Transplant vascular disease: role of lipids and proteoglycans.
The long-term success of cardiac allograft transplantation is limited by the development of a particular type of coronary atherosclerosis referred to as transplant vascular disease (TVD). Although the exact pathogenesis of TVD remains to be established, there is growing evidence that TVD involves immunological mechanisms operating in a milieu of nonimmunological risk factors. These immunological events constitute the principal initiating stimuli, resulting in endothelial injury with consequent myointimal hyperplasia, extracellular matrix synthesis and invocation of proteoglycan (PG)-lipoprotein interactions, leading, ultimately, to lipid retention in the vessel wall. The profound early 'insudation' of apolipoproteins along with uncertain endothelial 'intactness' in human coronary arteries in the transplanted heart, suggest that permeability of these vessel walls must be altered. Further, frequent and typically diffuse intracellular and extracellular accumulation of lipids and PGs in both the intimal and medial layers of cardiac allograft arteries has affirmed that the alloimmune environment accompanied with aberrant expression of extracellular matrix components, especially PGs, may strongly promote lipid imbibition in the allograft vascular bed, leading to TVD. In summary, the cumulative data support the view that profound lipid accumulation occurs in allograft arteries beginning very early post-transplantation, contributing to intimal thickening; that lipoproteins enter and are trapped in the subendothelial tissue, apparently through interactions with PGs; that with direct glycosaminoglycans, apolipoprotein interactions may occur, or they may occur through bridging molecules like phospholipase A2 and lipoprotein lipase; and that prolonged residence in the intima leads to lipoprotein modification, with subsequent modulation of biological processes that promote atherogenesis.


Prophylaxis--scope and limitations.
Attempts to prevent leprosy by one or another prophylactic method began with the use of dapsone as a chemoprophylaxis. Following early, small-scale studies, which were promising, large-scale studies with dapsone and acedapsone, both among contacts and in the general population, demonstrated that it is possible to prevent the occurrence of leprosy to a modest extent. With regard to immunoprophylaxis, BCG had long been considered a possibility, particularly in view of its potential to convert the skin test reaction to lepromin. Over the years, major, large-scale field trials of BCG had been carried out in Uganda, Burma, Papua New Guinea and India. All of the studies demonstrated that BCG was capable of preventing leprosy. However, protective efficacy varied from around 20% to greater than 80%. Killed Mycobacterium leprae mixed with BCG has also given varying results. Other vaccines based on cultivable mycobacteria have also been tried, and at least one of them appears promising. An approach to prophylaxis must take into account (a) the level of risk addressed and the perception of risk by the community; (b) the level of efficacy of the method of prophylaxis; (c) the possibility of easily identifying high-risk groups; (d) the operational feasibility; and (e) the focus of the prophylaxis, whether the individual or the community, or both. However, in view of the enormous progress being made towards elimination of leprosy by the widespread application of MDT, prophylaxis is becoming less and less relevant and less and less cost-effective, except in very special situations.


Post-extraction implant placement into infected versus non-infected sites: A multicenter retrospective clinical study.
The aim of this study was to assess whether immediate implant placement into post-extraction sites presenting a chronic infection poses a greater risk of implant failure than immediate placement in non-infected sites. Records of patients who underwent extraction and immediate implant placement into both infected and non-infected sites from January 1998 to September 2014 at 5 different dental centers were considered for inclusion. Included records were subjected to statistical analysis of survival rates, along with a number of other patient-, implant-, surgery-, and prosthesis-related variables. The inclusion criteria were met by 369 patients who received a total of 527 implants. The follow-up averaged 53.2 months (range 0.9-158.3) for implants placed into non-infected sockets (N = 334) and 50.1 months (range 1.6-146.1) for those placed into infected sites (N = 193). Seven implants failed in non-infected sites and 3 in infected ones. All failures occurred within 1 year of placement. Cumulative implant survival rate for non-infected and infected sites was, respectively, 97.9% ± 0.8% and 98.4% ± 0.9%, being not significantly different (P = .66). None of the investigated variables affected the outcome. Placement of implants into periodontally or endodontically infected sites immediately after tooth extraction is a safe option, even when the implants are loaded immediately or early.


Obesity and health system reform: private vs. public responsibility.
Obesity is a particularly vexing public health challenge, since it not only underlies much disease and health spending but also largely stems from repeated personal behavioral choices. The newly enacted comprehensive health reform law contains a number of provisions to address obesity. For example, insurance companies are required to provide coverage for preventive-health services, which include obesity screening and nutritional counseling. In addition, employers will soon be able to offer premium discounts to workers who participate in wellness programs that emphasize behavioral choices. These policies presume that government intervention to reduce obesity is necessary and justified. Some people, however, argue that individuals have a compelling interest to pursue their own health and happiness as they see fit, and therefore any government intervention in these areas is an unwarranted intrusion into privacy and one's freedom to eat, drink, and exercise as much or as little as one wants. This paper clarifies the overlapping individual, employer, and social interest in each person's health generally to avoid obesity and its myriad costs in particular. The paper also explores recent evidence on the impact of government interventions on obesity through case studies on food labeling and employer-based anti-obesity interventions. Our analysis suggests a positive role for government intervention to reduce and prevent obesity. At the same time, we discuss criteria that can be used to draw lines between government, employer, and individual responsibility for health, and to derive principles that should guide and limit government interventions on obesity as health reform's various elements (e.g., exchanges, insurance market reforms) are implemented in the coming years.


Additive enhancement of apoptosis by TRAIL and fenretinide in metastatic breast cancer cells in vitro.
Successful management of metastatic breast cancer still needs better chemotherapeutic approaches. The combination of fenretinide (4-HPR), a synthetic retinoid inducing apoptosis by ROS generation, and TRAIL, a cell death ligand inducing caspase-dependent apoptosis, might result in more powerful cytotoxic activity. We therefore investigated the cytotoxic activity and resulting cell death mode of this combination in MDA-MB-231 cell line as a representative of metastatic state. Cytotoxicity was assessed by the ATP viability assay while the mode of cell death was determined both morphologically using fluorescence microscopy and biochemically using Western blotting and ELISA. The combination resulted in an additive cytotoxic effect at the doses used. Fragmented and/or pyknotic nuclei, which is a feature of apoptosis, were observed after treatment with fenretinide or TRAIL. However, the combinatorial treatment further increased apoptotic figures. Confirming apoptosis, active caspase-3 and cleaved PARP were increased by fenretinide or TRAIL in both western blotting and ELISA. Again, apoptosis was further increased by the combination. The combination warrants further studies due to its superior cytotoxic activity in the metastatic setting of breast cancer.


Distinct epilepsy phenotypes and response to drugs in KCNA1 gain- and loss-of function variants.
A wide phenotypic spectrum of neurological diseases is associated with KCNA1 (Kv1.1) variants. To investigate the molecular basis of such a heterogeneous clinical presentation and identify the possible correlation with in vitro phenotypes, we compared the functional consequences of three heterozygous de novo variants (p.P403S, p.P405L, and p.P405S) in Kv1.1 pore region found in four patients with severe developmental and epileptic encephalopathy (DEE), with those of a de novo variant in the voltage sensor (p.A261T) identified in two patients with mild, carbamazepine-responsive, focal epilepsy. Patch-clamp electrophysiology was used to investigate the functional properties of mutant Kv1.1 subunits, both expressed as homomers and heteromers with wild-type Kv1.1 subunits. KCNA1 pore mutations markedly decreased (p. P405S) or fully suppressed (p. P403S, p. P405L) Kv1.1-mediated currents, exerting loss-of-function (LoF) effects. By contrast, channels carrying the p.A261T variant exhibited a hyperpolarizing shift of the activation process, consistent with a gain-of-function (GoF) effect. The present results unveil a novel correlation between in vitro phenotype (GoF vs LoF) and clinical course (mild vs severe) in KCNA1-related phenotypes. The excellent clinical response to carbamazepine observed in the patients carrying the A261T variant suggests an exquisite sensitivity of KCNA1 GoF to sodium channel inhibition that should be further explored.


A systemic challenge in dietetics: Methodological inadequacies, erroneous claims, and misleadinginterpretations, and transparency of post-publication scrutiny.
Background: Obesity is sweeping across the developed world. Yet, the public remains largely confused when it comes to the nature of dietary habits which would serve to counteract this trend. Aim: I highlight the responsibility that the scientific community bears when it comes to the confusion, and explain the kind of actions that are needed if the public trust in science is to be maintained. Methods: Starting from an example of a recently published and prominently featured article in a leading journal, I analyse various common methodological aspects of dietetics research and the consequent claims, contextualizing this within the broader environment which includes the scientific publishing process and the mainstream media. Results: Methodological inadequacies, erroneous claims, and misleading interpretations of findings are often found in dietetics research, highlighting the deficiencies of the system which fails to uphold the fundamental principles of scientific inquiry. Conclusion: It is imperative that individual scientists speak out and challenge poor science, unsatisfactory publishing processes, and bombastic and misleading communication of research.


Gefitinib in pretreated non-small-cell lung cancer (NSCLC): analysis of efficacy and correlation with HER2 and epidermal growth factor receptor expression in locally advanced or metastatic NSCLC.
To evaluate the correlation between HER2 expression and gefitinib (ZD 1839, Iressa; AstraZeneca, London, United Kingdom) efficacy in terms of response rate, time to progression (TTP), and overall survival (OS) time. Patients with pretreated advanced non-small-cell lung cancer (NSCLC) received gefitinib at a daily dose of 250 mg until disease progression. Tumor tissue specimens obtained at the time of primary diagnosis were collected to determine HER2/epidermal growth factor receptor (EGFR) status by immunohistochemistry. From February 2001 to June 2002, 63 consecutive patients were enrolled onto the study. The overall disease control rate was 58.7% (partial response [PR], 15.9%; stable disease [SD], 42.8%), median TTP was 3.3 months, and median OS was 4.1 months. Among the 43 patients in whom EGFR/HER2 status was determined, we observed six PRs (14%) and 18 SDs (42%). Disease control, including PR and SD, was 40% in the 15 patients overexpressing HER2 and 64.3% in the 28 patients not overexpressing HER2 (P =.126). No difference was found between the two groups in terms of TTP (3.5 v 3.7 months, respectively) and OS (5.7 v 6.8 months, respectively). In addition, we did not find any difference in TTP, OS, toxicity, and symptom outcome in the group of patients overexpressing both HER2 and EGFR compared with patients who had no overexpression of HER2 According to these data, efficacy, toxicity, and symptom outcome in patients with NSCLC treated with gefitinib do not seem to be related to HER2 expression.


Application of proteomics to the study of molecular mechanisms in neurotoxicology.
The proteome is the protein compliment of the genome and is the result of genetic expression, ribosomal synthesis and proteolytic degradation. Proteins participate in most major cell processes and their function is highly regulated by post-translational modifications such as phosphorylation and glycosylation. As a result, neurotoxicant-induced changes in protein levels, function or regulation could have a negative impact on neuronal viability. At the molecular level, direct oxidative or covalent modifications of individual proteins by various chemicals or drugs is likely to lead to perturbation of tertiary structure and a loss of function. The proteome and the functional determinants of its individual protein components are, therefore, likely targets of neurotoxicant action and resulting characteristic disruptions could be critically involved in corresponding mechanisms of neurotoxicity. Clearly, investigating changes in the proteome can provide important clues for deciphering mechanisms of toxicant action and, therefore, proteomics, the study of the proteome, is currently, and will likely remain, a significant experimental approach for mechanistic research in neurotoxicology. The purpose of this review is to discuss proteomics as a tool for neurotoxicological investigations. A variety of classic proteomic techniques (e.g. liquid chromatography (LC)/tandem mass spectroscopy, two-dimensional gel image analysis) as well as more recently developed approaches (e.g. two-hybrid systems, antibody arrays, protein chips, isotope-coded affinity tags, ICAT) are available to determine protein levels, identify components of multiprotein complexes and to detect post-translational changes. Proteomics, therefore, offers a comprehensive overview of cell proteins, and in the case of neurotoxicant exposure, can provide quantitative data regarding changes in corresponding expression levels and/or post-translational modifications that might be associated with neuron injury.


[Aluminum--occurrence and toxicity for organisms].
Aluminium (Al.) is an ubiquitous element found in every food product. The sources of Al. are especially corn, yellow cheese, salt, herbs, spices, tea and tap water. In household Al.-made ware is a major source of the element. Al. may cause diseases in humans, especially hampers many metabolic processes especially turnover of calcium, phosphorus and iron. Salts of Al. may bind to DNA, RNA, inhibit such enzymes as hexokinase, acid and alkaline phosphatases, phosphodiesterase and phosphooxydase. Al. salts are especially harmful to nervous, hematopoietic systems and to skeleton. Al. gets to organism with food, water, cosmetics, from aluminium ware and containers. Toxicity comes from substitution of Mg and Fe ions effecting in disturbances in intracellular signaling, excretory functions and cellular growth. Neurotoxic action of Al. probably comes from substitution of Mg ions in ATP, what finally influences function of every ATP using-enzymes. There are observations in experimental models proving Al. salts are responsible for Alzheimer disease development. Toxicity of Al. to skeletal system results in diminished resistance thus tendencies to breaking, and comes from lower collagen synthesis and slowing down of mineralisation. Low erythropoietin production, inhibition of hem-synthesing enzymes and binding of Al. to transferrin, effects in anaemia. Carcinogenic effects of Al. were nor proved nor denied, but high concentrations of Al. were found in many neoplastic cells. In conclusion, we should introduce prophylactic measures effecting in less Al. intake esp. avoiding use of Al.-made ware nad controlling food for Al. content.


Interstitial lung disease in infants: new classification system, imaging technique, clinical presentation and imaging findings.
Interstitial lung disease (ILD) is defined as a rare, heterogeneous group of parenchymal lung conditions that develop primarily because of underlying developmental or genetic disorders. Affected infants typically present with clinical syndromes characterized by dyspnea, tachypnea, crackles and hypoxemia. Until recently, the understanding of ILD in infants has been limited largely owing to a lack of evidence-based information of underlying pathogenesis, natural history, imaging findings and histopathological features. However, ILD in infants is now better understood and managed because of (1) advances in imaging methods that result in rapid and accurate detection, (2) improved thoracoscopic techniques for lung biopsy, (3) a consensus regarding the pathological criteria for these particular lung conditions and (4) a new classification system based on the underlying etiology of ILD. This article reviews the new classification system, imaging technique, clinical presentation and imaging findings of ILD in infants. Specialized knowledge of this new classification system in conjunction with recognition of characteristic imaging findings of ILD in infants has great potential for early and accurate diagnosis, which in turn can lead to optimal patient management.


Design participation as an insurance: risk-management and end-user participation in the development of information systems in healthcare organizations.
The aim of this paper is to build a theoretical framework for analysis of when decision-makers should use end-user participation as a form of insurance for unforeseen consequences of implementing information systems in healthcare organizations. Data were collected in a case study of an information system development project in a small clinical setting. During the initial phase, the future end-users of the system were allowed to actively influence the system design and test every new tool that was considered for implementation. The results of the case study suggest that when time and effort are invested in allowing healthcare staff to participate in information system development processes, the benefits can well exceed the costs throughout the life cycle of the project. Risk-averse decision-makers fearing negative secondary consequences of a HIS, with regard to clinical work flow, will always adopt measures to prevent future failures, if they can find a possibility of shifting these risks. Therefore, they calculate the present discounted value of the effects accrued over time to the unit and predict the amount of resources they are willing to pay to acquire on insurance (such as design participation) that will protect the organization from future losses. End-user participation in the design process can be the key positive influence on the quality of the service and, thereby, organizational effectiveness. Investments in broad design participation can, consequently, be a productive activity that transforms potential current income into future benefits.


Chemical and biological studies of a new cigarette that primarily heats tobacco. Part 2. In vitro toxicology of mainstream smoke condensate.
The genotoxic and cytotoxic potential of mainstream cigarette smoke condensate (CSC) from a new cigarette that primarily heats tobacco (TOB-HT) was compared with that of CSC from a Kentucky reference low "tar" cigarette (1R4F) representative of the current US cigarette market, and Kentucky Reference 1R5F, representative of ultra-low "tar" cigarettes on the US market. TOB-HT was evaluated at concentrations which induced concentration-dependent positive responses with 1R4F and 1R5F in an in vitro toxicology test battery which included sister chromatid exchange, chromosome aberration, and neutral red cytotoxicity assays in CHO cells, and the Ames bacterial mutagenicity assay. CSC from 1R4F and 1R5F was positive in the Ames assay with Salmonella typhimurium strains TA98, TA100, TA1538 and TA1537, and negative with TA1535, while CSC from TOB-HT was negative in all five strains. CSC from 1R4F and 1R5F cigarettes was positive in sister chromatid exchange (SCE), chromosome aberration (CA) and neutral red cytotoxicity assays, while CSC from the TOB-HT cigarette yielded negative results in all the above endpoints. These data indicate that in these assays the genotoxic and cytotoxic potential of CSC from the new cigarette that primarily heats tobacco is significantly less than CSC from Kentucky reference 1R4F and 1R5F cigarettes, which are representative of cigarettes currently sold in the US.


Multiresolution Self-Supervised Feature Integration via Attention Multiple Instance Learning for Histopathology Analysis.
Digital histopathology image analysis of tumor tissue sections has seen great research interest for automating standard diagnostic tasks, but also for developing novel prognostic biomarkers. However, research has mainly been focused on developing uniresolution models, capturing either high-resolution cellular features or low-resolution tissue architectural features. In addition, in the patch-based weakly-supervised training of deep learning models, the features which represent the intratumoral heterogeneity are lost. In this study, we propose a multiresolution attention-based multiple instance learning framework that can capture cellular and contextual features from the whole tissue for predicting patient-level outcomes. Several basic mathematical operations were examined for integrating multiresolution features, i.e. addition, mean, multiplication and concatenation. The proposed multiplication-based multiresolution model performed the best (AUC=0.864), while all multiresolution models outperformed the uniresolution baseline models (AUC=0.669, 0.713) for breast-cancer grading. (Implementation: https://github.com/tsikup/multiresolution-clam).


Nurses' Perceptions of Rooming-in for Caregivers of Infants with CCHD.
Congenital heart disease (CHD) is the most common congenital defect. Infants with critical congenital heart disease (CCHD) require complex medical care, and their caregivers need extensive training before being discharged home to safely care for their child. The rooming-in process provides caregivers with an opportunity to learn, practice, and manage the skills required for discharge to home during hospitalization. Although the literature reflects positive implications for the use of the rooming-in process in other populations (e.g., neonatal abstinence syndrome), literature about the rooming-in process in a pediatric cardiac care setting is limited. There remains a gap in the literature pertaining to the viewpoints of nurses, specifically as it relates to implementing a rooming-in process. Therefore, a qualitative study design was chosen to explore the nurses' perceptions of the rooming-in process using focus groups. The purpose of this study was to gain insight from nurses as to strategies to enhance the rooming-in process for caregivers of infants with CCHD. Additionally, we explored potential education and interventions to improve outcomes for infants with CCHD preparing to be discharged home.


[Parascalene block for shoulder arthroscopic surgery].
To evaluate the effectiveness of a parascalene block of the brachial plexus as the single form of anesthesia for arthroscopic surgery on the shoulder and for postoperative analgesia. A parascalene block was performed in 151 ASA I-III patients using a plumb-bob technique with the aid of nerve stimulation and with the needle entering at a point 3 cm cephalad to the clavicle and 0.5-1 cm lateral to (and outside) the sternocleidomastoid muscle. We recorded the success or not of blockade, the incidence of side effects, clinical course during and after surgery, and patient and surgeon satisfaction with the technique. A full block was achieved in all patients, although 19 (13%) requiered a second puncture. Midazolam was administered to 34 patients for anxiety and 48 required urapidil to normalize blood pressure. Complications (incidental blocks) were rare, transitory, and mild: 6 patients with Claude Bernard-Horner syndrome, 13 with dysphonia due to recurrent nerve blockade, and 1 with diaphragmatic paresis. Postoperative pain was practically nonexistent. Administration of diclofenac as indicated was sufficient for 91.2% of the patients. The remaining 8.8% needed top-up doses. Patients and surgeons assessed the block as excellent. The parascalene technique to provide a brachial plexus block is effective for arthroscopic shoulder surgery.


In Azotobacter vinelandii, the E1 subunit of the pyruvate dehydrogenase complex binds fpr promoter region DNA and ferredoxin I.
In Azotobacter vinelandii, deletion of the fdxA gene that encodes a well characterized seven-iron ferredoxin (FdI) is known to lead to overexpression of the FdI redox partner, NADPH:ferredoxin reductase (FPR). Previous studies have established that this is an oxidative stress response in which the fpr gene is transcriptionally activated to the same extent in response to either addition of the superoxide propagator paraquat to the cells or to fdxA deletion. In both cases, the activation occurs through a specific DNA sequence located upstream of the fpr gene. Here, we report the identification of the A. vinelandii protein that binds specifically to the paraquat activatable fpr promoter region as the E1 subunit of the pyruvate dehydrogenase complex (PDHE1), a central enzyme in aerobic respiration. Sequence analysis shows that PDHE1, which was not previously suspected to be a DNA-binding protein, has a helix-turn-helix motif. The data presented here further show that FdI binds specifically to the DNA-bound PDHE1.


Guidelines on Asset Management of Offshore Facilities for Monitoring, Sustainable Maintenance, and Safety Practices.
Recent activities in the oil and gas industry have shown an increasing need for monitoring engagements, such as in shipping, logistics, exploration, drilling, or production. Hence, there is a need to have asset management of these offshore assets (or facilities). Much of the offshore infrastructure is currently approaching or past its operational life expectancy. The study presents an overview on asset management of offshore facilities towards monitoring, safe practices, maintenance, and sustainability. This study outlines the major considerations and the steps to take when evaluating asset life extensions for an aging offshore structure (or asset). The design and construction of offshore structures require some materials that are used to make the structural units, such as offshore platform rigs, ships, and boats. Maintaining existing assets in the field and developing new platforms that are capable of extracting future oil and gas resources are the two key issues facing the offshore sector. This paper also discusses fault diagnosis using sensors in the offshore facilities. The ocean environment is constantly corrosive, and the production activities demand extremely high levels of safety and reliability. Due to the limited space and remote location of most offshore operations, producing cost-effective, efficient, and long-lasting equipment necessitates a high level of competence. This paper presents the guidelines on asset monitoring, sustainable maintenance, and safety practices for offshore structures. In this study, the management of offshore structures were also presented with some discussions on fault monitoring using sensors. It also proposes sustainable asset management approaches as guidelines that are advised, with policy implications.


Development of semiquantitative ultrasound scoring system to assess cartilage in rheumatoid arthritis.
To develop and test the reliability of a new semiquantitative scoring system for the assessment of cartilage changes by ultrasound in a web-based exercise as well as a patient exercise of patients with RA. A taskforce of the Outcome Measures in Rheumatology Ultrasound Working Group performed a systematic literature review on the US assessment of cartilage in RA, followed by a Delphi survey on cartilage changes and a new semiquantitative US scoring system, and finally a web-based exercise as well as a patient exercise. For the web-based exercise, taskforce members scored a dataset of anonymized static images of MCP joints in RA patients and healthy controls, which also contained duplicate images. Subsequently, 12 taskforce members used the same US to score cartilage in MCP and proximal interphalangeal joints of six patients with RA in in a patient reliability exercise. Percentage agreement and prevalence of lesions were calculated, as intrareader reliability was assessed by weighted kappa and interreader reliability by Light's kappa. The three-grade semiquantitative scoring system demonstrated excellent intrareader reliability (kappa: 0.87 and 0.83) in the web-based exercise and the patient exercise, respectively. Interreader reliability was good in the web-based exercise (kappa: 0.64) and moderate (kappa: 0.48) in the patient exercise. Our study demonstrates that ultrasound is a reliable tool for evaluating cartilage changes in the MCP joints of patients with RA and supports further development of a new reliable semiquantitative ultrasound scoring system for evaluating cartilage involvement in RA.


Effectiveness of speed enforcement through fixed speed cameras: a time series study.
To assess the effectiveness of speed cameras in reducing the numbers of crashes and people injured on the arterial roads of Barcelona, and to assess their long-term effectiveness on the beltway. Time series analyses were performed separately for the arterial roads and the beltway. The stretches of arterial roads encompassing 500 m before and after the location of a speed camera were considered the enforced stretches, the remaining stretches of arterial roads being considered the comparison group. The outcome measures were the numbers of crashes and of people injured. Quasi-Poisson regression models were fitted, controlling for time trend, seasonality and implementation of other road safety measures. Both on the enforced and non-enforced arterial road stretches, the risks of crashes and people injured were similar in the two periods. On the beltway, reductions of 30% (95% CI 38% to 20%) and 26% (95% CI 36% to 14%) were observed, respectively. Speed cameras do not reduce the numbers of crashes or people injured on the arterial roads of Barcelona. However, they are effective in the short and in the long-term on the beltway. Speed enforcement through fixed speed cameras is thus effective in medium-high-speed roads, although effectiveness could not be generalised to roads with lower speed limits and traffic lights.


Intravenous Carbetocin Versus Rectal Misoprostol for the Active Management of the Third Stage of Labor: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.
Globally, postpartum hemorrhage (PPH) is the top cause of maternal death. Multiple uterotonic medications are available to prevent PPH; however, it is still unclear whether one is the most effective. The current study compared the efficacy and safety of intravenous carbetocin with rectal misoprostol for the active management of the third stage of labor in order to prevent PPH. Eligible studies were found utilizing digital medical sources, including the Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science (WOS), PubMed, Scopus, and Google Scholar, from inception until September 2022. Only randomized controlled trials (RCTs) that matched the inclusion requirements were chosen. We used the Cochrane Risk of Bias scale (version 2) to assess the quality of the included studies. The Review Manager (version 5.4 for Windows) was used to conduct the meta-analysis. The results were summarized as mean difference (MD) or risk ratio (RR) with a 95% confidence interval (CI) in fixed- or random-effects models according to the degree of between-study heterogeneity. Collectively, we screened 621 articles after omitting duplicates and eventually included three RCTs for analysis. Overall, 404 patients were included in these studies; 202 patients were allocated to the intravenous carbetocin group whereas 202 patients were allocated to the rectal misoprostol group. Two RCTs were judged as "low" risk of bias, whereas one RCT was judged as having "some concerns" regarding the quality assessment. Regarding efficacy endpoints, the intravenous carbetocin group had significantly lower blood loss (n=3 RCTs, MD=-117.74 mL, 95% CI [-185.41, -50.07], p<0.001), need for additional uterotonics (n=2 RCTs, RR=0.06, 95% CI [0.01, 0.46], p=0.007), need for uterine massage (n=2 RCTs, RR=0.40, 95% CI [0.20, 0.80], p=0.009), and need for blood transfusion (n=2 RCTs, RR=0.38, 95% CI [0.15, 0.95], p=0.04) compared with the rectal misoprostol group. Regarding safety endpoints, the rates of diarrhea (n=3 RCTs, RR=0.18, 95% CI [0.06, 0.55], p=0.003) and chills (n=2 RCTs, RR=0.31, 95% CI [0.12, 0.83], p=0.02) were significantly lower in the intravenous carbetocin group compared with the rectal misoprostol group. However, there was no significant difference between both groups regarding the rates of headache (n=3 RCTs, RR=1.23, 95% CI [0.06, 1.91], p=0.35) and facial flushing (n=2 RCTs, RR=0.88, 95% CI [0.46, 1.68], p=0.70). In conclusion, it was discovered that intravenous carbetocin was a superior substitute for rectal misoprostol for the active management of the third stage of labor. With far fewer side effects, intravenous carbetocin decreased postpartum blood loss and further uterotonic use. For women who have a high risk of PPH, intravenous carbetocin is advised.


On the application of an environmental radiological assessment system to an anthropomorphic surrogate.
Recent developments have seen the expansion of the system of radiological protection for humans to one including protection of the environment against detrimental effects of radiation exposure, although a fully developed framework for integration of human and ecological risk assessment for radionuclides is only at an early stage. In the context of integration, significant differences exist between assessment methodologies for humans and the environment in terms of transfer, exposure, and dosimetry. The aim of this elaboration was to explore possible implications of the simplifications made within the system of environmental radiological protection in terms of the efficacy and robustness of dose-rate predictions. A comparison was conducted between human radiological assessment and environmental radiological assessment for an anthropomorphic surrogate, the results for which, produced by both the environmental and human-oriented risk assessment systems, were critically compared and contrasted. The adopted approach split the calculations into several parts, these being 1) physical transfer in an ecosystem, 2) transfer to humans, 3) internal doses to humans, and 4) external doses to humans. The calculations were carried out using both a human radiological assessment and ecological risk assessment system for the same surrogate. The results of this comparison provided indications as to where the 2 systems are amenable to possible integration and where such integration may prove difficult. Initial stage transport models seem to be an obvious component amenable for integration, although complete integration is arguably unattainable as the differences between endpoints mean that the relevant outputs from the models will not be the same. For the transfer and dosimetry components of 2 typical methodologies, it seems that the efficacy of the environmental system is radionuclide-dependent, the predictions given by the environmental system for (90) Sr and (60) Co being unsatisfactory and those for (239) Pu and (210) Po being evidently poor. Integration in this context might take the form of exploring the biokinetic models developed for humans with regard to selected animals and radionuclides. External dose assessment for environmental and human systems provide results for the surrogate that correspond quite closely providing an indication that integration in this regard is perhaps unnecessary.


A randomized study examining the effect of 3 SSRI on premature ejaculation using a validated questionnaire.
This study reports the results of a large prospective single-blinded clinical trial of 3 SSRI (paroxetine, fluoxetine and escitalopram) in PE using a validated questionnaire. A total of 100 normally potent men suffering from PE were enrolled in a randomized single-blinded comparative study of fluoxetine, paroxetine and escitalopram Patients were randomized into 3 treatment groups. Group 1 comprised 33 men who received fluoxetine 20 mg daily, group 2 comprised 37 men who received escitalopram 10 mg and group 3 comprised 30 men who received paroxetine 20 mg daily. All drug regimens were given in early morning dose and continued for 4 weeks. All 100 (100%) patients experienced a significant increase in their AIPE total score after drug treatment. There was no significant difference regarding any of the 7 items of the AIPE between the 3 treatment groups. All 3 drugs were generally well tolerated. Our relatively large study, using a validated questionnaire confirmed similar useful effect of paroxetine, fluoxetine and escitalopram on ejaculation time. Further large cohort studies with long-term follow up are needed to evaluate the sustained effects of these drugs on ejaculation latency.


A multiple-group confirmatory factor analysis of teacher perceptions of social and emotional learning in rural Malawi.
Social and emotional learning (SEL) positively impacts children's school achievement and adult productivity. Successful implementation of SEL relies on teachers' pedagogical beliefs and practices. We examined whether the Teachers' SEL Belief Scale designed in the United States is adoptable in low-income countries such as Malawi in response to a growing interest in teacher practices in SEL but a lack of research instruments in these countries. The data used in this study were from 432 teachers working in 34 randomly selected primary schools in Zomba, a rural district in Malawi. We used multiple-group confirmatory factory analysis to investigate the factor structure and the invariance of the adapted scale across teachers with different characteristics such as gender and training experience in SEL. When invariant, we compared group mean differences among teachers in our sample by gender and training experience. We found that the Teachers' SEL Belief Scale measured a similar construct of pedagogical perceptions of SEL among the sampled teachers, and it functioned equivalently across teachers with different genders and training experiences. Female teachers had lower perceived institutional support for SEL instruction compared to male teachers. Untrained teachers had lower levels of pedagogical comfort as well as perceived support for SEL compared to trained teachers. Our findings validate the adaptability of the Teachers' SEL Belief Scale in low-income contexts such as Malawi. We did not find evidence of systematic bias relative to group membership. In addition, significantly lower pedagogical comfort and institutional support among female and untrained teachers suggest areas for policy intervention to improve teacher performance in SEL in Malawi.


A systems approach for data compression and latency reduction in cortically controlled brain machine interfaces.
This paper suggests a new approach for data compression during extracutaneous transmission of neural signals recorded by high-density microelectrode array in the cortex. The approach is based on exploiting the temporal and spatial characteristics of the neural recordings in order to strip the redundancy and infer the useful information early in the data stream. The proposed signal processing algorithms augment current filtering and amplification capability and may be a viable replacement to on chip spike detection and sorting currently employed to remedy the bandwidth limitations. Temporal processing is devised by exploiting the sparseness capabilities of the discrete wavelet transform, while spatial processing exploits the reduction in the number of physical channels through quasi-periodic eigendecomposition of the data covariance matrix. Our results demonstrate that substantial improvements are obtained in terms of lower transmission bandwidth, reduced latency and optimized processor utilization. We also demonstrate the improvements qualitatively in terms of superior denoising capabilities and higher fidelity of the obtained signals.


Electron microscopy of biological macromolecules: bridging the gap between what physics allows and what we currently can get.
The resolution achieved in low-dose electron microscopy of biological macromolecules is significantly worse than what can be obtained on the same microscopes with more robust specimens. When two-dimensional crystals are used, it is also apparent that the high-resolution image contrast is much less than what it could be if the images were perfect. Because specimen charging is one factor that might limit the contrast and resolution achieved with biological specimens, we have investigated the use of holey support films that have been coated with a metallic film before depositing specimens onto a thin carbon film that is suspended over the holes. Monolayer crystals of paraffin (C44H90) are used as a test specimen for this work because of the relative ease in imaging Bragg spacings at 0.4 nm resolution, the relative ease of measuring the contrast in these images, and the similar degree of radiation sensitivity of these crystals when compared to biological macromolecules. A metallic coating on the surrounding support film does, indeed, produce a significant improvement in the high-resolution contrast for a small fraction of the images. The majority of images show little obvious improvement, however, and even the coated area of the support film continues to show a significant amount of beam-induced movement under low-dose conditions. The fact that the contrast in the best images can be as much as 25%-35% of what it would be in a perfect image is nevertheless encouraging, demonstrating that it should be possible, in principle, to achieve the same performance for every image. Routine data collection of this quality would make it possible to determine the structure of large, macromolecular complexes without the need to grow crystals of these difficult specimen materials.


Electron-to-nuclear spectral mapping via dynamic nuclear polarization.
We report on a strategy to indirectly read out the spectrum of an electronic spin via polarization transfer to nuclear spins in its local environment. The nuclear spins are far more abundant and have longer lifetimes, allowing for repeated polarization accumulation in them. Subsequent nuclear interrogation can reveal information about the electronic spectral density of states. We experimentally demonstrate the method by reading out the ESR spectrum of nitrogen vacancy center electrons in diamond via readout of lattice 13C nuclei. Spin-lock control on the 13C nuclei yields a significantly enhanced signal-to-noise ratio for the nuclear readout. Spectrally mapped readout presents operational advantages in being background-free and immune to crystal orientation and optical scattering. We harness these advantages to demonstrate applications in underwater magnetometry. The physical basis for the "one-to-many" spectral map is itself intriguing. To uncover its origin, we develop a theoretical model that maps the system dynamics, involving traversal of a cascaded structure of Landau-Zener anti-crossings, to the operation of a tilted "Galton board." This work points to new opportunities for "ESR-via-NMR" in dilute electronic systems and in hybrid electron-nuclear quantum memories and sensors.


Helminths of three species of White Sea fishes.
Parasitic fauna of the White Sea cod, Gadus morhua marisalbi; the navaga, Eleginus nawaga; and the shorthorn sculpin, Myoxocephalus scorpius, in the White Sea was repeatedly studied, but no large-scale parasitological surveys have been made in the recent three decades. To fill this gap, we conducted a survey of the helminths of these three fish species at the White Sea Biological Station (Karelia, Russia) of the Lomonosov Moscow State University in August 2021. The navaga (50 specimens studied) was found to be infected with 13 species of helminths; the White Sea cod (50 specimens), with 12 species; and the shorthorn sculpin (21 specimens), with 13 species. Plerocercoids of Diphyllobothrium schistochilus and third-stage juveniles of Pseudoterranova bulbosa were recorded in the White Sea for the first time. The helminth infracommunities of the navaga and the White Sea cod were closer in structure to each other than to those of the shorthorn sculpin. In general, the levels of helminth infection of the White Sea cod, the navaga, and shorthorn sculpin have been consistently high over 85 years of observations in the White Sea, but long-term trends in the abundance of some helminth species were multidirectional.


Effect of Direct Bilirubin Level on Clinical Outcome and Prognoses in Severely/Critically Ill Patients With COVID-19.
We aimed to investigate how changes in direct bilirubin (DBiL) levels in severely/critically ill the coronavirus disease (COVID-19) patients during their first week of hospital admission affect their subsequent prognoses and mortality. We retrospectively enrolled 337 severely/critically ill COVID-19 patients with two consecutive blood tests at hospital admission and about 7 days after. Based on the trend of the two consecutive tests, we categorized patients into the normal direct bilirubin (DBiL) group (224), declined DBiL group (44) and elevated DBiL group (79). The elevated DBiL group had a significantly larger proportion of critically ill patients (χ2-test, p < 0.001), a higher risk of ICU admission, respiratory failure, and shock at hospital admission (χ2-test, all p < 0.001). During hospitalization, the elevated DBiL group had significantly higher risks of shock, acute respiratory distress syndrome (ARDS), and respiratory failure (χ2-test, all p < 0.001). The same findings were observed for heart damage (χ2-test, p = 0.002) and acute renal injury (χ2-test, p = 0.009). Cox regression analysis showed the risk of mortality in the elevated DBiL group was 2.27 (95% CI: 1.50-3.43, p < 0.001) times higher than that in the normal DBiL group after adjusted age, initial symptom, and laboratory markers. The Receiver Operating Characteristic curve (ROC) analysis demonstrated that the second test of DBiL was consistently a better indicator of the occurrence of complications (except shock) and mortality than the first test in severely/critically ill COVID-19 patients. The area under the ROC curve (AUC) combined with two consecutive DBiL levels for respiratory failure and death was the largest. Elevated DBiL levels are an independent indicator for complication and mortality in COVID-19 patients. Compared with the DBiL levels at admission, DBiL levels on days 7 days of hospitalization are more advantageous in predicting the prognoses of COVID-19 in severely/critically ill patients.


Influence of Polymorphisms in the Interleukin-18 Gene on Allergic Rhinitis: A Meta-Analysis.
Reported associations of interleukin-18 (IL-18) single-nucleotide polymorphisms (SNPs) with allergic rhinitis (AR) have been inconsistent, prompting a meta-analysis to obtain more precise estimates. We synthesized data from 8 articles and examined 3 IL-18 SNPs. Two SNPs (rs360721 and rs187238), in linkage disequilibrium, were combined and termed RS1. The rs1946518 SNP was analyzed separately (termed RS2). The recessive, dominant, and codominant (multiplicative) genetic models were used to estimate ORs and 95% CIs. Subgroup analysis was ethnicity-based. Sources of heterogeneity were investigated with outlier treatment. Sensitivity analysis was used to assess robustness of the associative effects. Multiple comparisons were Holm-Bonferroni corrected. All significant (pa < 0.05) outcomes indicating increased risks were found in the dominant/codominant models in RS1 and RS2. Five aspects of differences marked the significant African (RS1) and overall (RS2) outcomes: (i) magnitude of effect (ORs): greater (3.01-5.15) versus less (1.20-1.47); (ii) precision of -effects (95% CIs): less (1.07-21.52) versus more (1.01-1.89); (iii) outlier treated: no versus yes; (iv) sensitivity outcomes: nonrobust versus robust (dominant model only); and (v) greater evidential strength for RS2 (pa = 0.002) compared to RS1 (pa = 0.02) rendered RS2 our core finding. These levels of statistical significance for RS1/RS2 enabled both to survive the Holm-Bonferroni correction. The core outcome indicating a 1.5-fold increased risk could render the IL-18 polymorphisms useful in the clinical genetics of AR. Future studies that could focus on other IL-18 SNPs may find deeper associations with AR than what we found here.


Current incidence of retinopathy of prematurity, 1989-1997.
To report the current incidence and the need for surgery for retinopathy of prematurity (ROP) in neonates (22-36 weeks' gestational age [GA], July 1, 1989 through June 30, 1997). Retrospective analyses using computerized perinatal database kept on all admissions, a review of patient charts, and eye examination log books. Level 3 regional referral NICU. A total of 2528 infants <37 weeks' GA were admitted during this time. Of these infants, 950 met the criteria for eye examination beginning at 4 to 6 weeks of age and repeated every 2 weeks until complete vascularization of the retina or death or discharge. The incidence of ROP was (202/950) 21.3% for any stage and 4.6% (44/950) for stage 3 ROP or greater. No ROP was noted in infants born at >32 weeks' GA. No infant born at >28 weeks needed retinal surgery. Using birth weight (BW) criteria, stage 3 ROP was not noted in infants with BWs >1500 g; retinal surgery was not needed in infants with BWs >1000 g. A number of perinatal factors were associated with ROP on univariate analysis. However, using multiple logistic regression analyses of these factors, only GA and days on supplemental oxygen therapy were associated significantly with the development of ROP. Despite increased survival of extremely low BW infants, we found a considerable reduction in incidence and severity of ROP compared with reports from an earlier chronological period. However, infants <28 weeks' GA or with BWs <1000 g were still at considerable risk for retinal surgical treatment for ROP. We conclude that the incidence and severity of ROP have decreased significantly in the present era of surfactant therapy.


Fatal renal vasculitis and minimal change glomerulonephritis complicating treatment with penicillamine. Report on two cases.
Two cases with different and not previously described fatal renal complications during treatment with penicillamine are reported. A man with seronegative rheumatoid arthritis with features of systemic lupus erythematosus was treated with penicillamine for six months and developed a mild membranous glomerulonephritis and a severe renal vasculitis leading to uremia and death. A woman with primary biliary cirrhosis was treated with penicillamine for nine months and developed a nephrotic syndrome, the renal biopsy showing minimal change glomerulonephritis. The nephrotic syndrome responded to prednisone but the patient died, probably from septicemia. Penicillamine may thus cause glomerular damage without deposition of immune complexes. A restricted use of the drug is recommended.


Cloning and expression of a queen pheromone-binding protein in the honeybee: an olfactory-specific, developmentally regulated protein.
Odorant-binding proteins (OBPs) are small abundant extracellular proteins thought to participate in perireceptor events of odor-pheromone detection by carrying, deactivating, and/or selecting odor stimuli. The honeybee queen pheromone is known to play a crucial role in colony organization, in addition to drone sex attraction. We identified, for the first time in a social insect, a binding protein called antennal-specific protein 1 (ASP1), which binds at least one of the major queen pheromone components. ASP1 was characterized by cDNA cloning, expression in Pichia pastoris, and pheromone binding. In situ hybridization showed that it is specifically expressed in the auxiliary cell layer of the antennal olfactory sensilla. The ASP1 sequence revealed it as a divergent member of the insect OBP family. The recombinant protein presented the exact characteristics of the native protein, as shown by mass spectrometry, and N-terminal sequencing and exclusion-diffusion chromatography showed that recombinant ASP1 is dimeric. ASP1 interacts with queen pheromone major components, opposite to another putative honeybee OBP, called ASP2. ASP1 biosynthetic accumulation, followed by nondenaturing electrophoresis during development, starts at day 1 before emergence, in concomitance with the functional maturation of olfactory neurons. The isobar ASP1b isoform appears simultaneously to ASP1a in workers, but only at approximately 2 weeks after emergence in drones. Comparison of in vivo and heterologous expressions suggests that the difference between ASP1 isoforms might be because of dimerization, which might play a physiological role in relation with mate attraction.


Generation and molecular recognition of melanoma-associated antigen-specific human γδ T cells.
Antigen recognition by T cells bearing αβ T cell receptors (TCRs) is restricted by major histocompatibility complex (MHC). However, how antigens are recognized by T cells bearing γδ TCRs remains unclear. Although γδ T cells can recognize nonclassical MHC, it is generally thought that recognition of antigens is not MHC restricted. Here, we took advantage of an in vitro system to generate antigen-specific human T cells and show that melanoma-associated antigens, MART-1 and gp100, can be recognized by γδ T cells in an MHC-restricted fashion. Cloning and transferring of MART-1-specific γδ TCRs restored the specific recognition of the initial antigen MHC/peptide reactivity and conferred antigen-specific functional responses. A crystal structure of a MART-1-specific γδ TCR, together with MHC/peptide, revealed distinctive but similar docking properties to those previously reported for αβ TCRs, recognizing MART-1 on HLA-A*0201. Our work shows that antigen-specific and MHC-restricted γδ T cells can be generated in vitro and that MART-1-specific γδ T cells can also be found and cloned from the naïve repertoire. These findings reveal that classical MHC-restricted human γδ TCRs exist in the periphery and have the potential to be used in developing of new TCR-based immunotherapeutic approaches.


Microbial characteristics in homes of asthmatic and non-asthmatic adults in the ECRHS cohort.
Microbial exposures in homes of asthmatic adults have been rarely investigated; specificities and implications for respiratory health are not well understood. The objectives of this study were to investigate associations of microbial levels with asthma status, asthma symptoms, bronchial hyperresponsiveness (BHR), and atopy. Mattress dust samples of 199 asthmatics and 198 control subjects from 7 European countries participating in the European Community Respiratory Health Survey II study were analyzed for fungal and bacterial cell wall components and individual taxa. We observed trends for protective associations of higher levels of mostly bacterial markers. Increased levels of muramic acid, a cell wall component predominant in Gram-positive bacteria, tended to be inversely associated with asthma (OR's for different quartiles: II 0.71 [0.39-1.30], III 0.44 [0.23-0.82], and IV 0.60 [0.31-1.18] P for trend .07) and with asthma score (P for trend .06) and with atopy (P for trend .02). These associations were more pronounced in northern Europe. This study among adults across Europe supports a potential protective effect of Gram-positive bacteria in mattress dust and points out that this may be more pronounced in areas where microbial exposure levels are generally lower.


[Ultrastructural changes in the pancreas of rats with acute pancreatitis after semax administration].
Semax favorably affects ultrastructural changes in the pancreas of rats with acute pancreatitis (AP): a single introduction of semax (0.1 mg/kg) into the pancreatic duct of rats with AP model prevents increased necrosis of the acinar tissues and inhibits purulent inflammation of the necrotised lobules by inducing their sclerosis and atrophy, thus retaining large areas of the pancreas intact.


Systemic, renal, and hepatic hemodynamic derangement in cirrhotic patients with spontaneous bacterial peritonitis.
Spontaneous bacterial peritonitis (SBP) is frequently associated with renal failure. This study assessed if systemic and hepatic hemodynamics are also affected by this condition. Standard laboratory tests, tumor necrosis factor alpha (TNF-alpha) in plasma and ascitic fluid, plasma renin activity (PRA) and norepinephrine (NE), and systemic and hepatic hemodynamics were determined in 23 patients with SBP at diagnosis and after resolution of infection. Eight patients developed renal failure during treatment. At diagnosis of infection, patients developing renal failure showed significantly higher values of TNF-alpha, blood urea nitrogen (BUN), PRA and NE, peripheral vascular resistance, and hepatic venous pressure gradient (HVPG) and lower cardiac output than patients not developing renal failure. During treatment, a significant reduction in cardiac output and arterial pressure and increase in PRA and NE, HVPG, and Child-Pugh score were observed in the first group but not in the second. Peripheral vascular resistance remained unmodified in both groups. Changes in PRA and NE correlated inversely with changes in arterial pressure and directly with changes in BUN, Child-Pugh score, and HVPG. Five patients in the renal failure group developed encephalopathy, and 6 died. In the group without renal failure, none of the patients developed encephalopathy or expired. In conclusion, patients with SBP frequently develop a rapidly progressive impairment in systemic hemodynamics, leading to severe renal and hepatic failure, aggravation of portal hypertension, encephalopathy, and death. This occurs despite rapid resolution of infection and is associated with an extremely poor prognosis.


Chronic stimulation of the left vagus nerve in epilepsy: balance effects.
Stimulation of the left vagus nerve (VNS) has been shown to control seizures in double blinded crossover studies in man. Animal studies have reported vagal afferent induced depression of nociceptive and motor reflexes which may be caused by an effect on the descending reticular system controlling spinal cord function. Anticonvulsant drug therapy may cause postural instability. The effects of VNS are assessed not only from the perspective of seizure control but also from the view of potential harm to other bodily systems. Long term (2 1/4 years) effects of VNS were compared to postural stability analyses. 8 subjects, 2 were females, mean age 34.5 +/- 8.23 SD years, with intractable complex partial seizures, taking 3 anticonvulsant drugs were assessed for postural stability in quiet standing and while moving forwards, backwards and sideways with eyes open (EO) and eyes closed (EC). Data were collected and collated using an AMTI Biomechanics immovable forceplate, Newton M.A. U.S.A. The study design was longitudinal with pre-operative baseline data collected prior to neurostimulation and at intervals post operatively. 4/8 balance measures showed significant changes from pre-operative values and after 2 1/4 years of stimulation. Area of sway (EO) in quiet standing p = .022 and total sway (EC) in the moving state p = .019 and total sway (EC) in quiet standing showed an increase in sway p = .003. Area of sway (EC) p = .004 tended to decrease. Regression analysis for frequency of stimulation showed an increase in sway with higher frequencies T = 1.99, P = .05. Chronic VNS does not augment postural instability.


Anatomic stereotactic catheter ablation on three-dimensional magnetic resonance images in real time.
Targets for radiofrequency (RF) ablation of atrial fibrillation, atrial flutter, and nonidiopathic ventricular tachycardia are increasingly being selected on the basis of anatomic considerations. Because fluoroscopy provides only limited information about the relationship between catheter positions and cardiac structures and is associated with radiation risk, other approaches to mapping may be beneficial. An electromagnetic catheter positioning system was superimposed on 3D MR images using fiducial markers. This allowed the dynamic display of the catheter position on the true anatomy of previously acquired MR images in real time. In vitro accuracy and precision during catheter navigation were assessed in a phantom model and were 1.11+/-0.06 and 0.30+/-0.07 mm (mean+/-SEM), respectively. Left and right heart catheterization was performed in 7 swine without the use of fluoroscopy, yielding an in vivo accuracy and precision of 2.74+/-0.52 and 1.97+/-0.44 mm, respectively. To assess the reproducibility of RF ablation, RF lesions were created repeatedly at the identical anatomic site in the right atrium (n=8 swine). Average distance of the repeated right atrial ablations was 3.92+/-0.5 mm. Straight 3-point lines were created in the right and left ventricles to determine the ability to facilitate complex ablation procedures (n=6 swine). The ventricular lesions deviated 1.70+/-0.24 mm from a straight line, and the point distance differed by 2.25+/-0.63 mm from the pathological specimen. Real-time display of the catheter position on 3D MRI allows accurate and precise RF ablation guided by the true anatomy. This may facilitate anatomically based ablation procedures in, for instance, atrial fibrillation or nonidiopathic ventricular tachycardia and decrease radiation times.


Virtual simulation of an osseointegrated trans-humeral prosthesis: A falling scenario.
Traditional prosthetic solutions expose the amputee to numerous problems that limit his ability to safely perform the normal activities of daily life. In order to eliminate the problems related to the use of the traditional prosthesis with socket, a new technique was developed for fixing the prosthesis to the amputees based on the principle of osseointegration. The aim of this paper is to study and analyze the stress distribution on the interface between a trans-humeral osseointegrated prosthetic implant and the residual bone, identifying the most stressed areas and thus foreseeing possible failure phenomena of the entire prosthetic system and, after, to compare the stress distribution on three different prosthetic designs that differ from each other for some geometric characteristics. A healthy individual mimics two fall scenarios of which the trans-humeral amputees can most likely be victims: Static fall and Dynamic fall. A force platform (P-6000, BTS Bioengineering) is required for load data acquisition. The CAD model of the trans-humeral osseointegrated implant was created following the guidelines of the OPRA implant. The bone model was created starting from the CAT scan of a left humerus. The FEM simulation was conducted throught a linear analysis. Both during static fall and dynamic fall, similar trends have been observed for the reaction force Fz, the torque moment Tz, the bending moments Mx and My. From the analysis of the von Mises stress distribution it was found that the stress distribution is more homogeneous in the case where the thread of the fixture is made by a triangular profile with height of the thread equal to 0.5 mm. However, it can be seen that, when passing from a thread with height of 0.5 mm to a 1 mm, there is a slight decrease in the stress on the whole contact zone between the fixture and the humerus. The same improvement can also be seen in the case of trapezoidal threading. By modifying the height and/or by varying the thread profile, are obtained slightly better results with respect to the case with a 0.5 mm height triangular thread.


Ramadan Fasting and Kidney Stones: A Systematic Review.
Ramadan fasting in Muslims may contain several hours of abstaining from food and drinking in any kind. This can potentially increase the risk of urinary stone disease. Current literature on possible effects of Ramadan fasting on urolithiasis is rather limited. Having the gap in scientific background, we decided to evaluate the available comparative information in this systematic review. We included all studies comparing fasting and non-fasting conditions, studies evaluating stone formation and clinical manifestations of kidney stone disease. All the English studies published from January 1980 to the end of 2019 were included. The exclusion criteria were as followed: fasting out of Ramadan, non-comparative studies, animal studies, patients with bladder stones, and studies evaluating conditions that are only indirectly related to the stone formation or clinical manifestations of it. Applying the Joanna Briggs Institute (JBI) methodology for systematic review showed the quality of included studies was not high. Only five studies remained after exclusion. Meta-analysis was not applicable due to the diversity in methods and evaluated population. Main trend of the included studies is toward showing no difference between fasting and non-fasting conditions in terms of renal stone formation. However, generalization of the findings to greater populations should be applied carefully considering the heterogeneity of results and quality of studies.


RNA transport to the vegetal cortex of Xenopus oocytes.
Xcat-2 RNA, a component of the germ plasm in Xenopus, localizes with the mitochondrial cloud material to the vegetal cortex in stage II oocytes. Vg1 RNA also localizes to the vegetal cortex, but later in stage III/IV oocytes, using a microtubule dependent pathway. To further analyze the mechanisms involved in RNA transport, in situ hybridization and autoradiography were used to follow the localization of endogenous Vg1 and injected Xcat-2 transcripts in stage IV oocytes. We show that Xcat-2 is competent to localize to the vegetal cortex quite independently of the mitochondrial cloud. Xcat-2 RNA appears to use the late Vg1 localization pathway, as depolymerization of microtubules by cold or nocodazole treatment prevented translocation of Xcat-2 transcripts, but did not result in the disruption of Xcat-2 anchored in the cortex. Furthermore, RNA transport was shown to be stage dependent for both Vg1 and Xcat-2 RNAs, as they did not localize in fully grown stage VI oocytes after injection. RNA sequences both required and sufficient to direct Xcat-2 to the vegetal cortex were mapped to a sequence of 150 nt immediately adjacent to the open reading frame and additional sequences at the end of the 3' untranslated region. Mapping was accomplished by injecting deletion mutant transcripts into stage IV oocytes and monitoring localization by RNase protection and autoradiography. All mutants competent for translocation were also capable of cortical anchoring, suggesting that the same signal is used for both steps. We speculate that two separate RNA pathways evolved during the course of Xenopus oogenesis. One pathway, specialized for the transport of germ plasm by way of the mitochondrial cloud, occurs early to ensure the segregation of the germ cell lineage. The other, late, pathway may serve as the more general transport system for localizing RNAs involved in somatic cell differentiation.


Transient focal neurological deficits in patients with hypoglycaemia and hyperglycaemia: report of four cases.
A case of hypoglycaemia and three cases of hyperglycaemia presenting with focal neurological deficits are presented. The focal presentations were hemiparesis and focal convulsion that returned to normal upon correction of the blood sugar. Elderly patients not uncommonly present with transient focal neurologic deficits related to abnormalities in blood sugar levels. In these patients correction of blood sugar levels per se may ameliorate symptoms and signs making it unnecessary to investigate for cerebrovascular disease. In diabetic patients on insulin or oral hypoglycaemic agents focal neurologic deficit should alert the clinician on the possibility of hypoglycaemia.


Nucleolar changes and fibrillarin redistribution following apatone treatment of human bladder carcinoma cells.
Ascorbate and menadione (Apatone) in a ratio of 100:1 kills tumor cells by autoschizis. In this study, vitamin-induced changes in nucleolar structure were evaluated as markers of autoschizis. Human bladder carcinoma (T24) cells were overlain with vitamins or with culture medium. Supernatants were removed at 1-hr intervals from 1 to 4 hr, and the cells were washed with PBS and prepared for assay. Apatone produced marked alterations in nucleolar structure including redistribution of nucleolar components, formation of ring-shaped nucleoli, condensation and increase of the proportion of perinucleolar chromatin, and the enlargement of nucleolar fibrillar centers. Immunogold labeling of the nucleolar rRNA revealed a granular localization in treated and sham-treated cells, and immunogold labeling of the rDNA revealed a shift from the fibrillar centers to the condensed perinucleolar chromatin. Fibrillarin staining shifted from the fibrillar centers and adjacent regions to a more homogeneous staining of the entire nucleolus and was consistent with the percentage of autoschizic cells detected by flow cytometry. Because autoschizis entails sequential reactivation of DNase I and DNase II, and because the fibrillarin redistribution following DNase I and Apatone treatment is identical, it appears that the nucleolar and fibrillarin changes are markers of autoschizis.


Maxillary first molar wear: a longitudinal study of children.
The aim of this study is to examine the correlation between tooth wear and age by quantitatively measuring maxillary first molar wear in children. A total of 150 maxillary dental models were analyzed in 30 subjects (male, 11; female, 19) with an age range of 6-14 years. Maxillary first molar wear were assessed based on area, volume and the shortest distance from the buccal occlusal plane to the central pit point (BCPH). The area and volume of the tooth cusps were measured at four different offset-plane heights (0.2, 0.4, 0.6, and 0.8 mm). Relationship between age and the amount of wear or BCPH were statistically analyzed. Correlation and regression analyses were also performed, and age estimation was obtained with linear regression analysis. Repeated measures analysis of variance (ANOVA) revealed significant differences between age and the amount of wear based on area, volume, and offset-plane height. Except age of 8 and 10, 12 and 14's 0.2-mm offset-plane-measured volume, all area and volume measurement of all ages and offset-plane height showed a significant amount of increase. Wear speeds were calculated using the BCPH. Among age and measurement variables, the correlation coefficient was strongest when the volume was measured from the 0.4-mm offset-plane. As age increases, the amount of wear, as quantified by area and volume measurements, also increases. According to this study, a regression equation that can be used for age estimation is follows: Age (y)=0.16×0.4V+0.85 (R 2=0.490) using volume.


Therapeutic effects of tender coconut water on oxidative stress in fructose fed insulin resistant hypertensive rats.
To investigate whether tender coconut water (TCW) mitigates oxidative stress in fructose fed hypertensive rats. Male Sprague Dawley rats were fed with fructose rich diet and treated with TCW (4 mL/100 g of body weight) for 3 subsequent weeks. Systolic blood pressure was measured every three days using the indirect tail cuff method. At the end of the experimental period, plasma glucose and insulin, serum triglycerides and free fatty acids, lipid peroxidation markers (MDA, hydroperoxides and conjugated dienes) and the activities of antioxidant enzymes were analyzed in all the groups. Treatment with TCW significantly lowered the systolic blood pressure and reduced serum triglycerides and free fatty acids. Plasma glucose and insulin levels and lipid peroxidation markers such as MDA, hydroperoxides and conjugated dienes were significantly reduced in fructose fed rats treated with TCW. Activities of antioxidant enzymes are up regulated significantly in TCW treated rats. Histopathological analysis of liver showed that TCW treatment reduced the lipid accumulation and inflammatory infiltration without any significant hepatocellular damage. The overall results suggest that, TCW treatment could prevent and reverse high blood pressure induced by high fructose diet probably by inhibition of lipid peroxidation, upregulation of antioxidant status and improved insulin sensitivity.


New Trends in Migraine Pharmacology: Targeting Calcitonin Gene-Related Peptide (CGRP) With Monoclonal Antibodies.
Migraine is a common neurologic disorder characterized by attacks consisting of unilateral, throbbing headache accompanied by photophobia, phonophobia, and nausea which remarkably reduces the patients' quality of life. Not migraine-specific non-steroidal anti-inflammatory drugs (NSAIDs) are effective in patients affected by mild episodic migraine whilst in moderate or severe episodic migraine and in chronic migraineurs triptans and preventative therapies are needed. Since these treatments are endowed with serious side effects and have limited effectiveness new pharmacological approaches have been investigated. The demonstrated pivotal role of calcitonin gene-related peptide (CGRP) has fostered the development of CGRP antagonists, unfortunately endowed with liver toxicity, and monoclonal antibodies (mAbs) toward circulating CGRP released during migraine attack or targeting its receptor. Currently, four mAbs, eptinezumab, fremanezumab, galcanezumab for CGRP and erenumab for CGRP canonical receptor, have been studied in clinical trials for episodic and chronic migraine. Apart from the proven effectiveness, these antibodies have resulted well tolerated and could improve the compliance of the patients due to their long half-lives allowing less frequent administrations. This study aims at investigating the still poorly clear pathogenesis of migraine and the potential role of anti-CGRP mAbs in the scenario of prophylaxis of migraine.


Peroxidase activity in the mouse uterus, placenta and fetus during pregnancy.
Changes in peroxidase activity during pregnancy were examined in CD-1 mice. Peroxidase activity was measured with guaiacol as the substrate in uterine extracts of nonpregnant mice and in uterine, placental, and fetal extracts of pregnant mice on days 9, 12, 14, 16, and 18 of gestation. Uterine peroxidase activity in nonpregnant mice was high, but declined logarithmically to only 0.2% by day 18 of pregnancy. In contrast to this decline, a concomitant 50-fold logarithmic increase in fetal peroxidase activity was observed between day 12 and 18. Activity in placental extracts did not change significantly throughout the gestational period examined. These results suggest that membrane bound peroxidase in mouse uterus and fetus undergoes major shifts during pregnancy.


Fusarium mycotoxins in cereals harvested from Hungarian fields.
The Fusarium mycotoxins deoxynivalenol (DON), zearalenone (ZEN) and T-2 frequently contaminate grain crops in Middle and Eastern Europe. In this survey, 116 cereal samples (maize, wheat, barley and oat) were examined for DON, ZEN and T-2 mycotoxins. Samples were collected from different areas in two Hungarian regions (North and South Transdanubia). The method of analysis was indirect competitive ELISA. Maize was the most contaminated grain regarding DON (86%), ZEN (41%) and T-2 (55%) toxins. The average results of the deoxynivalenol and zearalenone tests of maize proved to be significantly higher than those of barley or oat. DON was the most represented Fusarium mycotoxin followed by T-2 and ZEN. The examination of these mycotoxins would be necessary at a larger scale as to re-evaluate permissible levels, so increase of the monitoring programme would be advisable for the future.


Living emotions, avoiding emotions: behavioral investigation of the regulation of socially driven emotions.
Emotion regulation is important for psychological well-being. Although it is known that alternative regulation strategies may have different emotional consequences, the effectiveness of such strategies for socially driven emotions remains unclear. In this study we investigated the efficacy of different forms of reappraisal on responses to the selfish and altruistic behavior of others in the Dictator Game. In Experiment 1, subjects mentalized the intentions of the other player in one condition, and took distance from the situation in the other. Emotion ratings were recorded after each offer. Compared with a baseline condition, mentalizing led subjects to experience their emotions more positively when receiving both selfish and altruistic proposals, whereas distancing decreased the valence when receiving altruistic offers, but did not affect the perception of selfish behavior. In Experiment 2, subjects played with both computer and human partners while reappraising the meaning of the player's intentions (with a human partner) or the meaning of the situation (with a computer partner). Results showed that both contexts were effectively modulated by reappraisal, however a stronger effect was observed when the donor was a human partner, as compared to a computer partner. Taken together, these results demonstrate that socially driven emotions can be successfully modulated by reappraisal strategies that focus on the reinterpretation of others' intentions.


[Does the cerebellum play a part in cognitive processes?].
OBJECTIVE AND DEVELOPMENT: We review the different cognitive and behaviour disorders in whose genesis the cerebellum has been thought to play a part. These disorders include infantile autism, Williams' syndrome, attention-deficit hyperactivity disorder and congenital cerebellar hypoplasia. We also consider the consequences of an acquired cerebellar lesion in the light of the following neuropsychological sequelas. It would seem that the cerebellum is involved in the functioning of the executive system due to its relationship with the prefrontal operative system and in the function of the working memory, and may share some of the characteristics of the acquired frontal syndrome.


Factors Influencing Chemotherapy Goal Perception in Newly Diagnosed Cancer Patients.
Cancer patients who start receiving chemotherapy have difficulty in understanding the state of their disease, the prognosis, and the purpose of treatment. We used a survey to evaluate the extent of perception of chemotherapy goal among cancer patients. Two hundred sixteen cancer patients who received chemotherapy for the first time participated in the study. The presence of depression and anxiety was assessed using the "Hospital Anxiety and Depression Scale" (HAD). The consistency between the patients' perception of the chemotherapy goal and the physician's perception was described as "right," and the inconsistency was described as "wrong." Among the patients who participated in the survey, 53.2 % (n = 115) were receiving adjuvant treatment and 46.8 % (n = 101) were receiving palliative treatment for metastatic disease. The rate of right and wrong perception of the chemotherapy goal was 51.9 % (n = 108) and 32.2 % (n = 67), respectively, and the rate of confused patients was 18.9 % (n = 41). The level of education was shown to be the only parameter involved in accurate perception of the treatment purpose (hazard ratio (HR) = 0.444, p = 0.025, 95 % confidence interval (CI) 0.219-0.903). In this study, there was a 51.9 % consistency between the physician's perception and that of the patient regarding the purpose of treatment. We demonstrated that the level of education was the unique factor in accurate perception of chemotherapy goal among cancer patients.


Evaluation of a newborn screen for predicting out-of-home placement.
A newborn screen designed to predict family risk was examined to: (a) determine whether all families with newborns were screened; (b) evaluate its predictive validity for identifying risk of out-of-home placement, as a proxy for maltreatment; (c) determine which items were most predictive of out-of-home placement. All infants born in Manitoba, Canada from 2000 to 2002 were followed until March 31, 2004 (N = 40,886) by linking four population-based data sets: (a) newborn screening data on biological, psychological, and social risks; (b) population registry data on demographics; (c) hospital discharge data on newborn birth records; (d) data on children entering out-of-home care. Of the study population, 18.4% were not screened and 3.0% were placed in out-of-home care at least once during the study period. Infants not screened were twice as likely to enter care compared to those screened (4.9% vs. 2.5%). Infants screening at risk were 15 times more likely to enter care than those screening "not at risk." Sensitivity and specificity of the screen were 77.6% and 83.3%, respectively. Screening efforts to identify vulnerable families missed a substantial portion of families needing support. The screening tool demonstrated moderate predictive validity for identifying children at risk of entering care in the first years of life.


The effect of high intensity focused ultrasound on vascular endothelial growth factor and microvessel density in rabbit V-X2 hepatocellular carcinoma models.
To study the effect of high intensity focused ultrasound on vascular endothelial growth factor and microvessel density in the rabbit VX-2 hepatocellular carcinoma models. Rabbit VX-2 hepatocellular carcinoma models were built by implanting VX-2 tumor cells into the hepatic left lobes of 40 rabbits. After that, the rabbits were randomly divided into four groups: the control group (n=10), the postoperative one-day group (n=10), the postoperative three-day group (n=10) and the postoperative seven-day group (n=10). The expression of VEGF and the MVD in the HCC tissues were observed and measured by immunohistochemistry. After the HIFU treatment, the MVD and the expression of VEGF in the HCC tissues in the postoperative one-day group and post-operative three-day group decreased significantly as compared with the sham-HIFU group (p<0.01). The MVD and the expression of VEGF in the postoperative seven-day group were higher than those of the sham-HIFU group (p<0.05). No obvious difference was shown between the postoperative one-day group and the postoperative three-day group (p>0.05), while the two groups MVD and the expression of VEGF were different with those of the postoperative seven-day group (p<0.01). HIFU causes damage to the microvessels in the HCC tissues, effectively inhibits angiogenesis and reduces blood supply in these tissues.


A multidrug combination designed for reversing resistance to BCNU in glioblastoma multiforme.
Nitrosoureas constitute the main resource of chemotherapy for glioblastoma. However, because of chemoresistance, which is intrinsic or rapidly acquired after the first administration of chemotherapy, there have been few improvements in survival. Because O(6)-alkylguanine-DNA alkyltransferase (AGT) is the main target for increasing cell sensitivity to the nitrosoureas, we postulated that preexposure to other alkylating agents might increase the therapeutic index of the nitrosoureas by saturating all the copies of AGT present in the tumor cells. To investigate the response rate, toxic effects, time from start of chemotherapy to progression of disease or exit from the study for any reason (TTP), and progression-free survival at 6 months (PFS-6) associated with a multidrug combination that could reverse resistance to carmustine (BCNU) through AGT depletion. We conducted a phase 2 study of patients with glioblastoma at first relapse or progression after surgery and standard radiotherapy. Patients were treated with 100 mg/m(2) of procarbazine on days 1 to 5, 80 mg/m(2) of BCNU on days 3 to 5, and 1.4 mg/m(2) of vincristine on day 3 every 8 weeks. Fifty-eight patients were enrolled in the study, and all were assessable for response and toxic effects. Six patients (10.3%) had a complete response, 11 (19%) had a partial response, and 17 (29.3%) had stable disease. The median TTP was 4.8 months; 42.3% of patients had PFS-6, and 15.4% had PFS at 12 months. Response to chemotherapy was the only significant prognostic factor for TTP. Neutropenia was grade 3 in 8.6% of patients and grade 4 in 5.2% of patients, and thrombocytopenia was grade 3 in 17.2% of patients and grade 4 in 12% of patients; hepatic and pulmonary toxic effects were grade 3 in 5.2% and 8.6% of patients, respectively. This regimen proved active in chemotherapy-naive patients with recurrent glioblastoma even though toxic effects were substantial.


Comparison of oral fluconazole and clotrimazole troches as treatment for oral candidiasis in patients infected with human immunodeficiency virus.
Thirty-nine adult patients with human immunodeficiency virus infection and oral candidiasis were randomly assigned to receive either one fluconazole capsule (100 mg) or five clotrimazole troches (10 mg each) daily for 14 days. Among 36 evaluable patients, clinical resolution rates were 100 and 65%, respectively (P = 0.018). Mycological eradication rates were 75 and 20%, respectively (P = 0.004). Fluconazole-treated patients were more likely to remain disease free during follow-up than those treated with clotrimazole (P = 0.014 at 2 weeks). Prolonged clinical responses correlated with mycological eradication at the end of therapy (P = 0.043).


Risk factors associated with the prevalence of footrot in sheep from 1999 to 2000.
A postal survey of the techniques being used for the treatment and control of footrot in sheep flocks between November 1999 and October 2000 was conducted in England and Wales in November 2000. Of the 392 questionnaires circulated, 251 (64 per cent) were returned, and 209 of these were usable. Negative binomial regression analysis indicated that the isolation of bought-in sheep, and the separation and individual treatment of diseased sheep with parenteral antibiotics, foot trimming and topical foot sprays were associated with a significantly lower prevalence of footrot in a flock. In contrast, ewe flocks which were routinely foot trimmed more than once a year had a significantly higher prevalence of footrot. No evidence was found that footbathing a flock reduced the level of footrot, except on the 14 per cent of farms where the penning and race facilities for footbathing were reported by the farmer to be excellent. Vaccination had no significant beneficial effect on the level of footrot in a flock


Relationship between serum chromium concentrations and glucose utilization in normal and infected subjects.
Studies in healthy individuals demonstrate that serum chromium concentrations fall precipitiously following the intravenous administration of a 30-gm. glucose load. Significant decreases from baseline control fasting serum Cr concentrations were also observed when intravenous glucose was given during sandfly fever. Glucose disappearance rates also decreased significantly to approximately one half of pre-illness control values while serum Cr values declined still further. In addition, serum Cr disappearance rates could be calculated. When individual preexposure and postexposure serum glucose and Cr disappearance rates were compared, significant linear correlation was found (P smaller than 0.05). Acute infection appears to reduce the availability of circulating Cr, which may contribute to the altered glucose metabolism characteristic of acute infections even in the presence of elevated insulin levels and other hormonal changes.


Are Sex Differences in Preferences for Physical Attractiveness and Good Earning Capacity in Potential Mates Smaller in Countries With Greater Gender Equality?
On average, women show stronger preferences for mates with good earning capacity than men do, while men show stronger preferences for physically attractive mates than women do. Studies reporting that sex differences in mate preferences are smaller in countries with greater gender equality have been interpreted as evidence that these sex differences in mate preferences are caused by the different roles society imposes on men and women. Here, we attempted to replicate previously reported links between sex differences in mate preferences and country-level measures of gender inequality in a sample of 3,073 participants from 36 countries (data and code available at https://osf.io/4sr5f/ ). Although women preferred mates with good earning capacity more than men did and men preferred physically attractive mates more than women did, we found little evidence that these sex differences were smaller in countries with greater gender equality. Although one analysis suggested that the sex difference in preferences for good earning capacity was smaller in countries with greater gender equality, this effect was not significant when controlling for Galton's problem or when correcting for multiple comparisons. Collectively, these results provide little support for the social roles account of sex differences in mate preferences.


A whole-genome scan for 24-hour respiration rate: a major locus at 10q26 influences respiration during sleep.
Identification of genes causing variation in daytime and nighttime respiration rates could advance our understanding of the basic molecular processes of human respiratory rhythmogenesis. This could also serve an important clinical purpose, because dysfunction of such processes has been identified as critically important in sleep disorders. We performed a sib-pair-based linkage analysis on ambulatory respiration rate, using the data from 270 sibling pairs who were genotyped at 374 markers on the autosomes, with an average distance of 9.65 cM. Uni- and multivariate variance-components-based multipoint linkage analyses were performed for respiration rate during three daytime periods (morning, afternoon, and evening) and during nighttime sleep. Evidence of linkage was found at chromosomal locations 3q27, 7p22, 10q26, and 22q12. The strongest evidence of linkage was found for respiration rate during sleep, with LOD scores of 2.36 at 3q27, 3.86 at 10q26, and 1.59 at 22q12. In a simultaneous analysis of these three loci, >50% of the variance in sleep respiration rate could be attributed to a quantitative-trait loci near marker D10S1248 at 10q. Genes in this area (GFRA1, ADORA2L, FGR2, EMX2, and HMX2) can be considered promising positional candidates for genetic association studies of respiratory control during sleep.


SBMLsqueezer: a CellDesigner plug-in to generate kinetic rate equations for biochemical networks.
The development of complex biochemical models has been facilitated through the standardization of machine-readable representations like SBML (Systems Biology Markup Language). This effort is accompanied by the ongoing development of the human-readable diagrammatic representation SBGN (Systems Biology Graphical Notation). The graphical SBML editor CellDesigner allows direct translation of SBGN into SBML, and vice versa. For the assignment of kinetic rate laws, however, this process is not straightforward, as it often requires manual assembly and specific knowledge of kinetic equations. SBMLsqueezer facilitates exactly this modeling step via automated equation generation, overcoming the highly error-prone and cumbersome process of manually assigning kinetic equations. For each reaction the kinetic equation is derived from the stoichiometry, the participating species (e.g., proteins, mRNA or simple molecules) as well as the regulatory relations (activation, inhibition or other modulations) of the SBGN diagram. Such information allows distinctions between, for example, translation, phosphorylation or state transitions. The types of kinetics considered are numerous, for instance generalized mass-action, Hill, convenience and several Michaelis-Menten-based kinetics, each including activation and inhibition. These kinetics allow SBMLsqueezer to cover metabolic, gene regulatory, signal transduction and mixed networks. Whenever multiple kinetics are applicable to one reaction, parameter settings allow for user-defined specifications. After invoking SBMLsqueezer, the kinetic formulas are generated and assigned to the model, which can then be simulated in CellDesigner or with external ODE solvers. Furthermore, the equations can be exported to SBML, LaTeX or plain text format. SBMLsqueezer considers the annotation of all participating reactants, products and regulators when generating rate laws for reactions. Thus, for each reaction, only applicable kinetic formulas are considered. This modeling scheme creates kinetics in accordance with the diagrammatic representation. In contrast most previously published tools have relied on the stoichiometry and generic modulators of a reaction, thus ignoring and potentially conflicting with the information expressed through the process diagram. Additional material and the source code can be found at the project homepage (URL found in the Availability and requirements section).


Sequential studies of NK cell activity in human pregnancy.
We have assessed maternal NK cell function sequentially during and after 14 uncomplicated human pregnancies. As the pattern of response varied in different individuals, a single examination may not provide reliable information. Normally, there was depression of NK cell activity throughout pregnancy, most obvious in the first trimester. In one individual, no depression was seen at any stage. Cryopreservation of peripheral blood leucocytes had no effect on NK activity. In contrast to previous reports, we found no consistent effect of pregnancy serum or plasma on the NK cell activity of control normal lymphocytes.


Expectancy-induced placebo analgesia in children and the role of magical thinking.
Expectations and beliefs shape the experience of pain. This is most evident in context-induced, placebo analgesia, which has recently been shown to interact with the trait of magical thinking (MT) in adults. In children, placebo analgesia and the possible roles that MT and gender might play as modulators of placebo analgesia have remained unexplored. Using a paradigm in which heat pain stimuli were applied to both forearms, we investigated whether MT and gender can influence the magnitude of placebo analgesia in children. Participants were 49 right-handed children (aged 6-9 years) who were randomly assigned-stratified for MT and gender-to either an analgesia-expectation or a control-expectation condition. For both conditions, the placebo was a blue-colored hand disinfectant that was applied to the children's forearms. Independent of MT, the placebo treatment significantly increased both heat pain threshold and tolerance. The threshold placebo effect was more pronounced for girls than boys. In addition, independent of the expectation treatment, low-MT boys showed a lower tolerance increase on the left compared to the right side. Finally, MT specifically modulated tolerance on the right forearm side: Low-MT boys showed an increase, whereas high-MT boys showed a decrease in heat pain tolerance. This study documented a substantial expectation-induced placebo analgesia response in children (girls > boys) and demonstrated MT and gender-dependent laterality effects in pain perception. The findings may help improve individualized pain management for children. The study documents the first experimental evidence for a substantial expectancy-induced placebo analgesia response in healthy children aged 6 to 9 years (girls > boys). Moreover, the effect was substantially higher than the placebo response typically found in adults. The findings may help improve individualized pain management for children.


Preparation of glucagon-like peptide-1 loaded PLGA microspheres: characterizations, release studies and bioactivities in vitro/in vivo.
The gut hormone glucagon-like peptide-1 (GLP-1) is proposed for treatment of Type II diabetes mellitus. However, the short half life of GLP-1 in vivo is a major limitation for its application due to the frequent invasive administrations. To provide a optimal formulation to overcome this limitation, we developed a GLP-1 entrapped microspheres to achieve sustained release GLP-1 for 4-week. GLP-1 was stabilized by GLP-1-zinc complexation with zinc carbonate and encapsulated in poly(D,L-lactic-co-glycolic acid) (PLGA) with S/O/O solvent extraction to obtain GLP-1 loaded PLGA microspheres (MS). The characteristics of MS were evaluated as follows: The surface morphology was assessed by scanning electron microscopy (SEM); The drug encapsulation efficiency and GLP-1 controlled release profile was tested by HPLC; The sustained release of GLP-1 MS in vivo and pharmacological efficacy were studied in normal mice and streptozotocin (STZ)-induced diabetic mice model after subcutaneous administration of GLP-1 MS. GLP-1-zinc complexation significantly reduced initial burst release from 37.2 to 7.5%. The controlled release bioactive GLP-1 in vitro was achieved for 4-week period by zinc complexation and addition of ZnCO(3). The optimal and complete cumulative release of GLP-1 from MS was increased from 23 to 63% in 28 d by using low MW PLGA (MW 14000). The in vivo testing in normal mice and diabetic mice suggest that this zinc-stabilized technique combined with S/O/O method in the presence of water insoluble antacid additive ZnCO(3) preserve the biological activity of GLP-1. GLP-1 MS formulation achieved controlled released in vivo for 28 d and exhibit sustained long term pharmacological efficacy to decrease blood glucose level in diabetic mice. This GLP-1 MS formulation provides a practical formulation for long-term sustained delivery of GLP-1 to treat Type II diabetes.