Alternate binding mode of C-terminal phenethylamine analogs of G(t)alpha(340-350) to photoactivated rhodopsin.
The C-terminus of the Galpha-subunit of transducin plays an important role in receptor recognition. Synthetic peptides corresponding to the last 11 residues of the subunit have been shown to stabilize the photoactivated form of rhodopsin, Rh*. The Rh*-bound structure of the G(t)alpha(340-350) peptide has been determined using transferred nuclear overhauser effect NMR. In that structure, we observed two interactions between Lys341 and Phe350, a cation-pi interaction between the epsilon-amine and the aromatic ring of Phe350 and a salt-bridge between the epsilon-amine and the C-terminal carboxylate. A series of C-terminal phenethylamine analogs of the G(t)alpha(340-350) peptide were synthesized, lacking the C-terminal carboxylate group, to investigate the forces that contribute to the stability of the Rh*-bound conformation of the peptide. Rh*-stabilization assay data suggest that the C-terminal carboxylate is not necessary to maintain binding affinity. Transferred nuclear overhauser effect NMR experiments reveal that these C-terminal phenethylamine peptides adopt an Rh*-bound structure that is similar overall, but lacking some of the intramolecular interactions observed in the native Rh*-bound G(t)alpha(340-350) structure. These studies suggest that the binding site for G(t)alpha(340-350) on Rh* is adaptable, and we propose that the charged carboxylate of Phe350 does not play a significant role in the interaction with Rh*, but helps stabilize the Rh*-bound confirmation of the native peptide.


Genetic polymorphisms of CCND1 and PTEN in progression of esophageal squamous carcinoma.
Cyclin D1 (CCND1) plays a significant role in G1-S transition of cell cycle, and phosphatase and a tensin homologue (PTEN) negatively regulate cell cycle through phosphatidylinositol 3-kinase (PI3K)/AKT signaling. CCND1 and PTEN genetic polymorphisms might induce susceptibility to the occurrence of esophageal squamous cell carcinoma (ESCC). Three hundred and four ESCC patients and 413 healthy controls from Anyang, China, were enrolled in this study. All genotyping at CCND1 (807 G/A) and PTEN (rs701848 T/C and rs2735343 C/G) were identified by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. Unconditional logistic regression model was used to analyze the correlation between the polymorphisms and the susceptibility to develop ESCC. Statistically significant differences were observed between cases and controls in distribution of genotypes or alleles at PTEN rs701848 T/C and rs2735343 C/G, with either haplotype TG or CG possessing notably higher proportion in cases than in the controls. However, such difference could not be found in the distribution of the polymorphisms at CCND1 807 G/A. In summary, the polymorphisms of PTEN rs701848 T/C and rs2735343 C/G might represent crucial modifying factors for development of ESCC.


Ureaplasma isolates stimulate pro-inflammatory CC chemokines and matrix metalloproteinase-9 in neonatal and adult monocytes.
Being generally regarded as commensal bacteria, the pro-inflammatory capacity of Ureaplasma species has long been debated. Recently, we confirmed Ureaplasma-driven pro-inflammatory cytokine responses and a disturbance of cytokine equilibrium in primary human monocytes in vitro. The present study addressed the expression of CC chemokines and matrix metalloproteinase-9 (MMP-9) in purified term neonatal and adult monocytes stimulated with serovar 8 of Ureaplasma urealyticum (Uu) and serovar 3 of U. parvum (Up). Using qRT-PCR and multi-analyte immunoassay, we assessed mRNA and protein expression of the monocyte chemotactic proteins 1 and 3 (MCP-1/3), the macrophage inflammatory proteins 1α and 1β (MIP-1α/β) as well as MMP-9. For the most part, both isolates stimulated mRNA expression of all given chemokines and MMP-9 in cord blood and adult monocytes (p<0.05 and p<0.01). These results were paralleled by Uu and Up-induced secretion of MCP-1 protein in both cells (neonatal: p<0.01, adult: p<0.05 and p<0.01). Release of MCP-3, MIP-1α, MIP-1β and MMP-9 was enhanced upon exposure to Up (neonatal: p<0.05, p<0.01 and p<0.001, respectively; adult: p<0.05). Co-stimulation of LPS-primed monocytes with Up increased LPS-induced MCP-1 release in neonatal cells (p<0.05) and aggravated LPS-induced MMP-9 mRNA in both cell subsets (neonatal: p<0.05, adult: p<0.01). Our results document considerable expression of pro-inflammatory CC chemokines and MMP-9 in human monocytes in response to Ureaplasma isolates in vitro, adding to our previous data. Findings from co-stimulated cells indicate that Ureaplasma may modulate monocyte immune responses to a second stimulus.


[The IRIS® Registry : Purpose and perspectives. German Version].
The American Academy of Ophthalmology IRIS® Registry (Intelligent Research in Sight) launched about 2 years ago and has already become the largest national clinical specialty data registry with nearly 50 million patient visits and over 14 million unique patients. The purpose of the registry is to support and promote continued improvement in the delivery of eye care. The perspectives that "big data" encompass are the key issues facing ophthalmology and eye care, including public health and public policy concerning disease incidence and prevalence, utilization of eye care services, natural history of disease, disease surveillance, comparative effectiveness, safety and adverse event monitoring, compliance with "best practices" and clinical guidelines, etc. The valuable real-world and current-day insights provided by the IRIS Registry and other registries like it will accelerate scientific learning and improvements in care delivery, particularly in a cost-constrained environment.


'Led by Intelligence': A Scoping Review on the Experimental Evaluation of Intelligence-Led Policing.
Intelligence-led policing (ILP) was introduced in the 1990s as a proactive approach to policing, but to date, there is a lack of studies that have synthesized and summarized the central characteristics and insights of (quasi-)experimental studies related to ILP. This study aims to address this gap by synthesizing and characterizing the central characteristics of 38 quasi-experimental and experimental studies related to ILP. In this study, a scoping review is conducted on different quasi-experimental and experimental studies that relate to the framework of ILP. It was found that most studies within the domain of ILP focus on testing the crime reduction effects of using spatio-temporal crime intelligence to deploy police resources more efficiently and effectively. However, some studies have combined different types of crime intelligence or used solely offender-related intelligence. Several statistical-methodological challenges were also identified that should be considered when designing experimental research within the domain of ILP. Additionally, most studies focused solely on measuring crime reduction, with few focusing on secondary effects of interventions. The review concludes that future evaluation studies should consider evaluating the use of different types of crime intelligence and establish specific, objective, and realistic criteria for measuring specific performance measures such as crime disruption. Future experimental research within the domain of ILP should consider applying the 3-i model, evaluating each leg of ILP thoroughly. The limitations of the study are also discussed. This review provides valuable insights for future research and development of ILP-related approaches.


[Two kinds of lateral retinacular release for lateral patellar compression syndrome:a retrospective comparative study].
Objective: To compare the clinical effects of arthroscopic lateral retinacular proximal release and "L" type release for lateral patellar compression syndrome. Methods: Sixty four lateral patellar compression syndrome (LPCS) patients were recruited who had arthroscopic surgery during September 2004 to January 2019 at Department of Sports Medicine,Peking University Third Hospital by the same group of doctors and a retrospective comparative study was conducted accordingly. Among them,24 cases underwent the traditional proximal release of lateral patellar retinaculum (traditional group),including 7 males and 17 females with an age of (42.9±14.6)years(range:23 to 72 years); 40 cases were treated with novel lateral retinacular release of "L" type release revised based on the previous experiences (novel group), consisting of 12 males and 28 females with an age of (54.9±13.1) years (range:28 to 76 years).All the patients participated surveys for the visual analogue scale (VAS),Lysholm score and International Knee Documentation Committee (IKDC) knee function subjective evaluation before and after the operation. The comparison of scores within groups was performed by Wilcoxon test,and comparison between groups was performed by Mann-Whitney U test and Chi-square test. Multivariate analysis was used to evaluate the related factors affecting each score. Results: The follow-up durations of traditional group and novel group were (12.6±1.0) years (range:11.7 to 15.3 years) and (2.2±1.0)years(range:1.0 to 4.4 years) respectively. At the last follow-up,VAS(0(1.0)to 6.0(2.0),Z=-5.471,P<0.01),Lysholm score(98.0(10.0)to 48.0(40.0),Z=-5.511,P<0.01),and IKDC score(82.8(11.2)to 37.4(18.5),Z=-5.444,P<0.01) in novel group were statistically significantly improved,and the postoperative excellent rate of Lysholm score was 97.5% in general. There was no significant difference in the changes of the three scores (P>0.05) between the traditional group and the novel group. However,20.8% (5/24)patients in the traditional group reported significant weakness of the knee extension after surgery,while no such complain was received in the novel group (P<0.01).The results of univariate analysis showed that surgical method was a related factor affecting the changes of VAS before and after surgery (P<0.05).The results of multivariate analysis showed that whether or not with osteoarthritis and operation type were independent factors affecting the changes of Lysholm and IKDC scores (P<0.05). Conclusions: The long-term effect of arthroscopic lateral retinacular release for the treatment of LPCS is satisfactory. Compared with the traditional proximal release surgery,the "L" type release can effectively avoid the complication of significant weakness of the knee extension significantly.


Country-level and regional COVID-19 burden and determinants across OECD member states and partner countries.
COVID-19 pandemic is tremendously impacted by socioeconomic and health determinants worldwide. This study aimed to determine factors associated with COVID-19 fatality among member states and partner countries of the Organization for Economic Cooperation and Development (OECD). An ecological study was conducted using COVID-19 data of 48 countries for the period between 31 December 2019-31 December 2021. The outcome variables were COVID-19 case fatality rate (CFR) and years of life lost to COVID-19 (YLLs). Countries' sociodemographics and COVID-19-related data were extracted from OECD website, Our World in Data, John Hopkins Coronavirus Resource Center, Economist Intelligence Unit (EIU) and WHO. In the first year of the pandemic (December 2019-January 2021), highest CFR was observed in Mexico, 8.51%, followed by China, 5.17% and Bulgaria, 4.12%), and highest YLLs was observed in Mexico, 2,055 per 100,000. At regional level, highest CFR was observed in North & central America, 4.25 (3.71) %, followed by South America (2.5 (0.1) %); whereas highest YLLs was observed in South America region 1457.5 (274.8) per 100,000, followed by North & central America, 1207.3 (908.1) per 100,000. As of 31 December 2021, Mexico (7.52%) and Bulgaria (4.78%) had highest CFR; on the other hand, highest YLLs was observed in England, 26.5 per 1,000, followed by the United States, 25.9 per 1,000. At regional level, highest CFR (3.37(3.19) %) and YLLs (16.7 (13) per 1,000) were both observed in North & central America. Globally, the analysis of the 2-year cumulative data showed inverse correlation between CFR and nurse per 10,000 (R = -0.48; p < 0.05) and GDP per capita (R = -0.54; p < 0.001), whereas positive correlation was observed between YLLs and elderly population rate (R = 0.66; p < 0.05) and overweight/obese population rates (R = 0.55; p < 0.05). This study provides insights on COVID-19 burden among OECD states and partner countries. GDP per capita, overweight/obesity and the rate of elderly population emerged as major social and health determinants of COVID-19 related burden and fatality. Findings suggest that a robust economy and interventions designed to promote healthy longevity and prevent weight gain in at-risk individuals might reduce COVID-19 burden and fatality among OECD states and partner countries.


Determinants of Active and Healthy Ageing in Sub-Saharan Africa: Evidence from Cameroon.
This paper examines the determinants and policy implications of active and healthy ageing in Sub-Saharan Africa, taking the case of Bamenda, in Cameroon. Specifically, the study sought to identify and explore the determinants of active and healthy ageing using a mixed-methods approach involving qualitative and quantitative data collection and analysis. Focus group discussions were conducted complemented by a survey (random and snowball sampling) using a structured questionnaire. Narratives and thematic analysis were used to analyze the data generated from the focus group discussion and Tobit regression was employed to analyze the multiple determinants of active ageing by dimensions and on a global scale in Cameroon. Results identified three key dimensions of active and healthy ageing: employment/livelihood options (EL), community support and health (CH) and housing and living in Bamenda (HL). The regression results reveal gender bias in active ageing, a non-effect of education and health on active ageing, and a positive effect of income on active and healthy ageing. This study contributes, among others, to the competence-environmental press theory on active ageing with regards to unbundling context specific determinants of active and healthy ageing. It equally derives policy considerations with regards to gender mainstreaming and the identification of age friendly income earning options to enhance the active and healthy ageing process.


Virtual EPID standard phantom audit (VESPA) for remote IMRT and VMAT credentialing.
A virtual EPID standard phantom audit (VESPA) has been implemented for remote auditing in support of facility credentialing for clinical trials using IMRT and VMAT. VESPA is based on published methods and a clinically established IMRT QA procedure, here extended to multi-vendor equipment. Facilities are provided with comprehensive instructions and CT datasets to create treatment plans. They deliver the treatment directly to their EPID without any phantom or couch in the beam. In addition, they deliver a set of simple calibration fields per instructions. Collected EPID images are uploaded electronically. In the analysis, the dose is projected back into a virtual cylindrical phantom. 3D gamma analysis is performed. 2D dose planes and linear dose profiles are provided and can be considered when needed for clarification. In addition, using a virtual flat-phantom, 2D field-by-field or arc-by-arc gamma analyses are performed. Pilot facilities covering a range of planning and delivery systems have performed data acquisition and upload successfully. Advantages of VESPA are (1) fast turnaround mainly driven by the facility's capability of providing the requested EPID images, (2) the possibility for facilities performing the audit in parallel, as there is no need to wait for a phantom, (3) simple and efficient credentialing for international facilities, (4) a large set of data points, and (5) a reduced impact on resources and environment as there is no need to transport heavy phantoms or audit staff. Limitations of the current implementation of VESPA for trials credentialing are that it does not provide absolute dosimetry, therefore a Level I audit is still required, and that it relies on correctly delivered open calibration fields, which are used for system calibration. The implemented EPID based IMRT and VMAT audit system promises to dramatically improve credentialing efficiency for clinical trials and wider applications.


Molecular incidence and clearance of Plasmodium falciparum infection.
Although the epidemiology of malaria has been based primarily on microscopy and rapid diagnostic tests, molecular methods are necessary to understand the complexity of natural infection in regions where transmission is intense and simultaneous infection with multiple parasite genotypes is common such as sub-Saharan Africa. To compare microscopic and molecular estimates of the incidence and clearance of Plasmodium falciparum infection, we followed 80 children monthly for 1 year in the village of Bancoumana in Mali. Similar seasonal patterns were observed with both methods (rainy season peak, dry season nadir), although molecular methods detected more infections than microscopy (571 vs 331 in 906 specimens), more new infections (311 vs 104 during 829 person-months) and spontaneous clearance events (317 vs 116) and found higher incidence (0.38 vs 0.13 new genotypes/person/month, p < 0.001) and spontaneous clearance rates (0.38 vs 0.14 genotypes cleared/person/month, p < 0.001). These differences were greatest for persistently-infected subjects in whom neither new infections nor the clearance of old infections could be detected by microscopy (0.71 new infections and 0.73 cleared infections per month using molecular methods vs 0.000 by microscopy, p < 0.001). Molecular methods provide information about genetic diversity, the intensity of transmission and spontaneous clearance in the absence of drug treatment that cannot be obtained by microscopy. They will be necessary to evaluate the efficacy of vaccines, drugs and other control strategies for diseases such as malaria in which simultaneous infection with more than one organism (genotype) is common.


Idiopathic epilepsy in dogs: owners' perspectives on management with phenobarbitone and/or potassium bromide.
To explore seizure management from the perspective of the owners of dogs with idiopathic epilepsy. Questionnaires were mailed to owners of 29 dogs under management for suspected or diagnosed idiopathic epilepsy through the clinics of the Small Animal Hospital of the University of Glasgow Veterinary School, using either phenobarbitone or potassium bromide alone or in combination. The postal survey had an 86 per cent response rate. Analysis of the responses demonstrated that "the dog's quality of life", "adequate seizure frequency" and "acceptable side effects of antiepileptic drugs" were the three greatest concerns for owners; 52 per cent of owners strongly agreed that the seizure management for their dog was adequate, though the seizure frequency reported varied within this group; the majority of owners did not consider the administration of medication a nuisance. However, approximately 60 per cent of owners reported that caring for an epileptic dog had an effect on the organisation of their free time, though this was not dependent on perception of seizure control. Opinions as to the value of further diagnostic procedures, in particular intracranial imaging, were significantly affected by having pet health insurance. From the owners' perspective, adequacy of seizure control is determined by the balance between "the dog's quality of life", "adequate seizure frequency" and "acceptable side effects of antiepileptic drugs". A frequency of less than one seizure every three months is associated with the perception by owners of adequate seizure control.


Validation of an immunodiagnostic assay for detection of 13 Streptococcus pneumoniae serotype-specific polysaccharides in human urine.
To improve the clinical diagnosis of pneumococcal infection in bacteremic and nonbacteremic community-acquired pneumonia (CAP), a Luminex technology-based multiplex urinary antigen detection (UAD) diagnostic assay was developed and validated. The UAD assay can simultaneously detect 13 different serotypes of Streptococcus pneumoniae by capturing serotype-specific S. pneumoniae polysaccharides (PnPSs) secreted in human urine. Assay specificity is achieved by capturing the polysaccharides with serotype-specific monoclonal antibodies (MAbs) on spectrally unique microspheres. Positivity for each serotype was based on positivity cutoff values calculated from a standard curve run on each assay plate together with positive- and negative-control urine samples. The assay is highly specific, since significant signals are detected only when each PnPS was paired with its homologous MAb-coated microspheres. Validation experiments demonstrated excellent accuracy and precision. The UAD assay and corresponding positivity cutoff values were clinically validated by assessing 776 urine specimens obtained from patients with X-ray-confirmed CAP. The UAD assay demonstrated 97% sensitivity and 100% specificity using samples obtained from patients with bacteremic, blood culture-positive CAP. Importantly, the UAD assay identified Streptococcus pneumoniae (13 serotypes) in a proportion of individuals with nonbacteremic CAP, a patient population for which the pneumococcal etiology of CAP was previously difficult to assess. Therefore, the UAD assay provides a specific, noninvasive, sensitive, and reproducible tool to support vaccine efficacy as well as epidemiological evaluation of pneumococcal disease, including CAP, in adults.


Modeling brominated trihalomethane compounds in drinking water at a treatment plant in Beaumont, Texas.
The premise of this study is that the presence of bromide has a substantial effect on both the speciation and total formation of trihalomethane (THM). Consequently, models of water containing substantial bromide concentrations require refinement because they are only calibrated with raw water with high humic acid content. This study investigates and reports efforts on such refinement. The objectives of work reported in this paper are to formulate and validate a new correlative model that is based on physical principles and incorporates high levels of bromide that affect THM formation using raw water rich in both humic and fulvic acid. Two types of THM precursors are considered in the model discussed in this paper: (1) activated aromatic groups, which are more reactive with chlorine than with bromine, and (2) aliphatic groups, which are more reactive with bromine than with chlorine. Aliphatic and aromatic carbons are incorporated in the model by the inclusion of pertinent variables such as C/N and Br/Cl2 in the algorithm. The model also includes NH4+. This variable affects chlorine consumption that, in turn, potentially affects THM formation. For the first time ever, organic carbon to organic nitrogen and bromide to chlorine ratios is also used as variables potentially affecting THM formation when treating drinking water. The THM model formulated in this paper is an empirical model based on scientific principles and not simply a regression equation. The formulated model is pronounced valid based on a validation effort that employs a portion of an EPA database that was not used for model formulation.


[Circadian rhythm of cortisol and corticotropin (ACTH) in patients with rheumatoid arthritis in relation to inflammatory activity].
In patients with rheumatoid arthritis, corticosteroids are usually given as a single morning dose to minimize adrenal suppression, because of the well-known circadian rhythm of the secretion of cortisol and corticotropin. However, it has not been so far examined whether there really is a normal secretion pattern of those hormones in all patients with rheumatoid arthritis, as there is in healthy subjects. We therefore studied twelve patients with rheumatoid arthritis who had never been treated before with corticosteroids and disease-modifying drugs such as gold, D-penicillamine or immunosuppressive drugs. The study was designed to examine adrenal secretory activity by measuring the cortisol and corticotropin levels at 2 h intervals throughout a 24 h cycle. The circadian secretion patterns of cortisol and corticotropin were disturbed in most patients. High inflammatory activity of the disease was accompanied by a severe disturbance of the circadian rhythm, whereas patients with low inflammatory activity showed a nearly normal secretion pattern. Besides other causes, the influence of mediators of inflammation on hypothalamic centers, analogous to endogenous pyrogen in fever, must be discussed.


Combined biotic stresses trigger similar transcriptomic responses but contrasting resistance against a chewing herbivore in Brassica nigra.
In nature, plants are frequently exposed to simultaneous biotic stresses that activate distinct and often antagonistic defense signaling pathways. How plants integrate this information and whether they prioritize one stress over the other is not well understood. We investigated the transcriptome signature of the wild annual crucifer, Brassica nigra, in response to eggs and caterpillars of Pieris brassicae butterflies, Brevicoryne brassicae aphids and the bacterial phytopathogen Xanthomonas campestris pv. raphani (Xcr). Pretreatment with egg extract, aphids, or Xcr had a weak impact on the subsequent transcriptome profile of plants challenged with caterpillars, suggesting that the second stress dominates the transcriptional response. Nevertheless, P. brassicae larval performance was strongly affected by egg extract or Xcr pretreatment and depended on the site where the initial stress was applied. Although egg extract and Xcr pretreatments inhibited insect-induced defense gene expression, suggesting salicylic acid (SA)/jasmonic acid (JA) pathway cross talk, this was not strictly correlated with larval performance. These results emphasize the need to better integrate plant responses at different levels of biological organization and to consider localized effects in order to predict the consequence of multiple stresses on plant resistance.


Elimination of diffraction error in acoustic attenuation estimation via axial beam translation.
Optimized wideband attenuation estimations were performed on a tissue mimicking phantom in a water tank with and without axial beam translation (ABT), and the results were compared to those from standard substitution measurements. A -17 percent discrepancy between the results of the substitution method and the optimized estimation without ABT was noted in the far field. This discrepancy was eliminated when ABT was utilized.


Angry, old, male - and trustworthy? How expressive and person voice characteristics shape listener trust.
This study examined how trustworthiness impressions depend on vocal expressive and person characteristics and how their dependence may be explained by acoustical profiles. Sentences spoken in a range of emotional and conversational expressions by 20 speakers differing in age and sex were presented to 80 age and sex matched listeners who rated speaker trustworthiness. Positive speaker valence but not arousal consistently predicted greater perceived trustworthiness. Additionally, voices from younger as compared with older and female as compared with male speakers were judged more trustworthy. Acoustic analysis highlighted several parameters as relevant for being perceived as trustworthy (i.e., accelerated tempo, low harmonic-to-noise ratio, more shimmer, low fundamental frequency, more jitter, large intensity range) and showed that effects partially overlapped with those for perceived speaker affect, age, but not sex. Specifically, a fast speech rate and a lower harmonic-to-noise ratio differentiated trustworthy from untrustworthy, positive from negative, and younger from older voices. Male and female voices differed in other ways. Together, these results show that a speaker's expressive as well as person characteristics shape trustworthiness impressions and that their effect likely results from a combination of low-level perceptual and higher-order conceptual processes.


Q-angle: an invaluable parameter for evaluation of anterior knee pain.
Patellofemoral pain syndrome is a descriptive term applied to patients with nonspecific anterior knee pain, and is the most common knee problem. The pain in most patellofemoral disorders is generalized to the anterior part of the knee. One important concept in patellofemoral joint function is the quadriceps angle (Q-angle). Theoretically, a higher Q-angle increases the lateral pull of the quadriceps femoris muscle on the patella and potentiates patellofemoral disorders. This study was undertaken to evaluate the relationship between the anterior knee pain and Q-angle. This prospective study was performed on two groups; the case group consisted of 100 outpatients (44 men, and 56 women) aged between 15 and 35 years, with anterior knee pain. The control group consisted of 100 outpatients (50 men, and 50 women) with the same age distribution, who presented with different problems in the upper extremities and no knee problems. The Q-angle of each knee was measured in all participants, using a universal goniometer. The mean Q-angle for men, women, and all participants in the case group was 15.2, 20.1, and 18.0 degrees, respectively. In the normal control group the angles were 12.1, 16.7, and 14.9 degrees, respectively. All these differences were statistically significant (P < 0.001). These results substantiate the fact that patients with anterior knee pain have larger Q-angles than healthy individuals.


Emergence of rare sapovirus genotype among infants and children with acute gastroenteritis in Japan.
A total of 1,154 fecal specimens from infants and children with acute gastroenteritis in five cities in Japan (Maizuru, Tokyo, Sapporo, Saga, and Osaka), collected from July 2003 to June 2005, were tested for the presence of diarrheal viruses by reverse transcriptase multiplex PCR. Overall, 469 of 1,154 (40.6%) were positive for diarrheal viruses, of which 49 (10.4%) were positive for sapovirus. The peak of sapovirus infection shifted from April-June in 2003-2004 to October-December in 2004-2005. The observations show that maximum sapovirus prevalence can occur during warmer seasons. Sapovirus was subjected to molecular genetic analysis by sequencing. The results indicated that sapovirus genogroup I was a dominant group (100%). Sapovirus strains detected in this study were further classified into four genotypes (GI/1, GI/4, GI/6, and GI/8). Of these, sapovirus GI/1 was the most predominant, followed by sapovirus GI/6; these accounted for 93% (13 of 14) and 7% (1 of 14), respectively, in 2003-2004. However, it was noteworthy that sapovirus GI/6 suddenly emerged to become the leading genotype, accounting for 77% (27 of 35) of isolates in 2004-2005. This is believed to be the first report of the changing distribution of sapovirus genotypes and of the emergence of the rare sapovirus GI/6.


Coreactant Strategy for the Photoredox Catalytic Generation of Trifluoromethyl Radicals under Low-Energy Photoirradiation.
Photoredox catalysis has emerged as a valuable alternative to dark-state catalysis. For the full potential of photoredox catalysis to be utilized, it is imperative to make use of low-energy photons in photoinduced radical processes. We have demonstrated that the use of oxalate as a coreactant provides a useful principle for the photocatalytic production of trifluoromethyl radicals (•CF3) from CF3I upon green or red LED photoirradiation of narrow-bandgap photocatalysts. The photocatalytic cycle involves a radical anion of carbon dioxide (CO2(•-)) as a reductant for CF3I, which is generated through photoinduced oxidative decarboxylation of oxalate. Electrochemical characterizations and steady-state and transient photophysical investigations were performed to reveal that there are two photoinduced electron-transfer pathways for oxalate-mediated •CF3 generation.


[Frequency and etiology of noncarious cervical lesions with pulp exposure].
Noncarious cervical lesions have a multifactorial etiology encompassing occlusal trauma, toothbrush abrasion, and exposure of enamel to erosive factors. The purpose of this study was to determine the frequency of cervical lesions with exposure of pulp and to analyze their etiology. The study was done in 124 patients (59 women and 65 men) with a mean age of 44 years (15-72 years). Clinical assessment of cervical lesions was based on criteria of the universal tooth wear index for the cervical surface. Additionally, the following findings were recorded: frequency of cervical lesions depending on tooth type, pulp exposure, oral hygiene status, and type of occlusal guidance. The questionnaire consisted of detailed questions concerning toothbrushing, frequency of consumption of some foods, and parafunctional habits. The risk of cervical lesion was estimated with the logistic regression model. The frequency, localization, and depth of noncarious cervical lesions were related to age of the patient. Very deep defects with pulp exposure were found in 44 teeth. The effect of consumption of acid foods and drinks and of oral hygiene habits on the depth of wedge-shaped defects was corroborated. Correlations between lateral excursive tooth contact, bruxism, and formation of cervical lesions were disclosed, confirming the relationship between occlusal pathology and cervical lesions. Elucidation of the multifactorial etiology of cervical lesions is important for proper treatment and prevention of pulp exposure.


Long-term survival of orthotopic bowel allografts in the rat treated with short-term low-dose cyclosporine.
Orthotopic bowel transplantation continues to be a "difficult" procedure, both experimentally and clinically, despite the advent of cyclosporine. Even with high-dosage CsA administration, long-term survival has been sporadic and short-term mortality high. In the present study, a low-dosage CsA regimen (5 mg/kg/day for 2 weeks postoperatively) produced prolonged survival in BN-Lewis donor/recipient combinations utilizing an orthotopic bowel transplantation model with portal venous anastomosis. The transplanted bowel continued to survive despite the lack of maintenance dosage after initial induction. The recipient animals evinced donor-specific hyporesponsiveness as donor skin grafts were rejected in a slow, indolent fashion. Third-party skin grafts acutely rejected in normal fashion. It was remarkable that the bowel grafts continued to survive in good condition despite the rejection of donor-specific and nonspecific challenging skin grafts placed on the animals. The precise mechanism of this donor-specific hyporesponsiveness is not known.


Efficacy of Anakinra in Refractory Adult-Onset Still's Disease: Multicenter Study of 41 Patients and Literature Review.
Adult-onset Still's disease (AOSD) is often refractory to standard therapy. Anakinra (ANK), an interleukin-1 receptor antagonist, has demonstrated efficacy in single cases and small series of AOSD. We assessed the efficacy of ANK in a series of AOSD patients. Multicenter retrospective open-label study. ANK was used due to lack of efficacy to standard synthetic immunosuppressive drugs and in some cases also to at least 1 biologic agent. Forty-one patients (26 women/15 men) were recruited. They had a mean age of 34.4 ± 14 years and a median [interquartile range (IQR)] AOSD duration of 3.5 [2-6] years before ANK onset. At that time the most common clinical features were joint manifestations 87.8%, fever 78%, and cutaneous rash 58.5%. ANK yielded rapid and maintained clinical and laboratory improvement. After 1 year of therapy, the frequency of joint and cutaneous manifestations had decreased to 41.5% and to 7.3% respectively, fever from 78% to 14.6%, anemia from 56.1% to 9.8%, and lymphadenopathy from 26.8% to 4.9%. A dramatic improvement of laboratory parameters was also achieved. The median [IQR] prednisone dose was also reduced from 20 [11.3-47.5] mg/day at ANK onset to 5 [0-10] at 12 months. After a median [IQR] follow-up of 16 [5-50] months, the most important side effects were cutaneous manifestations (n = 8), mild leukopenia (n = 3), myopathy (n = 1), and infections (n = 5). ANK is associated with rapid and maintained clinical and laboratory improvement, even in nonresponders to other biologic agents. However, joint manifestations are more refractory than the systemic manifestations.


Bacterial infections in horses: a retrospective study at the University Equine Clinic of Bern.
Bacterial infections present a major challenge in equine medicine. Therapy should be based on bacteriological diagnosis to successfully minimize the increasing number of infections caused by multidrug-resistant bacteria. The present study is a retrospective analysis of bacteriological results from purulent infections in horses admitted at the University Equine Clinic of Bern from 2004 to 2008. From 378 samples analyzed, 557 isolates were identified, of which Staphylococcus aureus, Streptococcus equi subsp. zooepidemicus and coliforms were the most common. Special attention was paid to infections with methicillin-resistant S. aureus (MRSA) ST398 and a non-MRSA, multidrug-resistant S. aureus clone ST1 (BERN100). Screening of newly-admitted horses showed that 2.2 % were carriers of MRSA. Consequent hygiene measures taken at the Clinic helped to overcome a MRSA outbreak and decrease the number of MRSA infections.


[Vitamin D and calcium in the mirror of clinical evidence].
The biological mechanisms, ecological and observational studies indicate increased morbidity and mortality in vitamin D deficiency, while the controlled, randomized supplementation trials - carried out mostly in vitamin D deficient patients - have shown no or some marginal benefits, mostly in preventing institutionalized elderly individuals' falls and fractures. Clarity is also disturbed by that the primary end points of intervention studies were generally not extraskeletal. The ideal serum 25-hydroxyvitamin D levels also considerably controversial: there is clearly a J-curve, but the optimal range is uncertain. All of these uncertainties appear also in the vitamin D guidelines which are, however, concordant in that they do not recommend (i) a population-wide screening and (ii) vitamin D supplementation with extraskeletal aim - beyond the prevention of falls. Certain studies suggest that calcium supplementation increases the incidence of cardiovascular events, while others show a neutral effect in this respect. There are several ongoing vitamin D studies directly designed for extraskeletal events. Orv. Hetil., 2016, 157(31), 1242-1247.


Key for identification of the ladybirds (Coleoptera: Coccinellidae) of European Russia and the Russian Caucasus (native and alien species).
Although ladybirds of European Russia and the Caucasus have been the subject of numerous ecological and faunistic investigations, there is an evident lack of appropriate identification keys. New, original keys to subfamilies, tribes, genera, and species of ladybirds (Coccinellidae) of European Russia and the Russian Caucasus are presented here. The keys include all native species recorded in the region and all introduced alien species. Some species from adjacent regions are added. In total, 113 species are treated and illustrated with line drawings. Photographs of rare and endemic species are provided. Information on the distribution of species within the region under consideration is provided. Chilocorus kuwanae Silvestri, 1909 is recognized as a subjective junior synonym (syn. nov.) of Ch. renipustulatus (Scriba, 1791).


[A review on heat-wave early warning based on population health risk].
Global warming has caused frequent heat waves worldwide. In order to respond to heat waves and enhance the public's protection abilities, Europe, the United States and other countries have extensively carried out research on heat-health early warning, and initially achieved good health benefits based on a heat-health early warning system. However, the research on heat-health early warning is still limited in China, especially on health risks at the population level. Based on evidence-based thinking, our study combs the research progress of heat-health early warning from four aspects: early warning indicators, early warning models, early warning thresholds, and early warning ranks, and clarifies the key points of the construction of heat-health early warning models and rank schemes, in order to provide early warning technology for the rapid development of national heat-heath early warning in China.


A systematic review and critical appraisal of metagenomic and culture studies in hidradenitis suppurativa.
Hidradenitis suppurativa (HS), also known as acne inversa, is a chronic inflammatory skin disease with still largely unknown pathogenesis. While infectious organisms have been identified in lesions of the disease since the 1980s, questions remain over the role that bacteria and microbiome play. Recent studies using 16S ribosomal RNA gene sequencing and larger culture-based studies have begun to paint a clearer picture of the microbial world of HS. With this systematic review, we summarize all the work that has been done to date in HS bacteriology, analyse potential pitfalls and limitations of the current studies, and address future directions of investigation. This systematic review attempted to collate and analyse all bacteriology studies done to date. This review was prospectively registered with PROSPERO (1670769) performed in line with the PRISMA checklist. Twenty two studies were identified comprising 862 individual HS patients for culture studies and 206 HS patients for 16S rRNA gene sequencing studies. Methodology tended to be varied, with different sampling, culturing and sequencing methods as well as amount of analysis and stratification of patients. Bacteria identified as elevated in HS lesions in sequencing studies as well as grown from HS lesions in culture studies are identified and discussed. These primarily included the anerobic Gram-negative bacilli Prevotella, Porphyromonas and Fusibacterium, the Gram-positive bacilli Corynebacterium, and the Gram-positive cocci Staphylococcus, Streptococcus and Parvimonas. Potential interactions, as well as work in other disease models with related bacteria are also discussed. Areas of further investigation include in vitro studies of interactions between bacteria and keratinocytes, gut and oral microbiome studies and deep sequencing studies for virulence and phage factors.


Regulation of fibroblast migration on collagenous matrix by a cell surface peptidase complex.
The invasion of migratory cells through connective tissues involves metallo- and serine types of cell surface proteases. We show that formation of a novel protease complex, consisting of the membrane-bound prolyl peptidases seprase and dipeptidyl peptidase IV (DPPIV), at invadopodia of migratory fibroblasts is a prerequisite for cell invasion and migration on a collagenous matrix. Seprase and DPPIV form a complex on the cell surface that elicits both gelatin binding and gelatinase activities localized at invadopodia of cells migrating on collagenous fibers. The protease complex participates in the binding to gelatin and localized gelatin degradation, cellular migration, and monolayer wound closure. Serine protease inhibitors can block the gelatinase activity and the localized gelatin degradation by cells. Antibodies to the gelatin-binding domain of DPPIV reduce the cellular abilities of the proteases to degrade gelatin but do not affect cellular adhesion or spreading on type I collagen. Furthermore, expression of the seprase-DPPIV complex is restricted to migratory cells involved in wound closure in vitro and in connective tissue cells during closure of gingival wounds but not in differentiated tissue cells. Thus, we have identified cell surface proteolytic activities, which are non-metalloproteases, seprase and DPPIV, that are responsible for the tissue-invasive phenotype.


New insights into the functions of carbon-calcium inclusions in plants.
Carbon-calcium inclusions (CCaI) either as calcium oxalate crystals (CaOx) or amorphous calcium carbonate cystoliths are spread among most photosynthetic organisms. They represent dynamic structures with a significant construction cost and their appearance during evolution indicates an ancient origin. Both types of inclusions share some similar functional characteristics providing adaptive advantages such as the regulation of Ca levels, and the release of CO2 and water molecules upon decomposition. The latter seems to be essential under drought conditions and explains the intense occurrence of these structures in plants thriving in dry climates. It seems, however, that for plants CaOx may represent a more prevalent storage system compared with CaCO3 due to the multifunctionality of oxalate. This compound participates in a number of important soil biogeochemical processes, creates endosymbiosis with beneficial bacteria and provides tolerance against a combination of abiotic (nutrient deprivation, metal toxicity) and biotic (pathogens, herbivores) stress factors. We suggest a re-evaluation of the roles of these fascinating plant structures under a new and holistic approach that could enhance our understanding of carbon sequestration at the whole plant level and provide future perspectives.


A feature transferring workflow between data-poor compounds in various tasks.
Compound screening by in silico approaches has advantages in identifying high-activity leading compounds and can predict the safety of the drug. A key challenge is that the number of observations of drug activity and toxicity accumulation varies by target in different datasets, some of which are more understudied than others. Owing to an overall insufficiency and imbalance of drug data, it is hard to accurately predict drug activity and toxicity of multiple tasks by the existing models. To solve this problem, this paper proposed a two-stage transfer learning workflow to develop a novel prediction model, which can accurately predict drug activity and toxicity of the targets with insufficient observations. We built a balanced dataset based on the Tox21 dataset and developed a drug activity and toxicity prediction model based on Siamese networks and graph convolution to produce multitasking output. We also took advantage of transfer learning from data-rich targets to data-poor targets. We showed greater accuracy in predicting the activity and toxicity of compounds to targets with rich data and poor data. In Tox21, a relatively rich dataset, the prediction model accuracy for classification tasks was 0.877 AUROC. In the other five unbalanced datasets, we also found that transfer learning strategies brought the accuracy of models to a higher level in understudied targets. Our models can overcome the imbalance in target data and predict the compound activity and toxicity of understudied targets to help prioritize upcoming biological experiments.


A tale of two countries: how decentralized organization and long-term investment build resilient healthcare systems.
Healthcare systems are faced with unique challenges during the ongoing Covid-19 pandemic. This viewpoint compares the response to the Covid-19 pandemic in the UK and in Germany. Despite being two large European countries of comparable size with good healthcare systems and similar patterns of exposure to Covid-19, Covid-19 related deaths in the UK currently far outnumber those in Germany. This has several reasons, but two explanations stick out: 1. lower long-term investment into healthcare in the UK rendered the NHS more vulnerable to Covid-19; 2. the existence of a well-governed decentralised and partially redundant organisation of healthcare increased resilience in Germany' s healthcare systems, enhancing the ability to adapt in response to unexpected challenges to healthcare. The response to the current pandemic also illustrates the power and the necessity to learn from each other through transparent communication of successes and mistakes.


[Paleopathology of human tumors].
The occurrence and frequency of neoplastic lesions in ancient populations has been a subject of debate for both paleopathologists and medical historians. The available sources of information are both direct, i.e., deriving from the study of ancient skeletal or mummified samples, and indirect, i.e., deriving from the analysis of ancient works of art, and of written records. Often, however, indirect sources do not allow a precise nosographic identification of the disease. Therefore, paleopathology is critical for the study of tumors in antiquity. The paleopathological record is itself difficult to interpret, because of the relative scarcity and poor state of preservation of the samples generally available for analysis. The study of the antiquity of tumors can be conveniently approached following a geographic criterion. Tumors are already documented in fossil specimens referred to an early ancestor of modern humans, Homo erectus. However, neoplastic lesions become relatively abundant only from the Neolithic period. Altogether, in ancient populations from Africa, Eurasia and the Americas, some benign tumors and most malignant soft tissue tumors may have had a frequency comparable to that documented for modern populations. In contrast, carcinomas and hemopoietic tumors which occur frequently in modern populations appear to have been generally rare in antiquity. To a large extent, this was probably related to the demographic structure of ancient populations. However, some malignant tumors, including nasopharyngeal carcinoma in ancient Egypt, and multiple myeloma in Africa, Eurasia, and the Americas, may have occurred more frequently in the past.


Concurrent cisplatin and etoposide with radiotherapy in locally advanced non-small cell lung cancer.
Twenty consecutive patients with newly diagnosed or locally recurrent non-small cell lung cancer limited to the chest were treated with concurrent radiotherapy and cisplatin plus etoposide. No patient had received prior chemotherapy or radiotherapy. Sixteen of 20 patients (80%) responded to the treatment. Median survival has not been reached but is greater than 13.5 months. Twelve patients have relapsed at a median of 10 months after starting therapy (range, 4-12 months), with only one initial relapse within the radiotherapy port. Hematologic toxicity was mild, with four of 52 wbc count nadirs less than 1000/mm3. Esophageal toxicity was also mild, with all patients maintaining oral intake throughout therapy. We conclude that simultaneous radiotherapy, cisplatin, and etoposide can be safely administered in locoregional non-small cell carcinoma of the lung. A prospective trial of this regimen versus radiotherapy alone is warranted.


Invasiveness of mouse embryos to human ovarian cancer cells HO8910PM and the role of MMP-9.
Our previous work found that mouse embryos could invade malignant cancer cells. In the process of implantation, embryo trophoblast cells express matrix metalloproteinases and the invasive ability of trophoblast cells is proportional to matrix metalloproteinase-9 protein expression. So the purpose of this study is to observe the effects of mouse embryos on human ovarian cancer cells in the co-culture environment in vitro and explore the possible mechanism of matrix metalloproteinase-9. Several groups of human ovarian cancer cells HO8910PM were co-cultured with mouse embryos for different time duration, after which the effects of mouse embryos on morphology and growth behavior of HO8910PM were observed under the light microscope real-time or by H.E staining. Apoptosis was detected under laser confocal microscope by Annexin V-EGFP/PI staining in situ. Invasion ability of tumor cells was studied by transwell experiments. After matrix metalloproteinase 9 (MMP -9) activity was inhibited by MMP-9 Inhibitor I, the interaction between mouse embryos and human ovarian cancer cells HO8910PM was observed. Mouse embryos were able to invade co-cultured human ovarian cancer cell layer which extended in the bottom of the culture dish, and gradually pushed away tumor cells to form their own growth space. The number of apoptosis tumor cells surrounding the embryo increased under laser confocal microscope. After co-cultured with mouse embryos, tumor cells invasive ability was lowered compared with the control group. After MMP-9 activity was inhibited, the interaction between mouse embryos and HO8910PM cells had no significant difference compared with the normal MMP-9 activity group. Mouse embryos were able to invade human ovarian cancer cells in vitro and form their own growth space, promote apoptosis of human ovarian cancer cells and lower their invasive ability. The mouse embryo was still able to invade human ovarian cancer cells after MMP-9 activity was inhibited.


Regular Fluorescence of 4-Fluoro-N,N-dimethylaniline: No Charge Transfer and No Twisting.
Recently, two contradicting experimental investigations have been published on the fluorescence behavior of 4-fluoro-N,N-dimethylaniline (FDMA). Motivated by the discrepancies between these studies, we have examined the deactivation pathways of photoexcited FDMA using high-level quantum chemical methods such as time-dependent density functional theory (TDDFT), coupled cluster (CC2) theory, and the algebraic diagrammatic construction scheme (ADC(2), ADC(3)) simulating solvation using continuum solvation models. Our results show the initial population of the bright S2 (ππ*) state of FDMA relax to a linear, almost planar S1 state minimum from which emission occurs. Our study further reveals that TDDFT/B3LYP erroneously predicts a planar twisted intramolecular charge transfer (TICT) S1 state minimum that vanishes when the amount of nonlocal Hartree-Fock exchange in the functional is increased.


Etiologies of altered mental status in patients with presumed ethanol intoxication.
Altered mental status is a commonly evaluated problem in the ED. Ethanol intoxication is common, and prehospital history may bias emergency physicians to suspect this as the cause of altered mental status. Quantitative ethanol measurement can rapidly confirm the diagnosis, or if negative, prompt further evaluation. Our objective was to identify the etiologies of altered mental status in ED patients initially presumed to be intoxicated with ethanol but found to have negative quantitative ethanol levels. This was a 5-year (2012-2016) electronic medical record review of ED patients presenting with altered mental status. Patients were included if they presented with presumed ethanol intoxication and had an initial ethanol concentration of zero. Etiologies of altered mental status were categorized into medical, traumatic, psychiatric, and drug-related causes. 29,322 patients presented during the study period with presumed alcohol intoxication, 1875 patients had negative ethanol levels. The etiology of altered mental status was due to illicit substances in 1337 patients (71%), psychiatric causes in 354 patients (19%), medical causes in 166 patients (9%) and trauma in 18 patients (1%). A total of 179 patients (10%) were admitted to the hospital; 19 patients (1%) to the ICU. The presumptive diagnosis of ethanol intoxication in patients presenting to the ED with altered mental status was inaccurate in 5% of patients. The etiology of altered mental status was serious and required hospitalization in 10% of the cohort. Rapid assessment of quantitative ethanol levels should be performed, breathalyzers may be preferred over serum testing.


Fractures of the humerus treated by elastic nailing.
The Marchetti-Vicenzi elastic nail was used in the osteosynthesis of 15 diaphyseal or metadiaphyseal fractures of the humerus, 14 cases achieved consolidation, 1 resulted in nonunion. Surgical approach was always distal, transtricipital and the nail was always locked distally. In the cases that healed, the mean radiographic consolidation time was 90 days. There were no immediate postoperative complications.


Traffic-Related Air Pollution and Childhood Asthma: Recent Advances and Remaining Gaps in the Exposure Assessment Methods.
Background: Current levels of traffic-related air pollution (TRAP) are associated with the development of childhood asthma, although some inconsistencies and heterogeneity remain. An important part of the uncertainty in studies of TRAP-associated asthma originates from uncertainties in the TRAP exposure assessment and assignment methods. In this work, we aim to systematically review the exposure assessment methods used in the epidemiology of TRAP and childhood asthma, highlight recent advances, remaining research gaps and make suggestions for further research. Methods: We systematically reviewed epidemiological studies published up until 8 September 2016 and available in Embase, Ovid MEDLINE (R), and "Transport database". We included studies which examined the association between children's exposure to TRAP metrics and their risk of "asthma" incidence or lifetime prevalence, from birth to the age of 18 years old. Results: We found 42 studies which examined the associations between TRAP and subsequent childhood asthma incidence or lifetime prevalence, published since 1999. Land-use regression modelling was the most commonly used method and nitrogen dioxide (NO₂) was the most commonly used pollutant in the exposure assessments. Most studies estimated TRAP exposure at the residential address and only a few considered the participants' mobility. TRAP exposure was mostly assessed at the birth year and only a few studies considered different and/or multiple exposure time windows. We recommend that further work is needed including e.g., the use of new exposure metrics such as the composition of particulate matter, oxidative potential and ultra-fine particles, improved modelling e.g., by combining different exposure assessment models, including mobility of the participants, and systematically investigating different exposure time windows. Conclusions: Although our previous meta-analysis found statistically significant associations for various TRAP exposures and subsequent childhood asthma, further refinement of the exposure assessment may improve the risk estimates, and shed light on critical exposure time windows, putative agents, underlying mechanisms and drivers of heterogeneity.


Five years of follow-up after elemental mercury self-poisoning.
A case of attempted suicide by injection of elemental mercury is described. Radiographs demonstrated the presence of widespread opacities of metallic mercury in both the lungs and the abdomen. During a 5-year follow-up, even though the patient had high concentrations of mercury in the urine and blood, only mild clinical symptoms and moderate carbon monoxide diffusing capacity reduction appeared. No biochemical evidence of damage to any organ was found.


Further evidence for the existence of a clonal Ph-negative stage in some cases of Ph-positive chronic myelocytic leukemia.
The Ph chromosome abnormality is involved in the pathogenesis of almost all patients with chronic myelocytic leukemia (CML). Previous studies on the B-lymphoid cell lineage in two patients with Ph-positive CML suggest that there may also be a clonal Ph-negative stage in CML and that the Ph-positive stage arises by subclonal expansion. To determine whether this is a frequent or a rare occurrence, 14 additional glucose-6-phosphate dehydrogenase (G6PD)-heterozygous patients with CML were studied. In five of these patients there was a statistically significant excess of Ph-negative B-lymphoid cell lines expressing the same G6PD type expressed in the corresponding CML clone. In no case was an excess of B-lymphoid lines expressing the opposite G6PD type recovered. These data provide further evidence that in some patients the Ph chromosome arises in a pluripotent stem cell from a pre-existing Ph-negative clone that enjoys a growth advantage.


[Tumors of the phrenic nerve].
A schwannoma of the phrenic nerve is a rare disorder which presents as a tumour of the anterior mediastinum. It is seen in adults and is usually latent. We report two cases in elderly subjects in whom the phrenic nerve tumour had achieved a significant size. One of these schwannomas had degenerated into sarcomatous change which is the first case reported to the present time.


High thiopurine metabolite concentrations associated with lymphopenia in inflammatory bowel disease (IBD) pediatric patients receiving aminosalicylates combined with azathioprine.
Aminosalicylates are widely used with azathioprine in the treatment of IBD. The association results in an increase in 6-TGN levels in adults with IBD with a difference in the occurrence of myelotoxic effects. Scarce data are available in pediatric population. We proposed to investigate the effect of the coadministration of aminosalicylates on thiopurine concentrations in pediatric IBD patients. Data from 71 patients treated for at least 1 y by azathioprine and aminosalicylates were recorded. 6-TGN and 6-MeMPN concentrations, blood cell counts and liver function tests were compared between patients taking and those not taking aminosalicylates. Aminosalicylate therapy was associated with a significant increase in mean 6-TGN but also 6-MeMPN concentrations. In patients in remission, 6-TGN level was related to aminosalicylate dosage (r = 0.561, p = 0.010). Lymphopenia rate was higher in patients receiving combined therapy compared to monotherapy whereas a slight rise in leucopenia was found. This observation suggests that the higher frequency of lymphopenia may be associated with the elevated 6-TGN concentrations recovered in patients treated with aminosalicylates. This combination does not improve remission rate but could increase adverse effects especially lymphopenia.


Evaluation of tRNA gene PCR for identification of mollicutes.
We evaluated the applicability of tRNA gene PCR in combination with fluorescent capillary electrophoresis with an ABI310 genetic analyzer (Applied Biosystems, Calif.) for the identification of different mollicute species. A total of 103 strains and DNA extracts of 30 different species belonging to the genera Acholeplasma, Mycoplasma, and Ureaplasma were studied. Reproducible peak profiles were generated for all samples, except for one M. genitalium isolate, the three M. gallisepticum isolates, and 8 of the 24 Ureaplasma cultures, where no amplification could be obtained. Clustering revealed numerous discrepancies compared to the identifications that had been previously obtained by means of biochemical and serological tests. Final identification was obtained by 16S rRNA gene amplification followed by sequence analysis and/or restriction digestion. This confirmed the identification obtained by tRNA gene PCR in all cases. Seven samples yielded an unexpected tRNA gene PCR profile. Sequence analysis of the 16S rRNA genes showed that six of these samples were mixed and that one had a unique sequence that did not match any of the published sequences, pointing to the existence of a not-yet-described species. In conclusion, we found tRNA gene PCR to be a rapid and discriminatory method to correctly identify a large collection of different species of the class of Mollicutes and to recognize not-yet-described groups.


Mind Your Manners! A Dataset and a Continual Learning Approach for Assessing Social Appropriateness of Robot Actions.
To date, endowing robots with an ability to assess social appropriateness of their actions has not been possible. This has been mainly due to (i) the lack of relevant and labelled data and (ii) the lack of formulations of this as a lifelong learning problem. In this paper, we address these two issues. We first introduce the Socially Appropriate Domestic Robot Actions dataset (MANNERS-DB), which contains appropriateness labels of robot actions annotated by humans. Secondly, we train and evaluate a baseline Multi Layer Perceptron and a Bayesian Neural Network (BNN) that estimate social appropriateness of actions in MANNERS-DB. Finally, we formulate learning social appropriateness of actions as a continual learning problem using the uncertainty of Bayesian Neural Network parameters. The experimental results show that the social appropriateness of robot actions can be predicted with a satisfactory level of precision. To facilitate reproducibility and further progress in this area, MANNERS-DB, the trained models and the relevant code are made publicly available at https://github.com/jonastjoms/MANNERS-DB.


Retaining and transferring nursing knowledge through a hospital internship program.
In healthcare, organizations recognize that human capital is their most valuable asset. The importance of investing in knowledge workers is imperative given the current and future shortage of health professionals. Knowledge acquisition occurs through continuous learning and the transfer of information from those who are highly experienced to those who are less qualified. At St. Michael's Hospital, two innovative and unique programs were created for the transfer of knowledge. The first was a nurse fellowship program that enabled experienced nurses to spend two to three months learning new skills to advance clinical practice. The second was a nurse internship program in which new graduates spend three to four months in their area of hire to enhance clinical practice through skill development and prioritization of patient care needs. This paper describes both programs and presents an evaluation of the new-graduate internship program as an opportunity for professional development and career enhancement For nurse interns, the program promotes self-esteem and professional confidence, improves job satisfaction and rewards nurses for their contribution. For nurse preceptors, the program provides job enrichment, experience in teaching and recognition by the organization and peers that they are knowledge experts. In healthcare, organizations have come to acknowledge that their most valuable asset is human capital, in particular, knowledge workers (Horibe 1999). Knowledge workers contribute a composite of information, intellectual property and experience (Horibe 1999), acquired by study, investigation, observation or practice (Webster's Dictionary 1989). Investing in knowledge workers is investing in the future. In this regard, organizations have implemented recruitment and retention strategies to attract, retain and advance the highest calibre of health professional. Knowledge workers contribute to an organization through their ideas, analyses of complex situations and sound judgment in decision-making (Horibe 1999). They further develop these skills over the course of their career through continuous learning. This paper will focus on the importance of investing in nurses as knowledge workers. In particular, given the shortage of nurses and the reality that 25% of today's nurses can retire over the next 10 years (CNA 2001), it is imperative that knowledge transfer occur from highly experienced to less experienced nurses.


One-Pot Sequential Synthesis of 3,3'- or 2,3'-Bis(indolyl)methanes by Using 1,3-Dithiane as the Methylene Source.
A simple and efficient method for structurally diverse symmetrical and unsymmetrical 3,3'- and 2,3'-bisindolylmethanes has been developed through a one-pot sequential reaction using 1,3-dithiane as the methylene source. The important AhR agonists ICZ and malassezin were synthesized with excellent efficiency by this straightforward approach.


Leptin improves pulmonary bacterial clearance and survival in ob/ob mice during pneumococcal pneumonia.
The adipocyte-derived hormone leptin is an important regulator of appetite and energy expenditure and is now appreciated for its ability to control innate and adaptive immune responses. We have reported previously that the leptin-deficient ob/ob mouse exhibited increased susceptibility to the Gram-negative bacterium Klebsiella pneumoniae. In this report we assessed the impact of chronic leptin deficiency, using ob/ob mice, on pneumococcal pneumonia and examined whether restoring circulating leptin to physiological levels in vivo could improve host defences against this pathogen. We observed that ob/ob mice, compared with wild-type (WT) animals, exhibited enhanced lethality and reduced pulmonary bacterial clearance following Streptococcus pneumoniae challenge. These impairments in host defence in ob/ob mice were associated with elevated levels of lung tumour necrosis factor (TNF)-alpha, macrophage inflammatory peptide (MIP)-2 [correction added after online publication 28 September 2007: definition of MIP corrected], prostaglandin E(2) (PGE(2)), lung neutrophil polymorphonuclear leukocyte (PMN) counts, defective alveolar macrophage (AM) phagocytosis and PMN killing of S. pneumoniae in vitro. Exogenous leptin administration to ob/ob mice in vivo improved survival and greatly improved pulmonary bacterial clearance, reduced bacteraemia, reconstituted AM phagocytosis and PMN H(2)O(2) production and killing of S. pneumoniae in vitro. Our results demonstrate, for the first time, that leptin improves pulmonary bacterial clearance and survival in ob/ob mice during pneumococcal pneumonia. Further investigations are warranted to determine whether there is a potential therapeutic role for this adipokine in immunocompromised patients.


Serological detection of Toxoplasma gondii, Leishmania infantum and Neospora caninum in cats from an area endemic for leishmaniasis in Brazil.
An investigation was made into the occurrence of antibodies to Toxoplasma gondii, Leishmania infantum and Neospora caninum in 151 domestic cats, based on the indirect fluorescent antibody test (IFAT). Serum samples were collected from 151 domestic cats (65 free-roaming and 86 domiciled cats; 55 males and 96 females) in Campo Grande, Mato Grosso do Sul, Brazil between January and April 2013. IgG antibodies to T. gondii, L. infantum and N. caninum were found, respectively, in 49 (32.5%), 34 (22.5%) and 10 (6.6%) sampled cats. A positive correlation was found between T. gondii and N. caninum, T. gondii and L. infantum, and N. caninum and L. infantum (p <0.05) infections. Also, a significant interaction was identified between gender and area of activity on the probability of T. gondii (p = 0.0324) infection. However, no significant interaction was observed between gender and area of activity on infections by either N. caninum or L. infantum. This study showed that cats from an area endemic for visceral leishmaniasis in Brazil are exposed to three different protozoans, two of which are causal agents of important zoonosis.


The p53-dependent G1 cell cycle checkpoint pathway and ataxia-telangiectasia.
The p53 protein is a critical participant in a signal transduction pathway which mediates a G1 cell cycle arrest and apoptotic cell death in mammalian cells after ionizing irradiation. Cells from patients with the cancer-prone, radiation-sensitive disorder, ataxia-telangiectasia (AT), exhibit suboptimal (delayed and/or defective) induction of p53 protein after ionizing radiation with some dependence on dose. Other protein products which participate in this signal transduction pathway, including p21WAF1/CIP1, Gadd45, and Mdm2, are also suboptimally induced in AT cells after ionizing radiation. Induction of p53 is also abnormal in AT cells following treatment with methylmethanesulfonate and bleomycin but appears relatively normal following treatment with UV-C irradiation or the topoisomerase inhibitors, etoposide and camptothecin. These results demonstrate a specific defect in this p53-dependent signal transduction pathway in AT cells. Potential models for this observed specificity of the AT defect as measured by p53 induction include problems with responses to: (a) single-strand, but not double-strand, DNA breaks; or (b) chemically, but not enzymatically, generated DNA ends.


Endoscopic retrograde cholangiopancreatography in the elderly: outcomes, safety and complications.
As the population ages, the incidence of biliary tract pathologies also increases, leading to an increase in the demand for endoscopic retrograde cholangiopancreatography (ERCP) interventions. Our aims are to assess the outcomes, safety and complications associated with ERCP performed in an elderly population. Patients aged 80 years or over referred for ERCP from January 1999 to September 2002, were identified and retrospectively reviewed. 103 patients (68 females, mean age 84.6 +/- 3.9 years old) underwent 144 procedures (1-6 procedures/patient). The main indications were cholangitis (51.4 percent), choledocholithiasis (19.4 percent) and blocked stents (14.6 percent). Malignancies represented 5.6 percent of indications. The mean procedure time was 38 +/- 16 minutes. The overall success rate was 80.5 percent. Minor events occurred in 23 percent (tachycardia 13, desaturation six, transient hypotension six, self-limiting bleed four, extravasations three, and mild pancreatitis one). Major events were post sphincterotomy bleeding (five days post-procedure) one, duodenal perforation one (Billroth-II gastrectomy, survived after surgery), cholangitis two, and one death was probably procedure-related (acute myocardial event five days post-stenting in a patient with Klatskin tumour). Seven deaths occurred within one month of ERCP, due to advanced malignancies (four), sepsis (two) and acute myocardial infarction (one). Patients who died within one month had significantly higher serum urea (p-value equals 0.001), and creatinine (p-value equals 0.007) levels, and lower haemoglobin (p-value equals 0.014) level. More patients had an underlying malignancy (p-value less than 0.001). In addition, they were given significantly less conscious sedation (midazolam [p-value equals 0.002] and fentanyl [p-value equals 0.018]). Our study showed that ERCP is safe in an elderly Asian population. Minor complications are usually transient and related to sedation, and mortality is usually related to severity of illness and underlying malignancies.


Differential bicodon usage in lowly and highly abundant proteins.
Degeneracy in the genetic code implies that different codons can encode the same amino acid. Usage preference of synonymous codons has been observed in all domains of life. There is much evidence suggesting that this bias has a major role on protein elongation rate, contributing to differential expression and to co-translational folding. In addition to codon usage bias, other preference variations have been observed such as codon pairs. In this paper, I report that codon pairs have significant different frequency usage for coding either lowly or highly abundant proteins. These usage preferences cannot be explained by the frequency usage of the single codons. The statistical analysis of coding sequences of nine organisms reveals that in many cases bicodon preferences are shared between related organisms. Furthermore, it is observed that misfolding in the drug-transport protein, encoded by MDR1 gene, is better explained by a big change in the pause propensity due to the synonymous bicodon variant, rather than by a relatively small change in codon usage. These findings suggest that codon pair usage can be a more powerful framework to understand translation elongation rate, protein folding efficiency, and to improve protocols to optimize heterologous gene expression.


The Relationship Between Depression and Anxiety Symptoms of Adult PWE and Caregivers in a Tertiary Center.
Although several studies have emphasized the association between epilepsy and psychiatric disorders, fewer have investigated the impact of epilepsy on caregivers' emotional status, mainly in adult people with epilepsy (PWE). Here we investigated depressive symptoms, suicidal ideation, and anxiety symptoms in a large group of adult PWE and their caregivers. We analyzed symptoms of depression [with the Beck Depression Inventory-II (BDI-II)], suicidal ideation (with BDI-II item 9), and anxiety symptoms (with the Beck Anxiety Inventory) in a large group of adult PWE [N = 548 (60% women; median age 41)] and caregivers [N = 191 (72% women; median age 47)] from a Brazilian tertiary center, considering sociodemographic and clinical aspects. We also applied the Liverpool Adverse Events Profile to assess anti-seizure drugs adverse events. While the presence (p = 0.026) (and intensity, p = 0.007) of depressive symptoms and suicidal ideation (p = 0.02) were higher in PWE compared to caregivers, the proportion of clinical anxiety symptoms (p = 0.32) (and the intensity, p = 0.13) was similar in both groups. Although the rates of suicidal ideation were higher in focal epilepsy (20%), both generalized genetic epilepsy and caregivers also presented elevated frequencies (11%) of suicidal ideation. The analyses of 120 patient-caregiver dyads revealed that the intensity of depressive symptoms in PWE (but not anxiety) correlated with the intensity of depressive (r = 0.35; p < 0.001) and anxiety (r = 0.25; p = 0.01) symptoms in their caregivers. In the multivariate analyses of PWE, focal epilepsy (compared to GGE) was associated with clinical depressive symptoms (odds ratio, OR 2.1) and suicidal ideation (OR 3.2), while recurrent seizures (compared to the seizure-free group) were associated with suicidal ideation (OR 2.6) and anxiety symptoms (OR 2.1). Also, caregivers with anxiety symptoms were 8 times more likely to exhibit depressive symptoms, and those with depressive symptoms were 8 times more likely to present anxiety symptoms. Our study suggests that specific attention for the caregivers' mental health is as essential as PWE. There is an urgent need for more studies involving caregivers to identify their emotional distress and provide adequate treatment.


Adjuvant interferon treatment and the late development of cerebral metastases in a patient with osteosarcoma.
A consecutive series of patients with osteocarcoma have been receiving adjuvant interferon therapy at the Karolinska Hospital in Stockholm. We report here a case of tibial chondroblastic Grade III osteosarcoma, a boy aged 17 years, who received interferon therapy for 15 months and survived more than 5 years. The first sign of tumour spread was multiple cerebral metaseases--an observation suggesting an antitumour effect of human leucocyte interferon on osteosarcoma.


Joint inversion for transponder localization and sound-speed profile temporal variation in high-precision acoustic surveys.
This letter develops a Bayesian inversion for localizing underwater acoustic transponders using a surface ship which compensates for sound-speed profile (SSP) temporal variation during the survey. The method is based on dividing observed acoustic travel-time data into time segments and including depth-independent SSP variations for each segment as additional unknown parameters to approximate the SSP temporal variation. SSP variations are estimated jointly with transponder locations, rather than calculated separately as in existing two-step inversions. Simulation and sea-trial results show this localization/SSP joint inversion performs better than two-step inversion in terms of localization accuracy, agreement with measured SSP variations, and computational efficiency.


[Examination of the Influence of Age and Cardiopulmonary Bypass on Cerebral Autoregulation in Pediatric Patients for the Cardiac Surgery by Using Near-infrared Spectroscopy].
We evaluated the impact of age and cardiopulmonary bypass (CPB) on cerebral autoregulation in pediatric patients for the cardiac surgery with near-infrared spectroscopy. This retrospective study was conducted with 67 children undergoing closure of atrial or ventricular septal defects with CPB. The regression coefficient ((see symbol)regional cerebral oxygenation index ((see symbol)SO2)/ mean arterial blood pressure (mABP)) for each patient was calculated by simple regression analysis, assuming that higher regression coefficients indicate less functional cerebral autoregulation. In addition, to determine the vital parameters affecting rSO2 values during CPB, we analyzed the data from on-line continuous blood gas monitor with random effects-mixed model. The regression coefficients were frequently high among younger children (0-4 years), suggesting that the cerebral autoregulation was immature. Although regression coefficient values in younger children remained high through the operation, those in older children (5-14 years) increased significantly only during CPB, suggesting that cerebral autoregulation was dysfunctional during CPB. With random effects-mixed model, we revealed that mABP had the most significant effect on rSO2 values during CPB. Cerebral autoregulation in younger children is immature. Moreover, it does not work during CPB even in older children, and clinicians must ensure perfusion pressure carefully during CPB in pediatric patients.


Influence of capillary multifilament sutures on the antibacterial action of inflammatory cells in infected wounds.
Implants of two capillary multifilament suture materials, braided polyester and twisted polyamide with cover, in tissue infected with Staphylococcus aureus were studied with light microscopy and transmission electron microscopy. In the tissue around both suture materials there was a pronounced inflammatory cell reaction. Staphylococci were found between the filaments of both materials. Some ingrowth of granulation tissue with inflammatory cells close to the exterior thread surface was seen in braided polyester suture. No such infiltration was seen in the suture consisting of twisted polyamide with cover. Bacteriologic studies showed faster elimination of staphylococci from the braided polyester than from the twisted polyamide implants. The capacity of leukocytes to penetrate into a capillary multifilament material presumably is dependent on the structure of the suture thread. Bacteria which are enclosed in the interstices of multifilament suture material, and protected from the phagocytic activity of leukocytes, can sustain and prolong an infection.


Activation of a signaling pathway by the physical translocation of a chromosome.
In every organism, the cell cycle requires the execution of multiple processes in a strictly defined order. However, the mechanisms used to ensure such order remain poorly understood, particularly in bacteria. Here, we show that the activation of the essential CtrA signaling pathway that triggers cell division in Caulobacter crescentus is intrinsically coupled to the initiation of DNA replication via the physical translocation of a newly replicated chromosome, powered by the ParABS system. We demonstrate that ParA accumulation at the new cell pole during chromosome segregation recruits ChpT, an intermediate component of the CtrA signaling pathway. ChpT is normally restricted from accessing the selective PopZ polar microdomain until the new chromosome and ParA arrive. Consequently, any disruption to DNA replication initiation prevents ChpT polarization and, in turn, cell division. Collectively, our findings reveal how major cell-cycle events are coordinated in Caulobacter and, importantly, how chromosome translocation triggers an essential signaling pathway.


An accelerated convergent ordered subsets algorithm for emission tomography.
We propose an algorithm, E-COSEM (enhanced complete-data ordered subsets expectation-maximization), for fast maximum likelihood (ML) reconstruction in emission tomography. E-COSEM is founded on an incremental EM approach. Unlike the familiar OSEM (ordered subsets EM) algorithm which is not convergent, we show that E-COSEM converges to the ML solution. Alternatives to the OSEM include RAMLA, and for the related maximum a posteriori (MAP) problem, the BSREM and OS-SPS algorithms. These are fast and convergent, but require ajudicious choice of a user-specified relaxation schedule. E-COSEM itself uses a sequence of iteration-dependent parameters (very roughly akin to relaxation parameters) to control a tradeoff between a greedy, fast but non-convergent update and a slower but convergent update. These parameters are computed automatically at each iteration and require no user specification. For the ML case, our simulations show that E-COSEM is nearly as fast as RAMLA.


Infectious anastomotic pseudoaneurysm complicating renal allograft: case report and review of literature.
Infectious anastomotic pseudoaneurysm complicating renal transplant is rare, but probably under-reported with <30 cases worldwide. We report a 45-year-old man with hypertension, diabetes mellitus and end stage renal failure, who had a renal transplant anastomosed to the right external iliac artery and vein. Postoperatively, he made a slow recovery with malaise and persistent vague right iliac fossa discomfort. Ultrasound scan 1 month postoperatively showed perinephric collection, and fluid culture grew Enterococcus faecium and Pseudomonas aeruginosa. He was started on vancomycin, daptomycin and colistin. MAG-3 scan also showed suboptimal function in the renal allograft. His symptoms persisted with fever, and blood culture yielded P. aeruginosa. Repeated ultrasound scan, and subsequent computed tomography scan a few weeks later, showed perinephric collection and a large, 3.8×3.5 cm pseudoaneurysm posteromedial to the graft kidney. He underwent emergency graft excision, together with resection of the pseudoaneurysm with in situ reversed great saphenous vein interposition graft, and made a good recovery on hemodialysis. The aneurysm wall grew P. aeruginosa, and he was put on imipenem and cilastatin (tienam), colistin, ciprofloxacin and daptomycin. To our knowledge, this is one of very few cases in the world's literature in which a P. aeruginosa infectious anastomotic pseudoaneurysm developed after a renal allograft.


Providing clinicians and patients with actual prognosis: cancer in the context of competing causes of death.
To isolate progress against cancer from changes in competing causes of death, population cancer registries have traditionally reported cancer prognosis (net measures). But clinicians and cancer patients generally want to understand actual prognosis (crude measures): the chance of surviving, dying from the specific cancer and from competing causes of death in a given time period. To compare cancer and actual prognosis in the United States for four leading cancers-lung, breast, prostate, and colon-by age, comorbidity, and cancer stage and to provide templates to help patients, clinicians, and researchers understand actual prognosis. Using population-based registry data from the Surveillance, Epidemiology, and End Results (SEER) Program, we calculated cancer prognosis (relative survival) and actual prognosis (five-year overall survival and the "crude" probability of dying from cancer and competing causes) for three important prognostic determinants (age, comorbidity [Charlson-score from 2012 SEER-Medicare linkage dataset] and cancer stage at diagnosis). For younger, healthier, and earlier stage cancer patients, cancer and actual prognosis estimates were quite similar. For older and sicker patients, these prognosis estimates differed substantially. For example, the five-year overall survival for an 85-year-old patient with colorectal cancer is 54% (cancer prognosis) versus 22% (actual prognosis)-the difference reflecting the patient's substantial chance of dying from competing causes. The corresponding five-year chances of dying from the patient's cancer are 46% versus 37%. Although age and comorbidity lowered actual prognosis, stage at diagnosis was the most powerful factor: The five-year chance of colon cancer death was 10% for localized stage and 83% for distant stage. Both cancer and actual prognosis measures are important. Cancer registries should routinely report both cancer and actual prognosis to help clinicians and researchers understand the difference between these measures and what question they can and cannot answer. We encourage them to use formats like the ones presented in this paper to communicate them clearly.


Major Constituents From Brucea javanica and Their Pharmacological Actions.
Brucea javanica (Ya-dan-zi in Chinese) is a well-known Chinese herbal medicine, which is traditionally used in Chinese medicine for the treatment of intestinal inflammation, diarrhea, malaria, and cancer. The formulation of the oil (Brucea javanica oil) has been widely used to treat various types of cancer. It has also been found that B. javanica is rich in chemical constituents, including quassinoids, triterpenes, alkaloids and flavonoids. Pharmacological studies have revealed that chemical compounds derived from B. javanica exhibit multiple bioactivities, such as anti-cancer, anti-bacterial, anti-diabetic, and others. This review provides a comprehensive summary on the pharmacological properties of the main chemical constituents presented in B. javanica and their underlying molecular mechanisms. Moreover, the review will also provide scientific references for further research and development of B. javanica and its chemical constituents into novel pharmaceutical products for disease management.


Concomitant pseudomembranous colitis in colonic resection for acute diverticulitis.
Diverticulitis and Clostridium difficile infection (CDI) are common conditions in the surgical population. However, they are usually 2 distinct clinical entities. Here, we report the case of acute diverticulitis with concomitant pseudomembranous colitis, presumably due to CDI. The clinical course as well as gross and microscopic pathology findings are discussed. A literature search revealed a single previous report of these findings concomitant in a surgical specimen. A brief discussion of the pathophysiology of CDI and acute diverticulitis is included.


GABAergic dysfunction in pediatric neuro-developmental disorders.
The GABAergic system is central to the development and functional maturation of the nervous system. Emerging evidence support the role of GABAergic dysfunction in neuro-developmental disorders. This review presents the molecules and mechanisms that underlie GABA system dysfunction in several neuro-developmental disorders presenting in childhood. The impact on synaptic plasticity, neuronal circuit function and behavior, followed by targeted treatment strategies are discussed.


Comparison of conventional anterior surgery and laparoscopic surgery for inguinal-hernia repair.
Inguinal hernias can be repaired by laparoscopic techniques, which have had better results than open surgery in several small studies. We performed a randomized, multicenter trial in which 487 patients with inguinal hernias were treated by extraperitoneal laparoscopic repair and 507 patients were treated by conventional anterior repair. We recorded information about postoperative recovery and complications and examined the patients for recurrences one and six weeks, six months, and one and two years after surgery. Six patients in the open-surgery group but none in the laparoscopic-surgery group had wound abscesses (P=0.03), and the patients in the laparoscopic-surgery group had a more rapid recovery (median time to the resumption of normal daily activity, 6 vs. 10 days; time to the return to work, 14 vs. 21 days; and time to the resumption of athletic activities, 24 vs. 36 days; P<0.001 for all comparisons). With a median follow-up of 607 days, 31 patients (6 percent) in the open-surgery group had recurrences, as compared with 17 patients (3 percent) in the laparoscopic-surgery group (P=0.05). All but three of the recurrences in the latter group were within one year after surgery and were caused by surgeon-related errors. In the open-surgery group, 15 patients had recurrences during the first year, and 16 during the second year. Follow-up was complete for 97 percent of the patients. Patients with inguinal hernias who undergo laparoscopic repair recover more rapidly and have fewer recurrences than those who undergo open surgical repair.


Hybrid model of Monte Carlo simulation and diffusion theory for light reflectance by turbid media.
Light reflectance by semi-infinite turbid media is modeled by a hybrid of Monte Carlo simulation and diffusion theory, which combines the accuracy of Monte Carlo simulation near the source and the speed of diffusion theory distant from the source. For example, when the turbid medium has the following optical properties--absorption coefficient 1 cm-1, scattering coefficient 100 cm-1, anisotropy 0.9, and refractive-index-matched boundary--the hybrid simulation is 7 times faster than the pure Monte Carlo simulation (100,000 photon packets were traced), and the difference between the two simulations is within 2 standard deviations of the Monte Carlo simulation.


Assessing environmental and physiological controls over water relations in a Scots pine (Pinus sylvestris L.) stand through analyses of stable isotope composition of water and organic matter.
This study investigated the influence of meteorological, pedospheric and physiological factors on the water relations of Scots pine, as characterized by the origin of water taken up, by xylem transport as well as by carbon isotope discrimination (Delta13C) and oxygen isotope enrichment (Delta18O) of newly assimilated organic matter. For more than 1 year, we quantified delta2H and delta18O of potential water sources and xylem water as well as Delta13C and Delta18O in twig and trunk phloem organic matter biweekly, and related these values to continuously measured or modelled meteorological parameters, soil water content, stand transpiration (ST) and canopy stomatal conductance (G(s)). During the growing season, delta18O and delta2H of xylem water were generally in a range comparable to soil water from a depth of 2-20 cm. Long residence time of water in the tracheids uncoupled the isotopic signals of xylem and soil water in winter. Delta18O but not Delta13C in phloem organic matter was directly indicative of recent environmental conditions during the whole year. Delta18O could be described applying a model that included 18O fractionation associated with water exchange between leaf and atmosphere, and with the production of organic matter as well as the influence of transpiration. Phloem Delta13C was assumed to be concertedly influenced by G(s) and photosynthetically active radiation (PAR) (as a proxy for photosynthetic capacity). We conclude that isotope signatures can be used as effective tools (1) to characterize the seasonal dynamics in source and xylem water, and (2) to assess environmental effects on transpiration and G(s) of Scots pine, thus helping to understand and predict potential impacts of climate change on trees and forest ecosystems.


gamma-Carboxyglutamic acid content of hepatocellular carcinoma-associated des-gamma-carboxy prothrombin.
Serum des-gamma-carboxy prothrombin (DCP) is a useful marker for the diagnosis of hepatocellular carcinoma (HCC), but the exact mechanism of its synthesis and its structural properties in liver diseases are unknown. DCP is measured by the monoclonal antibody MU-3. The purpose of this study was to examine the epitope of MU-3 and to characterize the differences in DCP between HCC and benign liver diseases. The epitope of MU-3 was examined by ELISA using prothrombin Gla domain polypeptides and was determined to be amino acid residues 17-27 of the prothrombin Gla domain, which has four gamma-carboxyglutamic acid residues (Gla) at positions 19, 20, 25 and 26. Peptides having a glutamic acid residue (Glu) at these positions reacted strongly to MU-3 but lost reactivity when Glu 19 or 20 was changed to Gla. In the order of gamma-carboxylation, MU-3 reacted strongly to DCP containing 0-1 Gla, weakly to 2-4 Gla and not at all to DCP containing more than five Gla. After adsorbing normal prothrombin with barium carbonate, DCP reaction to MU-3 was measured by determining the amount of DCP that was adsorbed by MU-3-coated beads. The proportion of DCP reacting to MU-3 in HCC was 41.0-76.8%, whereas in patients with benign liver diseases, only 0-42.1% reacted to MU-3. These results indicate that DCP variants preferentially synthesized in HCC have less than four Gla, which are restricted to positions 16, 25, 26 and 29, whereas DCP variants in benign liver diseases have more than five Gla.


Prospect of rindopepimut in the treatment of glioblastoma.
Rindopepimut (CDX-110) is a peptide vaccine that targets epidermal growth factor receptor variant III (EGFRvIII), a tumor-specific epitope expressed in the most common and lethal primary malignant neoplasm of the brain - glioblastoma (GBM). Areas covered: The EGFRvIII mutation introduces an 801 base pair in-frame deletion of the extracellular domain of the transmembrane tyrosine kinase, resulting in constitutive kinase activity, amplification of cell growth, and inhibition of apoptosis. Rindopepimut contains a 14mer amino acid peptide spanning the EGFRvIII mutation site that is conjugated to keyhole limpet hemocyanin (KLH). The EGFRvIII neoantigen is exclusively present on GBM cells, providing rindopepimut tumor-specific activity. The authors review rindopepimut's clinical efficacy, administration, safety, and prospects in the treatment of GBM. Expert opinion: Rindopepimut showed clinical benefit and significant efficacy in phase II clinical trials, including as part of a multi-immunotherapy approach. A phase III clinical trial was terminated early, however, as it was deemed likely the study would fail to meet its primary endpoint. Longer term and sub-group analyses will be necessary to better understand rindopepimut's future role in GBM therapy.