADP-mediated PR. The clinical implications of these findings need to be evaluated in future trials.


Emotional and Behavioural Problems among Preschool Children in Northeast Peninsular Malaysia: Parent Report Version.
The rising prevalence of mental health disorders among children is a serious concern. Young children who exhibit early warning signs of mental health issues are more likely to develop symptoms in the same or overlapping regions years later. The research aimed to identify emotional and behavioural problems and associated factors in Malaysian preschools. A sample of young children aged 4-6 years from public and private preschools was chosen using a multistage random sampling method. Data were collected from 18 preschools via a parent survey using the Strengths and Difficulties Questionnaire (SDQ). The sample involved 557 children in the SDQ assessment (92%). The overall estimated prevalence of emotional and behavioural problems was 8.4%. Peer problems were the most prevalent attribute, with a percentage of 19.7%. Conduct problems were found in 5.2%, hyperactivity problems in 5.6%, prosocial behaviours in 13.5%, and emotional problems in 6.8%. Girls showed a significant increase in behavioural and emotional problems compared to boys. Having one parent working, having more than two siblings, and having a single-parent family were associated with emotional and behavioural problems. The prevalence of emotional and behavioural problems in Malaysian children was relatively low compared to data from previous studies and other Asian countries but consistent with European studies. Measuring mental health disparities in young children helps stakeholders launch local early intervention programmes.


Preservation of pancreatic islets in rodent models.
Islet-cell transplantation has some advantages over vascularized pancreas transplantation, but data from clinical islet cells transplantation have shown that some serious problems need to be overcome. One of them is the storage of islet cells. We investigated methods of preserving islet cells using culture-preservation and cryopreservation. Cryopreservation is thought to be effective for long-term preservation of large quantities of islet cells, because they can be cryopreserved without loss of their physiologic activity using a relatively rapid cooling rate of 25 degrees C/min. Moreover, in the allogenic transplantation models of cryopreservation of dissociated islet cells, there was a significant prolongation of survival time. These results suggest that cryopreservation of islet cells involves not only variable preservation methods but may also lead to a modification of graft immunogenicity.


Pain profiles in a community dwelling population following spinal cord injury: a national survey.
While as many as 60% of patients with spinal cord injury (SCI) develop chronic pain, limited data currently exists on the prevalence and profile of pain post-SCI in community dwelling populations. A cross-sectional population survey. Primary care. Community dwelling adults with SCI. Following ethical approval members registered to a national SCI database (n=1,574) were surveyed. The survey included demographic and SCI characteristics items, the International Spinal Cord Injury Pain Basic Data Set (version 1) the Douleur Neuropathique 4 questionnaire (interview) and questions relating to health care utilisation. Data were entered into the Statistical Package for the Social Sciences (version 20) Significance was set P < 0.05 for between group comparisons. In total 643 (41%) surveys were returned with 458 (71%) respondents experiencing pain in the previous week. Neuropathic pain (NP) was indicated in 236 (37%) of responses and nociceptive pain in 206 (32%) Common treatments for pain included medications n=347 (76%) massage n=133 (29%) and heat n=115 (25%). Respondents with NP reported higher pain intensities and increased healthcare service utilisation (P= < 0.001) when compared to those with nociceptive pain presentations. A higher proportion of females than males reported pain (P = 0.003) and NP (P = 0.001) and those unemployed presented with greater NP profiles compared with those in education or employment (P = 0.006). Pain, in particular NP post SCI interferes with daily life, increases health service utilisation and remains refractory to current management strategies. Increased availability of multi-disciplinary pain management and further research into management strategies is warranted.


Organic hydroperoxide-induced activation of liver microsomal glutathione S-transferase of rats in vitro.
The effect of t-butyl hydroperoxide (t-BuOOH), cumene hydroperoxide (CuOOH) or linoleic acid hydroperoxide (linoleic-OOH) on liver microsomal glutathione S-transferase of rats was studied in vitro. When microsomes were incubated with either 100 microM t-BuOOH or 25 microM CuOOH, glutathione S-transferase activity was increased 1.5-fold; activity was further increased to 2.2-fold in the presence of small amounts of glutathione. The same amounts of dithiothreitol or cysteine did not enhance the t-BuOOH or CuOOH-induced increase in transferase activity. The transferase activity was also increased 1.4-fold by 10 microM linoleic-OOH plus 1 microM glutathione. The increase in microsomal glutathione S-transferase activity after treatment of microsomes with t-BuOOH in the presence of glutathione was completely reversed by addition of dithiothreitol, whereas the activation of the transferase caused by t-BuOOH in the absence of glutathione was not reversed. Although microsomal glutathione S-transferase also possesses glutathione peroxidase activity, only transferase activity was increased by t-BuOOH in either the presence or absence of glutathione. These data indicate that microsomal glutathione S-transferase is activated by organic hydroperoxides in either the absence or presence of small amounts of glutathione, suggesting an activation of the transferase by thiol oxidation of the cysteine residue.


Combination of cataract surgery with intravitreal injection of dexamethasone intravitreal implant (Ozurdex) for uveitis-induced cataract.
To evaluate the long-term results of patients with chronic uveitis-induced cataract by phacoemulsification with IOL implantation and intravitreal injection of dexamethasone (DEX) intravitreal implant (Ozurdex). The study included 32 eyes of 26 patients treated with DEX implant due to chronic uveitis-induced cataract and followed up for at least a year. Best-corrected visual acuity (BCVA), intraocular pressure (IOP), anterior chamber reaction, central macular thickness (CMT), intraoperative and postoperative complications and uveitis recurrence were analyzed retrospectively. A successful surgery was performed in all patients. The average follow-up period was 12mo. The female/male ratio was 13/13. Mean age was 45.65±3.83y (range 26 to 65y). Etiologically, rheumatic arthritis occurred in 6 patients (18.75%), ankylosing spondylitis in 4 (12.50%), HLA-B27 associated uveitis in 3 (9.38%), Vogt-Koyanagi-Harada-associated uveitis in 4 (12.50%) , Behcet's disease in 2 (6.25%), and 7 (21.88%) suffered from unknown diseases. All 32 eyes had varying degrees of improvement at 12mo after surgery, with 2 eyes showing BCVA of 0.1 or below (6.25%), 6 having 0.1-0.5 (18.75%), 18 of 0.5-1.0 (56.25%), and 6 of 1.0 or above (18.75%). No cases with increased IOP were observed. The values of mean CMT was increased at day 1, decreased at 1, 3mo after surgery and increased at 6, 12mo after surgery. No severe uveitis reactions, such as fibrinous exudates in the anterior chamber and exudative membrane formation on the anterior surface of the IOL, were observed after surgery. The present studies show that intravitreal injection of Ozudex during cataract operation can provide a new option for the clinical treatment of uveitis-induced cataract.


Safety and efficacy of "Alice" influenza virus vaccine in normal healthy adults.
A live influenza virus candidate vaccine, "Alice" strain, was evaluated in normal healthy adults. It proved to be safe, with minimal clinical reactions. Thirteen of 21 volunteers (61.9%) with pre-existing titers of hemagglutination-inhibiting antibody of less than or equal to 1:4 and three of nine (33.3%) with initial titers of 1:8-1:16 had four-fold increases in titers of serum antibody. A second dose of vaccine did not increase the frequency or the magnitude of the serum antibody response. Nasal neutralizing antibody responses occurred in six of 18 subjects tested (38.8%). The vaccine virus appeared to produce its effect by replication since vaccine virus was recovered from six of 17 subjects (35%), administration of a vaccine inactivated by ultraviolet irradiation did not produce a response, a 1:10 dilution of virus infected two of five subjects, and a 1:100 dilution infected none of six subjects. The virus was not transmitted to the antibody-negative controls who were confined with infected volunteers. Challenge of 20 volunteers and 26 control subjects with wild-type influenza A/Udorn/307/72 (H3N2) virus revealed a significant reduction in the frequency of infection and illness among subjects who responded to "Alice" vaccine compared with the frequency among unvaccinated controls.


Effects of non-steroidal anti-inflammatory drugs on the pharmacokinetics and elimination of aciclovir in rats.
This study aims to investigate the effect of commonly used non-steroidal anti-inflammatory drugs (NSAIDs) on the pharmacokinetics and the renal elimination of aciclovir in rats. Pharmacokinetic parameters were determined following an intravenous administration of aciclovir (5 mg kg(-1)) to rats in the presence and absence of ketoprofen or naproxen (25 mg kg(-1)). Compared with the control (given aciclovir alone), pre-treatment with ketoprofen or naproxen 30 min before aciclovir administration significantly altered the pharmacokinetics of aciclovir. Renal clearance of aciclovir was reduced by approximately two fold in the presence of ketoprofen or naproxen. Consequently, the systemic exposure (AUC) to aciclovir in the rats pre-treated with ketoprofen or naproxen was significantly (P < 0.05) higher than that from the control group given aciclovir alone. Furthermore, the mean terminal plasma half-life of aciclovir was enhanced by 4-5 fold by pre-treatment with ketoprofen or naproxen. These results suggest that NSAIDs, such as ketoprofen and naproxen, are effective in altering the pharmacokinetics of aciclovir by inhibiting the organic anion transporter-mediated tubular secretion of aciclovir. Therefore, concomitant use of ketoprofen or naproxen with aciclovir should require close monitoring for clinical consequence of potential drug interaction.


Thalamic nucleus reuniens coordinates prefrontal-hippocampal synchrony to suppress extinguished fear.
Traumatic events result in vivid and enduring fear memories. Suppressing the retrieval of these memories is central to behavioral therapies for pathological fear. The medial prefrontal cortex (mPFC) and hippocampus (HPC) have been implicated in retrieval suppression, but how mPFC-HPC activity is coordinated during extinction retrieval is unclear. Here we show that after extinction training, coherent theta oscillations (6-9 Hz) in the HPC and mPFC are correlated with the suppression of conditioned freezing in male and female rats. Inactivation of the nucleus reuniens (RE), a thalamic hub interconnecting the mPFC and HPC, reduces extinction-related Fos expression in both the mPFC and HPC, dampens mPFC-HPC theta coherence, and impairs extinction retrieval. Conversely, theta-paced optogenetic stimulation of RE augments fear suppression and reduces relapse of extinguished fear. Collectively, these results demonstrate a role for RE in coordinating mPFC-HPC interactions to suppress fear memories after extinction.


Differential autonomic control of SAN and AVN regions of the canine heart: structure and function.
Both anatomical and physiologic evidence for relatively rich autonomic innervation of sinoatrial (SAN) and atrioventricular (AVN) regions of the canine heart exist, with indication that SAN is especially responsive to parasympathetic, while AVN is preferentially sensitive to sympathetic regulation. The distribution of autonomic pathways are sufficiently separate and discrete that careful surgical intervention can selectively delete either parasympathetic or sympathetic nerve supplies to either (or both) SAN and AVN regions. Selective blockade by restricted injections of lidocaine (general neuronal blocker) or hexamethonium (ganglionic blocker) indicate that the vast majority (perhaps all) of vagal ganglia supplying SAN reside in the pulmonary vein fat pad and associated adipose tissues. In contrast, the vagal ganglia supplying AVN are found within a smaller fat pad overlying epicardium at the junction of inferior vena cava-inferior left atrium. These vagal pathways to either automatic cells of SAN or conductile tissues of AVN can be selectively interrupted without interfering with vagal regulation of the remaining intact system. Electroneurograms from large neurons situated within PVFP of the anesthetized, open-chest animal, reveal vigorous, phasic electrical activity associated with the cardiac and respiratory cycles, as well as with sensory stimulation of the heart, great vessels, and lungs. Spontaneous electrical activity of presently unknown origin is also observed. Direct neuronal stimulation, plus retrograde transport of fluorescent markers suggest that highly selective postganglionic intracardiac pathways may regulate discharge patterns of the sinus automatic cells.


Puerarin alleviates hyperosmotic stress-induced oxidative stress, inflammation, apoptosis and barrier damage of human corneal epithelial cells by targeting SIRT1/NLRP3 signaling.
The increase of tear osmolarity caused by excessive evaporation of tear phase is the main pathological mechanism of dry eye disease (DED). Puerarin, the major bioactive ingredient isolated from the root of the Pueraria lobata (Willd.) Ohwi, has been reported to improve ophthalmic diseases in clinic. However, the effect and the potential regulatory mechanism related to silent information regulator sirtuin 1 (SIRT1)/NOD-like receptor family pyrin domain containing 3 (NLRP3) signaling of puerarin in DED has not been evaluated. In this study, we aimed to explore the effect and mechanism of hyperosmotic stress (Hyp)-induced human corneal epithelial cell line (HCE-2). The viability of HCE-2 cells induced by Hyp with or without puerarin treatment was assessed by a CCK-8 assay. Results indicated that puerarin treatment enhanced cell viability, reduced reactive oxygen species (ROS) content, increased CAT and SOD activities, and elevated the ratio of GSH/GSSG in HCE-2 cells exposed to Hyp. Besides, TNF-α, IL-1β and IL-6 contents were decreased by puerarin. Additionally, puerarin inhibited Hyp-induced apoptosis and barrier disruption of HCE-2 cells. Moreover, molecular docking method suggested that puerarin bound to SIRT1, and upregulated SIRT1 and downregulated NLRP3 inflammasome proteins after puerarin treatment was observed. Furthermore, SIRT1 silencing alleviated the protective effects of puerarin on Hyp-induced HCE-2 cell damage. Collectively, puerarin attenuates Hyp-induced injury of HCE-2 cells by targeting regulating SIRT1/NLRP3 signaling.


Induced flocculation of animal cells in suspension culture.
Recycle unit operations for suspension cell cultures may be improved by flocculation of the cells. A flocculant search was conducted, and it was found that where strongly cationic polymers were severly toxic to the cells, neutral and anionic polymers were nontoxic and ineffective at flocculating the cells. A weak and poorly soluble polycation, poly-L-histidine, was capable of flocculating cultures of CHO, HeLa, U-937, and CRL 1606 hybridoma cells with no toxicity to the majority of cells. In addition to the lowered acute toxicity, the polymer treatment left the cells in a growing state for recycle. Flocculation was found to be mediated by precipitates of the polymer. The low toxicity of poly-L-histidine is probably due to its low solubility and charge at physiological pH. Nonelectrostatic interactions may also play a role.


Combined macro- and microrheometer for use with Langmuir monolayers.
A Langmuir monolayer trough that is equipped for simultaneous microrheology and standard rheology measurements has been constructed. The central elements are the trough itself with a full range of optical tools accessing the air-water interface from below the trough and a portable knife-edge torsion pendulum that can access the interface from above. The ability to simultaneously measure the mechanical response of Langmuir monolayers on very different length scales is an important step for our understanding of the mechanical response of two-dimensional viscoelastic networks.


Predictors of initiation, continuation and transition of drug use in south-eastern Iran.
To identify factors associated with the initiation continuation, transition and cessation of substance abuse in Zahedan, Iran. The retrospective study reviewed the profile of 536 addicts admitted to both public and private outpatient treatment centres in the study area. For each individual, data were collected on sociodemographic characteristics, initiation and patterns of drug abuse and any changes in the patterns. To analyze the data, Kruskal-Wallis, Chi-square, Log-rank test, Logistic regression and Cox proportional hazards models were used. The median age of the first drug abuse was 20 (95% CI: 19.7 - 20.3) years with significant heterogeneity by gender and marital status (p < 0.001). The age of the first drug use and maritaI status were significant factors for the continuation of drug use (p < 0.001). The study also indicated that male gender, single life, low level of education, early onset of substance use and type of first used drug act as facilitators for transition to new drugs (p < 0.05). Besides, the present study revealed the significant effect of marital status, education and type of first used drug on personal decisions towards drug use cessation (p < 0.05). A number of predictive factors of substance abuse identified in the study are of utmost important for any preventive effort.


Tunable inhibition and denaturation of alpha-chymotrypsin with amino acid-functionalized gold nanoparticles.
Water-soluble gold nanoparticles bearing diverse l-amino acid terminals have been fabricated to probe the effect of receptor surface on protein surface binding. The interaction of these nanoparticles with alpha-chymotrypsin (ChT) was investigated by activity assay, gel electrophoresis, zeta-potential, circular dichroism, and fluorescence spectroscopy. The results show that both electrostatic and hydrophobic interactions between the hydrophobic patches of receptors and the protein contribute to the stability of the complex. The microscopic binding constants for these receptor-protein systems are 10(6)-10(7) M(-1), with the capacity of the nanoparticle receptors to bind proteins determined by both their surface area and their surface charge density. Furthermore, it is found that the hydrophilic side chains destabilize the ChT structure through either competitive hydrogen bonding or breakage of salt bridges, whereas denaturation was much slower with hydrophobic amino acid side chains. Significantly, correlation between the hydrophobicity index of amino acid side chains and the binding affinity and denaturation rates was observed.


Scurvy, Starvation, and Flea Infestation - A Case Report From 21st Century Europe.
Scurvy is a disease caused by vitamin C deficiency, historically associated with long sea voyages, periods of famine and war. Currently, it is often misdiagnosed and underreported, as physicians tend to consider it a disease of the past. We present the case of a 79-year-old female who was admitted to the Emergency Department complaining of pruritus. The patient lived alone and in poor hygiene conditions. Diet was scarce. One week before admission she was in contact with flea-ridden stray dogs. Sometime later she noted several fleas and multiple pruritic small papules, crusts, and excoriations on her torso, limbs, palms, soles, and scalp. Physical examination showed the patient to be pale, emaciated, and poorly groomed. Laboratory analysis showed microcytic anemia. Flea bites were treated with oral antihistamines and prednisolone. Follow-up one month later showed weight gain and partial resolution of skin lesions. However, multiple small ecchymosis on both lower and upper limbs, and occasional perifollicular petechias on her lower extremities, were noted. Additional workup showed undetectable serum vitamin C levels. A diagnosis of scurvy was made. The patient was treated with 1000 mg per day of oral vitamin C for one month leading to complete recovery. We present this case to remind that early recognition of vitamin C deficiency and appropriate supplementation are essential in patients with scurvy. Physicians should be aware of classic signs, symptoms, and social factors associated with this forgotten disease.


Development of immunoradiometric assay for detection of Plasmodium falciparum antigen in blood using monoclonal antibody.
Specific monoclonal antibody (MAB) F2W22C1) produced by hybridoma technology against blood stage common antigens shared by almost all isolates of P. falciparum was selected. The 125I-labelled prepared from this MAB (125I-MIgG) was used as probe for detection of low grade P. falciparum infection. Recently, a two-site monoclonal antibody sandwich immunoradiometric assay (Mab-IRMA) has been developed. The assay showed good correlation with parasitaemia with the ability to detect as few as 2.4 parasites/10(8) erythrocytes. Two surveys were made in people living in a malaria endemic area during transmission and non-transmission season to detect the antigen of Plasmodium falciparum by using the Mab-IRMA. In the first survey involving 101 people, the IRMA positive rate was 56.4% and then significantly declined to 16.5% during the second survey involving 79 people of the same group. The parasitological positive rates were likewise decreased from 11.9% to 1.3% (p = 0.015) during these two seasons. IRMA positive rates were significantly higher than the corresponding parasitological positive rates (p less than 0.0001 and less than 0.002 for the first and the second surveys respectively). Regression analysis showed that IRMA activities were linearly correlated with the parasite counts by microscopic examinations (r = 0.629, p = 0.022). IRMA was specific for P. falciparum since all 30 healthy controls and six of seven vivax malaria cases were negative. IRMA has potential for use to monitor the malaria control and to assess the efficacy of the future field trial of malaria vaccine.


Empowerment-Based Diabetes Self-Management Education to Maintain Glycemic Targets During Ramadan Fasting in People With Diabetes Who Are on Conventional Insulin: A Feasibility Study.
This study aims to assess the feasibility of promoting safe Ramadan fasting through diabetes self-management education (DSME) and to determine the effect of such education on hypoglycemic episodes. This prospective study included subjects attending Ramadan reinforcement sessions for participants in the Educational Program for People with Diabetes (EPPWD) at the Ain-Shams University Diabetes Center in Cairo, Egypt. The DSME sessions started 2-3 weeks before Ramadan and included one experimental fasting day during the first week and one during the second week. Participants' A1C and serum fructosamine levels were measured before and after Ramadan, and they completed weekly self-monitoring of blood glucose (SMBG) logs. Among 21 participants who were intending to fast for Ramadan, 14 completed the program. Their mean A1C was 6.7 ± 1.6%, and SMBG results showed a statistically nonsignificant difference in mean blood glucose levels before and after Ramadan (123.84 ± 39.96 and 123.84 ± 25.92 mg/dL, respectively; P >0.05). Serum fructosamine after Ramadan declined by 10% from pre-Ramadan levels. The mean number of hypoglycemic events before Ramadan was 3 ± 1.04, which declined to 1.4 ± 0.5 during Ramadan. Differences between group 1 (those without hypoglycemia, n = 8) and group 2 (those with hypoglycemia, n = 6) were nonsignificant for all variables, including A1C. Ramadan fasting is feasible for people with diabetes who are on a multiple daily injection insulin regimen and participate in the EPPWD. The number of hypoglycemic events per month declined with the attainment of DSME.


Ethylglucuronide as a potential marker for alcohol-induced elevation of urinary testosterone/epitestosterone ratios.
The potential influence of alcohol consumption on endogenous steroids has already been described in the literature. In those studies the ethanol level after ingestion was monitored using its concentration in blood, urine or saliva. Corresponding methods are not commonly used in anti-doping laboratories. Ethylglucuronide (EtG), which can be easily detected by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS), appears to be a more suitable parameter for this purpose. It is slowly excreted into the urine and indicates alcohol intake for a much longer period than blood or urinary alcohol and it is therefore routinely used for legal purposes as an alcohol consumption marker. In pharmacokinetic studies that aimed to establish calculation models after ethanol intake, the formation of EtG was observed to coincide with elevated urinary testosterone/epitestosterone (T/E) ratios. Similarly, large amounts of EtG were correlated with abnormal steroid profiles found in routine doping samples. In this pilot study, several cases with significantly elevated T/E ratios were associated with urinary EtG concentrations higher than 50 microg/mL. These findings confirmed recent intake of ethanol in considerable amounts and suggest a connection to changes in specific steroid profile parameters. Owing to the ease with which procedures to determine EtG can be carried out, and the potential for such procedures to be introduced into screening schemes, the inclusion of this marker in the final evaluation of suspicious outliers in T/E ratio longitudinal studies would seem to be very useful.


[Intracavitary electrocardiogram (IC-ECG) guidance for peripherally inserted central catheter (PICC) placement].
intracavitary electrocardiogram (IC-ECG) guidance has been recently proposed for peripherally inserted central catheter (PICC) placement since it may reduce the time of placement and avoid radiological control. to evaluate IC-ECG compared to conventional radiological control. METHOS: prospective study of 532 consecutive patients. Those with arrhythmias or on antiarrhythmic drugs were excluded. In all cases, PICC tip placement was checked by IC-ECG guidance and by a chest X-ray, which was considered as the reference test. PICC placement with IC-ECG guidance was achieved in 96.8% of patients (applicability). PICC correct placement according to IC-ECG guidance was confirmed by chest X-ray in 94% of patients (accuracy). In 13 patients (2.7%) the catheter had to be repositioned after radiological control. The κ concordance index was 0.356 (p < 0.001). The IC-ECG sensitivity was 0.98, with a PPV of 0.97 and a positive likelihood ratio of 1.5. However, the specificity was only 0.35 with a NPV of 0.41 and a negative likelihood ratio of 0.06. PICC placement by IC-ECG guidance is plausible, safe, presents adequate indexes of validity and reliability, and allows reducing the time of catheter placement. However, radiological verification is still necessary, especially in cases of negative or uncertain ECG.


Infinite swapping replica exchange molecular dynamics leads to a simple simulation patch using mixture potentials.
Replica exchange molecular dynamics (REMD) becomes more efficient as the frequency of swap between the temperatures is increased. Recently Plattner et al. [J. Chem. Phys. 135, 134111 (2011)] proposed a method to implement infinite swapping REMD in practice. Here we introduce a natural modification of this method that involves molecular dynamics simulations over a mixture potential. This modification is both simple to implement in practice and provides a better, energy based understanding of how to choose the temperatures in REMD to optimize efficiency. It also has implications for generalizations of REMD in which the swaps involve other parameters than the temperature.


Enhancing Gravitational Interaction between Quantum Systems by a Massive Mediator.
In 1957 Feynman suggested that the quantum or classical character of gravity may be assessed by testing the gravitational interaction due to source masses in superposition. However, in all proposed experimental realizations using matter-wave interferometry, the extreme weakness of this interaction requires pure initial states with extreme squeezing to achieve measurable effects of nonclassical interaction for reasonable experiment durations. In practice, the systems that can be prepared in such nonclassical states are limited to small masses, which in turn limits the strength of their interaction. Here we address this key challenge-the weakness of gravitational interaction-by using a massive body as an amplifying mediator of gravitational interaction between two test systems. Our analysis shows that this results in an effective interaction between the two test systems that grows with the mass of the mediator, is independent of its initial state and, therefore, its temperature. This greatly reduces the requirement on the mass and degree of delocalization of the test systems and, while still highly challenging, brings experiments on gravitational source masses a step closer to reality.


Magnetically-assisted viral transduction (magnetofection) medical applications: An update.
Gene therapy involves replacing a faulty gene or adding a new gene inside the body's cells to cure disease or improve the body's ability to fight disease. Its popularity is evident from emerging concepts such as CRISPR-based genome editing and epigenetic studies and has been moved to a clinical setting. The strategy for therapeutic gene design includes; suppressing the expression of pathogenic genes, enhancing necessary protein production, and stimulating the immune system, which can be incorporated into both viral and non-viral gene vectors. Although non-viral gene delivery provides a safer platform, it suffers from an inefficient rate of gene transfection, which means a few genes could be successfully transfected and expressed within the cells. Incorporating nucleic acids into the viruses and using these viral vectors to infect cells increases gene transfection efficiency. Consequently, more cells will respond, more genes will be expressed, and sustained and successful gene therapy can be achieved. Combining nanoparticles (NPs) and nucleic acids protects genetic materials from enzymatic degradation. Furthermore, the vectors can be transferred faster, facilitating cell attachment and cellular uptake. Magnetically assisted viral transduction (magnetofection) enhances gene therapy efficiency by mixing magnetic nanoparticles (MNPs) with gene vectors and exerting a magnetic field to guide a significant number of vectors directly onto the cells. This research critically reviews the MNPs and the physiochemical properties needed to assemble an appropriate magnetic viral vector, discussing cellular hurdles and attitudes toward overcoming these barriers to reach clinical gene therapy perspectives. We focus on the studies conducted on the various applications of magnetic viral vectors in cancer therapies, regenerative medicine, tissue engineering, cell sorting, and virus isolation.


C-reactive protein increase in acute myocardial infarction.
Considering acute myocardial infarctions (AMI), data demonstrate that C-reactive protein (CRP) levels reflect the severity of myocardial damage and that high CRP level is associated with a worse outcome. This study evaluates the prognostic value of CRP and the determinants of its increase during AMI. A retrospective observational study of 126 patients with a ST-segment elevation myocardial infarction (STEMI); 101 patients had reperfusion therapy (93 thrombolysis, 8 PTCA). Peak CRP (median: 3.5 mg/dl) was achieved the third day. A correlation existed between this peak and age (r = 0.1838; p = 0.0408). Diabetic patients not requiring insulin showed peaks double those of other patients (10.4 versus 6.1 mg/dl; p = 0.0165). The peak was higher in anterior infarctions (anterior: 8.4, lateral: 6.9, inferior: 6.4, posterior: 3.9 mg/dl; p = 0.0206) and for those showing a Q-wave (7.5 versus 3.9 mg/dl; p = 0.0020). It was correlated with the CK (r = 0.246; p = 0.0188) and troponin Ic (r = 0.242; p = 0.0224) peaks among thrombolysed patients. There was an increasing relationship between the occurrence of cardiac failure and the magnitude of the CRP peak. An inverse linear relationship existed between the ejection fraction of the left ventricle and the CRP peak (r = -0.4187; p = 0.0000). CRP peak was lower with statins (3.8 versus 7.0 mg/dl; p = 0.0446). Fibrates were only associated with lower CRP levels at admission (0.6 versus 0.9 mg/dl; p = 0.0010). CRP is an indicator of the severity of STEMI. It is also an indicator for the occurrence of complications during hospitalization. The effect of statins and fibrates on CRP levels in AMI should be studied further.


Changing Lens: Broadening the Research Agenda of Women in Management in China.
Human resource management (HRM) is underpinned by, and contributes to, the business ethics of the organization. Opportunities available to men and women as managers, and the role of managers more broadly, are critical in shaping business ethics in contemporary organizations. Research on women in management therefore provides an important lens through which to understand the institutional and cultural context of HR ethics as part of the business ethics of a country. To date, women in management in China remains an under-charted topic of research in the HRM field. Extant research and recommendations on the improvement of the position of women in management in China focus primarily on women themselves from a traditional, gender norm angle, instead of challenging the political and patriarchal system or any institutionalized discriminatory practice. This is, in part, due to the absence in China of a critical feminism approach or feminist movement, as found in Western societies, and the continuing strong influence of the state and media in portraying women's (stereotypical) image. There is significant room for research capacity building in scholarship on women in management research, for example, and through cross-fertilization of different disciplines and more rigorous research design and execution. This paper provides a critical analysis of extant literature on women in management and the ideologies underpinning it, and offers some suggestions for future research and conceptualization.


Multiple brain atlas database and atlas-based neuroimaging system.
For the purpose of developing multiple, complementary, fully labeled electronic brain atlases and an atlas-based neuroimaging system for analysis, quantification, and real-time manipulation of cerebral structures in two and three dimensions, we have digitized, enhanced, segmented, and labeled the following print brain atlases: Co-Planar Stereotaxic Atlas of the Human Brain by Talairach and Tournoux, Atlas for Stereotaxy of the Human Brain by Schaltenbrand and Wahren, Referentially Oriented Cerebral MRI Anatomy by Talairach and Tournoux, and Atlas of the Cerebral Sulci by Ono, Kubik, and Abernathey. Three-dimensional extensions of these atlases have been developed as well. All two- and three-dimensional atlases are mutually preregistered and may be interactively registered with an actual patient's data. An atlas-based neuroimaging system has been developed that provides support for reformatting, registration, visualization, navigation, image processing, and quantification of clinical data. The anatomical index contains about 1,000 structures and over 400 sulcal patterns. Several new applications of the brain atlas database also have been developed, supported by various technologies such as virtual reality, the Internet, and electronic publishing. Fusion of information from multiple atlases assists the user in comprehensively understanding brain structures and identifying and quantifying anatomical regions in clinical data. The multiple brain atlas database and atlas-based neuroimaging system have substantial potential impact in stereotactic neurosurgery and radiotherapy by assisting in visualization and real-time manipulation in three dimensions of anatomical structures, in quantitative neuroradiology by allowing interactive analysis of clinical data, in three-dimensional neuroeducation, and in brain function studies.


Cross recurrence quantification analysis of precision grip following peripheral median nerve block.
Precision grip by the thumb and index finger is vulnerable to sensorimotor deficits. Traditional biomechanical parameters offer limited insight into the dynamical coordination between digits during precision grip. In this study, the thumb and index finger were viewed as "coupled systems", and a cross recurrence quantification analysis (CRQA) was used to examine the changes of interdigit dynamics and synchronization caused by peripheral median nerve block. Seven subjects performed a precision grip by holding an instrumented handle before and after median nerve block at the wrist. The forces and the torques at each digit-handle interface were recorded with two six-component transducers. For CRQA, the percentage of recurrence rate (%RR), percentage of determinism (%DET), longest diagonal line (Lmax) and percentage of laminarity (%LAM) were computed for the force, torque and center of pressure (COP) signals. Phase synchronization of the thumb and index finger was examined based on the τ-recurrence rate. Paired t-tests and Wilcoxon signed-rank tests were used for statistical comparisons. The twin-surrogate hypothesis test was used to examine phase synchronization. Nerve block led to significant increases (p < 0.05) for %DET, Lmax and %LAM in all components of force, torque, and COP. Only the normal force met the conditions of phase synchronization for all successfully completed pre- and post-block grasping trials. The probability of synchronization with larger time lags (τ > 0.1 s) increased after nerve block. The percentage of trials that the thumb led the index finger increased from 52% (pre-block) to 86% (post-block). Nerve block caused more deterministic structures in force, torque and COP when the thumb interacted with the index finger. A compensatory mechanism may be responsible for this change. Phase synchronization between the opposite normal forces exerted by the thumb and index finger would be an essential dynamical principle for a precision grip. The nerve block resulted in an increased interdigit phase delay and increased probability that the thumb leads the index finger. The CRQA provides an effective tool to examine interdigit coordination during precision grip and has the potential for clinical evaluation of hand dysfunction.


Israeli youth in the Second Intifada: PTSD and future orientation.
To examine the relationship between exposure to political violence and posttraumatic symptoms, future orientation, and attitudes toward peace. A total of 740 boys and girls aged 11.5-15 years from Jerusalem, Gilo, and the Jewish settlements in the disputed territories were assessed in the summer of 2001 using an exposure to terror questionnaire, Child Posttraumatic Stress Reaction Index, Children's Future Orientation Scale, and a question regarding the future of peace talks. A substantially higher percentage of youths in the settlements (27.6%) than in Jerusalem (12.4%) or Gilo (11.2%) reported moderate to very severe levels of posttraumatic symptoms. Children's Future Orientation responses were moderately optimistic. About two thirds of the adolescents in the settlements rejected the idea of peace talks at any time, whereas around half of the youths in Jerusalem and Gilo supported the continuation of peace talks. Exposure was related to both PTSD symptoms and attitudes toward peace but not to future orientation. Our findings present the complex interrelationship of political violence, posttraumatic stress disorder, and attitudes toward peace and raise the need for a combined mental health and peace education intervention to prevent the often overlooked vicious cycle of violence and traumatization.


[Assessing PM10 and SO2 networks using positive matrix factorization in Beijing city].
The aim of this study was to identify city areas with similar air pollution characteristics and determine which sites may be providing redundant information. Positive matrix factorization (PMF) was applied in this study to assess the mass concentrations of sulfur dioxide (SO2) and particulate matter with an aerodynamic diameter less than 10 microm (PM010), collected in the air quality monitoring network in the year of 2000. The analysis indicated that there were obviously seasonal variations for PM10 and SO2 in Beijing. The PM10 concentrations were higher in spring and lower in summer, but the SO2 concentrations were higher in winter and lower in summer. The results of the PMF showed that the sites of PM10 network in Beijing could be identified as three regions, which represented city areas characterized by the same specific air pollution. These three regions represented Gucheng site/Chegongzhuang site, Qianmen site/National Olympic Sports Center site/Tiantan site/Nongzhanguan site, and Ming Tombs site, respectively. Some sites in region 2 which included four sites may be redundant and can be removed. SO2 network can be divided into six regions including Chegongzhuang site/Qianmen site, Tiantan site/Nongzhanguan stie, Ming Tombs site, National Olympic Sports Center site, Dongsi site, and Gucheng site. It indicated that some sites in Beijing PM10 and SO2 monitoring networks might be redundant and could be removed or relocated to other areas.


The role of de novo mutations in the development of amyotrophic lateral sclerosis.
The genetic basis combined with the sporadic occurrence of amyotrophic lateral sclerosis (ALS) suggests a role of de novo mutations in disease pathogenesis. Previous studies provided some evidence for this hypothesis; however, results were conflicting: no genes with recurrent occurring de novo mutations were identified and different pathways were postulated. In this study, we analyzed whole-exome data from 82 new patient-parents trios and combined it with the datasets of all previously published ALS trios (173 trios in total). The per patient de novo rate was not higher than expected based on the general population (P = 0.40). We showed that these mutations are not part of the previously postulated pathways, and gene-gene interaction analysis found no enrichment of interacting genes in this group (P = 0.57). Also, we were able to show that the de novo mutations in ALS patients are located in genes already prone for de novo mutations (P < 1 × 10-15 ). Although the individual effect of rare de novo mutations in specific genes could not be assessed, our results indicate that, in contrast to previous hypothesis, de novo mutations in general do not impose a major burden on ALS risk.


Effect of continuous melatonin infusions on steady-state plasma melatonin levels in rats under near physiological conditions.
It was the aim of this study to measure the actual amount of melatonin required for elevating the circulating hormone from low daytime levels to the 10-fold higher nocturnal steady-state concentrations in rats. For this purpose, escalating doses of melatonin were continuously infused into the right jugular vein and blood samples were repeatedly drawn from the left jugular vein for a period of 2 hr in freely moving catheterized rats. In order to achieve an about 10-fold elevation of the plasma melatonin concentration, 500 ng melatonin/hr had to be infused, i.e., about 300 times the normal nocturnal melatonin content of the pineal. Infusions of up to 61 ng melatonin/hr (equivalent to the melatonin content of 40 pineals at darkness) failed to cause a significant rise of the low daytime steady-state concentrations in the blood. If the dose of 500 ng melatonin/h was infused at night, a less-pronounced rise of the blood levels was observed, as compared to that caused by the infusion of the same dose during daytime. No differences were found in the rate of metabolism between daytime and nighttime. The results of this study indicate 1) that the low basal concentrations of melatonin in the blood are not affected by an increased melatonin supply up to a certain critical threshold, 2) that the rat pineal gland would have to release all its melatonin content almost every 10 sec in order to sustain the elevated steady-state level of melatonin in the circulation during the dark period, and 3) that significant day/night differences exist in the disposition of circulating melatonin if administered in near physiological amounts and under near physiological conditions.


Commodity specific rates of temporal discounting: does metabolic function underlie differences in rates of discounting?
Discounting rates vary as a function of commodity type. Previous studies suggest five potential characteristics of the commodity that could explain these differences: type of reinforcer (primary or secondary), if the commodity is perishable, if the commodity is satiable, if the commodity can be directly consumed, and immediacy of consumption. This paper suggests that these characteristics may best be viewed as related to a more fundamental characteristic: metabolic processing. In order to explore the possibility that metabolic processing underlies changes in discount rates, the difference in discounting between food, money, music CDs, DVDs, and books are compared. Music CDs, DVDs, and books share many characteristics in common with food, including gaining value through a physiological process, but are not directly metabolized. Results are consistent with previous findings of commodity specific discount rates and show that metabolic function plays a role in determining discount rates with those commodities that are metabolized being discounted at a higher rate. These results are interpreted as evidence that the discount rate for different commodities lies along a continuum with those that serve an exchange function rather than a direct function (money) anchoring the low end and those that serve a direct metabolic function capping the high end (food, alcohol, drugs).


Structural and Catalytic Characterization of a Fungal Baeyer-Villiger Monooxygenase.
Baeyer-Villiger monooxygenases (BVMOs) are biocatalysts that convert ketones to esters. Due to their high regio-, stereo- and enantioselectivity and ability to catalyse these reactions under mild conditions, they have gained interest as alternatives to chemical Baeyer-Villiger catalysts. Despite their widespread occurrence within the fungal kingdom, most of the currently characterized BVMOs are from bacterial origin. Here we report the catalytic and structural characterization of BVMOAFL838 from Aspergillus flavus. BVMOAFL838 converts linear and aryl ketones with high regioselectivity. Steady-state kinetics revealed BVMOAFL838 to show significant substrate inhibition with phenylacetone, which was more pronounced at low pH, enzyme and buffer concentrations. Para substitutions on the phenyl group significantly improved substrate affinity and increased turnover frequencies. Steady-state kinetics revealed BVMOAFL838 to preferentially oxidize aliphatic ketones and aryl ketones when the phenyl group are separated by at least two carbons from the carbonyl group. The X-ray crystal structure, the first of a fungal BVMO, was determined at 1.9 Å and revealed the typical overall fold seen in type I bacterial BVMOs. The active site Arg and Asp are conserved, with the Arg found in the "in" position. Similar to phenylacetone monooxygenase (PAMO), a two residue insert relative to cyclohexanone monooxygenase (CHMO) forms a bulge within the active site. Approximately half of the "variable" loop is folded into a short α-helix and covers part of the active site entry channel in the non-NADPH bound structure. This study adds to the current efforts to rationalize the substrate scope of BVMOs through comparative catalytic and structural investigation of different BVMOs.


Can paraprofessional home visitation enhance early intervention service delivery?
A 1-year randomized trial compared intensive case management (ICM) versus basic case management (BCM) in facilitating early intervention (EI) service use among children in an urban health system. Of 159 participating families with delayed or at-risk preschool-aged children, 88 received ICM from paraprofessionals versus 71 families who received less comprehensive BCM from a nurse. In the ICM versus BCM group, a shorter interval to assessment (98 vs 140 d, p =.05) but similar assessment rate (86% vs 80%, p =.29) was observed. The ICM group had more services recommended per child (1.64 vs 1.16, p < .004) and initiated (1.20 vs 0.85, p < .04). There was no difference in median time to EI program initiation for ICM versus BCM (228 vs 200 d, p = .88) or initiation and visit compliance rate for EI services. Specific efforts to improve outcomes (e.g., decrease initiation time and increase use of EI services) are still needed.


Randomized controlled trial of chest tube removal aided by a party balloon.
Background Recurrent pneumothorax is one of the most common complications after thoracostomy tube removal. The purpose of this study was to assess the optimal method of thoracostomy tube removal by comparing party balloon-assisted Valsalva and classic Valsalva techniques. Methods Trauma patients with indications for tube thoracostomy from 2014 to 2015 were recruited. Exclusion criteria were age < 15- or > 64-years-old, history of chronic lung disease, Glasgow Coma Scale < 13, latex allergy, or tracheostomy. Participants were randomly allocated by randomized block design into 4 groups using different Valsalva maneuvers: group A: classic inspired, group B: classic expired, group C: balloon-inspired; and group D: balloon-expired. The primary and secondary outcomes were recurrent pneumothorax and respiratory complications. Results Forty-eight tube thoracostomies were randomized for analysis; 4 patients had bilateral tube thoracostomies. The mean patient age was 38.1 ± 19.9 years. The incidence of recurrent pneumothorax confirmed by chest radiography was 15.4% in group A, 16.8% in group B, and none in groups C and D ( p = 0.31). When group A combined with group B was compared with groups C and D, the incidence was 16% vs. 0%, respectively ( p = 0.11). The thoracostomy tube reinsertion rate in all 4 groups was 0%, 8.33%, 0%, and 0%, respectively, which was not significant ( p = 0.38). Conclusions Performing the Valsalva maneuver correctly during full inspiration may be the method of choice for removing thoracostomy tubes. Using a party balloon forces the patient perform the Valsalva maneuver adequately and is simpler to explain.


The impact of etiological factors on mortality in retroperitoneal hematomas.
Retroperitoneal hematomas (RPH) mostly occur after blunt and penetrating traumas. However, these hematomas may develop spontaneously in the elderly and the patients who use anticoagulants. Between January 2006 and December 2011, 31 patients with RPH were evaluated retropectively. The patients were allocated into three groups according to the underlying etiological factor: Group I; spontaneous RPH, group II; RPH caused by penetrating trauma, group III; RPH caused by blunt trauma. There were 22 (71%) male and 9 (29%) female patients with a mean age of 35.7 ± 18.7 (range: 15-88 years). Spontaneous RPH was diagnosed in eight patients (25.8%) while RPH caused by penetrating trauma in 13 patients (41.9%) and RPH induced by blunt trauma in 10 (32.3%) patients. Retroperitoneal hematomas were located at zone I in 2 patients (6.5%) whereas zone II in 19 patients (61.3%) and zone III in 9 patients (29%). On the other hand, RPH was regarded to be at zone II-III in 1 patient (3.2%). Additional organ injury was defined in 18 patients (58.1%). Twenty patients (65%) were treated surgically. The morbidity rates were 12.5%, 7.7% and 20% and the mortality rates were denoted as 12.5%, 15.4% and 50%, for group I, group II and group III, respectively. Additional organ injury, massive blood transfusion, the route of injury and the need for surgery are defined as the most significant factors associated with increased mortality.


Evaluation of focused multipolar stimulation for cochlear implants in acutely deafened cats.
The conductive nature of the fluids and tissues of the cochlea can lead to broad activation of spiral ganglion neurons using contemporary cochlear implant stimulation configurations such as monopolar (MP) stimulation. The relatively poor spatial selectivity is thought to limit implant performance, particularly in noisy environments. Several current focusing techniques have been proposed to reduce the spread of activation with the aim towards achieving improved clinical performance. The present research evaluated the efficacy of focused multipolar (FMP) stimulation, a relatively new focusing technique in the cochlea, and compared its efficacy to both MP stimulation and tripolar (TP) stimulation. The spread of neural activity across the inferior colliculus (IC), measured by recording the spatial tuning curve, was used as a measure of spatial selectivity. Adult cats (n = 6) were acutely deafened and implanted with an intracochlear electrode array before multi-unit responses were recorded across the cochleotopic gradient of the contralateral IC. Recordings were made in response to acoustic and electrical stimulation using the MP, TP and FMP configurations. FMP and TP stimulation resulted in greater spatial selectivity than MP stimulation. However, thresholds were significantly higher (p < 0.001) for FMP and TP stimulation compared to MP stimulation. There were no differences found in spatial selectivity and threshold between FMP and TP stimulation. The greater spatial selectivity of FMP and TP stimulation would be expected to result in improved clinical performance. However, further research will be required to demonstrate the efficacy of these modes of stimulation after longer durations of deafness.


Pulsed-field gel electrophoresis associated to phage typing improves the discrimination of epidemiologically unrelated Salmonella enterica serovar typhimurium isolates.
A combination of phage typing and pulsed-field gel electrophoresis (PFGE) of Xbal- and Blnl-digested chromosomal DNA has been used to study 18 epidemiologically unrelated human Salmonella enterica serovar Typhimurium isolates, which were collected during 2007 within a single Romanian county. Phage typing could assign only four of the isolates to three definitive phage types (DT41, DT86, and DT116), the rest being untypable by this classical method. PFGE analysis of the double enzyme-digested DNA, performed in an attempt to further discriminate the strains, allowed the typing of all the studied isolates. Xbal-digested genomic DNA segregated the isolates into 7 X-types and Blnl restriction differentiated them into 8 B-types. Our PFGE results documented the circulation of a rather homogeneous population of S. Typhimurium strains within the same county. As in the case of other human pathogens, epidemiological conclusions might be more accurate if based on both phenotypic and genotypic methods, therefore molecular typing should be added within the national laboratory-based surveillance of Salmonella infections.


Construction of a recA mutant of Azospirillum lipoferum and involvement of recA in phase variation.
The plant-growth promoting rhizobacterium Azospirillum lipoferum strain 4B generates in vitro a stable phase variant designated 4VI at frequencies of 10(-4) to 10(-3) per cell per generation. Variant 4VI displays pleitropic modifications, such as the loss of swimming motility and the inability to assimilate certain sugars compared to the wild type. The mechanism underlying phase variation is unknown. To determine whether RecA-mediated processes are involved in phase variation, the recA gene of A. lipoferum 4B was cloned and sequenced and a recA mutant (termed 4BrecA) was constructed by allelic exchange. Strain 4BrecA showed increased sensitivity to UV and MMS compared with 4B and impaired recombinase activity. The ability to generate variants in vitro was not altered; the variants from 4BrecA exhibited all morphological and biochemical features characteristic of the variant generated by strain 4B. However, the frequency of variants generated by 4BrecA was increased by up to 10-fold. So, in contrast with many studies showing the abolition or a large reduction of the frequency of phase variation in recA mutants, this study describes an enhancement of phase variation in the absence of a functional recA.


Recent Advances in Therapeutic Applications of Induced Pluripotent Stem Cells.
Induced pluripotent stem (iPS) cells are generated by reprogramming of differentiated somatic cells. These cells are identical to human embryonic stem cells (hESCs) in gene expression pattern and the ability to differentiate. iPS cells can be used in in vitro modeling of diseases, testing drugs, assessing gene therapy methods, and cell therapy. Yet, the most important and promising application of iPS cells is in regenerative medicine. Regenerative medicine is a novel area in medicine aiming at the treatment of impaired or lost tissues by replacing them with functional and healthy ones. Currently, organ transplantation, which is considered the only treatment and cure for a number of diseases, is limited by shortage of organ donors and availability of the right match. Therefore, utilization of an alternative source of cells and tissues is critical in transplantation therapy. In this study, we review recent advances in therapeutic application of iPS cells in diseases where organ transplantation remains the only solution and will discuss the potential and usage of iPS cells in different areas of regenerative medicine. The primary theory of using iPS cells in regenerative medicine has brought lots of promises due to its potential for solving the immunological, social, and ethical problems of using ESCs. Nevertheless, several issues and problems have to be resolved before applying iPS cells in therapeutic applications.


P067 Immune Checkpoint Inhibitor Colitis in a Community-Based Hospital System.
Immune checkpoint inhibitors (ICIs) have significantly changed the oncologic treatment landscape for a wide array of cancers over the past few decades. While these medications can produce a durable remission for patients they also come with a risk of inflammatory toxicities. With the widespread use of immune checkpoint inhibitors there have been increased reports of immune-related adverse events (irAEs) including severe gastrointestinal toxicities such as colitis. While multiple studies have assessed ICI colitis in tertiary care settings little is reported on the characteristics and treatment outcomes of ICI colitis in a community-based population. Additionally, the utility of gastroenterologists in the diagnosis and management of ICI colitis is poorly defined. The aim of this study is to report the characteristics and treatment outcomes of ICI colitis in a community-based hospital system. This is a single-center retrospective case-series of patients with ICI colitis. Charts were reviewed from patients in the Prisma Health Upstate Network from 2/1/2016 to 12/31/2020. Potential cases of ICI colitis were identified using a diagnosis code of "toxic colitis", "indeterminate colitis", "unspecified colitis", and "noninfective gastroenteritis and colitis" (ICD-10 K52.1, K 52.3, K 52.89 and K52.9) as well as a prior infusion (within 12 months) of pembrolizumab, nivolumab, cemiplimab, atezolizumab, avelumab, durvalumab, or ipilimumab. Charts were abstracted for demographics, tumor type, checkpoint inhibitor used, mode of colitis diagnosis, endoscopic severity of inflammation, and treatments used. Study was approved by the Institutional Review Board at Prisma Health Upstate. The mean (±SD) age for the 37 patients was 64.1 ± 13.2 years. The patient population was predominantly male (62%) and Caucasian (100%). The cancer type in the patient population were melanoma (43.2%), non-small cell lung cancer (18.9%), renal cell carcinoma (10.8%), and other (27%). Patients with ICI colitis were most-commonly treated with ipilimumab (35.1%), nivolumab (35%), pembrolizumab (10.8%), and other (13.5%). The mean time to colitis onset was 25.7 ± 29.7 weeks. Over 56% of the patient population reported abdominal pain and 45.9% were hospitalized. Only 64.8% were evaluated by a gastroenterologist. Cross sectional abdominal imaging by computed tomography (CT) was obtained in 20 (54.0%) and showed colitis in 13. 54% obtained a colonoscopy with inflammation severity stratified into normal (25.0%), mild (40.0%), moderate (20.0%) and severe (15.0%). Endoscopic extent showed proctitis (0%), left-sided disease (5.0%), right-sided disease (5.0%), pancolitis (55.0%), and isolated ileal disease (25%). Histology showed 90.0% with active inflammation and 10.0% with microscopic colitis. Outcomes were resolution with steroids (64.8%), antibiotics (5.4%), biologic (10.8%), surgery (5.4%), hospice (8.1%). Of those that received biologic therapy, 6 received infliximab and 1 received vedolizumab. As immune checkpoint inhibitors gain approval in more cancer treatment ICI-colitis is being seen in a community-based setting. The most common treatment were steroids and often required a prolonged course. Biologic use in our series (18.9%) was much lower than prior reports from academic tertiary referral centers (>50%). Only 64.8% of patients saw a gastroenterologist for ICI-colitis symptoms. Early gastroenterology referral in the community setting could help to identify more severe disease and patients necessitating escalation to biologic therapy.


Comparison of Campylobacter isolates from poultry and humans: association between in vitro virulence properties, biotypes, and pulsed-field gel electrophoresis clusters.
The in vitro virulence properties of 197 temporally and geographically related Campylobacter isolates from chicken broilers and humans were compared. Comparisons of the virulence properties associated with genotypes and biotypes were made. All isolates adhered to, and 63% invaded, INT-407 cells, whereas 13% were cytotoxic for CHO cells. CHO cell-cytotoxic extracts were also cytotoxic for INT-407 cells, but the sensitivity for Vero cells was variable. The proportion of isolates demonstrating a high invasiveness potential (>1,000 CFU ml(-1)) or Vero cell cytotoxicity was significantly higher for human than for poultry isolates. Invasiveness was associated with Campylobacter jejuni isolates of biotypes 1 and 2, whereas CHO and INT-407 cell cytotoxicity was associated with C. jejuni isolates of biotypes 3 and 4. Cytotoxic isolates were also clustered according to pulsed-field gel electrophoresis profiles.


Spatiotemporal Context Awareness for Urban Traffic Modeling and Prediction: Sparse Representation Based Variable Selection.
Spatial-temporal correlations among the data play an important role in traffic flow prediction. Correspondingly, traffic modeling and prediction based on big data analytics emerges due to the city-scale interactions among traffic flows. A new methodology based on sparse representation is proposed to reveal the spatial-temporal dependencies among traffic flows so as to simplify the correlations among traffic data for the prediction task at a given sensor. Three important findings are observed in the experiments: (1) Only traffic flows immediately prior to the present time affect the formation of current traffic flows, which implies the possibility to reduce the traditional high-order predictors into an 1-order model. (2) The spatial context relevant to a given prediction task is more complex than what is assumed to exist locally and can spread out to the whole city. (3) The spatial context varies with the target sensor undergoing prediction and enlarges with the increment of time lag for prediction. Because the scope of human mobility is subject to travel time, identifying the varying spatial context against time lag is crucial for prediction. Since sparse representation can capture the varying spatial context to adapt to the prediction task, it outperforms the traditional methods the inputs of which are confined as the data from a fixed number of nearby sensors. As the spatial-temporal context for any prediction task is fully detected from the traffic data in an automated manner, where no additional information regarding network topology is needed, it has good scalability to be applicable to large-scale networks.