Extended-field radiotherapy is superior to MOPP chemotherapy for the treatment of pathologic stage I-IIA Hodgkin's disease: eight-year update of an Italian prospective randomized study.
To compare the effectiveness of chemotherapy (CHT) with extended-field radiotherapy (RT) in the treatment of early-stage Hodgkin's disease (ESHD), we report an 8-year updated analysis of a study in which treatment with six cycles of mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) CHT was randomly compared with extended-field RT. From August 1979 to December 1982, 89 adult patients with pathologic stage I-IIA Hodgkin's disease (HD) were randomly allocated to receive either RT with mantle field followed by periaortic irradiation (n = 45) or six monthly courses of MOPP CHT (n = 44). All patients in the RT arm and 40 of 44 in the CHT arm achieved complete remission. Twelve relapses occurred in each group. Eight patients treated with MOPP and two of the RT arm died of HD. Three other patients of the CHT group died because of a second cancer. With a median follow-up greater than 8 years, the overall survival rate is significantly higher in the RT than in the CHT group (93% v 56%; P less than .001), whereas the rates of freedom from progression and relapse-free survival (RFS) were similar in the two groups (76% v 64% and 70% v 71%, respectively). Of the 12 patients relapsing after RT, 11 (92%) achieved a second CR, compared with only six of the 12 (50%) in the MOPP group. Analysis of the response rate to salvage treatments showed that the type of relapse in the MOPP group was a prognostic indicator for the achievement of a second CR, whereas in the RT group, a second CR was obtained regardless of the characteristics of the relapses. At 80 months, the probability of survival of relapsing patients calculated from time of relapse was 85% and 15% in the RT and CHT groups, respectively (P = .02). We conclude that RT alone is the treatment of choice for adult patients with ESHD with favorable prognostic factors.


[Inhibition of Bacillus pumilus AR03 on Alternaria alternata and Erysiphe cichoracearum on tobacco].
This study aimed to evaluate the efficiency of Bacillus pumilus AR03 against Altenaria alternata and Erysiphe cichoracearum. The antagonistic activities were studied in the way of co-culture on plate, inhibition of pathogen conidia germination on concave slides and LB agar medium. In the investigation, the water suspension of living cells of strain AR03, at 3 x 10(8) cfu . mL-1 had a remarkable inhibition effect on hyphae growth and conidia germination of A. alternata and caused hyphae deformation, shorter and swollen nodes, winding hyphae accumulation, abnormal tubes with tips expanded or deformed. Conidia did not germinate and the tissues of compartment became swollen or formed a round spherical bubble. In addition, the inhibition rate of conidia germination of E. cichoracearum was 91. 3% and 69. 3%, respectively when treated with strain AR03 at 1 x 10(7) cfu . mL-1 and 1.5 x 10(6) cfu . mL-1. Conidia treated by living cells of AR03 became swollen, deformed, the protoplasm of conidia shrinked, disintegrated gradually and separated from the conidia wall. And some conidia were hollow because the protoplasm leaked out from inside. Greenhouse results revealed that the effects of living cells of AR03 with different concentrations were significantly different. Bacterial suspension of AR03 at 3 x 10(8) cfu . mL-1 was strongly antagonistic to E. cichoracearum with the control efficiencies 7 days and 15 days after treatment of two spays being 83.8% and 90.3%, respectively, while the control efficiencies of AR03 at 3 x 10(6) cfu . mL-1 were 70.0% and 73.3%, respectively. Strain AR03 had a long persistence against powdery mildew more than 30 days.


Intestinal atresia.
Intestinal atresia accounts for about one third of all cases of neonatal intestinal obstruction. The survival rate has improved to 90% in most of the series with the operative mortality being < 1%. The survival rate improves with distal atresias. An increased mortality is observed in multiple atresias (57%), apple peel atresia (71%), and when atresia is associated with meconium ileus (65%), meconium peritonitis (50%) and gastroschisis (66%). Although appearance of echogenic bowel on prenatal ultrasonography is suggestive of GI, it is confirmed in only 27% cases. Prenatal ultrasonography is more reliable in detection of duodenal atresia than more distal lesions. Short bowel syndrome is the major impediment in the management of jejunoileal atresia. Although total parenteral nutrition (TPN) is the main adjunctive treatment, it delays intestinal adaptation and may cause cholestasia and subsequent liver damage. Graduated enteric feedings, use of growth hormone, glutamine and modified diets containing low fat, complex carbohydrates and protein supplements have been used in a adults with short bowel syndrome to successfully diminish TPN requirements and enhance nutrient absorption in nearly half of the patients. Utilization of growth factors to facilitate intestinal adaptation and advances in small bowel transplant may improve the long-term outcomes in future.


TNPO2 operates downstream of DYNC1I1 and promotes gastric cancer cell proliferation and inhibits apoptosis.
The import of proteins into the nucleus plays an important role in tumor development. In addition to the classical nuclear import proteins importin-β and importin-α, there are many nonclassical nuclear import proteins that include TNPO2. The role of TNPO2 as a nonclassical nuclear import protein in tumors is limited. Our previous studies have shown that DYNC1I1 is a poor prognostic factor for gastric cancer and can promote the proliferation and metastasis of gastric cancer cells. An expression profile chip showed that TNPO2 was its potential downstream. DYNC1I1 upregulated TNPO2 expression by upregulating SP1, following which, SP1 recruited and bound to the P300-acetylated TNPO2 promoter region histones, and thus promoted TNPO2 expression. At the same time, TNPO2 promoted gastric cancer cell proliferation and inhibited apoptosis by a mechanism that might be depending on the functional expression of P21.


Two-Pronged Dormant Photosensitizer-Antibiotic Bacterial Inactivation: Mechanism, Dosage, and Cellular Evolution Visualized at the Single-Cell Level.
Innovative therapeutic approaches are required to battle the rise of antibiotic-resistant bacterial strains. Tapping on reactive oxygen species (ROS) generation in bacteria induced by bactericidal antibiotics, here we report a two-pronged strategy for bacterial inactivation relying on the synergistic combination of a bactericidal antibiotic and newly designed dormant photosensitizers (DoPSs) that activate in the presence of ROS. Intramolecular quenching renders DoPS inert in the presence of light. ROS trapping by DoPS aborts the quenching mechanism unmasking, in equal proportions, singlet oxygen (1O2) sensitization and fluorescence emission. Juxtaposed antioxidant-prooxidant activity built within our DoPS enables (i) initial activation of a few molecules by ROS and (ii) subsequent rapid activation of all DoPS in a bacterium via a domino effect mediated by photogenerated 1O2. Bulk colony forming unit studies employing the minimum inhibitory concentration of the antibiotic illustrate rapid and selective inactivation of Escherichia coli and Pseudomonas aeruginosa only in the presence of light, antibiotic, and DoPS. Single-cell, real-time imaging studies on E. coli reveal an autocatalytic progression of DoPS activation from focal points, providing a unique amplification system for sensing. Single-cell analysis further illustrates the impact of DoPS cellular loading on the rate of DoPS activation and cell death times and on the 1O2 dosing necessary for cell death to occur. Our two-pronged therapy discriminates based on cell metabolites and has the potential to result in lower toxicity, pave the way to reduced drug resistance, and provide insightful mechanistic information about bacterial membrane response to 1O2.


[Efficacy and safety of atorvastatin in major cardiovascular events: Meta-analysis].
Atorvastatin has been used in the management of dyslipidemia and little is known about the efficacy and safety of high-dose atorvastatin administration for secondary prevention of Major Cardiovascular Events (MACE). To evaluate the impact of high-dose atorvastatin on secondary prevention of MACE and adverse events. A systematic review and meta-analysis of Pubmed, Embase, Bireme and Cochrane Library Plus databases was performed, with a time scope from 1990 to July 2022. Six randomized clinical trials were included with a total of 29,333 patients who were treated with 80 mg, 10 mg or placebo doses of Atorvastatin where the main outcomes evaluated were Major Cardiovascular Events (MACE), mortality and treatment safety. In the comparative study between the use of Atorvastatin 80 mg and other therapies, a relative risk (RR) of 0.8 (95%CI 0.69-0.92) was found, representing a 20% reduction in risk (RRR) and a number needed to treat (NNT) of 30-55. In the analysis of adverse effects, an RR of 2.37 (95% CI 0.86-6.53) and a number needed to harm (NNH) of 14-19 were observed. The use of 80 mg atorvastatin is associated with similar adverse events at lower doses. The use of atorvastatin 80 mg is effective in the secondary prevention of Major Cardiovascular Event (MACE). The drug has adverse events that should be taken into account in secondary prevention.


Anti-idiotypic network induced by T cell vaccination against experimental autoimmune encephalomyelitis.
In a study of the mechanism of resistance to autoimmune disease induced by T cell vaccination, rats were vaccinated against experimental autoimmune encephalomyelitis (EAE) by injecting them once in the hind footpads with a subencephalitogenic dose (10(4)) of a clone of T lymphocytes specific for myelin basic protein (BP). The response to vaccination was assayed by challenging the rats with an encephalitogenic dose (3 X 10(6)) of T lymphocytes of this BP-specific clone. Five to six days after vaccination, the cells responsible for mediating resistance to adoptively transferred EAE were concentrated in the popliteal lymph nodes draining the vaccination site. Transfer of the draining lymph node cells to unvaccinated rats led to loss of resistance in the donor rats and acquisition of resistance by the recipient rats. Limiting-dilution cultures of the draining lymph node cells were established with irradiated cells of the BP-specific clone as stimulators. Two sets of T lymphocytes specifically responsive to the BP-specific T cells from the clone were isolated: CD4+CD8- helper and CD4-CD8+ suppressor cells. The helper T cells, like the BP antigen, specifically stimulated the BP-specific vaccinating clone. In contrast, the suppressor T cells specifically suppressed the response of the BP-specific vaccinating clone to its BP antigen. These results suggest that T cell vaccination induces resistance to autoimmune disease by activating an antiidiotypic network.


Deletion of p120-catenin results in a tumor microenvironment with inflammation and cancer that establishes it as a tumor suppressor gene.
p120-catenin (p120ctn) interacts with E-cadherin, but to our knowledge, no formal proof that p120ctn functions as a bona fide tumor suppressor gene has emerged to date. We report herein that p120ctn loss leads to tumor development in mice. We have generated a conditional knockout model of p120ctn whereby mice develop preneoplastic and neoplastic lesions in the oral cavity, esophagus, and squamous forestomach. Tumor-derived cells secrete granulocyte macrophage colony-stimulating factor (GM-CSF), macrophage colony-stimulating factor (M-CSF), monocyte chemotactic protein-1 (MCP-1), and tumor necrosis factor-α (TNFα). The tumors contain significant desmoplasia and immune cell infiltration. Immature myeloid cells comprise a significant percentage of the immune cells present and likely participate in fostering a favorable tumor microenvironment, including the activation of fibroblasts.


[Current interest of antipneumococcal vaccination].
Pneumonia acquired in Community (CAP) may be a primary disease occurring in healthy individuals or secondary to predisposing factors or comorbidity. Prevalence of CAP is 2.6 to 5% for all ages, in USA 12%, for over 65 years 30%. Streptococcus pneumoniae is the commonest pathogen 30-50%, H. influenzae in COPD, the atypical pneumonia Mycoplasma pn., M. catharralis, Legionella pn., Enterobacteria, anaerobics often in hospital survey. In children is different RSV, Parainfluenzae type 3, Rhinovirus in the first 2 years old. Others are S. pneumoniae, H. influenzae, Chlamydia sp., etc. Appropriate empiric antibiotic therapy choices are based in guidelines. The most common pathogen is S. pneumoniae, isolates raised resistance rates to Penicillin to 20-50%, 40% in our country and also to Macrolides, with potential clinical failure (21-40%). Specially in elderly people and with the comorbidity are recommended the 23 valent polysaccharide vaccine, effective in bacteremic pneumonia 70-80%. Is not effective in children under 2 years, for that is important conjugated vaccine Hib (toxoids T, D, CRM197, OMP Nm) to prevent carriers, otitis media and reduce exacerbation of these respiratory infections.


Quality of Life after Brain Injury (QOLIBRI): scale development and metric properties.
The consequences of traumatic brain injury (TBI) for health-related quality of life (HRQoL) are poorly investigated, and a TBI-specific instrument has not previously been available. The cross-cultural development of a new measure to assess HRQoL after TBI is described here. An international TBI Task Force derived a conceptual model from previous work, constructed an initial item bank of 148 items, and then reduced the item set through two successive multicenter validation studies. The first study, with eight language versions of the QOLIBRI, recruited 1528 participants with TBI, and the second with six language versions, recruited 921 participants. The data from 795 participants from the second study who had complete Glasgow Coma Scale (GCS) and Glasgow Outcome Scale (GOS) data were used to finalize the instrument. The final version of the QOLIBRI consists of 37 items in six scales (see Appendix ). Satisfaction is assessed in the areas of "Cognition," "Self," "Daily Life and Autonomy," and "Social Relationships," and feeling bothered by "Emotions," and "Physical Problems." The QOLIBRI scales meet standard psychometric criteria (internal consistency, alpha = 0.75-0.89, test-retest reliability, r(tt) = 0.78-0.85). Test-retest reliability (r(tt) = 0.68-0.87) as well as internal consistency (alpha = 0.81-0.91) were also good in a subgroup of participants with lower cognitive performance. Although there is one strong HRQoL factor, a six-scale structure explaining additional variance was validated by exploratory and confirmatory factor analyses, and with Rasch modeling. The QOLIBRI is a new cross-culturally developed instrument for assessing HRQoL after TBI that fulfills standard psychometric criteria. It is potentially useful for clinicians and researchers conducting clinical trials, for assessing the impact of rehabilitation or other interventions, and for carrying out epidemiological surveys.


Demonstration of an ethane spectrometer for methane source identification.
Methane is an important greenhouse gas and tropospheric ozone precursor. Simultaneous observation of ethane with methane can help identify specific methane source types. Aerodyne Ethane-Mini spectrometers, employing recently available mid-infrared distributed feedback tunable diode lasers (DFB-TDL), provide 1 s ethane measurements with sub-ppb precision. In this work, an Ethane-Mini spectrometer has been integrated into two mobile sampling platforms, a ground vehicle and a small airplane, and used to measure ethane/methane enhancement ratios downwind of methane sources. Methane emissions with precisely known sources are shown to have ethane/methane enhancement ratios that differ greatly depending on the source type. Large differences between biogenic and thermogenic sources are observed. Variation within thermogenic sources are detected and tabulated. Methane emitters are classified by their expected ethane content. Categories include the following: biogenic (<0.2%), dry gas (1-6%), wet gas (>6%), pipeline grade natural gas (<15%), and processed natural gas liquids (>30%). Regional scale observations in the Dallas/Fort Worth area of Texas show two distinct ethane/methane enhancement ratios bridged by a transitional region. These results demonstrate the usefulness of continuous and fast ethane measurements in experimental studies of methane emissions, particularly in the oil and natural gas sector.


Three-dimensional imaging of human cutaneous forearm bite marks in human volunteers over a 4 day period.
Human bite marks are often sustained during sexual, domestic or child abuse. Currently, analysis of these marks involves digital photography techniques along with an expert forensic odontologist opinion. Photographs often focus closely on the bite mark and give little context to the anatomical location of the injury. Due to variation in camera models and expertise of the photographer, photograph quality can affect its interpretation. Additionally, it can sometimes be days between injury and examination, allowing the injury pattern and colour to alter, making it harder to analyse. To investigate if a 3D imaging technique, creating a time-lapse image of a bite mark in three dimensions, can provide context to the injury in terms of nature and location, and also allow analysis of the change in appearance of a bite mark over time. Participants had an experimental bite mark produced on their forearm by dental casts mounted on a dental articulator. The forearms were photographed immediately following the bite, and at intervals of 3, 6, 24, 48, 72 and 96 h. A DI3D(®) (Dimensional Imaging 3D) photogrammetry system and Autodesk Maya 2015(®) software was used to create a 3D animation from the images obtained. The clearest, long lasting bite mark injuries were selected for animation, enabling the 3D imaging technique to be used optimally. 3D time-lapse animations were successfully created with the ability to be viewed on most electronic devices. With further refinement this technique could be valuable in a number of areas. We anticipate animations produced in this way to have significant benefit to the presentation of photographic evidence in a court setting, and in age estimation of injuries.


Internal friction in an intrinsically disordered protein-Comparing Rouse-like models with experiments.
Internal friction is frequently found in protein dynamics. Its molecular origin however is difficult to conceptualize. Even unfolded and intrinsically disordered polypeptide chains exhibit signs of internal friction despite their enormous solvent accessibility. Here, we compare four polymer theories of internal friction with experimental results on the intrinsically disordered protein ACTR (activator of thyroid hormone receptor). Using nanosecond fluorescence correlation spectroscopy combined with single-molecule Förster resonance energy transfer (smFRET), we determine the time scales of the diffusive chain dynamics of ACTR at different solvent viscosities and varying degrees of compaction. Despite pronounced differences between the theories, we find that all models can capture the experimental viscosity-dependence of the chain relaxation time. In contrast, the observed slowdown upon chain collapse of ACTR is not captured by any of the theories and a mechanistic link between chain dimension and internal friction is still missing, implying that the current theories are incomplete. In addition, a discrepancy between early results on homopolymer solutions and recent single-molecule experiments on unfolded and disordered proteins suggests that internal friction is likely to be a composite phenomenon caused by a variety of processes.


Scorpion sting envenomation outbreak in Mexico. Strategies for prevention and control.
In Mexico occurs 25% of all worldwide cases of scorpion sting envenomation (SSE). An outbreak of SSE was identified in Villa Unión, Sinaloa, Mexico. The objective of this study is to describe the outbreak, and prevention and control strategies implemented. The design was a cross-sectional study. Eligibility criteria included confirmed cases (n = 425) identified from the date the outbreak was recognized (from November 08, 2023 to July 10, 2023). The cases from Villa Unión (n = 231) were included for the analysis of epidemiological and clinical findings. The research followed the recommendations of the Initiative Reporting of studies Conducted Using Observational Routinely collected Data (RECORD). Of the total cases (n = 425), 398 (93.6%) were from the municipality of Mazatlán, and 231 (58%) were from Villa Unión. The incidence rate was 13.64 per 1000 persons. The average cases per week was 51.5(SD ± 12). The male-to-female ratio was 3:4, the average age was 30.7(SD ± 19) years. Most of cases occurred in the 25-44 age group. The sting occurred mostly inside houses (n = 200, 86.5%). The predominant symptoms were local pain (95.2%), and local paresthesia (75.8%). The Case fatality rate was 0%. Implementation of prevention and control strategies based on field epidemiological research and scientific evidence are necessary to reduce the incidence and prevent fatal complications.


Infections and antimicrobial resistance in long term care facilities: a national prevalence study.
A point prevalence survey (PPS) was conducted in Italy in 2010, as part of the first European PPS in Long Term Care Facilities (LTCFs), conducted within the HALT Project. The PPS was aimed at estimating the prevalence of infections, antimicrobial resistance, and antibiotic use and to assess the status of infections control programs in this setting. Ninety two LTCFs, located in 11 different Italian regions, participated to the study: 9391 residents were enrolled, 9285 of whom were eligible according to the study criteria. The prevalence of residents with signs/symptoms of infection was 6.5% (606 residents); 438 residents were on antimicrobial treatment (4.7%) and 526 had signs/symptoms (5.7%) but in 324 residents only (3.5/100 residents) the infection satisfied the modified McGeer criteria and was considered confirmed. The most frequent infection site was the respiratory tract (1.27/100 residents). Mostly of the antibiotics were prescribed for respiratory tract infections (42.8% of the antibiotics) and for urinary tract infections (26.6%). The most frequently prescribed classes were quinolones, followed by penicillin plus beta-lactamase inhibitor and 3rd generation cephalosporins. Few infection had a microbiological confirmation, but among the 143 isolated microorganisms 24% were multidrug resistant. The burden of infections and antimicrobial resistance in LTCFs is significant and infection control and surveillance program are urgently needed.


Grid-based International Network for Flu observation (g-INFO).
The 2009 H1N1 outbreak has demonstrated that continuing vigilance, planning, and strong public health research capability are essential defenses against emerging health threats. Molecular epidemiology of influenza virus strains provides scientists with clues about the temporal and geographic evolution of the virus. In the present paper, researchers from France and Vietnam are proposing a global surveillance network based on grid technology: the goal is to federate influenza data servers and deploy automatically molecular epidemiology studies. A first prototype based on AMGA and the WISDOM Production Environment extracts daily from NCBI influenza H1N1 sequence data which are processed through a phylogenetic analysis pipeline deployed on EGEE and AuverGrid e-infrastructures. The analysis results are displayed on a web portal (http://g-info.healthgrid.org) for epidemiologists to monitor H1N1 pandemics.


Asymptomatic immune responders to Leishmania among HIV positive patients.
Concomitant infection with human immunodeficiency virus (HIV) and the Leishmania parasite is a growing public health problem, the result of the former spreading to areas where the latter is endemic. Leishmania infection is usually asymptomatic in immunocompetent individuals, but the proportion of HIV+ individuals in contact with the parasite who remain asymptomatic is not known. The aim of the present work was to examine the use of cytokine release assays in the detection of asymptomatic immune responders to Leishmania among HIV+ patients with no previous leishmaniasis or current symptomatology. Eighty two HIV+ patients (all from Fuenlabrada, Madrid, Spain, where a leishmaniasis outbreak occurred in 2009) were examined for Leishmania infantum infection using molecular and humoral response-based methods. None returned a positive molecular or serological result for the parasite. Thirteen subjects showed a positive lymphoproliferative response to soluble Leishmania antigen (SLA), although the mean CD4+ T lymphocyte counts of these patients was below the normal range. Stimulation of peripheral blood mononuclear cells (PBMC) or whole blood with SLA (the lymphoproliferative assay and whole blood assay respectively), led to the production of specific cytokines and chemokines. Thus, despite being immunocompromised, HIV+ patients can maintain a Th1-type cellular response to Leishmania. In addition, cytokine release assays would appear to be useful tools for detecting these individuals via the identification of IFN-γ in the supernatants of SLA-stimulated PBMC, and of IFN-γ, MIG and IL-2 in SLA-stimulated whole blood. These biomarkers appear to be 100% reliable for detecting asymptomatic immune responders to Leishmania among HIV+ patients.


Directional control of π-conjugation enabled by distortion of the donor plane in diarylaminoanthracenes: a photophysical study.
We designed and synthesized a series of diarylaminoanthracenes in which the planarity of the diarylamine moiety is controlled by methylene- or ethylene- bridges. The X-ray crystallographic structures confirm that the methylene- and ethylene bridges gradually decrease the disorder of the diarylamine planes. To quantitatively analyze the photophysical properties and underlying electronic structures of these compounds, we carried out UV-vis and fluorescence spectroscopy, fluorescence quantum yield, and fluorescence lifetime measurements. The results reveal that enhanced planarity of the diarylamine moiety optically forbids the charge-transfer transition between the diarylamine and anthracene moieties. Although it is generally accepted that a planar π-conjugated system favors electron delocalization, our results indicate that distortion of the donor plane induces interchromophoric conjugation rather than conjugation within the local structure. Density functional theory calculations further illustrate that the frontier orbitals of diarylamine and anthracene interpenetrate as the donor plane is distorted. Additionally, natural bonding orbital analyses reveal that distortion of the donor plane changes the directionality of the π-conjugation of the nitrogen n-orbital from intrachromophoric to interchromophoric.


Benzo pyrene-induced DNA adducts and gene expression profiles in target and non-target organs for carcinogenesis in mice.
Gene expression changes induced by carcinogens may identify differences in molecular function between target and non-target organs. Target organs for benzo[a]pyrene (BaP) carcinogenicity in mice (lung, spleen and forestomach) and three non-target organs (liver, colon and glandular stomach) were investigated for DNA adducts by 32P-postlabelling, for gene expression changes by cDNA microarray and for miRNA expression changes by miRNA microarray after exposure of animals to BaP. BaP-DNA adduct formation occurred in all six organs at levels that did not distinguish between target and non-target. cDNA microarray analysis showed a variety of genes modulated significantly by BaP in the six organs and the overall gene expression patterns were tissue specific. Gene ontology analysis also revealed that BaP-induced bioactivities were tissue specific; eight genes (Tubb5, Fos, Cdh1, Cyp1a1, Apc, Myc, Ctnnb1 and Cav) showed significant expression difference between three target and three non-target organs. Additionally, several gene expression changes, such as in Trp53 activation and Stat3 activity suggested some similarities in molecular mechanisms in two target organs (lung and spleen), which were not found in the other four organs. Changes in miRNA expression were generally tissue specific, involving, in total, 21/54 miRNAs significantly up- or down-regulated. Altogether, these findings showed that DNA adduct levels and early gene expression changes did not fully distinguish target from non-target organs. However, mechanisms related to early changes in p53, Stat3 and Wnt/β-catenin pathways may play roles in defining BaP organotropism.


Neural and Pupillometric Correlates of Error Perception in an Immersive VR Flight Simulation.
Algorithms detecting erroneous events, as used in brain-computer interfaces, usually rely solely on neural correlates of error perception. The increasing availability of wearable displays with built-in pupillometric sensors enables access to additional physiological data, potentially improving error detection. Hence, we measured both electroencephalographic (EEG) and pupillometric signals of 19 participants while performing a navigation task in an immersive virtual reality (VR) setting. We found EEG and pupillometric correlates of error perception and significant differences between distinct error types. Further, we found that actively performing tasks delays error perception. We believe that the results of this work could contribute to improving error detection, which has rarely been studied in the context of immersive VR.


Information technology capability, open technological innovation and firm growth.
The aim of this paper is to investigate the effects of information technology (IT) capability on firm growth in the context of open technological innovation. The paper utilized a logical deductive approach to develop hypotheses and analytical frameworks, and collected empirical data from 256 Chinese new ventures. Regression analysis and structural equation models were used to test the hypotheses and analyze the data. The results showed that IT capability, including flexibility and integration of information technology, significantly influenced firm growth, and open technological innovation partially mediated the relationship between IT flexibility and firm growth, and significantly mediated the relationship between IT integration and firm growth. The paper's limitations include the cross-sectional design, limited sample size, and potential unobserved variables such as organizational learning that could affect the relationship between IT capability and firm growth. The research is the first to investigate the effects of IT capability on firm growth based on the mediation of open technological innovation in China, contributing to the literature on IT capability and providing insights for managerial practice in the sharing economy era.


Cost effectiveness analysis of Avonex and CinnoVex in Relapsing Remitting MS.
Multiple sclerosis is a chronic and degenerative neurological disease characterized by loss of myelin sheath of some neurons in brain and spinal cord. It is associated with high economic burden due to premature deaths and high occurrence of disabilities. The aim of the current study was to determine cost effectiveness of two major products of interferon 1a in patients with relapsing-remitting multiple sclerosis. Altogether, 140 patients who have consumed Avonex and CinnoVex in Relapsing Remitting MS for at least two years were randomly selected (70 patients in each group). Health-related quality of life (HRQoL) was assessed using the adopted MSQoL-54 instrument. Costs were measured and valued from Ministry of Health and Medical Education (MOHME) perspective. Two-way sensitivity analysis was used to check robustness of the results. Patients in CinnoVex group reported significantly higher scores in both physical (69.5 vs. 50.9, P<0.001) and mental (63.3 vs. 56.6, P=0.03) aspects of HRQoL than Avonex group. On the other hand, annual cost of CinnoVex and Avonex were 2410 US$ and 4515US$ per patient, respectively (P<0.001). The results showed that CinnoVex was dominant option over the study period. It is suggested that results of the current study should be considered in allocating resources to MS treatments in Iran. Of course, our findings should be interpreted with caution duo to short term horizon and lack of HRQoL scores at baseline (before the intervention).


Nuclear export of influenza virus ribonucleoproteins: identification of an export intermediate at the nuclear periphery.
A critical phase of the influenza virus life cycle is the regulated translocation of genomic ribonucleoproteins (vRNPs) from the nuclear interior, across the nuclear envelope, and into the cytoplasm. Two viral proteins, M1 and NS2, have previously been implicated as mediators of vRNP export. We show here that vRNP nuclear export is prevented by leptomycin B (LMB), an inhibitor of the cellular factor CRM1. In LMB-treated cells, vRNPs were found in a peripheral nuclear location that localized with the nuclear lamina. vRNPs were not colocalized with either M1 or NS2. In situ extraction of cells late in infection also revealed a peripheral localization of nuclear vRNPs, whereas early in infection vRNPs were dispersed throughout the nuclear interior. We believe that vRNPs at the nuclear periphery represent a novel intermediate in the influenza virus nuclear export pathway.


Evaluating echocardiogram and indirect blood pressure results in male western lowland gorillas (Gorilla gorilla gorilla) during three phases of an anesthetic protocol.
Until the majority of the great ape population is trained for conscious cardiac evaluations, most individuals will require general anesthesia to perform echocardiograms. Within the veterinary community, concern exists that certain anesthetic protocols may exacerbate or artificially induce signs of cardiac disease. Because of potential cardiovascular effects, medetomidine has generally been used cautiously in patients with cardiac disease. The combination of ketamine and medetomidine is frequently used by many institutions because of its reversibility. To date, no published studies have obtained physiologic or echocardiographic parameters comparing different anesthetic protocols. In this study, with the use of seven adult male gorillas (Gorilla gorilla gorilla) with and without cardiac disease, echocardiographic and indirect blood pressure data during three phases of an anesthetic protocol were collected. The initial echocardiographic study was completed with ketamine/ medetomidine alone (5-7 mg/kg, i.m., and 0.05-0.07 mg/kg, i.m., respectively); the second study was completed after the addition of sevoflurane inhalant anesthesia to this procedure; and the third study was completed after reversal of medetomidine by administration of atipamezole (5:1 with the medetomidine dose given at induction). Without exception, ejection fractions were 15-25% lower under anesthesia with medetomidine as compared to ejection fractions after administration of atipamezole. Indirect blood pressures were higher on ketamine/ medetomidine, lower with addition of sevoflurane, and considerably lower after administration of atipamezole.


Eyelid Drive System: An Assistive Technology Employing Inductive Sensing of Eyelid Movement.
This paper presents the design, development, and validation of the eyelid drive system (EDS), an assistive technology comprising a specialized pair of glasses and millimeter-sized passive resonators, attached to the user's eyelids, that transduce eyelid movement (blinking and winking) through inductive sensing. The theory of operation and design optimization with simulations are presented. A proof-of-concept prototype EDS was constructed using a pair of nonprescription glasses and commercial-off-the-shelf components. In benchtop tests with model eyelids, the EDS demonstrated basic functionality. Initial trials were performed involving six human subjects interacting with custom designed graphical user interfaces on a computer. A group mean accuracy of 96.3% was achieved using a set of four different commands at a response rate of 3 s. A mean information transfer rate (ITR) of 56.1 b/min over all subjects was achieved with a set of six different commands at a response rate of 1.5 s. This proof-of-concept device consumes 51.6 mW of power. The EDS compares favorably with related eye-interfacing assistive technologies and provides a unique combination of advantages, including high accuracy and ITR, wearability, insensitivity to lighting and noise conditions, obviation of facial electrodes, and the use of nonexaggerated gestures.


Psychological distress leads to reduced physical activity and fitness in children: the Australian longitudinal LOOK study.
Stress and depression can affect an individual's level of physical activity and fitness, which may place them at risk of developing cardiovascular disease. This study investigates the longitudinal effects of stress and depression on physical activity and cardiorespiratory fitness among youth. Six hundred and seventy-six children, initially aged 8 years, from the LOOK study completed a modified version of the Children's Depression Inventory, the Children's Stress Questionnaire, and objective physical activity and cardiorespiratory fitness assessments on three occasions, every 4 years. Depressive symptoms had a direct effect (longitudinal) on the cardiorespiratory fitness of girls, with a similar trend for boys. In cross-sectional analyses, a child who identified with more symptoms of depression and stress was likely to be less fit and less physically active, which in girls extended to less moderate-to-vigorous physical activity. Our findings, that both physical activity and fitness are impacted by depression and stress may contribute to strategies directed towards achieving enhanced physical activity and reductions in obesity.


Perineal Richter's herniation following proctectomy.
In a Richter's hernia, only part of the anti-mesenteric border of the bowel is incarcerated within the underlying defect. We report three cases presenting between 18 days and 11 years following proctectomy. As all patients had functioning stomas a high index of suspicion is necessary to avoid a delay in diagnosis.


Long-term lithium therapy and risk of chronic kidney disease in bipolar disorder: A historical cohort study.
Long-term lithium therapy (LTLT) has been associated with kidney insufficiency in bipolar disorder (BD). We aimed to investigate the risk factors of chronic kidney disease (CKD) development and progression among BD patients receiving LTLT. We included adult patients with BD on LTLT (≥1 year) who were enrolled in the Mayo Clinic Bipolar Biobank, Rochester, Minnesota. We reviewed electronic medical records to extract information related to lithium therapy and kidney-related data to assess changes in the estimated glomerular filtration rate (eGFR). CKD severity was assessed based on eGFR. Among 154 patients who received LTLT, 41 patients (27%) developed CKD, of whom 20 (49%) patients continued lithium (continuers) and 19 (46%) discontinued it (discontinuers). The median time to stage 3 CKD development was 21.7 years from the start of Li treatment. Type-2 diabetes mellitus and benzodiazepine use were independent predictors for CKD development in the survival analysis, after controlling for age. The subsequent CKD progression rate did not differ between continuers and discontinuers (mean GFR 48.6 vs. 44.1, p = 0.13) at the end of follow-up duration (mean duration: 3.5 ± 4.4 years for continuers and 4.9 ± 5.3 years for discontinuers). CKD was observed in one fourth of patients with BD receiving LTLT. There was no significant difference in the progression of CKD among Li continuers versus discontinuers, at the mean follow-up duration of 4.2 years, after the CKD diagnosis. Progression of CKD could be influenced by existing comorbidities and may not necessarily be due to lithium alone.


The metabolic syndrome, oxidative stress, environment, and cardiovascular disease: the great exploration.
The metabolic syndrome affects 30% of the US population with increasing prevalence. In this paper, we explore the relationship between the metabolic syndrome and the incidence and severity of cardiovascular disease in general and coronary artery disease (CAD) in particular. Furthermore, we look at the impact of metabolic syndrome on outcomes of coronary revascularization therapies including CABG, PTCA, and coronary collateral development. We also examine the association between the metabolic syndrome and its individual component pathologies and oxidative stress. Related, we explore the interaction between the main external sources of oxidative stress, cigarette smoke and air pollution, and metabolic syndrome and the effect of this interaction on CAD. We discuss the apparent lack of positive effect of antioxidants on cardiovascular outcomes in large clinical trials with emphasis on some of the limitations of these trials. Finally, we present evidence for successful use of antioxidant properties of pharmacological agents, including metformin, statins, angiotensin II type I receptor blockers (ARBs), and angiotensin II converting enzyme (ACE) inhibitors, for prevention and treatment of the cardiovascular complications of the metabolic syndrome.


Chronic treatment with N-acetylcysteine decreases extinction responding and reduces cue-induced nicotine-seeking.
N-acetylcysteine (NAC), a promising glutamatergic therapeutic agent, has shown some clinical efficacy in reducing nicotine use in humans and has been shown to reverse drug-induced changes in glutamatergic neurophysiology. In rats, nicotine-seeking behavior is associated with alterations in glutamatergic plasticity within the nucleus accumbens core (NAcore). Specifically, cue-induced nicotine-seeking is associated with rapid, transient synaptic plasticity (t-SP) in glutamatergic synapses on NAcore medium spiny neurons. The goal of the present study was to determine if NAC reduces nicotine-seeking behavior and reverses reinstatement-associated NAcore glutamatergic alterations. Rats were extinguished from nicotine self-administration, followed by subchronic NAC administration (0 or 100 mg/kg/d) for 4 days prior to cue-induced reinstatement. NAcore synaptic potentiation was measured via dendritic spine morphology and mRNA and protein of relevant glutamatergic genes were quantified. Nicotine-seeking behavior was not reduced by subchronic NAC treatment. Also, NAcore transcript and protein expression of multiple glutamatergic genes, as well as spine morphological measures, were unaffected by subchronic NAC. Finally, chronic NAC treatment (15 days total) during extinction and prior to reinstatement significantly decreased extinction responding and reduced reinstatement of nicotine-seeking compared to vehicle. Together, these results suggest that chronic NAC treatment is necessary for its therapeutic efficacy as a treatment strategy for nicotine addiction and relapse.


Facile and versatile strategy to prepare magnetic molecularly imprinted particles based on the coassembly of magnetic nanoparticles and amphiphilic random copolymers.
Magnetic molecularly imprinted polymer nanoparticles for bisphenol A were prepared by coassembling magnetic nanoparticles and amphiphilic random copolymers. Under optimized conditions, bisphenol A as template molecules, magnetic molecularly imprinted polymer particles with regular morphology, small size, good monodispersity, and high content of OA-Fe3 O4 were prepared by the coassembly method using P(MMA-co-MAA) with monomer ratio of 9:1. These magnetic molecularly imprinted polymer particles could be rapidly collected by an external magnet within 1 min. The saturated adsorption capacity of the magnetic molecularly imprinted polymer for bisphenol A was 201.5 mg/g, and the imprinting factor was 2.5. The separation factors for bisphenol A to β-estradiol, estriol, and diethylstilbestrol was 3.1, 2.9, and 3.7, respectively. Unlike assembling amphiphilic copolymer in the selective solvent, the coassembly process was simple and rapid. Therefore, the present work provided a facile and versatile approach to construct magnetic molecularly imprinted polymer nanoparticles under mild conditions.


Hydroxyl-Bonded Ru on Metallic TiN Surface Catalyzing CO2 Reduction with H2O by Infrared Light.
Synchronized conversion of CO2 and H2O into hydrocarbons and oxygen via infrared-ignited photocatalysis remains a challenge. Herein, the hydroxyl-coordinated single-site Ru is anchored precisely on the metallic TiN surface by a NaBH4/NaOH reforming method to construct an infrared-responsive HO-Ru/TiN photocatalyst. Aberration-corrected high-angle annular dark-field scanning transmission electron microscopy (ac-HAADF-STEM) and X-ray absorption spectroscopy (XAS) confirm the atomic distribution of the Ru species. XAS and density functional theory (DFT) calculations unveil the formation of surface HO-RuN5-Ti Lewis pair sites, which achieves efficient CO2 polarization/activation via dual coordination with the C and O atoms of CO2 on HO-Ru/TiN. Also, implanting the Ru species on the TiN surface powerfully boosts the separation and transfer of photoinduced charges. Under infrared irradiation, the HO-Ru/TiN catalyst shows a superior CO2-to-CO transformation activity coupled with H2O oxidation to release O2, and the CO2 reduction rate can further be promoted by about 3-fold under simulated sunlight. With the key reaction intermediates determined by in situ diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS) and predicted by DFT simulations, a possible photoredox mechanism of the CO2 reduction system is proposed.


To ingest or rest? Specialized roles of lateral hypothalamic area neurons in coordinating energy balance.
Survival depends on an organism's ability to sense nutrient status and accordingly regulate intake and energy expenditure behaviors. Uncoupling of energy sensing and behavior, however, underlies energy balance disorders such as anorexia or obesity. The hypothalamus regulates energy balance, and in particular the lateral hypothalamic area (LHA) is poised to coordinate peripheral cues of energy status and behaviors that impact weight, such as drinking, locomotor behavior, arousal/sleep and autonomic output. There are several populations of LHA neurons that are defined by their neuropeptide content and contribute to energy balance. LHA neurons that express the neuropeptides melanin-concentrating hormone (MCH) or orexins/hypocretins (OX) are best characterized and these neurons play important roles in regulating ingestion, arousal, locomotor behavior and autonomic function via distinct neuronal circuits. Recently, another population of LHA neurons containing the neuropeptide Neurotensin (Nts) has been implicated in coordinating anorectic stimuli and behavior to regulate hydration and energy balance. Understanding the specific roles of MCH, OX and Nts neurons in harmonizing energy sensing and behavior thus has the potential to inform pharmacological strategies to modify behaviors and treat energy balance disorders.


Signal pathways mediating oxytocin stimulation of prostaglandin synthesis in select target cells.
A major action of oxytocin is to stimulate prostaglandin production in reproductive tissues. The two major enzyme systems involved are cytosolic phospholipase A2 (cPLA2), which catalyses the formation of arachidonic acid from membrane glycerophospholipids, and prostaglandin endoperoxide-H synthases-1 and -2, which allow conversion of arachidonic acid to prostaglandins. During gestation, the concentrations of all three enzymes rise in the rabbit amnion. Agonists, including oxytocin, increase cPLA2 activity, in part, by elevating intracellular Ca2+ concentration, which causes cPLA2 to be translocated from the cytosol to intracellular membrane binding sites. Cytosolic PLA2 is then activated by a mitogen-activated protein kinase (MAPK)-dependent step. Our studies have elucidated signal pathways involved in oxytocin-stimulated prostaglandin output in both rabbit amnion cells and Chinese hamster ovary cells stably transfected with the rat oxytocin receptor. The two cell types are alike with respect to oxytocin-stimulated intracellular Ca2+ transients, mediation via Gq, and the specific MAPK that catalyses the phosphorylation of cPLA2. However, they differ with respect to the mechanisms of upregulation of key enzymes involved in prostaglandin E2 synthesis. These findings illustrate the tiers of complementary mechanisms involved in oxytocin stimulation of prostaglandin E2, and the extent of the diversity in the cellular signalling pathways involved.


High-frequency, short-latency disinhibition bursting of midbrain dopaminergic neurons.
During reinforcement and sequence learning, dopaminergic neurons fire bursts of action potentials. Dopaminergic neurons in vivo receive strong background excitatory and inhibitory inputs, suggesting that one mechanism by which bursts may be produced is disinhibition. Unfortunately, these inputs are lost during slice preparation and are not precisely controlled during in vivo experiments. In the present study we show that dopaminergic neurons can be shifted into a balanced state in which constant synaptic N-methyl-d-aspartate (NMDA) and GABA(A) conductances are mimicked either pharmacologically or using dynamic clamp. From this state, a disinhibition burst can be evoked by removing the background inhibitory conductance. We demonstrate three functional characteristics of network-based disinhibition that promote high-frequency, short-latency bursting in dopaminergic neurons. First, we found that increasing the total background NMDA and GABA(A) synaptic conductances increased the intraburst firing frequency and reduced its latency. Second, we found that the disinhibition burst is sensitive to the proportion of background inhibitory input that is removed. In particular, we found that high-frequency, short-latency bursts were enhanced by increasing the degree of disinhibition. Third, the time course over which inhibition is removed had a large effect on the burst, namely, that synchronous removal of weak inhibitory inputs produces bursts of high intraburst frequency and shorter latency. Our results suggest that fast, more precisely timed bursts can be evoked by complete and synchronous disinhibition of dopaminergic neurons in a high-conductance state.


Delineation of La Crosse virus in developmental stages of transovarially infected Aedes triseriatus.
The tropisms and development of La Crosse (LAC) virus in stages of transovarially infected Aedes triseriatus were studied with fluorescent antibody (FA) stained dissected organs and titrations of individual arthropods in suckling mice. Viral antigen was detected by FA in 95 of 387 dissected larvae, pupae, and adults. In larvae highest levels of fluorescence were detected in the alimentary tract, followed by ganglia, malpighian tubule, muscle, and other tissues. No specific organs or germ layer-derived tissues appeared to be the sole source of viral replication. Most tissues and organs of A. triseriatus are capable of maintaining LAC virus. Antigen was detected in the identifiable organs immediately upon emergence from the egg. In pupae and adults antigen was detected at high levels in foregut, gonadal and associated tissues, and in salivary glands, which would indicate females could be infective upon emergence. Virus was isolated from all arthropod stages, in 32 of 130 individuals inoculated into suckling mice. Titrations ranged from less than 1.0 log10 SMICLD50 per 0.02 ml for eggs and 1st instar larvae to 3.0 log10 SMICLD50 for 4th instar larvae. Adults and pupae averaged between 2.0 and 3.0 log10 SMICLD50. Increases in titer during maturation were mainly related to increases in size of the organism rather than in titer per unit volume.


Positional mapping of PRKD1, NRP1 and PRDM1 as novel candidate disease genes in truncus arteriosus.
Truncus arteriosus (TA) is characterised by failure of septation of the outflow tract into aortic and pulmonary trunks and is associated with high morbidity and mortality. Although ranked among the least common congenital heart defects, TA provides an excellent model for the role of individual genes in cardiac morphogenesis as exemplified by TBX1 deficiency caused by point mutations or, more commonly, hemizygosity as part of the 22q11.2 deletion syndrome. The latter genetic lesion, however, is only observed in a proportion of patients with TA, which suggests the presence of additional disease genes. To identify novel genes that cause Mendelian forms of TA. We exploited the occurrence of monogenic forms of TA in the Saudi population, which is characterised by high consanguinity, a feature conducive to the occurrence of Mendelian phenocopies of complex phenotypes as we and others have shown. Indeed, we demonstrate in two multiplex consanguineous families that we are able to map TA to regions of autozygosity in which whole-exome sequencing revealed homozygous truncating mutations in PRKD1 (encoding a kinase derepressor of MAF2) and NRP1 (encoding a coreceptor of vascular endothelial growth factor (VEGFA)). Previous work has demonstrated that Prkd1(-/-) is embryonic lethal and that its tissue-specific deletion results in abnormal heart remodelling, whereas Nrp1(-/-) develops TA. Surprisingly, molecular karyotyping to exclude 22q11.2 deletion syndrome in the replication cohort of 17 simplex TA cases revealed a de novo hemizygous deletion that encompasses PRDM1, deficiency of which also results in TA phenotype in mouse. Our results expand the repertoire of molecular lesions in chromatin remodelling and transcription factors that are implicated in the pathogenesis of congenital heart disease in humans and attest to the power of monogenic forms of congenital heart diseases as a complementary approach to dissect the genetics of these complex phenotypes.


Granulomatous Rhinitis in a Horse due to Mycobacterium intracellulare Infection.
Mycobacterial infections in horses are uncommon, but are caused most frequently by Mycobacterium bovis of the Mycobacterium tuberculosis complex or Mycobacterium avium of the M. avium complex. Disease caused by Mycobacterium intracellulare, the second most common species within the M. avium complex, has not been reported in horses to date. Mycobacteriosis in horses most often presents as enteric, pulmonary or, rarely, systemic disease. Here we report a case of M. intracellulare infection in a horse presenting as a granulomatous nasal mass.


The rate of facultative sex governs the number of expected mating types in isogamous species.
It is unclear why sexually reproducing isogamous species frequently contain just two self-incompatible mating types. Deterministic theory suggests that since rare novel mating types experience a selective advantage (by virtue of their many potential partners), the number of mating types should consistently grow. However, in nature, species with thousands of mating types are exceedingly rare. Several competing theories for the predominance of species with two mating types exist, yet they lack an explanation for how many are possible and in which species to expect high numbers. Here, we present a theoretical null model that explains the distribution of mating type numbers using just three biological parameters: mutation rate, population size and the rate of sex. If the number of mating types results from a mutation-extinction balance, the rate of sexual reproduction plays a crucial role. If sex is facultative and rare (a very common combination in isogamous species), mating type diversity will remain low. In this rare sex regime, small fitness differences between the mating types lead to more frequent extinctions, further lowering mating type diversity. We also show that the empirical literature supports the role of drift and facultativeness of sex as a determinant of mating type dynamics.


Differential phospholipid substrates and directional transport by ATP-binding cassette proteins ABCA1, ABCA7, and ABCA4 and disease-causing mutants.
ABCA1, ABCA7, and ABCA4 are members of the ABCA subfamily of ATP-binding cassette transporters that share extensive sequence and structural similarity. Mutations in ABCA1 cause Tangier disease characterized by defective cholesterol homeostasis and high density lipoprotein (HDL) deficiency. Mutations in ABCA4 are responsible for Stargardt disease, a degenerative disorder associated with severe loss in central vision. Although cell-based studies have implicated ABCA proteins in lipid transport, the substrates and direction of transport have not been firmly established. We have purified and reconstituted ABCA1, ABCA7, and ABCA4 into liposomes for fluorescent-lipid transport studies. ABCA1 actively exported or flipped phosphatidylcholine, phosphatidylserine, and sphingomyelin from the cytoplasmic to the exocytoplasmic leaflet of membranes, whereas ABCA7 preferentially exported phosphatidylserine. In contrast, ABCA4 transported phosphatidylethanolamine in the reverse direction. The same phospholipids stimulated the ATPase activity of these ABCA transporters. The transport and ATPase activities of ABCA1 and ABCA4 were reduced by 25% in the presence of 20% cholesterol. Nine ABCA1 Tangier mutants and the corresponding ABCA4 Stargardt mutants showed significantly reduced phospholipid transport activity and subcellular mislocalization. These studies provide the first direct evidence for ABCA1 and ABCA7 functioning as phospholipid transporters and suggest that this activity is an essential step in the loading of apoA-1 with phospholipids for HDL formation.


A new genetic basis for hemoglobin-H disease.
We studied 11 families with alpha-thalassemia from the Qatif population of eastern Saudi Arabia to determine the genetic and molecular basis of hemoglobin-H disease, which is being encountered in this area with increasing frequency. The results show that there are two common alpha-thalassemia haplotypes, a deletion (-alpha/) determinant and a nondeletion (alpha alpha T/) determinant, which interact to produce a series of overlapping phenotypes. The most severe, hemoglobin-H disease, results from the homozygous state for the nondeletion determinant--a pattern of inheritance not previously recognized for this condition. Its molecular and genetic properties are thus different from those that produce the condition in Oriental or Mediterranean populations.


[Comparison of iodine scintigraphy and computerized tomography in the localization of pheochromocytoma].
A comparison is made of the results of CT scanning and MIBG scintigraphy in the localization of phaeochromocytoma. In 21 out of 24 patients with clinically diagnosed phaeochromocytoma in the University Medical Hospital, Groningen in 1983-1990, MIBG scintigraphy provided accurate localization, while in 16 out of 18 patients with phaeochromocytoma who underwent CT scanning a correct localization was obtained. False negative results were mainly present when lesions were smaller than 2 cm. There were no false positive results. It is concluded that the sensitivity of the two methods in the localization of phaeochromocytoma is about equal. The use of one of the methods rather than of both is advised.


Semantic similarity measures in the biomedical domain by leveraging a web search engine.
Various researches in web related semantic similarity measures have been deployed. However, measuring semantic similarity between two terms remains a challenging task. The traditional ontology-based methodologies have a limitation that both concepts must be resided in the same ontology tree(s). Unfortunately, in practice, the assumption is not always applicable. On the other hand, if the corpus is sufficiently adequate, the corpus-based methodologies can overcome the limitation. Now, the web is a continuous and enormous growth corpus. Therefore, a method of estimating semantic similarity is proposed via exploiting the page counts of two biomedical concepts returned by Google AJAX web search engine. The features are extracted as the co-occurrence patterns of two given terms P and Q, by querying P, Q, as well as P AND Q, and the web search hit counts of the defined lexico-syntactic patterns. These similarity scores of different patterns are evaluated, by adapting support vector machines for classification, to leverage the robustness of semantic similarity measures. Experimental results validating against two datasets: dataset 1 provided by A. Hliaoutakis; dataset 2 provided by T. Pedersen, are presented and discussed. In dataset 1, the proposed approach achieves the best correlation coefficient (0.802) under SNOMED-CT. In dataset 2, the proposed method obtains the best correlation coefficient (SNOMED-CT: 0.705; MeSH: 0.723) with physician scores comparing with measures of other methods. However, the correlation coefficients (SNOMED-CT: 0.496; MeSH: 0.539) with coder scores received opposite outcomes. In conclusion, the semantic similarity findings of the proposed method are close to those of physicians' ratings. Furthermore, the study provides a cornerstone investigation for extracting fully relevant information from digitizing, free-text medical records in the National Taiwan University Hospital database.


Cardiac electrophysiologic measurements in dogs before and after intravenous administration of atropine and propranolol.
To assess baseline cardiac electrophysiologic (EP) measurements in dogs undergoing a clinically used anesthetic protocol, and to study the effects of i.v. administered atropine and propranolol on these EP variables. 15 adult dogs with cardiac function within reference ranges, as assessed by physical examination, electrocardiography, and echocardiography. 13 cardiac EP variables were measured in isofluorane-anesthetized dogs before and after i.v. administration of atropine and propranolol. Multipolar electrode catheters were positioned against the endocardium of the dorsal portion of the right atrium, His bundle region, and right ventricular apex. Incremental pacing and pacing-extrastimulus techniques were used to obtain EP measurements of the sinoatrial node, atrioventricular node, and atrial and ventricular myocardia in the control state and after i.v. administration of 0.04 mg of atropine and 0.2 mg of propranolol/kg of body weight. Only the atrial effective refractory period changed significantly after muscarinic and beta-adrenergic receptor antagonism. Marked individual variation in response to these agents, however, was apparent. Two dogs had substantial decreases in sinoatrial and/or atrioventricular nodal measurements, and 7 dogs had notable increases in atrioventricular nodal measurements. Cardiac EP measurements vary widely among clinically normal, isofluorane-anesthetized dogs. Individual dogs can have variable degrees of autonomic tone, which can be minimized by pharmacologic receptor antagonism. Although effects of receptor antagonism at clinically applicable dosages were not significant for 12 of 13 measurements, withdrawal of vagal tone can induce marked EP changes and may be important during a clinical study.


Do different substitution patterns or plant origin in hydroxyethyl starches affect blood coagulation in vitro?
The effect of hydroxyethyl starches (HES) on blood coagulation is affected by their molecular weight, their molar substitution and the C2/C6 ratio. The solutions of 6% HES 130/0.4 and 6% HES 130/0.42 have similar molecular weight and molar substitution but different C2/C6 ratio and plant origin. In the present study, the comparative effect of 6% HES 130/0.4 versus 6% HES 130/0.42 on blood coagulation was investigated in vitro. Thirty milliliter of blood was obtained from 10 healthy volunteers and was diluted by 10, 30 and 50% using either 6% HES 130/0.4 or HES 130/0.42, respectively. Blood coagulation was assessed using thrombelastography measurements (clotting time, clot formation time, maximal clot firmness and alpha-angle). The assessment of platelet function was performed with whole blood aggregometry after adding thrombin-receptor-activating protein. No differences were noted between respective dilutions of the two HES. Both colloids produced significant reductions below the reference values range in clotting time at 10, 30 and 50% dilutions. The 50% dilution of both colloids resulted in significant reduction of maximal clot firmness, alpha-angle and platelet aggregation. The present study showed that the corn-derived 6% HES 130/0.4 and the potato-derived 6% HES 130/0.42 have the same effect on blood coagulation in vitro.


Cux1 regulation of the cyclin kinase inhibitor p27kip1 in polycystic kidney disease is attenuated by HDAC inhibitors.
Cux1 is a homeodomain protein involved in cell cycle regulation and kidney development. Cux1 represses the cyclin kinase inhibitor p27 during early kidney development, promoting cell proliferation in the nephrogenic zone. Promoter reporter analysis of p27 revealed that Cux1 represses p27 in a concentration dependent manner, and immunoprecipitation showed that Cux1 interacts with the co-repressor Grg4 and the histone deacetylases HDAC1 and HDAC3. Chromatin immunoprecipitation (ChIP) identified the interaction of Cux1, Grg4, HDAC1, and HDAC3 at two different sites in the p27 promoter. To determine whether there was an interaction between these two loci in the developing kidney, we performed chromatin conformation capture (3C) assay. Analysis of newborn kidney tissue with 3C and ChIP-loop showed that the p27 promoter forms a loop intersecting at these two loci and that Cux1 bridges these two sites. To determine whether HDACs are required for Cux1 repression of p27 we analyzed p27 promoter activity in the presence of the HDAC inhibitor trichostatin A (TSA). TSA treatment completely relieved the repression of p27 by Cux1 and Grg4, demonstrating that Cux1 represses p27 in an HDAC dependent manner. To begin to test whether HDAC inhibitors could be used to target Cux1 repression of p27 for the treatment of PKD, we treated Pkd1 targeted pregnant mice with TSA or vehicle beginning at embryonic day 10.5 until embryonic day 18.5. Newborn Pkd1 mutant mice that received vehicle exhibited extensive collecting duct cysts, while newborn Pkd1 mutant mice that received TSA showed a significant reduction in cysts. Moreover, p27 expression was upregulated in TSA treated Pkd1 mice. Taken together, these results suggest that HDACs are required for cyst growth, and further support studies indicating that HDAC inhibitors may be an effective treatment for PKD.


Enhancement of activity and stability of the formaldehyde dehydrogenase by immobilizing onto phenyl-functionalized mesoporous silica.
Formaldehyde dehydrogenase (FDH, molecular size of 8.6 nm × 8.6 nm × 19.0 nm) was immobilized on seven types of mesoporous silica (MPS), whose pores were from 2.4 to 31.2 nm sized, and their catalytic activities were evaluated by oxidation of formaldehyde. Among MPSs, FDH immobilized on MPS-4 (pore size of 12.3 nm) showed the best catalytic activity. Enhancement of catalytic activity was obtained by immobilizing onto MPS, whose pore (mesopore) size was similar to the molecular size of FDH. In addition, FDH was immobilized on five types of organo-functionalized MPS-4. Results from assays of enzyme activity showed that FDH immobilized on phenyl-functionalized MPS-4 (MPS-4-Ph) had higher activity than FDH immobilized on non-functionalized one. Immobilized FDH on MPS-4-Ph was active for low formaldehyde concentration form 6.0 μM and more sensitive than conventional formaldehyde detectors. Stability of FDH activity was also evaluated under the various conditions, in which protein denaturation could occur by solvent treatment, such as methanol or sodium dodecyl sulfate. As a result, FDH stability was strongly improved by the immobilization on MPS materials. Further investigation using tryptophan fluorescence and circular dichroism (CD) indicated that the high-order structure of the FDH did not alter upon binding to the non-functionalized MPS surface. On the other hand, FDH immobilized on functionalized-MPS was changed by hydrophobic interaction or covalent binding. Consequently, substrate affinity was improved by the change in the structure of FDH and then the orientation of the active site.


Urgent-start peritoneal dialysis: a chance for a new beginning.
Peritoneal dialysis (PD) remains greatly underutilized in the United States despite the widespread preference of home modalities among nephrologists and patients. A hemodialysis-centric model of end-stage renal disease care has perpetuated for decades due to a complex set of factors, including late end-stage renal disease referrals and patients who present to the hospital requiring urgent renal replacement therapy. In such situations, PD rarely is a consideration and patients are dialyzed through a central venous catheter, a practice associated with high infection and mortality rates. Recently, the term urgent-start PD has gained momentum across the nephrology community and has begun to change this status quo. It allows for expedited placement of a PD catheter and initiation of PD therapy within days. Several published case reports, abstracts, and poster presentations at national meetings have documented the initial success of urgent-start PD programs. From a wide experiential base, we discuss the multifaceted issues related to urgent-start PD implementation, methods to overcome barriers to therapy, and the potential impact of this technique to change the existing dialysis paradigm.


Detachment of compliant films adhered to stiff substrates via van der Waals interactions: role of frictional sliding during peeling.
The remarkable ability of some plants and animals to cling strongly to substrates despite relatively weak interfacial bonds has important implications for the development of synthetic adhesives. Here, we examine the origins of large detachment forces using a thin elastomer tape adhered to a glass slide via van der Waals interactions, which serves as a model system for geckos, mussels and ivy. The forces required for peeling of the tape are shown to be a strong function of the angle of peeling, which is a consequence of frictional sliding at the edge of attachment that serves to dissipate energy that would otherwise drive detachment. Experiments and theory demonstrate that proper accounting for frictional sliding leads to an inferred work of adhesion of only approximately 0.5 J m(-2) (defined for purely normal separations) for all load orientations. This starkly contrasts with the interface energies inferred using conventional interface fracture models that assume pure sticking behaviour, which are considerably larger and shown to depend not only on the mode-mixity, but also on the magnitude of the mode-I stress intensity factor. The implications for developing frameworks to predict detachment forces in the presence of interface sliding are briefly discussed.


Neuroimaging features in posterior reversible encephalopathy syndrome: A pictorial review.
Posterior reversible encephalopathy syndrome (PRES) is a radioclinical entity associating nonspecific neurological symptoms (headache, seizures, impairment of alertness, visual disturbances…) occurring in evocative clinical condition (hypertension, eclampsia, immunosuppressor agents, systemic lupus erythematosus…). In the acute stage, the typical imaging finding is a vasogenic edema predominant in the subcortical parietal-occipital white matter. The purpose of this pictorial review is to illustrate the different neuroimaging features of PRES and present key radiological elements to assert diagnosis. In this overview, we examine the following points: the distributions of vasogenic edema, hemorrhage, the varying patterns in diffusion and perfusion, the different types of enhancement encountered and the vascular modifications demonstrated by angiography. The cause of PRES is still unknown. Nevertheless, catheter angiography, MR angiography and MR perfusion features in PRES render further insight into its pathophysiology. Follow-up imaging shows evidence of radiologic improvement in the very large majority of cases in 1 or 2weeks, sometimes in up to 1month. Recurrent PRES attacks are uncommon. Atypical imaging presentation should not reject the diagnosis of PRES in a compatible clinical situation.


A Scalable Open-Source Pipeline for Large-Scale Root Phenotyping of Arabidopsis.
Large-scale phenotyping of multicellular organisms is one of the current challenges in biology. We present a comprehensive and scalable pipeline that allows for the efficient phenotyping of root growth traits on a large scale. This includes a high-resolution, low-cost acquisition setup as well as the automated image processing software BRAT. We assess the performance of this pipeline in Arabidopsis thaliana under multiple growth conditions and show its utility by performing genome-wide association studies on 16 root growth traits quantified by BRAT each day during a 5-d time-course experiment. The most significantly associated genome region for root growth rate is a locus encoding a calcium sensing receptor. We find that loss of function and overexpression of this gene can significantly alter root growth in a growth condition dependent manner and that the minor natural allele of the Calcium Sensor Receptor locus is highly significantly enriched in populations in coastal areas, demonstrating the power of our approach to identify regulators of root growth that might have adaptive relevance.


[Interpretation of the Implant Dentistry Core Outcome Set and Measurement international consensus report].
Selection and measurement of clinical outcome are key components of clinical research in implant dentistry. Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine took the lead and collaborated with multiple internationally renowned colleges of stomatology to develop an international consensus on the core outcome set and measurement in implant dentistry, which took two years and was published in May, 2023 in Journal of Clinical Periodontology and Clinical Oral Implants Research simultaneously. The consensus, aiming at identifying the full spectrum of benefits and harms of interventions, provides a comprehensive, agreed, and standardized set of outcomes that should be measured and reported as a minimum in clinical trials relating with implant dentistry, bone augmentation, and soft tissue augmentation. The present review describes the methodology and key elements of the consensus to help Chinese clinical researchers fully understand and appropriately apply the core outcome set and improve the overall quality of Chinese clinical research in implant dentistry.


Genetic continuity in the Franco-Cantabrian region: new clues from autochthonous mitogenomes.
The Late Glacial Maximum (LGM), ∼20 thousand years ago (kya), is thought to have forced the people inhabiting vast areas of northern and central Europe to retreat to southern regions characterized by milder climatic conditions. Archaeological records indicate that Franco-Cantabria might have been the major source for the re-peopling of Europe at the beginning of the Holocene (11.5 kya). However, genetic evidence is still scarce and has been the focus of an intense debate. Based on a survey of more than 345,000 partial control region sequences and the analysis of 53 mitochondrial DNA (mtDNA) genomes, we identified an mtDNA lineage, HV4a1a, which most likely arose in the Franco-Cantabrian area about 5.4 kya and remained confined to northern Iberia. The HV4a1a lineage and several of its younger branches reveal for the first time genetic continuity in this region and long-term episodes of isolation. This, in turn, could at least in part explain the unique linguistic and cultural features of the Basque region.


Biogenic fabrication of CuNPs, Cu bioconjugates and in vitro assessment of antimicrobial and antioxidant activity.
In the present study, the authors synthesised copper nanoparticles (CuNPs) by using extract of Zingiber officinale (ginger) and later the NPs were bioconjugated with nisin, which shows antimicrobial activity against food spoilage microorganisms. CuNPs and its bioconjugate were characterised by ultraviolet-vis spectroscopy, NP tracking analysis, Zetasizer, transmission electron microscopy analysis, X-ray diffraction and Fourier transform infra-red (FTIR) spectroscopy. Zeta potential of CuNPs and its bioconjugate were found to be very stable. They evaluated in vitro efficacy of CuNPs and its bioconjugate against selected food spoilage bacteria: namely, Staphylococcus aureus, Pseudomonas fluorescens, Listeria monocytogenes and fungi including Fusarium moniliforme and Aspergillus niger. Antimicrobial activity of CuNPs was found to be maximum against F. moniliforme (18 mm) and the least activity was noted against L. monocytogenes (13 mm). Antioxidant activity of CuNPs and ginger extract was performed by various methods such as total antioxidant capacity reducing power assay, 1-1-diphenyl-2-picryl-hydrazyl free radical scavenging assay and hydrogen peroxide assay. Antioxidant activity of CuNPs was higher as compared with ginger extract. Hence, CuNPs and its bioconjugate can be used against food spoilage microorganisms.


Marginal zone B cells: virtues of innate-like antibody-producing lymphocytes.
Protective responses to microorganisms involve the nonspecific but rapid defence mechanisms of the innate immune system, followed by the specific but slow defence mechanisms of the adaptive immune system. Located as sentinels at the interface between the circulation and lymphoid tissue, splenic marginal zone B cells rapidly respond to blood-borne antigens by adopting 'crossover' defensive strategies that blur the conventional boundaries of innate and adaptive immunity. This Review discusses how marginal zone B cells function as innate-like lymphocytes that mount rapid antibody responses to both T cell-dependent and T cell-independent antigens. These responses require the integration of activation signals from germline-encoded and somatically recombined receptors for microorganisms with helper signals from effector cells of the innate and adaptive immune systems.


Role of Dietary Factors, Food Habits, and Lifestyle in Childhood Obesity Development: A Position Paper From the European Society for Paediatric Gastroenterology, Hepatology and Nutrition Committee on Nutrition.
Childhood obesity has high societal and economic impact but current treatment approaches are sub-optimal. In the last decade, important studies have been conducted aiming to identify strategies to prevent obesity during critical periods of life. Updated recommendations for childhood obesity prevention are needed. We present data from systematic reviews and meta- analysis, randomised controlled trials (RCTs) and large observational studies, published from 2011 onwards that consider the possible role of the following factors in obesity development: breast-feeding; macronutrient composition and method of complementary feeding; parenting style; dietary patterns; sugar-sweetened beverage consumption; eating behaviour (eg, skipping breakfast, family dinners. etc); meal frequency and composition (fast foods, snacking), portion size; dietary modulators of gut microbiota (including pre-, pro-, and synbiotics); physical activity and sedentary behaviour. We used the Medline database and the Cochrane Library to search for relevant publications. Important research gaps were also identified. This position paper provides recommendations on dietary factors, food habits, and lifestyle to prevent childhood obesity development, based on the available literature and expert opinion. Clinical research and high-quality trials are urgently needed to resolve numerous areas of uncertainty.


In vivo efficacy of anidulafungin and caspofungin against Candida glabrata and association with in vitro potency in the presence of sera.
In vitro studies have demonstrated that anidulafungin has greater potency than caspofungin against Candida glabrata. However, data from in vivo studies demonstrating that it has superior efficacy are lacking. The objective of this study was to compare the activities of anidulafungin and caspofungin against C. glabrata in a murine model of disseminated candidiasis. Two clinical C. glabrata isolates were used, including one with reduced caspofungin susceptibility. MICs were determined by broth microdilution in the presence and absence of sera. For the animal studies, mice were immunosuppressed with 5-fluorouracil one day prior to intravenous inoculation. Treatment with anidulafungin and caspofungin (0, 0.5, 1, 5, and 10 mg/kg of body weight per day) was begun 24 h later and was continued through day 7 postinoculation. The CFU were enumerated from kidney tissue. According to the standard microdilution methodology, anidulafungin had superior in vitro activity. However, this enhanced potency was attenuated by the addition of mouse and human sera. Caspofungin reduced the kidney fungal burden at lower doses compared to that achieved with anidulafungin in mice infected with the isolate with the lower MIC. Against the strain with the elevated caspofungin MIC, both anidulafungin and caspofungin were effective in reducing the kidney fungal burden at the higher doses studied. Despite the greater in vitro activity of anidulafungin in the absence of sera, both echinocandins were similarly effective in reducing the fungal burden in kidney tissue. The superior in vitro activity of anidulafungin did not confer enhanced in vivo efficacy against C. glabrata.


Cerebral performance category at hospital discharge predicts long-term survival of cardiac arrest survivors receiving targeted temperature management*.
Despite recent advancements in post-cardiac arrest resuscitation, the optimal measurement of postarrest outcome remains unclear. We hypothesized that Cerebral Performance Category score can predict the long-term outcome of postarrest survivors who received targeted temperature management during their postarrest hospital care. Retrospective chart review. Two academic medical centers from May 2005 to December 2012. The medical records of 2,417 out-of-hospital and in-hospital patients post cardiac arrest were reviewed to identify 140 of 582 survivors who received targeted temperature management. None. The Cerebral Performance Category scores at hospital discharge were determined by three independent abstractors. The 1-month, 6-month, and 12-month survival of these patients was determined by reviewing hospital records and querying the Social Security Death Index and by follow-up telephone calls. The association of unadjusted long-term survival and adjusted survival with Cerebral Performance Category was calculated. Of the 2,417 patients who were identified to have undergone cardiac arrest, 24.1% (582/2,417) were successfully resuscitated, of whom 24.1% (140/582) received postarrest targeted temperature management. Overall, 42.9% of patients (60/140) were discharged with Cerebral Performance Category 1, 27.1% (38/140) with Cerebral Performance Category 2, 18.6% (26/140) with Cerebral Performance Category 3, and 11.4% (16/140) with Cerebral Performance Category 4. Cerebral Performance Category 1 survivors had the highest long-term survival followed by Cerebral Performance Categories 2 and 3, with Cerebral Performance Category 4 having the lowest long-term survival (p < 0.001, log-rank test). We found that Cerebral Performance Category 3 (hazard ratio = 3.62, p < 0.05) and Cerebral Performance Category 4 (hazard ratio = 12.73, p < 0.001) remained associated with worse survival after adjusting for age, gender, race, shockable rhythm, time to targeted temperature management initiation, total duration of resuscitation, withdrawal of care, and location of arrest. Patients with different Cerebral Performance Category scores at discharge have significantly different survival trajectories. Favorable Cerebral Performance Category at hospital discharge predicts better long-term outcomes of survivors of cardiac arrest who received targeted temperature management than those with less favorable Cerebral Performance Category scores.


Engaging Men and Boys in Maternal Health: Results from a Participatory Film Project in Maputo Province.
Research has demonstrated that men often play a critical role in increasing access to and use of maternal health services. Improving male involvement in maternal health can contribute to better health outcomes for the mother, the newborn, and the father. Assess barriers and facilitators for male involvement in maternal health in a local community in Mozambique and analyze perceived benefits and challenges of using a participatory approach. Participants engaged in a participatory video project involving different components: a workshop around gender norms, a video workshop, a filming phase, a feedback screening, and a dissemination phase of the final film. Qualitative data were gathered throughout the participatory process and analyzed thematically by an inductive approach. In addition, the participatory video framework was used to analyze the participatory process. Our research project showed that participants faced several barriers for their involvement in maternal health, including strong patriarchal gender norms in the community, unwelcoming health care facilities, and economic challenges. Facilitators for their engagement included a strong sense of responsibility for taking care of the family, the willingness to generate change among the younger generation and the valorization of women as equal partners. Our findings suggest that the project empowered the participants to take up a more active and supporting role in maternal health and inspire other men's involvement. The participatory approach used in our study helped to identify and tackle barriers for male involvement in maternal health at community level, and dissemination of findings. Community campaigns should consider both barriers and facilitators for more male involvement in maternal health. In addition, governments and program planners should invest on male-friendliness of health facilities and to minimize the incidence of bribery and other illegal practices for health services.


Effect of the disulfide bridge and the C-terminal extension on the oligomerization of the amyloid peptide ABri implicated in familial British dementia.
Familial British dementia (FBD) is a rare neurodegenerative disorder and shares features with Alzheimer's disease, including amyloid plaque deposits, neurofibrillary tangles, neuronal loss, and progressive dementia. Immunohistochemical and biochemical analysis of plaques and vascular amyloid of FBD brains revealed that a 4 kDa peptide named ABri is the main component of the highly insoluble amyloid deposits. In FBD patients, the ABri peptide is produced as a result of a point mutation in the usual stop codon of the BRI gene. This mutation produces a BRI precursor protein 11 amino acids longer than the wild-type protein. Mutant and wild-type precursor proteins both undergo furin cleavage between residues 243 and 244, producing a peptide of 34 amino acids in the case of ABri and 23 amino acids in the case of the wild-type (WT) peptide. Here we demonstrate that the intramolecular disulfide bond in ABri and the C-terminal extension are required to elongate initially formed dimers to oligomers and fibrils. In contrast, the shorter WT peptide did not aggregate under the same conditions. Conformational analyses indicate that the disulfide bond and the C-terminal extension of ABri are required for the formation of beta-sheet structure. Soluble nonfibrillar ABri oligomers were observed prior to the appearance of mature fibrils. A molecular model of ABri containing three beta-strands, and two beta-hairpins annealed by a disulfide bond, has been constructed, and predicts a hydrophobic surface which is instrumental in promoting oligomerization.


Merkel cell polyomavirus DNA sequences in peripheral blood and tissues from patients with Langerhans cell histiocytosis.
Langerhans cell histiocytosis (LCH) is a group of granulomatous disorders in which abnormal Langerhans cells proliferate as either a localized lesion in a single bone or disseminated disease involving two or more organs or systems. Because the different LCH forms exhibit significantly elevated levels of inflammatory molecules, including pro-inflammatory cytokines and tissue-degrading enzymes, we investigated for a possible viral trigger in LCH pathogenesis. We looked for Merkel cell polyomavirus (MCPyV) in peripheral blood cells and tissues using quantitative real-time PCR and immunohistochemistry staining with anti-MCPyV large T-antigen antibody. Our findings revealed elevated amounts of MCPyV DNA in the peripheral blood cells of 2 of 3 patients affected by LCH with high-risk organ involvement (RO+) and absence of MCPyV DNA in the blood cells in all 12 LCH-RO- patients (P = .029). With lower viral loads (0.002-0.033 copies/cell), an elevated number of MCPyV DNA sequences was detected in 12 LCH tissues in comparison with control tissues obtained from patients with reactive lymphoid hyperplasia (0/5; P = .0007), skin diseases not related to LCH in children younger than 2 years (0/11; P = .0007), or dermatopathic lymphadenopathy (5/20; P = .0002). The data, including frequent but lower viral loads and low large-T antigen expression rate (2/13 LCH tissues), suggest that development of LCH as a reactive rather than a neoplastic process may be related to MCPyV infection.


RBD-Fc-based COVID-19 vaccine candidate induces highly potent SARS-CoV-2 neutralizing antibody response.
The pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has posed serious threats to global health and economy, thus calling for the development of safe and effective vaccines. The receptor-binding domain (RBD) in the spike protein of SARS-CoV-2 is responsible for its binding to angiotensin-converting enzyme 2 (ACE2) receptor. It contains multiple dominant neutralizing epitopes and serves as an important antigen for the development of COVID-19 vaccines. Here, we showed that immunization of mice with a candidate subunit vaccine consisting of SARS-CoV-2 RBD and Fc fragment of human IgG, as an immunopotentiator, elicited high titer of RBD-specific antibodies with robust neutralizing activity against both pseudotyped and live SARS-CoV-2 infections. The mouse antisera could also effectively neutralize infection by pseudotyped SARS-CoV-2 with several natural mutations in RBD and the IgG extracted from the mouse antisera could also show neutralization against pseudotyped SARS-CoV and SARS-related coronavirus (SARSr-CoV). Vaccination of human ACE2 transgenic mice with RBD-Fc could effectively protect mice from the SARS-CoV-2 challenge. These results suggest that SARS-CoV-2 RBD-Fc has good potential to be further developed as an effective and broad-spectrum vaccine to prevent infection of the current SARS-CoV-2 and its mutants, as well as future emerging SARSr-CoVs and re-emerging SARS-CoV.


Fluorescence-labeled lectins, glycoconjugates, and the development of the mouse AOP.
The development of the aqueous outflow pathway (AOP) in early postnatal mouse eyes was examined for the presence of a variety of lectin receptors using fluorescein isothiocyanate (FITC) conjugated lectins, 1 micron araldite plastic sections, and computer-aided fluorescence photography. The trabecular meshwork anlage (days 1-4) was characterized by the presence of loosely arranged cells and an extracellular matrix that exhibited intense areas of Con A- and RCA-lectin staining, and absence of WGA- and LPA-lectin staining. By day 6, trabecular meshwork LPA- and WGA-positive materials were observed as focal areas of staining. By day 10, LPA- and WGA-positive materials were present as diffuse areas of staining, as the AOP differentiated into an organized and functional biological filter. The age-dependent pattern of LPA- and WGA-positive materials indicated that there were time-dependent points in the synthesis of glycoconjugates in the developing AOP. The results suggest: The composition and/or conformation of the glycoconjugates on cells and extracellular matrix changed as the AOP differentiated into a functional tissue. The use of FITC lectins as biological markers for studies of the AOP provided information on the potential role of glycoconjugates in the development of the normal AOP. Modification in the type, amount, and distribution of glycoconjugates may provide a basis for understanding the cellular mechanisms of abnormal development of the AOP, eg, congenital glaucoma.


Serum uric Acid as a prognostic predictor in pulmonary arterial hypertension with connective tissue disease.
Pulmonary arterial hypertension (PAH) has been identified as a life threatening complication of connective tissue disease. However, the association between serum uric acid (UA) levels and long-term outcome in PAH with connective tissue disease has not been evaluated. We therefore assessed whether serum UA levels are related to the mortality of such patients. We investigated 90 consecutive patients with connective tissue disease who were initially diagnosed with PAH by echocardiography, and assessed the long-term clinical outcome in populations with higher (> or = 4.7 mg/dL) and lower serum UA levels. Kaplan-Meier analysis showed that patients with higher median serum UA values had a significantly worse survival rate for any cause of death (54.5% versus 84.7%, log-rank, P < 0.01) and PAH-related death (72.7% versus 93.4%, log-rank, P < 0.01) than those with low values. Multivariate analysis showed that an elevated serum UA level was an independent predictor for survival (hazard ratio, 1.88, 95% CI [1.24- 2.84], P < 0.01). Elevated serum UA levels are associated with a poor prognosis and can serve as a prognostic predictor for patients with PAH secondary to connective tissue disease.


Regional increase of extracellular potassium leads to electrical instability and reentry occurrence through the spatial heterogeneity of APD restitution.
The heterogeneities of electrophysiological properties of cardiac tissue are the main factors that control both arrhythmia induction and maintenance. Although the local increase of extracellular potassium ([K(+)](o)) due to coronary occlusion is a well-established metabolic response to acute ischemia, the role of local [K(+)](o) heterogeneity in phase 1a arrhythmias has yet to be determined. In this work, we created local [K(+)](o) heterogeneity and investigated its role in fast pacing response and arrhythmia induction. The left marginal vein of a Langendorff-perfused rabbit heart was cannulated and perfused separately with solutions containing 4, 6, 8, 10, and 12 mM of K(+). The fluorescence dye was utilized to map the voltage distribution. We tested stimulation rates, starting from 400 ms down to 120 ms, with steps of 5-50 ms. We found that local [K(+)](o) heterogeneity causes action potential (AP) alternans, 2:1 conduction block, and wave breaks. The effect of [K(+)](o) heterogeneity on electrical stability and vulnerability to arrhythmia induction was largest during regional perfusion with 10 mM of K(+). We detected three concurrent dynamics: normally propagating activation when excitation waves spread over tissue perfused with normal K(+), alternating 2:2 rhythm near the border of [K(+)](o) heterogeneity, and 2:1 aperiodicity when propagation was within the high [K(+)](o) area. [K(+)](o) elevation changed the AP duration (APD) restitution and shifted the restitution curve toward longer diastolic intervals and shorter APD. We conclude that spatial heterogeneity of the APD restitution, created with regional elevation of [K(+)](o), can lead to AP instability, 2:1 block, and reentry induction.


Activated protein C resistance as measured by residual factor V after Russell's viper venom and activated protein C treatment analyzed as a continuous variable in multiple myeloma and normal controls.
Increased risk of venous thromboembolism (VTE) has been described in multiple myeloma patients, particularly when exposed to immunomodulatory drugs. Epidemiological studies have shown that monoclonal gammopathy of undetermined significance (MGUS) patients also have an increased risk of VTE compared with normal individuals. Acquired activated protein C resistance (APC-R) is an independent risk factor for VTE in hematologic malignancies. We reviewed the records of patients with multiple myeloma and MGUS for APC-R by PEFAKIT APC-R test and compared them to normal individuals. We excluded from the analysis patients with a documented factor V Leiden mutation. The PEFAKIT APC-R is a plasma-based functional prothrombin assay based on ratio of patient clotting time with and without APC. Thirty-three MGUS and 93 multiple myeloma patients were compared with 39 normal individuals. Baseline characteristics from the three groups were similar in terms of age, sex, and performance status. The median APC-R for multiple myeloma, MGUS, and controls were 1, 1.06, and 1.1, respectively. Multiple myeloma patients compared to normal individuals had significantly shorter APC-R (P=0.0012). No significant difference was observed between MGUS and normal individuals (P=0.17). After analyzing APC-R values and multiple coagulation parameters, a significant inverse correlation was found between APC-R and fibrinogen (P=0.0000001) and D-dimer (P=0.045) serum levels and a direct correlation with prothrombin time value (P=0.034). The Pefakit APC-R test measured as continuous variable shows a statistically significant decrease in patients with myeloma compared to normal individuals.


Meta-analytic review of event-related potential studies in post-traumatic stress disorder.
In recent years there has been an accumulation of studies that have utilized the measurement of event-related potentials (ERP) to examine the neuroelectric correlates of hypothesized alterations in information processing in persons with post-traumatic stress disorder (PTSD). The objective of this meta-analysis was to summarize the findings of ERP PTSD research, including studies that have examined P50 auditory sensory gating, augmenting-reducing P200, and P300 in target detection oddball tasks. The results suggest that persons with PTSD exhibit alterations in the amplitude and latency of ERP within these paradigms that support the hypothesis that changes in information processing can accompany PTSD. The results were also consistent with recent cognitive neuropsychological findings in PTSD research.