Evaluating health risks from inhaled polychlorinated biphenyls: research needs for addressing uncertainty.
Indoor air concentrations of polychlorinated biphenyls (PCBs) in some buildings are one or more orders of magnitude higher than background levels. In response to this, efforts have been made to assess the potential health risk posed by inhaled PCBs. These efforts are hindered by uncertainties related to the characterization and assessment of source, exposure, and exposure-response. We briefly describe some common sources of PCBs in indoor air and estimate the contribution of inhalation exposure to total PCB exposure for select age groups. Next, we identify critical areas of research needed to improve assessment of exposure and exposure response for inhaled PCBs. Although the manufacture of PCBs was banned in the United States in 1979, many buildings constructed before then still contain potential sources of indoor air PCB contamination. In some indoor settings and for some age groups, inhalation may contribute more to total PCB exposure than any other route of exposure. PCB exposure has been associated with human health effects, but data specific to the inhalation route are scarce. To support exposure-response assessment, it is critical that future investigations of the health impacts of PCB inhalation carefully consider certain aspects of study design, including characterization of the PCB mixture present. In certain contexts, inhalation exposure to PCBs may contribute more to total PCB exposure than previously assumed. New epidemiological and toxicological studies addressing the potential health impacts of inhaled PCBs may be useful for quantifying exposure-response relationships and evaluating risks.


Evaluation of a flipped classroom approach to learning introductory epidemiology.
Although the flipped classroom model has been widely adopted in medical education, reports on its use in graduate-level public health programs are limited. This study describes the design, implementation, and evaluation of a flipped classroom redesign of an introductory epidemiology course and compares it to a traditional model. One hundred fifty Masters-level students enrolled in an introductory epidemiology course with a traditional format (in-person lecture and discussion section, at-home assignment; 2015, N = 72) and a flipped classroom format (at-home lecture, in-person discussion section and assignment; 2016, N = 78). Using mixed methods, we compared student characteristics, examination scores, and end-of-course evaluations of the 2016 flipped classroom format and the 2015 traditional format. Data on the flipped classroom format, including pre- and post-course surveys, open-ended questions, self-reports of section leader teaching practices, and classroom observations, were evaluated. There were no statistically significant differences in examination scores or students' assessment of the course between 2015 (traditional) and 2016 (flipped). In 2016, 57.1% (36) of respondents to the end-of-course evaluation found watching video lectures at home to have a positive impact on their time management. Open-ended survey responses indicated a number of strengths of the flipped classroom approach, including the freedom to watch pre-recorded lectures at any time and the ability of section leaders to clarify targeted concepts. Suggestions for improvement focused on ways to increase regular interaction with lecturers. There was no significant difference in students' performance on quantitative assessments comparing the traditional format to the flipped classroom format. The flipped format did allow for greater flexibility and applied learning opportunities at home and during discussion sections.


Fibrillar fibronectin plays a key role as nucleator of collagen I polymerization during macromolecular crowding-enhanced matrix assembly.
Macromolecular crowding is used by tissue engineers to accelerate extracellular matrix assembly in vitro, however, most mechanistic studies focus on the impact of crowding on collagen fiber assembly and largely ignore the highly abundant provisional matrix protein fibronectin. We show that the accelerated collagen I assembly as induced by the neutral crowding molecule Ficoll is regulated by cell access to fibronectin. Ficoll treatment leads to significant increases in the amount of surface adherent fibronectin, which can readily be harvested by cells to speed up fibrillogenesis. FRET studies reveal that Ficoll crowding also upregulates the total amount of fibronectin fibers in a low-tension state through upregulating fibronectin assembly. Since un-stretched fibronectin fibers have more collagen binding sites to nucleate the onset of collagen fibrillogenesis, our data suggest that the Ficoll-induced upregulation of low-tension fibronectin fibers contributes to enhanced collagen assembly in crowded conditions. In contrast, chemical cross-linking of fibronectin to the glass substrate prior to cell seeding prevents early force mediated fibronectin harvesting from the substrate and suppresses upregulation of collagen I assembly in the presence of Ficoll, even though the crowded environment is known to drive enzymatic cleavage of procollagen and collagen fiber formation. To show that our findings can be exploited for tissue engineering applications, we demonstrate that the addition of supplemental fibronectin in the form of an adsorbed coating markedly improves the speed of tissue formation under crowding conditions.


Evaluation of agomelatine for the treatment of sleep problems in adults with autism spectrum disorder and co-morbid intellectual disability.
Intellectual disability (ID) and autism spectrum disorder (ASD) are common, co-occurring developmental disorders and are frequently associated with sleep problems. This study aimed to assess the effectiveness and tolerability of agomelatine as a pharmacotherapy for sleep problems in ASD adults with ID. A randomised, crossover, triple-blind, placebo-controlled clinical trial, with two three-month periods of treatment starting with either agomelatine or placebo and a washout period of two weeks. Ambulatory circadian monitoring (24 hours/7 days) evaluated total sleep time (TST) as the primary outcome variable. Participants (N=23; 35±12 years old; 83% male) had a median of three (interquartile range (IQR) 1-4) co-morbidities and were taking a median of five (IQR 2-7) prescribed drugs. Before agomelatine or placebo treatment, all subjects presented with insomnia symptoms, including sleep latency (100% abnormal, 55±23 minutes) or TST (55% abnormal, 449±177 minutes), and 66% had circadian rhythm sleep-wake abnormalities with rhythm phase advancements according to the M5 sleep phase marker values. During the three-month agomelatine treatment, night TST significantly increased by a mean of 83 minutes (16% abnormal, 532±121 minutes), together with a phase correction (M5 1:45±2:28 hours vs. 3:15±2:20 hours), improving sleep stability in wrist temperature rhythm (0.43±0.29 vs. 0.52±0.18 AU). Adverse events were mild and transient. Agomelatine was effective and well tolerated for treating insomnia and circadian rhythm sleep problems present in adults with ASD and ID.


Role of tetrahydrobiopterin in the function of nitric oxide synthase, and its cytoprotective effect (Review).
This review discusses the role of (6R)-5,6,7,8-tetrahydrobiopterin (H4 biopterin) in the function of nitric oxide synthase (NOS), and the protective effect of H4 biopterin against nitric oxide (NO)- and/or reactive oxygen species-induced cytotoxicity. Although NOS releases NO, which regulates vascular tone and immune surveillance under normal conditions, NOS seems to produce superoxide anion and hydrogen peroxide when H4 biopterin, one of the cofactors, or L-arginine, a substrate, is decreased, suggesting the possibility that NOS is a source of reactive oxygen species under pathological conditions. Moreover, simultaneous release of NO and reactive oxygen species in the presence of suboptimal concentrations of H4 biopterin and/or L-arginine may be highly toxic, since NO reacts with superoxide anion and hydrogen peroxide to form peroxynitrite, singlet oxygen and the hydroxyl radical, which are toxic. An increase in H4 biopterin content in cells obviates NOS dysfunction (production of reactive oxygen species instead of NO) and protects the cells against NOS dysfunction-related cell injury. Moreover, H4 biopterin has a strong scavenging activity for reactive oxygen species, and inhibits thier cytotoxicity. H4 biopterin is also likely to reduce NO-induced cytotoxicity. Thus, H4 biopterin is not only an important regulator of NOS function, but is also an intracellular antioxidant. NO and reactive oxygen species are known to be implicated in the development of many pathological states. It is possible that H4 biopterin could be effective for treating many diseases, such as ischemia-reperfusion injury, inflammation and diabetes mellitus.


Identification of a Novel Serum Proteomic Signature for Primary Sjögren's Syndrome.
Primary Sjögren's syndrome (pSS) is a complex heterogeneous autoimmune disease (AID) which can mimic rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE). Our exploratory study investigated serum biomarkers that may discriminate pSS from RA and SLE. Serum concentrations of 63 biomarkers involved in immune cell trafficking, inflammatory response, cellular movement, and cell-to-cell signaling were measured in AID patients, included prospectively into the study at the Montpellier University Hospital. A multivariate analysis by multiple logistic regression was performed, and discriminative power assessed using logistic regression adjusted on significant demographic factors. Among the 95 patients enrolled, 42 suffered from pSS, 28 from RA, and 25 from SLE. Statistical analysis showed that concentrations of BDNF (OR = 0.493 with 95% CI [0.273-0.891]; p = 0.0193) and I-TAC/CXCL11 (OR = 1.344 with 95% CI [1.027-1.76]; p = 0.0314) can significantly discriminate pSS from RA. Similarly, greater concentrations of sCD163 (OR = 0.803 with 95% CI [0.649-0.994]; p = 0.0436), Fractalkine/CX3CL1 (OR = 0.534 with 95% CI [0.287-0. 991]; p = 0.0466), MCP-1/CCL2 (OR = 0.839 with 95% CI [0.732-0.962]; p = 0.0121), and TNFa (OR = 0.479 with 95% CI [0.247-0.928]; p = 0.0292) were associated with SLE diagnosis compared to pSS. In addition, the combination of low concentrations of BDNF and Fractalkine/CX3CL1 was highly specific for pSS (specificity 96.2%; positive predictive value 80%) compared to RA and SLE, as well as the combination of high concentrations of I-TAC/CXCL11 and low concentrations of sCD163 (specificity 98.1%; positive predictive value 75%). Our study highlights biomarkers potentially involved in pSS, RA, and SLE pathophysiology that could be useful for developing a pSS-specific diagnostic tool.


Plastic responses of leaves.
In their development leaves exhibit plastic responses in both shape and size. Variations in shape are often associated with changes in size also but the reverse is not always true. Plastic responses in leaf form resulting from ontogenetic or external influences are initiated very early in primordial development and are brought about by effects on the rate and direction of cell division and expansion in different regions of the primordium. Effects on leaf size are often induced over much longer periods including the phase of lamina expansion. In Phaseolus vulgaris the primary leaves exhibit increases in size when one of the pair is removed or when the stem is decapitated above the primary leaf node. These compensatory growth effects are not the result of a change in cell number but are caused by an increase in mean cell size. Cell wall extensibility is not increased by treatment and the evidence suggests that a small increase in the (turgor-wall yield stress) term may be the cause of the very rapid response to defoliation. The usefulness of leaf systems for the analysis of plastic responses of shape and size is indicated and the importance of a better understanding of the factors determining the siting and development of the cell wall is stressed.


The relationship between acute alcohol consumption and consequent injury type.
The aim of this study was to quantify the relationship between acute alcohol consumption and injury type (nature of injury, body region injured), while adjusting for the effect of known confounders (i.e. demographic and situational variables, usual drinking patterns, substance use and risk-taking behaviour). A cross-sectional study was conducted between October, 2000 and October, 2001 of patients aged >or=15 years presenting to a Queensland Emergency Department for treatment of an injury sustained in the preceding 24 h. There were three measures of acute alcohol consumption: drinking setting, quantity, and beverage type consumed in the 6 h prior to injury. Two variables were used to quantify injury type: nature of injury (fracture/dislocation, superficial, internal, and CNS injury) and body part injured (head/neck, facial, chest, abdominal, external, and extremities). Both were derived from patient medical records. Five hundred and ninety three patients were interviewed. Logistic regression analyses indicated that, after controlling for relevant confounding variables, there was no significant association between any of the three measures of acute alcohol consumption and injury type. The effects of acute alcohol consumption are not specific to injury type. Interventions aimed at reducing the incidence of alcohol-related injury should not be targeted at specific injury types.


The Clinical Characteristics and Outcomes of Infantile Seizures in the First Year of Life: A Single-Center Study.
Epilepsy has a high incidence among infants during their first year of life, yet the prognosis can vary significantly. Although considerable research has been conducted on infantile spasms, studies examining infantile-onset epilepsy, excluding infantile spasms, remain limited, particularly concerning the factors influencing outcomes. Therefore, our study aims to elucidate seizure control, developmental outcomes, and prognostic factors in infants with epilepsy during their first year of life, within a single-center study in Malaysia. We retrieved data from patients who experienced seizures before age 12 months and were followed for over two years, using electronic patient records at Hospital Raja Perempuan Zainab II in Kelantan, a state in Malaysia's east coast. We retrospectively reviewed these records and assessed clinical outcomes based on the last follow-up. Of 75 patients, 61 (81.3%) achieved good seizure control or remission. At the last follow-up, 24 (32%) exhibited developmental delay, whereas 19 (25.3%) displayed abnormal neuroimaging. Patients with abnormal background electroencephalographic (EEG) activity, as well as abnormal radiological findings, were more likely to experience poor seizure control and unfavorable developmental outcomes (P < 0.05). Our study underscores that most infants with epilepsy can achieve seizure remission. However, poor seizure control and developmental delay are associated with abnormal EEG background and characteristics, as well as neuroimaging abnormalities. The management of infantile-onset epilepsies may necessitate substantial resources and precise interventions to enhance overall outcomes.


Postoperative chemoradiotherapy in high risk locally advanced gastric cancer.
To evaluate treatment outcome of patients with high risk locally advanced gastric cancer after postoperative chemoradiotherapy. Between May 2003 and May 2012, thirteen patients who underwent postoperative chemoradiotherapy for gastric cancer with resection margin involvement or adjacent structure invasion were retrospectively analyzed. Concurrent chemotherapy was administered in 10 patients. Median dose of radiation was 50.4 Gy (range, 45 to 55.8 Gy). The median follow-up duration for surviving patients was 48 months (range, 5 to 108 months). The 5-year overall survival rate was 42% and the 5-year disease-free survival rate was 28%. Major pattern of failure was peritoneal seeding with 46%. Locoregional recurrence was reported in only one patient. Grade 2 or higher gastrointestinal toxicity occurred in 54% of the patients. However, there was only one patient with higher than grade 3 toxicity. Despite reported suggested role of adjuvant radiotherapy with combination chemotherapy in gastric cancer, only very small portion of the patients underwent the treatment. Results from this study show that postoperative chemoradiotherapy provided excellent locoregional control with acceptable and manageable treatment related toxicity in patients with high risk locally advanced gastric cancer. Thus, postoperative chemoradiotherapy may improve treatment result in terms of locoregional control in these high risk patients. However, as these findings are based on small series, validation with larger cohort is suggested.


Multilevel modeling of geographically distributed vitamin A deficiency.
Vitamin A deficiency is a common health problem in developing countries like India. Present study involves data on children aged between 6-36 months from northern part of India collected geographically, to find prevalence and important factors for risk of nightblindness. Both traditional logistic models and multilevel logistic models were applied to achieve our aim. All Individual level variables vitamin A diet intake, age, vitamin A capsule intake and awareness about vitamin A were found significant for risk of night-blindness (p < 0.05) in individual level analysis. The effect of risk factors for night-blindness was smaller in multilevel modeling as compared to individual level model. The reason is that the previous model takes into account the within-block as well as among-block variations. Multilevel analysis, did not find, individual level variables vitamin A diet intake, awareness of vitamin A and vitamin A capsule intake significant for the outcome variable (p > 0.10). There was about 139% change in odd-ratio for vitamin A capsule taken once. Block level variable, average age of subjects in blocks comes out as significant factor (p = 0.01) for night-blindness. Thus, this paper demonstrates the usefulness of multilevel modeling in the analysis for epidemiology of disease risk, which is structured in a hierarchiary, with particular reference to geographical analyses of small area data.


p53 protein expression and CA19.9 values in differential cytological diagnosis of pancreatic cancer complicated with chronic pancreatitis and chronic pancreatitis.
To evaluate p53 protein overexpression and to measure serum CA19.9 concentrations in cytological diagnosis of patients with suspected pancreatic cancer. 24 patients with suspected pancreatic cancer due to chronic pancreatitis, had a pancreatic mass determined by imaging methods. The serum CA19.9 concentration was measured by solid phase radioimmunoassay. On laparotomy, puncture biopsy was performed, and specimens were divided into two parts for cytological diagnosis and detection of p53 protein. Cytology offered a sensitivity of 0.63, a specificity of 1.00, and an accuracy of 0.63. p53 protein analysis offered a sensitivity of 0.44, a specificity of 1.00, and an accuracy of 0.73. CA19.9 offered a sensitivity of 0.44, a specificity of 0.80, and an accuracy of 0.67. The combined cytology and p53 protein analysis showed a sensitivity of 0.78, a specificity of 1.00, and an accuracy of 0.92. Cytology and CA19.9 showed a sensitivity of 0.67, a specificity of 0.80, an accuracy of 0.67. combined cytology and p53 protein analysis and CA19.9 showed a sensitivity of 0.78, a specificity of 0.80,and an accuracy of 0.79. Superior to any single test, the combined approach is helpful for the differential diagnosis of pancreatic cancer complicated with chronic pancreatitis. The combined cytology and p53 protein analysis offers the best diagnostic efficacy.


Quantitative structure activity analysis of 2-alkoxydihydrocinnamates as PPARalpha/gamma dual agonist.
To optimize the physiochemical properties of 2-alkoxydihydrocinnamates as PPARalpha/gamma dual agonist, a quantitative structure activity relationship, Hansch approach was made using combination of various thermodynamic, electronic and spatial descriptors. Several regression expressions are obtained using multiple linear regression analysis. The best QSAR model is further validated by leave-one-out cross validation method. Analyses of results from the present QSAR study suggest that for favorable dual PPARalpha/gamma agonist activity electronic property of the substituents in hydrophobic tail phenyl ring plays a key role. The contribution of Hammett constant and dipole moment in the models deduced the importance of electron withdrawing substituents for dual activity. Additionally the study also indicates that bulky substituents in head acid moiety not confer selectivity towards the PPAR activity. Thus the QSAR study brings important structural insight to aid the design of dual PPARalpha/gamma receptor agonist.


SARS-CoV-2 hijacks fragile X mental retardation proteins for efficient infection.
Viruses interact with numerous host factors to facilitate viral replication and to dampen antiviral defense mechanisms. We currently have a limited mechanistic understanding of how SARS-CoV-2 binds host factors and the functional role of these interactions. Here, we uncover a novel interaction between the viral NSP3 protein and the fragile X mental retardation proteins (FMRPs: FMR1 and FXR1-2). SARS-CoV-2 NSP3 mutant viruses preventing FMRP binding have attenuated replication in vitro and have delayed disease onset in vivo. We show that a unique peptide motif in NSP3 binds directly to the two central KH domains of FMRPs and that this interaction is disrupted by the I304N mutation found in a patient with fragile X syndrome. NSP3 binding to FMRPs disrupts their interaction with the stress granule component UBAP2L through direct competition with a peptide motif in UBAP2L to prevent FMRP incorporation into stress granules. Collectively, our results provide novel insight into how SARS-CoV-2 hijacks host cell proteins for efficient infection and provides molecular insight to the possible underlying molecular defects in fragile X syndrome.


Imaging cerebral 2-ketoisocaproate metabolism with hyperpolarized (13)C magnetic resonance spectroscopic imaging.
The branched chain amino acid transaminase (BCAT) has an important role in nitrogen shuttling and glutamate metabolism in the brain. The purpose of this study was to describe the cerebral distribution and metabolism of hyperpolarized 2-keto[1-(13)C]isocaproate (KIC) in the normal rat using magnetic resonance modalities. Hyperpolarized KIC is metabolized to [1-(13)C]leucine (leucine) by BCAT. The results show that KIC and its metabolic product, leucine, are present at imageable quantities 20 seconds after end of KIC administration throughout the brain. Further, significantly higher metabolism was observed in hippocampal regions compared with the muscle tissue. In conclusion, the cerebral metabolism of hyperpolarized KIC is imaged and hyperpolarized KIC may be a promising substrate for evaluation of cerebral BCAT activity in conjunction with neurodegenerative disease.


[Biological features and problems in detection of extrapulmonary tuberculosis pathogen].
The viability, enzymatic activity and Mycobacterium tuberculosis drug resistance was compared in pulmonary and extrapulmonary tuberculosis. To decrease oxygen in the culture medium baseline values and to use various oxidants as protectors were shown to be promising in enhancing the efficiency of cultural diagnosis of extrapulmonary tuberculosis.


Lung volume equipment and infection control. ERS/ATS Workshop Report Series. European Respiratory Society/American Thoracic Society.
As part of the consensus workshop regarding lung volume measurements for the American Thoracic Society and European Respiratory Society, this background paper reviews mechanisms and risks of cross-infection resultant from performing measurements of absolute lung volumes either by body plethysmography, gas dilution, or gas wash-out techniques. Published reports of infection attributable to the performance of lung volume measurements are extremely rare. Nevertheless, because some infectious agents could be transmitted during measurements of lung volumes, and because of widespread concerns both of patients and some medical personnel about the risks of transmission of infections during inspiration from equipment used by other patients, a variety of measures have been advocated to minimize the risks of cross-infection. Workshop participants were divided in opinion about whether such testing does indeed pose significant risk of cross-infection, and also could not agree regarding optimal measures to prevent cross-infection. Although there is conflicting information regarding the efficacy of particulate filters for protecting cross-contamination of downstream equipment and tubing, the author recommends that such filters be used when making lung volume measurements, but only if the filter has acceptably low resistance (e.g. <0.15 kPa x L(-1) x s (1.5 cmH2O x L(-1) x s)), and the measurements are adjusted for the impact of the added resistance and dead space.


Integrative relational machine-learning for understanding drug side-effect profiles.
Drug side effects represent a common reason for stopping drug development during clinical trials. Improving our ability to understand drug side effects is necessary to reduce attrition rates during drug development as well as the risk of discovering novel side effects in available drugs. Today, most investigations deal with isolated side effects and overlook possible redundancy and their frequent co-occurrence. In this work, drug annotations are collected from SIDER and DrugBank databases. Terms describing individual side effects reported in SIDER are clustered with a semantic similarity measure into term clusters (TCs). Maximal frequent itemsets are extracted from the resulting drug x TC binary table, leading to the identification of what we call side-effect profiles (SEPs). A SEP is defined as the longest combination of TCs which are shared by a significant number of drugs. Frequent SEPs are explored on the basis of integrated drug and target descriptors using two machine learning methods: decision-trees and inductive-logic programming. Although both methods yield explicit models, inductive-logic programming method performs relational learning and is able to exploit not only drug properties but also background knowledge. Learning efficiency is evaluated by cross-validation and direct testing with new molecules. Comparison of the two machine-learning methods shows that the inductive-logic-programming method displays a greater sensitivity than decision trees and successfully exploit background knowledge such as functional annotations and pathways of drug targets, thereby producing rich and expressive rules. All models and theories are available on a dedicated web site. Side effect profiles covering significant number of drugs have been extracted from a drug ×side-effect association table. Integration of background knowledge concerning both chemical and biological spaces has been combined with a relational learning method for discovering rules which explicitly characterize drug-SEP associations. These rules are successfully used for predicting SEPs associated with new drugs.


[Glutaminergic hypothesis of schizophrenia: clinical research studies with ketamine].
Several lines of evidence suggest that the glutamatergic N-methyl-D-aspartate (NMDA) receptor is involved in schizophrenia pathophysiology. Post-mortem studies have revealed a lower density of glutamatergic receptors in patients with schizophrenia. Other studies of cerebrospinal fluid reported lower levels of glutamate in patients with schizophrenia in healthy comparison subjects. The most compelling evidence is provided by the psychomimetic effects of the NMDA antagonists phencyclidine and ketamine. Recently, much interest has been given to the study related to the role of NMDA receptor in pathophysiology of schizophrenia by administration of sub-anesthetic doses of ketamine. A phencyclidine hydrochloride derivate, ketamine, is a dissociative anesthetic and a non competitive antagonist of the NMDA receptor. In healthy subjects, ketamine produces: 1) positive symptoms of psychosis, such as illusions, thought disorder and delusions; 2) negative symptoms similar to those associated with schizophrenia including blunted emotional responses, emotional detachment, and psychomotor retardation; 3) cognitive impairments, in particular impairments on tests of frontal cortical function including increased distractibility, reduced verbal fluency and poorer performance on the Wisconsin Card Sorting Test. During smooth pursuit eye tracking, ketamine induces nystagmus as well as abnormalities which are among the characteristics of schizophrenia. In patients with schizophrenia, the administration of ketamine produces an activation of their psychotic symptoms, which have striking similarities to symptoms of their usual psychotic episodes. Ketamine effects on memory and other cognitive functions in schizophrenic patients are controversial. The psychomimetic effects of ketamine are transitional, reversible and influenced by time, dose and administration conditions. Susceptibility to the psychotomimetic effects of ketamine is minimal or absent in children and becomes maximal in early adulthood. The similarity between ketamine effects and endogenous psychoses created interest in the capacity of antipsychotic medications to block ketamine effects. Haloperidol failed to block this ketamine-induced psychomimetic effects in healthy subjects and in schizophrenic patients. However, clozapine, the prototype of atypical antipsychotic agents significantly reduced the ketamine-induced increase in positive symptoms in schizophrenic patients. Recently, lamotrigine significantly decreased ketamine-induced positive and negative symptoms in healthy subjects. Brain regions responsible for NMDA-mediated psychosis have not been established. Using positron emission tomography and [18F] fluorodeoxyglucose, the sub-anesthetic ketamine administration produces bilateral increases in metabolic activity in the prefrontal cortex. In a [15O] H2O positron emission tomography study, ketamine selectively increases cerebral blood flow in the anterior cingulate cortex and reduces cerebral blood flow in the hippocampus and primary visual cortex. The mechanism of neuropsychiatric effects of sub-anesthetic ketamine is not clear. A dysfunction in glutamate-dopaminergic interactions has been suggested as a mechanism for these effects of ketamine. Ketamine has been reported to primarily block NMDA receptor complex giving support to a glutamate deficiency hypothesis in schizophrenia. In addition, ketamine caused increases in cortical and striatal synaptic dopamine concentrations. The effects of NMDA receptor antagonist administration are argued to support a neurobiological hypothesis of schizophrenia, which includes pathophysiology within several neurotransmitter systems, manifested in behavioral pathology. Pharmacological modulation of the effects of NMDA receptor antagonists, such as ketamine, may lead to development of novel therapeutic agents for psychiatric illnesses such as schizophrenia.


Advances towards circular economy policies in the EU: The new Ecodesign regulation of enterprise servers.
The concept of a circular economy has been widely accepted by governments and industries. In Europe, the European Commission adopted the Circular Economy package in 2015. The Ecodesign Directive has been identified as one of the most suitable legislative tools for achieving some of the objectives in the package because it has the potential to translate the circular economy principles into specific product material efficiency requirements. This paper applies the Ecodesign policy process to "enterprise servers" to illustrate how circular economy strategies can be implemented by European product policies. Indeed, the paper introduces a potential novel approach to "operationalize" circular economy principles in product policies. The evolution of the material efficiency requirements for a more circular economy is described up to their final formulation, which is the one in the published Ecodesign regulation. This legal act includes requirements on design for disassembly, firmware availability, data deletion, and presence of critical raw materials. The process for enterprise servers has been successful as the early discussions between stakeholders, policymakers and experts, supported by appropriate metrics along an iterative debate, comes to the publications of material efficiency requirements in a regulation. This study represents a 'first-of-a-kind' experience, and sets precedents for the development of similar requirements for other product groups.


Telephone-guided self-help for mental health difficulties in neurological conditions: a randomised pilot trial.
This study aimed to conduct a randomised pilot trial to assess the feasibility of a randomised controlled trial (RCT) to investigate the effect of telephone-guided self-help for the treatment of mental health difficulties in children with neurological conditions. Preliminary RCT. The primary outcome measure was the Strengths and Difficulties Questionnaire. Neurology clinics in a national tertiary paediatric hospital. Young people attending neurology clinics who met criteria for mental health difficulties according to the Development and Wellbeing Assessment. 12 weeks of telephone-guided self-help based on a modular approach to psychological therapy for children delivered to children and/or their parents (n=17; eight males; mean age 12.04 years, SD=3.34) or a waiting list for telephone-guided self-help with no additional intervention over 12 weeks (n=17; nine males; mean age 10.53 years, SD=3.14). 124 participants completed the DAWBA, and 34 children and young people were entered into the trial. 65% of those randomised to the intervention arm completed the full intervention, and the intervention was acceptable to those completing it. However, there were significant problems related to lack of data completion (38% data loss for primary outcome measure), choice of control comparator and outcome measures. Due to significant loss of data at follow-up, the effect size findings are considered unreliable. Further feasibility work should be conducted to improve data completeness before progression to a definitive trial of guided self-help for mental health problems in children with neurological conditions can be recommended. ISRCTN21184717.


Chelating agents for the sequestration of mercury(II) and monomethyl mercury(II).
Both mercury(II) and monomethyl mercury(II) poisonings are of great concern for several reasons. As it happens for other metals, chelation therapy is the most indicated treatment for poisoned patients. The efficacy of the therapy and the reduction of side-effects can be sensibly enhanced by an accurate knowledge of all the physiological mechanisms involved in metal uptake, transport within and between various tissues, and (possibly) clearance. All these aspects, however, are strictly dependent on the chemical speciation (i.e., the distribution of the chemical species of a component in a given system) of both the metal and the chelating agent in the systems where they are present. In this light, this review analyzes the state of the art of research performed in this field for mercury(II) and methylmercury(II). After a brief summary of their main sources, the physiological patterns for the treatment of mercury poisoning have also been considered. The binding ability of various chelating agents toward mercury has been then analyzed by modeling the behavior of the main classes of ligands present in biological fluids and/or frequently used in chelation therapy. Their sequestering ability has been successively evaluated by means of a semiempirical parameter already proposed for its objective quantification, and the main characteristics of an efficient chelating agent have been evaluated on this basis.


Effect of Encapsulation Techniques on Aroma Retention of Pistacia terebinthus L. Fruit Oil: Spray Drying, Spray Freeze Drying, and Freeze Drying.
The primary aim of this investigation was to assess the impact of varying the ratio of gum arabic to maltodextrin and employing diverse encapsulation techniques on the properties of the powdered substance and the capacity to retain the aromatic attributes of terebinth fruit oil. Distinct ratios of gum arabic to maltodextrin (75:25, 50:50, and 25:75) were employed to fabricate oil-in-water emulsions. The utmost stability of the emulsion was realized at a gum arabic to maltodextrin ratio of 75:25, characterized by a minimal creaming index and an even and small-scale dispersion. The encapsulation techniques employed included spray drying (SD), spray freeze-drying (SFD), and freeze-drying (FD). These methodologies were compared based on encapsulation efficiency, desiccation yield, powder attributes, and the capacity to retain aroma. The encapsulation efficiencies were notably higher (>90%) in SD, particularly with the application of an ultrasonic nozzle and a two-fluidized nozzle (2FN), in contrast to those obtained through SFD and FD. Notably, SD employing an ultrasonic nozzle exhibited superior preservation of volatiles (73.19%) compared to FD (24.45%), SD-2FN (62.34%), and SFD (14.23%). Among the various components, α-pinene and linalool stood out with near-perfect retention rates, close to 100%.


[Tuberculosis treatment drop out prevalence and associated factors in Sapucaia do Sul County (RS), Brazil, 2000-2008].
To estimate the Tuberculosis treatment drop out prevalence and the variables associated in the patients registered in the Tuberculosis Control Program in Sapucaia do Sul (Brazil), between 2000 and 2008. A cross-sectional study was conducted, which was based on the notified data in Information System for Disease Surveillance of the City Health Secretariat. From the 632 cases included in the study, 65 (10.3%; CI95%=7.9-12.7) were classified as treatment abandonment. Between 2000 and 2004, the prevalence of noncompliance was 12.7% (95%CI=9.1-16.2), and in the period 2005 to 2008 decreased to 7.0% (95%CI=4.0-9.9). In the crude analysis, we find association with sex, age and AIDS presence. The adjusted analysis with the Poisson regression didn't show significant differences between the independent variables. The analysis showed reduction in the prevalence of noncompliance with the creation of Tuberculosis Control Program, from 2005, although the confidence intervals are shown superimposed. Still, the prevalence of noncompliance was high and stove above the 5% target, agreed between levels of government.


Transcriptional collision between convergent genes in budding yeast.
Transcriptional interference between genes and the regulatory elements of simple eukaryotes such as Saccharomyces cerevisiae is an unavoidable consequence of their compressed genetic arrangement. We have shown previously that with the tandem arranged genes GAL10 and GAL7, inefficient transcriptional termination of the upstream gene inhibits initiation of transcription on the downstream gene. We now show that transcriptional interference can occur also with S. cerevisiae RNA polymerase II genes arranged convergently. We demonstrate that when the GAL10 and GAL7 genes are rearranged in a convergent orientation, transcriptional initiation occurs at full levels. However, as soon as the two transcripts begin to overlap, elongation is restricted, resulting in a severe reduction in steady-state mRNA accumulation. This effect is observed only in cis arrangement, arguing against RNA-interference effects acting on the potential generation of antisense transcripts. These data reinforce the necessity of separating adjacent RNA polymerase II transcription units by efficient termination signals.


Functional consensus for mammalian osmotic response elements.
The molecular mechanisms underlying adaptation to hyperosmotic stress through the accumulation of organic osmolytes are largely unknown. Yet, among organisms, this is an almost universal phenomenon. In mammals, the cells of the renal medulla are uniquely exposed to high and variable salt concentrations; in response, renal cells accumulate the osmolyte sorbitol through increased transcription of the aldose reductase (AR) gene. In cloning the rabbit AR gene, we found the first evidence of an osmotic response region in a eukaryotic gene. More recently, we functionally defined a minimal essential osmotic response element (ORE) having the sequence CGGAAAATCAC(C) (bp -1105 to -1094). In the present study, we systematically replaced each base with every other possible nucleotide and tested the resulting sequences individually in reporter gene constructs. Additionally, we categorized hyperosmotic response by electrophoretic mobility shift assays of a 17-bp sequence (-1108 to -1092) containing the native ORE as a probe against which the test constructs would compete for binding. In this manner, binding activity was assessed for the full range of osmotic responses obtained. Thus we have arrived at a functional consensus for the mammalian ORE, NGGAAAWDHMC(N). This finding should accelerate the discovery of genes previously unrecognized as being osmotically regulated.


Novel configuration for an enhanced and compact all-fiber Faraday rotator with matched birefringence.
We propose a novel configuration for an improved and compact all fiber Faraday rotator based on phase matching between the Faraday rotation and bend-induced birefringence. The device utilizes a coiled fiber within two electro-magnetic toroids, such that the fiber length required for getting the beat length is quite long and several rounds of fiber are needed. Analysis of the capabilities of the proposed device and its sensitivity to different parameters is presented. Faraday rotation of 13° was experimentally measured in six meters of single mode silica fiber, with a magnetic field of about 0.06T at a wavelength of 1064nm. We show that phase matching between the two phenomena significantly improves the polarization rotation by a factor of 4-10. In addition, we demonstrate the ability to achieve higher rotation by using Fabry Perot resonator in low terbium doped glass.


Chromatin conformations of HSP12 during transcriptional activation in the Saccharomyces cerevisiae stationary phase.
During evolution, living cells have developed sophisticated molecular and physiological processes to cope with a variety of stressors. These mechanisms, which collectively constitute the Environmental Stress Response, involve the activation/repression of hundreds of genes that are regulated to respond rapidly and effectively to protect the cell. The main stressors include sudden increases in environmental temperature and osmolarity, exposure to heavy metals, nutrient limitation, ROS accumulation, and protein-damaging events. The growth stages of the yeast S. cerevisiae proceed from the exponential to the diauxic phase, finally reaching the stationary phase. It is in this latter phase that the main stressor events are more active. In the present work, we aim to understand whether the responses evoked by the sudden onset of a stressor, like what happens to cells going through the stationary phase, would be different or similar to those induced by a gradual increase in the same stimulus. To this aim, we studied the expression of the HSP12 gene of the HSP family of proteins, typically induced by stress conditions, with a focus on the role of chromatin in this regulation. Analyses of nucleosome occupancy and three-dimensional chromatin conformation suggest the activation of a different response pathway upon a sudden vs a gradual onset of a stress stimulus. Here we show that it is the three-dimensional chromatin structure of HSP12, rather than nucleosome remodeling, that becomes altered in HSP12 transcription during the stationary phase.


The COVID-19 Pandemic and Ophthalmic Care: A Qualitative Study of Patients with Neovascular Age-Related Macular Degeneration (nAMD).
Concerns have been expressed about the relationship between reduced levels of health care utilisation and the COVID-19 pandemic. This study aimed to elicit and explore the views of patients with neovascular age-related macular degeneration (nAMD) regarding the COVID-19 pandemic and their ophthalmic care. Semi-structured telephone interviews were conducted with thirty-five patients with nAMD taking part in a larger diagnostic accuracy study of home-monitoring tests. Participants were recruited using maximum variation sampling to capture a range of key characteristics including age, gender and time since initial treatment. Transcribed interview data were analysed using a deductive and inductive thematic approach. Three themes emerged from the analysis: i. access to eye clinic care. ii. COVID-19-mitigating factors and care delivery and iii. social and personal circumstances. Participants reported anxieties about cancelled or delayed appointments, limited communication from clinic-based services about appointments, and the impact of this on their ongoing care. Despite these concerns, there was apprehension about attending appointments due to infection risk and a perception that nAMD patients are a 'high risk' group. Views of those who attended clinics during the study period were, however, positive, with social distancing and infection control measures providing reassurance. These findings contribute to our understanding about experiences of patients with nAMD during the COVID-19 pandemic and may have potential implications for future planning of care services in similar circumstances. Innovative approaches may be required to address issues related to access to care, including concerns about delayed or cancelled appointments.


Interleukin-41 as a biomarker of the anti-inflammatory response associated with hyperuricemia.
Interleukin (IL)-41 is a recently discovered secreted protein that is expressed in a variety of tissues, and it is associated with several immune and metabolic diseases. However, IL-41 has not been studied in hyperuricemia (HUA). Forty-four HUA patients and 44 healthy controls (HCs) were included in this study, and we collected theirgeneral and biochemical parameters, including white blood cell, neutrophil, lymphocyte, and platelet counts, mean platelet volume, platelet distribution width, serum creatinine, blood urea nitrogen, fasting blood glucose, total triglyceride, total cholesterol, high-density lipoprotein, low-density lipoprotein, total protein, albumin, alkaline phosphatase, gamma-glutamyltransferase, and hemoglobin concentration. The level of serum IL-41 was determined using an enzyme-linked immunosorbent assay. Multivariate logistic regression analysis was exploited to identify the independent risk factors associated with HUA, and the clinical diagnostic value of IL-41 was analyzed by applying the receiver operating characteristic (ROC) curve. We assessed the association between IL-41 and clinical parameters with Spearman's rank correlation. Circulating IL-41 levels were significantly higher in HUA patients than in the HCs group (460.3 pg/mL vs. 261.3 pg/mL, respectively; P < 0.001). The area under the ROC curve (AUC) for IL-41 in HUA patients was 0.7443 (with a cut-off value of 311.055 pg/mL, a sensitivity of 68.18 %, and a specificity of 72.73 %), while the AUC for IL-41 combined with the platelet count was 0.8109. Correlation analysis revealed that the circulating IL-41 level was positively correlated with age in HCs and HUA patients. We herein demonstrated that serum IL-41 was elevated in HUA patients and that it may constitute a novel biomarker of anti-inflammatory response related to HUA.


Applications of tunable resistive pulse sensing.
Tunable resistive pulse sensing (TRPS) is an experimental technique that has been used to study and characterise colloidal particles ranging from approximately 50 nm in diameter up to the size of cells. The primary aim of this Review is to provide a guide to the characteristics and roles of TRPS in recent applied research. Relevant studies reflect both the maturation of the technique and the growing importance of submicron colloids in fields such as nanomedicine and biotechnology. TRPS analysis of extracellular vesicles is expanding particularly swiftly, while TRPS studies also extend to on-bead assays using DNA and aptamers, drug delivery particles, viruses and bacteria, food and beverages, and superparamagnetic beads. General protocols for TRPS measurement of particle size, concentration and charge have been developed, and a summary of TRPS technology and associated analysis techniques is included in this Review.


Cardioprotective effect of curcumin and piperine combination against cyclophosphamide-induced cardiotoxicity.
Curcumin is a well-established cardioprotective phytoconstituent, but the poor bioavailability associated with it is always a matter of therapeutic challenge. The present study was undertaken to increase the therapeutic efficacy of curcumin by combining with bio-enhancer like piperine against cyclophosphamide (CP)-induced cardiotoxicity in rats. Rats (n = 8) were treated with curcumin (200 mg/kg, p.o.) alone and different dose combination of curcumin (100, 50, 25 mg/kg, p.o.) and piperine (20 mg/kg, p.o.) for 10 days. All the treated groups were subjected to CP (200 mg/kg, i.p.) toxicity on day 1. Twenty-four hours after the last treatment, the effects were evaluated by changes in electrocardiographic (ECG) parameters, serum biomarkers, lipid profile, tissue antioxidants, and histopathological examination. Serum and tissue homogenate parameters were measured by semi-autoanalyzer and spectrophotometer, respectively. Results obtained were assessed by one-way analysis of variance followed by Tukey-Karmer multiple comparison test. Incorporation of piperine with the doses of 50 and 25 mg/kg with curcumin exhibited significant beneficial effect compared to curcumin alone-treated group. The best effective group was a combination of curcumin 50 mg/kg with piperine 20 mg/kg which showed extremely significant (P < 0.001) decrease and increase in ECG and serum biomarker level, respectively, and moderate significant (P < 0.01) decrease in lipid profile, antioxidant levels, and histopathological score, compared to curcumin alone-treated group. From this study, it can be concluded that a novel dose combination of curcumin (50 mg/kg) with piperine (20 mg/kg) exhibited profound cardioprotection compared to curcumin (200 mg/kg) alone-treated group.


Structure of an insect delta-class glutathione S-transferase from a DDT-resistant strain of the malaria vector Anopheles gambiae.
Glutathione S-transferases (GSTs) are a major family of detoxification enzymes which possess a wide range of substrate specificities. Most organisms possess many GSTs belonging to multiple classes. Interest in GSTs in insects is focused on their role in insecticide resistance; many resistant insects have elevated levels of GST activity. In the malaria vector Anopheles gambiae, elevated GST levels are associated with resistance to the organochlorine insecticide DDT [1,1,1-trichloro-2,2-bis-(p-chlorophenyl)ethane]. This mosquito is the source of an insect GST, agGSTd1-6, which metabolizes DDT and is inhibited by a number of pyrethroid insecticides. The crystal structure of agGSTd1-6 in complex with its inhibitor S-hexyl glutathione has been determined and refined at 2.0 A resolution. The structure adopts a classical GST fold and is similar to those of other insect delta-class GSTs, implying a common conjugation mechanism. A structure-based model for the binding of DDT to agGSTd1-6 reveals two subpockets in the hydrophobic binding site (H-site), each accommodating one planar p-chlorophenyl ring.


Bibliometrix analysis of medical tourism.
Medical tourism is an expanding phenomenon. Scientific studies address the changes and challenges of the present and future trend. However, no research considers the study of bibliometric variables and area of business, management and accounting. This bibliometric analysis discovered the following elements: (1) The main articles are based on guest services, management, leadership principles applied, hotel services associated with healthcare, marketing variables and elements that guide the choice in medical tourism; (2) The main authors do not deal with tourism but are involved in various ways in the national health system of the countries of origin or in WHO; (3)cost-efficiency and analytical accounting linked to medical tourism structures and destination choices are not yet developed topics.


Global fishery development patterns are driven by profit but not trophic level.
Successful ocean management needs to consider not only fishing impacts but drivers of harvest. Consolidating post-1950 global catch and economic data, we assess which attributes of fisheries are good indicators for fishery development. Surprisingly, year of development and economic value are not correlated with fishery trophic levels. Instead, patterns emerge of profit-driven fishing for attributes related to costs and revenues. Post-1950 fisheries initially developed on shallow ranging species with large catch, high price, and big body size, and then expanded to less desirable species. Revenues expected from developed fisheries declined 95% from 1951 to 1999, and few high catch or valuable fishing opportunities remain. These results highlight the importance of economic attributes of species as leading indicators for harvest-related impacts in ocean ecosystems.


[The catamnesis of children with celiac disease].
A prospective follow-up was conducted of 29 patients with celiac disease 3 to 10 years in duration. Of these, 8 were on a spare agluten diet, in whom the time-related course of clinical manifestations of the illness was characterized by stabilization of the primary symptoms of disturbed intestinal absorption, improvement in the psychoemotional state at year of their prophylactic management. The glucose tolerance test had gotten normalized after two years of being on a spare diet, lactose tolerance test remaining below the normal range in 37.5 percent of cases at year 3 of the observation, with the content of IgG antibodies to gliadine exceeding the threshold values in 33.3% on an average three times as much as the norm. In those patients having not been on a spare diet, retardation in physical development was recordable together with bone abnormalities manifested by pathologic fractures of the tubular bones. The level of anti-gliadine antibodies of both classes was found to be augmented in 71.4 percent of cases, their values having been fifty times as much as the norm. Glucose tolerance test suggested to us a steady decline in the absorption that was still to be seen at year 10 of the prospective follow-up. Lactase intolerance was somewhat less, remaining at lower values in the half of the patient population.


["MEDDOS", a computer program for constructing treatment plans in pediatric intensive care units].
We attempted to facilitate the establishment of treatment regimens in paediatric intensive care units by means of a computer programme and to increase drug safety by standardization of dosage and avoidance of calculation errors. The programme has the following features: the user can enter drugs, oral nutrition and i.v. solutions into data files. Drugs and solutions can be chosen from these data files for the individual patient. Drug dosage is calculated from preselected dosages and the patient's data for individual dosage regimens. The desired intake of fluid volume and glucose can be chosen. Due to this preselection the quantity and concentration of the glucose solution is calculated. The total daily intake of electrolytes, calories, carbohydrates, protein and fat is shown on a balance sheet. Complete schedules can be saved and, if needed, restored for other patients.


Multivariate analysis of tronchuda cabbage (Brassica oleracea L. var. costata DC) phenolics: influence of fertilizers.
A field experiment was carried out to investigate the effect of fertilization level on the phenolic composition of tronchuda cabbage ( Brassica oleracea L. var. costata DC) external and internal leaves. Eight different plots were constituted: a control without fertilization, one with organic matter, and six experiments with conventional fertilizers (nitrogen, boron, and sulfur, two levels each). The phenolic compounds were analyzed by reversed-phase HPLC-DAD. External and internal leaves revealed distinct qualitative composition. In the internal leaves were found 15 phenolics (5 kaempferol and 10 cinnamic acid derivatives), whereas the external leaves presented 3- p-coumaroylquinic acid and 13 kaempferol derivatives. Principal component analysis (PCA) was applied to assess the relationships between phenolic compounds, agronomical practices, and harvesting time. Samples obtained with conventional practices were quite effectively separated from organic samples, for both types of leaves. In general, samples developed without any fertilization presented the highest phenolics amounts: external and internal leaves contained 1.4- and 4.6-fold more phenolic compounds than the ones that received conventional fertilizer, respectively, and the internal leaves presented 2.4 times more phenolics than the ones grown with organic amendment. Additionally, samples from organic production exhibited higher total phenolics content than those from conventional practices, collected at the same time. Samples harvested first were revealed to be distinct from the ones collected later. The results show that it is possible to grow tronchuda cabbage without excess fertilizers, with highest amounts of phenolics and reduced environment contamination.


Hemocyanin of the molluscan Concholepas concholepas exhibits an unusual heterodecameric array of subunits.
We describe here the structure of the hemocyanin from the Chilean gastropod Concholepas concholepas (CCH), emphasizing some attributes that make it interesting among molluscan hemocyanins. CCH exhibits a predominant didecameric structure as revealed by electron microscopy and a size of 8 MDa by gel filtration, and, in contrast with other mollusc hemocyanins, its stabilization does not require additional Ca(2+) and/or Mg(2+) in the medium. Polyacrylamide gel electrophoresis studies, analyses by a MonoQ FPLC column, and Western blots with specific monoclonal antibodies showed that CCH is made by two subunits noncovalently linked, named CCH-A and CCH-B, with molecular masses of 405 and 350 kDa, respectively. Interestingly, one of the subunits undergoes changes within the macromolecule; we demonstrated that CCH-A has an autocleavage site that under reducing conditions is cleaved to yield two polypeptides, CCH-A1 (300 kDa) and CCH-A2 (108 kDa), whereas CCH-B remains unchanged. The CCH-A nick occurs at 4 degrees C, increases at 37 degrees C, and is not inhibited by the addition of protease inhibitors and/or divalent cations. Since the CCH structure is a heterodimer, we investigated whether subunits would be either intermingled, forming heterodecamers, or assembled as two homogeneous decamers. Light scattering and electron microscope studies of the in vitro reassociation of purified CCH subunits demonstrated that the sole addition of Mg(2+) is needed for its reassembly into the native decameric molecule; no homodecamer reorganization was found with either CCH-A or CCH-B subunits alone. Our evidence showed that C. concholepas hemocyanin is an unusual example of heterodecameric organization.


The influence of experimental manipulations on chewing speed during in vivo laboratory research in tufted capuchins (Cebus apella).
Even though in vivo studies of mastication in living primates are often used to test functional and adaptive hypotheses explaining primate masticatory behavior, we currently have little data addressing how experimental procedures performed in the laboratory influence mastication. The obvious logistical issue in assessing how animal manipulation impacts feeding physiology reflects the difficulty in quantifying mechanical parameters without handling the animal. In this study, we measured chewing cycle duration as a mechanical variable that can be collected remotely to: 1) assess how experimental manipulations affect chewing speed in Cebus apella, 2) compare captive chewing cycle durations to that of wild conspecifics, and 3) document sources of variation (beyond experimental manipulation) impacting captive chewing cycle durations. We find that experimental manipulations do increase chewing cycle durations in C. apella by as much as 152 milliseconds (ms) on average. These slower chewing speeds are mainly an effect of anesthesia (and/or restraint), rather than electrode implantation or more invasive surgical procedures. Comparison of captive and wild C. apella suggest there is no novel effect of captivity on chewing speed, although this cannot unequivocally demonstrate that masticatory mechanics are similar in captive and wild individuals. Furthermore, we document significant differences in cycle durations due to inter-individual variation and food type, although duration did not always significantly correlate with mechanical properties of foods. We advocate that the significant reduction in chewing speed be considered as an appropriate qualification when applying the results of laboratory-based feeding studies to adaptive explanations of primate feeding behaviors.


Misinterpretation and misuse of exposure limits.
Users of occupational exposure limits (OELs) often fail to distinguish between the complementary processes of risk assessment and exposure (risk) management. The former refers to those activities that lead to the selection of a reasonably protective exposure limit and often includes an analysis of exposure databases and an evaluation of group-based risk. The latter focuses on individual risk, and refers to those actions required of employers to ensure that each employee is unlikely to incur harm to health. This presentation focuses on how this failure to distinguish leads to misinterpretation and misuse of OELs. A typical OEL definition consists of at least three components: a concentration, an averaging time, and a target (usually the individual worker). OELs are occasionally improperly applied, resulting in a reduction of the expected level of protection. For example, sampling strategies proposed by the American Industrial Hygiene Association (AIHA) and Comité Européen de Normalisation (CEN) permit workers to be aggregated into exposure groups. Under certain circumstances this practice can leave some workers unevaluated and unprotected. Protection is also reduced when the averaging time is extended from a single shift to multiple shifts. Frequently, OELs are misinterpreted as upper limits to exposures averaged over weeks, months, or even years, rather than a single shift. Much of this confusion can be traced to the desire of some to reconcile research (epidemiology) sampling strategies with compliance sampling strategies. But the two have fundamentally different goals and objectives. Others are simply attracted to alternative OEL interpretations that permit frequent overexposures (i.e., measurements that exceed the OEL), thus making compliance easier. Given the current limitations of industrial hygiene and occupational epidemiology, and the general unwillingness of employers to routinely collect exposure data, OELs should continue to be defined as upper limits for single shift exposures. The current OEL model, which permits the use of proximate risk management goals to realize long-range objectives, should be retained. There are, however, valid reasons for augmenting this model to include criteria for evaluating compliance with long-range objectives. The augmented OEL model would be applicable to future new and revised OELs. The author suggests that OEL setting organizations consider harmonizing definitions and statistical interpretations for both existing and new OELs, thus minimizing future misinterpretation and misuse.


Glycation is regulated by isoflavones.
The effect of soy isoflavones on the Maillard reaction (MR) was investigated. Model systems composed of the soy protein glycinin (10 mg mL(-1)) and fructose (40 mg mL(-1)) under basic pH (∼12) conditions were employed for testing the anti-glycative effect of the major antioxidant soy isoflavones (genistin and genistein at 10 μg mL(-1)) and a soy isoflavone-rich extract. The contents of total phenols (TPCs) and total flavonoids (TFCs) of the isoflavone-rich extract were determined. Glycinin was pre-incubated with isoflavones for 1 h and 16 h at 60 °C prior to MR. The progress of MR was estimated by analysis of free amino groups by OPA assay; carbohydrate covalently bound to the protein backbone using phenol-sulfuric acid assay, protein-bound N(ε)-(carboxymethyl)lysine (CML) by UPLC-MS and spectral analysis of fluorescent protein-bound AGEs. Genistin (10 μg mL(-1), 23 μM) and its aglycone genistein (10 μg mL(-1), 37 μM) did not prevent protein glycation (p > 0.05). The soy isoflavone-rich extract containing 2.5 mg mL(-1) of TFC efficiently decreased the amount of carbohydrate bound to the protein skeleton (20%) (p < 0.05) and formation of advanced glycation end products (AGEs) (>80%) (p < 0.05). The anti-glycative mechanism of isoflavones may be related to its conjugation to glycation sites of the protein structure (free amino groups), their antioxidant character and trapping of dicarbonyl intermediates. Extracts based on mixtures of isoflavones may be useful for producing glycated conjugates avoiding the substantial formation of AGEs bound to protein.


Optimizing Connectivity-Driven Brain Parcellation Using Ensemble Clustering.
This work addresses the problem of constructing a unified, topologically optimal connectivity-based brain atlas. The proposed approach aggregates an ensemble partition from individual parcellations without label agreement, providing a balance between sufficiently flexible individual parcellations and intuitive representation of the average topological structure of the connectome. The methods exploit a previously proposed dense connectivity representation, first performing graph-based hierarchical parcellation of individual brains, and subsequently aggregating the individual parcellations into a consensus parcellation. The search for consensus-based on the hard ensemble (HE) algorithm-approximately minimizes the sum of cluster membership distances, effectively estimating a pseudo-Karcher mean of individual parcellations. Computational stability, graph structure preservation, and biological relevance of the simplified representation resulting from the proposed parcellation are assessed on the Human Connectome Project data set. These aspects are assessed using (1) edge weight distribution divergence with respect to the dense connectome representation, (2) interhemispheric symmetry, (3) network characteristics' stability and agreement with respect to individually and anatomically parcellated networks, and (4) performance of the simplified connectome in a biological sex classification task. Ensemble parcellation was found to be highly stable with respect to subject sampling, outperforming anatomical atlases and other connectome-based parcellations in classification as well as preserving global connectome properties. The HE-based parcellation also showed a degree of symmetry comparable with anatomical atlases and a high degree of spatial contiguity without using explicit priors.


Comprehensive targeted next-generation sequencing in patients with slow-flow vascular malformations.
Recent studies have shown that the PI3K signaling pathway plays an important role in the pathogenesis of slow-flow vascular malformations (SFVMs). Analysis of genetic mutations has advanced our understanding of the mechanisms involved in SFVM pathogenesis and may identify new therapeutic targets. We screened for somatic variants in a cohort of patients with SFVMs using targeted next-generation sequencing. Targeted next-generation sequencing of 29 candidate genes associated with vascular anomalies or with the PI3K signaling pathway was performed on affected tissues from patients with SFVMs. Fifty-nine patients with SFVMs (venous malformations n = 21, lymphatic malformations n = 27, lymphatic venous malformations n = 1, and Klippel-Trenaunay syndrome n = 10) were included in the study. TEK and PIK3CA were the most commonly mutated genes in the study. We detected eight TEK pathogenic variants in 10 samples (16.9%) and three PIK3CA pathogenic variants in 28 samples (47.5%). In total, 37 of 59 patients (62.7%) with SFVMs harbored pathogenic variants in these three genes involved in the PI3K signaling pathway. Inhibitors of this pathway may prove useful as molecular targeted therapies for SFVMs.


Complement C3 Produced by Macrophages Promotes Renal Fibrosis via IL-17A Secretion.
Complement synthesis in cells of origin is strongly linked to the pathogenesis and progression of renal disease. Multiple studies have examined local C3 synthesis in renal disease and elucidated the contribution of local cellular sources, but the contribution of infiltrating inflammatory cells remains unclear. We investigate the relationships among C3, macrophages and Th17 cells, which are involved in interstitial fibrosis. Here, we report that increased local C3 expression, mainly by monocyte/macrophages, was detected in renal biopsy specimens and was correlated with the severity of renal fibrosis (RF) and indexes of renal function. In mouse models of UUO (unilateral ureteral obstruction), we found that local C3 was constitutively expressed throughout the kidney in the interstitium, from which it was released by F4/80+macrophages. After the depletion of macrophages using clodronate, mice lacking macrophages exhibited reductions in C3 expression and renal tubulointerstitial fibrosis. Blocking C3 expression with a C3 and C3aR inhibitor provided similar protection against renal tubulointerstitial fibrosis. These protective effects were associated with reduced pro-inflammatory cytokines, renal recruitment of inflammatory cells, and the Th17 response. in vitro, recombinant C3a significantly enhanced T cell proliferation and IL-17A expression, which was mediated through phosphorylation of ERK, STAT3, and STAT5 and activation of NF-kB in T cells. More importantly, blockade of C3a by a C3aR inhibitor drastically suppressed IL-17A expression in C3a-stimulated T cells. We propose that local C3 secretion by macrophages leads to IL-17A-mediated inflammatory cell infiltration into the kidney, which further drives fibrogenic responses. Our findings suggest that inhibition of the C3a/C3aR pathway is a novel therapeutic approach for obstructive nephropathy.


Blood pressure variability in relation to outcome in the International Database of Ambulatory blood pressure in relation to Cardiovascular Outcome.
Ambulatory blood pressure (BP) monitoring provides information not only on the BP level but also on the diurnal changes in BP. In the present review, we summarized the main findings of the International Database on Ambulatory BP in relation to Cardiovascular Outcome (IDACO) with regard to risk stratification based on BP variability. The predictive accuracy of daytime and nighttime BP and the night-to-day BP ratio depended on the disease outcome under study and treatment status, and differed for fatal outcomes compared with the composite of fatal and nonfatal diseases. An exaggerated morning surge, exceeding the 90th percentile of the population, is an independent risk factor for mortality and cardiovascular and cardiac events. Conversely, a sleep-trough or preawakening morning surge in systolic BP below 20 mm Hg is probably not associated with an increased risk of death or cardiovascular events. BP variability as captured by the average of the daytime and nighttime s.d. weighted for the duration of the daytime and nighttime interval (s.d.(dn)) and the average real variability (ARV(24)) predicted the outcome, but improved the prediction of the composite of all cardiovascular events by only 0.1%. In conclusion, the IDACO observations support the concept that BP variability adds to risk stratification, but above all highlight that 24-h ambulatory BP level remains the main predictor to be considered in clinical practice.


Effects of protein size, thermodynamic stability, and net charge on cotranslational folding on the ribosome.
During the last five decades, studies of protein folding in dilute buffer solutions have produced a rich picture of this complex process. In the cell, however, proteins can start to fold while still attached to the ribosome (cotranslational folding) and it is not yet clear how the ribosome affects the folding of protein domains of different sizes, thermodynamic stabilities, and net charges. Here, by using arrest peptides as force sensors and on-ribosome pulse proteolysis, we provide a comprehensive picture of how the distance from the peptidyl transferase center in the ribosome at which proteins fold correlates with protein size. Moreover, an analysis of a large collection of mutants of the Escherichia coli ribosomal protein S6 shows that the force exerted on the nascent chain by protein folding varies linearly with the thermodynamic stability of the folded state, and that the ribosome environment disfavors folding of domains of high net-negative charge.


Polio Patients in Northern Italy, a 50 Year Follow-up.
Poliomyelitis was before the immunization an important medical problem. Nowadays polio prior patients (PP) suffer from polio sequelae or have developed post-polio-syndrome (PPS) with increasing paresis, pain and fatigue. To analyze the medical situation 50 years after acute polio. The degree of paresis was compared between the recovery 1952-1961 and 2012.The prevalence of patients fulfilling the criteria for PPS was estimated. The study was performed in Italy. Included were PP with rehabilitation after acute polio 1952-1961 and in 2012. During the years PP underwent yearly evaluation. A thorough neurological examination was performed in 2012. A telephone interview with questions concerning pain, paresis, fatigue, walking aids and concomitant diseases was performed in 2012. The patients were divided in two groups, if they fulfilled the criteria for PPS or not. Included were 67(94%) patients receiving rehabilitation after acute poliomyelitis and 2012. 78% were walkers, half of the PPS used wheelchair. Eight out of ten suffered from pain. Four out of ten fulfilled the PPS criteria. Pain was slightly more common in PPS. Female gender, fatigue and wheelchair dependency were significantly more common in PPS while pain was common in both groups.


Macrophage-specific Mycobacterium tuberculosis genes: identification by green fluorescent protein and kanamycin resistance selection.
Mycobacterium tuberculosis survives and multiplies inside macrophages of its host by modulating the expression of several genes essential for in vivo survival. An in vivo expression system has been developed, based on green fluorescent protein and kanamycin resistance, to identify M. tuberculosis genes which appear to be up-regulated in infected macrophages. A promoter-trap shuttle vector, pLL192, was constructed, containing a streptomycin resistance gene as selection marker and an artificial bicistronic operon composed of the promoterless green fluorescent protein (gfp) gene, followed by the kanamycin resistance gene. A unique BamHI site upstream of the gfp gene allowed for insertion of promoter libraries. The vector was validated by the use of known regulated or constitutive M. tuberculosis promoters. In addition, an M. tuberculosis genomic DNA library was inserted into pLL192 and then introduced into Mycobacterium bovis BCG. The recombinant BCG cells were then used to infect the J774A.1 murine macrophage-like cell line in the presence of kanamycin. Several recombinant BCG cells were thereby selected that were resistant to kanamycin within infected macrophages, but were sensitive to kanamycin when grown in vitro. The kanamycin resistance phenotype was paralleled by the fluorescence phenotype. After nucleotide sequencing, the corresponding genes were identified as mce1A, PE_PGRS63(RV3097c), Rv2232, Rv1026, Rv1635c, viuB, Rv2231(cobC) and Rv0997. Real-time PCR analysis using RNA isolated at various time points from M. tuberculosis and M. bovis BCG grown in vitro and within macrophages, confirmed the up-regulation of these genes. The level of up-regulation varied from 2- to 40-fold in macrophages compared to growth in vitro.


[A community-based study of stroke code users in northern Portugal].
By 2002 Portugal had one of the highest mortality rates due to cerebrovascular diseases among the European Countries. Meanwhile, several strategies have been adopted to improve prevention and treatment in the acute phase, amongst which the Stroke Code. The purpose of this study is to describe how this measure has been used and its outcome as part of a prospective community based study of stroke/TIA incidence in Northern Portugal. Between 1st October 2009 and 30th September 2010 all strokes occurred in patients registered at Western Porto, Mirandela and Vila Pouca de Aguiar health centres have been recorded. For cases ascertainment multiple sources of information were used, including the WEB, letter, e-mail and Alert P1, as well as systematic searches on databases provided by the entities involved in this study: hospital emergency, discharge records, diagnosis procedures, death certificates, Stroke Code admissions and health centre emergency records. Six hundred strokes were recorded in a population of 241 000 (incidence rate of 250 / 100 000 person-years) and 434 were first-ever-in-the-lifetime (180 / 100 000). There were 72 Stroke Code calls and in 66.7% of them a stroke was confirmed. Considering the criteria for Stroke Code call (age = 80 years, functional independency, the stroke signs/symptoms, and time after episode = 3 hours), only 15.9% patients "could" have access to it. Of those who used the Stroke Code, only 56.3% fulfilled the criteria. Considering all patients fulfilling Stroke Code criteria, 96.3% that used prehospital Stroke Code were inpatients, as well as 83.3% that used intra/interhospital Stroke Code and 64.0% of the remainder; this trend is also present in patients with ischaemic stroke submitted to fibrinolysis, 77.3%, 36.4% and 17.4%, respectively. A high post-stroke Rankin was more frequent among Stroke Code users (70.3% vs. 35.3%), but they exhibit more often the three stroke signs/symptoms (44.0% vs. 16.2%). After adjusting for age, sex and number of signs, the risk of a more severe post-stroke Rankin is not significantly different among patients using the prehospital Stroke Code (OR = 2.9, 95% CI: 0.8 - 10.2). The criteria for accessing the Stroke Code are currently restrictive. Though the Stroke Code is accessed in case of more severe patient's conditions, the proportion of patients treated with fibrinolysis is relatively high in comparison with other studies.


Pioglitazone reduces smooth muscle cell density of rat carotid arterial intima induced by balloon catheterization.
The effect of pioglitazone on balloon catheterization-induced carotid arterial intimal thickening lesion of male Wistar fatty rats and its littermates (Wistar lean rats) was investigated. Pioglitazone was administered via gastric tube at 10 mg/kg/day to 12-week-old rats for 7 days. Age-matched rats without pioglitazone were used as respective controls. Each rat was catheterized using a balloon catheter inserted from the left femoral artery to the left common carotid artery, and the endothelium in the left common carotid artery was denuded. Rats were then treated with pioglitazone for 14 days post catheterization and the left common carotid artery was removed and stained with Elastica-Masson and anti-alpha-smooth muscle actin antibody. In addition, for smooth muscle cell (SMC) culture, pioglitazone was administered at 10 mg/kg/day for 28 days to a separate group of 12-week-old rats, and the aortic medial outgrowth rate of their SMCs was measured. Age-matched rats without pioglitazone were prepared as respective controls. In comparison with the area ratio of the thickened intima/media of fatty rats without treatment, those of fatty rats with treatment and lean rats without treatment were significantly decreased by approximately 60%, and also that of lean rats with treatment to 27%. With anti-alpha-smooth muscle actin antibody staining, almost all cells present in intimal thickening were positive. Treatment with pioglitazone reduced the amount of anti-alpha-smooth muscle actin antibody-staining cells. In addition, the outgrowth rate of SMCs at day 10 compared to that in fatty rats without treatment decreased to 42% in fatty rats with treatment, 29% in lean rats without treatment and 23% in lean rats with treatment, respectively. Therefore, pioglitazone has an inhibitory effect on the growth of SMCs, and consequently suppressed carotid intimal thickening. Furthermore, this inhibitory effect was enhanced in diabetes.


Canonical and Non-Canonical Autophagy in HIV-1 Replication Cycle.
Autophagy is a lysosomal-dependent degradative process essential for maintaining cellular homeostasis, and is a key player in innate and adaptive immune responses to intracellular pathogens such as human immunodeficiency virus type 1 (HIV-1). In HIV-1 target cells, autophagy mechanisms can (i) selectively direct viral proteins and viruses for degradation; (ii) participate in the processing and presentation of viral-derived antigens through major histocompatibility complexes; and (iii) contribute to interferon production in response to HIV-1 infection. As a consequence, HIV-1 has evolved different strategies to finely regulate the autophagy pathway to favor its replication and dissemination. HIV-1 notably encodes accessory genes encoding Tat, Nef and Vpu proteins, which are able to perturb and hijack canonical and non-canonical autophagy mechanisms. This review outlines the current knowledge on the complex interplay between autophagy and HIV-1 replication cycle, providing an overview of the autophagy-mediated molecular processes deployed both by infected cells to combat the virus and by HIV-1 to evade antiviral response.


Stem cell transplantation in acute myelogenous leukemia in first remission: what are the options?
Most newly diagnosed patients with acute myeloid leukemia (AML) in first remission will relapse without additional consolidation therapy. The options for consolidation therapy include repeated cycles of high-dose cytosine arabinoside-based chemotherapy and autologous or allogeneic stem cell transplantation (SCT). Chemotherapy alone is associated with the highest risk of relapse, but it has the lowest treatment-related mortality (TRM). Allogeneic SCT has the lowest risk of relapse with the highest TRM, whereas autologous SCT has an intermediate risk of relapse and TRM. Cytogenetic status of patients with AML is the single most important prognostic factor. However, it is increasingly recognized that this factor alone is inadequate for risk stratification. Based on cytogenetic stratification, a good-risk group of patients in first complete remission (CR1) would benefit most from high-dose consolidation chemotherapy. The risks of a SCT outweigh the benefit in this group. In the unfavorable-risk group, an allogeneic sibling SCT in CR1 would be acceptable, whereas the outcomes with chemotherapy alone or with an autologous SCT are dismal. Based on minimal data, a matched-unrelated donor SCT for this group of patients should be recommended. In the intermediate-risk group, strategies are evolving and the use of additional prognosticators will help in decision making. Autologous or allogeneic sibling SCT is a reasonable option in a subset of patients within this group at a high risk of relapse. There are insufficient data to recommend a haploidentical or cord blood transplant for patients with AML in CR1.


Backbone resonance assignment of the BCL6-BTB/POZ domain.
BCL6 is a transcriptional repressor. Two domains of the protein, the N-terminal BTB-POZ domain and the RD2 domain are responsible for recruitment of co-repressor molecules and histone deacetylases. The BTB-POZ domain is found in a large and diverse range of proteins that play important roles in development, homeostasis and neoplasia. Crystal structures of several BTB-POZ domains, including BCL6 have been determined. The BTB-POZ domain of BCL6 not only mediates dimerisation but is also responsible for recruitment of co-repressors such as SMRT, NCOR and BCOR. Interestingly both SMRT and BCOR bind to the same site within the BCL6 BTB-POZ domain despite having very different primary sequences. Since both peptides and small molecules have been shown to bind to the co-repressor binding site it would suggest that the BTB_POZ domain is a suitable target for drug discovery. Here we report near complete backbone 15N, 13C and 1H assignments for the BTB-POZ domain of BCL6 to assist in the analysis of binding modes for small molecules.


Behavioral and neuropathological effects of prenatal methylmercury exposure in mice.
Pregnant C3H/HeN mice were orally administered a single dose of 20 mg/kg methylmercuric chloride on one of days 13 through 17 of pregnancy. They were allowed to give birth and the newborn mice were foster mothered, but the weaning rate was low. Long-term behavioral impairment was manifest in mice of every treated group. The righting movement was mildly disturbed when animals were dropped from about 40 cm high. The tail position was low during walking. Some animals showed strong flexion of the hind limbs when held by the tail. Spontaneous locomotor activity was reduced. At 10-12 weeks of age, the animals were sacrificed and the brain was histologically examined. The brain weight was reduced. The nucleus caudatus putamen was slightly reduced in size leaving the lateral ventricles dilated. Cerebellar folial patterns were slightly simplified. These neurobehavioral symptoms and pathological changes tended to be comparatively more severe in animals treated on days 13 and 14 of pregnancy than those of the other groups, but the differences were small.


An information theory analysis of spatial decisions in cognitive development.
Performance in a cognitive task can be considered as the outcome of a decision-making process operating across various knowledge domains or aspects of a single domain. Therefore, an analysis of these decisions in various tasks can shed light on the interplay and integration of these domains (or elements within a single domain) as they are associated with specific task characteristics. In this study, we applied an information theoretic approach to assess quantitatively the gain of knowledge across various elements of the cognitive domain of spatial, relational knowledge, as a function of development. Specifically, we examined changing spatial relational knowledge from ages 5 to 10 years. Our analyses consisted of a two-step process. First, we performed a hierarchical clustering analysis on the decisions made in 16 different tasks of spatial relational knowledge to determine which tasks were performed similarly at each age group as well as to discover how the tasks clustered together. We next used two measures of entropy to capture the gradual emergence of order in the development of relational knowledge. These measures of "cognitive entropy" were defined based on two independent aspects of chunking, namely (1) the number of clusters formed at each age group, and (2) the distribution of tasks across the clusters. We found that both measures of entropy decreased with age in a quadratic fashion and were positively and linearly correlated. The decrease in entropy and, therefore, gain of information during development was accompanied by improved performance. These results document, for the first time, the orderly and progressively structured "chunking" of decisions across the development of spatial relational reasoning and quantify this gain within a formal information-theoretic framework.


Adipose tissue tumor necrosis factor and interleukin-6 expression in human obesity and insulin resistance.
Adipose tissue expresses tumor necrosis factor (TNF) and interleukin (IL)-6, which may cause obesity-related insulin resistance. We measured TNF and IL-6 expression in the adipose tissue of 50 lean and obese subjects without diabetes. Insulin sensitivity (S(I)) was determined by an intravenous glucose tolerance test with minimal-model analysis. When lean [body mass index (BMI) <25 kg/m(2)] and obese (BMI 30-40 kg/m(2)) subjects were compared, there was a 7.5-fold increase in TNF secretion (P < 0.05) from adipose tissue, and the TNF secretion was inversely related to S(I) (r = -0.42, P < 0.02). IL-6 was abundantly expressed by adipose tissue. In contrast to TNF, plasma (rather than adipose) IL-6 demonstrated the strongest relationship with obesity and insulin resistance. Plasma IL-6 was significantly higher in obese subjects and demonstrated a highly significant inverse relationship with S(I) (r = -0.71, P < 0.001). To separate the effects of BMI from S(I), subjects who were discordant for S(I) were matched for BMI, age, and gender. By use of this approach, subjects with low S(I) demonstrated a 3.0-fold increased level of TNF secretion from adipose tissue and a 2.3-fold higher plasma IL-6 level (P < 0.05) compared with matched subjects with a high S(I). Plasma IL-6 was significantly associated with plasma nonesterified fatty acid levels (r = 0.49, P < 0.002). Thus the local expression of TNF and plasma IL-6 are higher in subjects with obesity-related insulin resistance.


Isolated juvenile xanthogranuloma in the larynx of a three-year-old child.
Juvenile xanthogranuloma (JXG) is a benign manifestation of non-Langerhans cell histiocytosis characterized by yellowish cutaneous nodules. Its occurrence in the larynx is very rare, but laryngeal JXG may cause severe respiratory distress. We report a patient with isolated laryngeal JXG treated by laryngomicrosurgery, and this is the first report of JXG extending to vocal fold. A 3-year-old girl presented with hoarseness and inspiration stridor. A bulky tumor was found in right glottic to subglottic region. Subtotal resection of the tumor was carried out by laryngomicrosurgery, and airway distress was diminished after the operation. In pathological examination, the resected specimen showed proliferation of histiocytic cells and spindle cells with Touton giant cells that are characterized by polynuclei or wreath nuclei and are known to appear in JXG but not in LCH. Immunohistochemistry of histiocytic cell markers demonstrated positivity for CD68, lysozyme, alpha1-anti-chymotrypsin, factor XIIIa and vimentin, and negativity for CD1a and S-100, leading to diagnosis of JXG, but not LCH. The patient was thus expected with benign prognosis, and additional resection of the tumor including vocal fold was not indicated in the initial treatment. Six weeks later, the JXG recurred and a second procedure using CO₂ laser was needed. The tumor did not re-grow thereafter, and there was no residual voice handicap. Because of its favorable prognosis and tendency for spontaneous regression, JXG in the larynx needs to be considered carefully with regard to whether reduction surgery and/or tracheotomy are necessary, and thus precise diagnosis is required.


The Dutch Renal Artery Stenosis Intervention Cooperative (DRASTIC) Study: rationale, design and inclusion data.
Renal artery stenosis may lead to renovascular hypertension, risking multiple organ damage including damage to the contralateral kidney. Progression of stenosis may impair the function of the affected kidney. It is important to identify individuals with this disease among hypertensive patients. The first aim of the Dutch Renal Artery Stenosis Intervention Cooperative (DRASTIC) study is to assess the prevalence of renal artery stenosis in patients with well-defined forms of drug-resistant hypertension, and to determine the predictive value of clinical characteristics and diagnostic tests in these pre-selected patients. With regard to treatment, the effect of renal angioplasty on hypertension is disappointing in atherosclerotic stenosis and technical failure frequently occurs. Therefore, the second aim is to compare the effects of balloon angioplasty and antihypertensive medication on blood pressure in patients with atherosclerotic renal artery stenosis. patients receiving standard antihypertensive medication in whom diastolic blood pressure remained > or =95 mmHg during three consecutive visits to the outpatient clinic underwent full diagnostic work-up, including renal arteriography. The prevalence of renal artery stenosis in this well-defined patient group was then established, and the predictive value of the various diagnostic tests was assessed. Patients with an atherosclerotic renal artery stenosis of > or =50% were then randomly assigned to balloon angioplasty or to treatment with antihypertensive drugs. After 1 year of intensive follow-up of blood pressure and renal function, re-arteriography was performed. In total, 1205 patients have been included in the study, about 500 have received diagnostic work-up, and it is expected that 100 patients will be randomly assigned for renal angioplasty or medical treatment.


Characterization of a major antigenic region on gp55 of human cytomegalovirus.
A major antigenic region localized to the C-terminal part of the 55K glycoprotein of human cytomegalovirus (HCMV) was mapped using synthetic peptides. Analysis of the region with six sera from healthy anti-HCMV seropositive blood donors showed that the length of the reactive sequence varied between four and eight amino acids (aa). The shortest sequence recognized was VTSG (aa 798 to 801 of the 130K precursor protein), but most sera required the three or four residues C-terminal to this to react, giving a major site of VTSGSTKD (aa 798 to 805). Using peptides immobilized on polyethylene pins, the importance of both interior (between aa essential for the binding of an antibody) and extension spacer residues was evident. Free peptides containing the reactive sequence were prepared for use in a conventional ELISA and optimal pH conditions for coating were determined. The best results were achieved at pH 2 to 3, which is in agreement with the advantageous net charge of these peptides at this low pH. Anti-HCMV positive sera showed a sensitivity of approximately 50% for both peptides on polyethylene pins and peptides coated onto plates.


Influence of visual acuity, manual dexterity and handgrip strength on oral and denture hygiene ability of non-frail older people: Development of the Gerostomatological Assessment Battery.
Due to the heterogeneity of older people, it is difficult to identify reliable factors influencing oral health. The aim was to illustrate the influence of visual acuity, manual dexterity, and handgrip strength on the oral and denture hygiene ability of older non-frail people. In a cross-sectional study, conducted at a specialized dental clinic, at baseline, all participants received professional prophylaxis and instruction on daily oral and denture hygiene regimes for a 6-week intervention period. Data on the Quigley and Hein modified plaque index (QHI), respectively, the Denture Hygiene Index (DHI), visual acuity, manual dexterity and handgrip strength in non-frail participants (≥ 65 years) were collected. Recruitment was done within the clinic's patient clientele and within the staff (control cohort). Women showed significantly better manual dexterity than men (Mann-Whitney U, p = .01), while women's mean handgrip strength was significantly lower (Mann-Whitney U, p < .01). Manual dexterity (Mann-Whitney U, p = .003) and handgrip strength (Mann-Whitney U, p = .052) were associated with age. However, visual acuity, manual dexterity and handgrip strength had no influence on oral or denture hygiene. Visual acuity, manual dexterity and handgrip strength have no influence on oral and denture hygiene ability in older non-frail people. Further studies should investigate whether these factors also have no influence on oral and denture hygiene in vulnerable older patients. Therefore, an assessment tool for the evaluation of potential influencing factors of oral and denture hygiene is proposed in a dental context. This Gerostomatological Assessment Battery (G-AB) can be used as a helpful tool to check the individual cognitive function and comprehension, dental therapy approaches and their individual adaption.


The development of children's early memory skills.
A multitask battery tapping nonverbal memory and language skills was used to assess 60 children at 18, 24, and 30 months of age. Analyses focused on the degree to which language, working memory, and deliberate memory skills were linked concurrently to children's Elicited Imitation task performance and whether the patterns of association varied across the different ages. Language ability emerged as a predictor of immediate Elicited Imitation performance by 24 months of age and predicted delayed performance at each age. In addition to the contributions of language, children's abilities to search for and retrieve toys in the deliberate memory task were associated with their immediate Elicited Imitation performance at each age. In addition to language, working memory was positively associated with aspects of both immediate and delayed performance at all ages. The extent to which it was possible to replicate and extend previous cross-sectional work in this longitudinal study is discussed.