The transfusion services committee--responsibilities and response to adverse transfusion events.
Healthcare institutions in the United States must review blood transfusion practices and adverse outcomes in order to receive payments from the Centers for Medicare/Medicaid program, but it is not required for a specific committee to be assigned to oversee the review process. Regardless of the group or individuals responsible, the review process must include a program of quality assessment and performance improvement that is ongoing, hospital-wide, and data-driven, reflects the complexity of the hospital's organization and services, and involves all hospital departments and services (including those contracted). To be most effective, the performance improvement activity should be prioritized around high-risk, high-volume activities and/or in problem-prone areas. Even if a hospital elects not to receive payments from Medicare, it must still comply with applicable sections of the Code of Federal Regulations pertaining to transfusion services such as the follow up of adverse outcomes of transfusion.


Nitazoxanide inhibits paramyxovirus replication by targeting the Fusion protein folding: role of glycoprotein-specific thiol oxidoreductase ERp57.
Paramyxoviridae, a large family of enveloped viruses harboring a nonsegmented negative-sense RNA genome, include important human pathogens as measles, mumps, respiratory syncytial virus (RSV), parainfluenza viruses, and henipaviruses, which cause some of the deadliest emerging zoonoses. There is no effective antiviral chemotherapy for most of these pathogens. Paramyxoviruses evolved a sophisticated membrane-fusion machine consisting of receptor-binding proteins and the fusion F-protein, critical for virus infectivity. Herein we identify the antiprotozoal/antimicrobial nitazoxanide as a potential anti-paramyxovirus drug targeting the F-protein. We show that nitazoxanide and its circulating-metabolite tizoxanide act at post-entry level by provoking Sendai virus and RSV F-protein aggregate formation, halting F-trafficking to the host plasma membrane. F-protein folding depends on ER-resident glycoprotein-specific thiol-oxidoreductase ERp57 for correct disulfide-bond architecture. We found that tizoxanide behaves as an ERp57 non-competitive inhibitor; the putative drug binding-site was located at the ERp57-b/b' non-catalytic domains interface. ERp57-silencing mimicked thiazolide-induced F-protein alterations, suggesting an important role of this foldase in thiazolides anti-paramyxovirus activity. Nitazoxanide is used in the clinic as a safe and effective antiprotozoal/antimicrobial drug; its antiviral activity was shown in patients infected with hepatitis-C virus, rotavirus and influenza viruses. Our results now suggest that nitazoxanide may be effective also against paramyxovirus infection.


Thymoquinone is protective against 2,3,7,8-tetrachlorodibenzo-p-dioxin induced hepatotoxicity.
We investigated changes in rat liver tissues following administration of thymoquinone (TQ) against 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induced hepatotoxicity. Fifty rats were assigned randomly to five groups of 10 as follows: control, corn oil, TCDD, TQ and TCDD + TQ. Biochemical and histopathological analyses were conducted on liver tissue. We found that 30 day TCDD administration caused histopathological changes in liver including thickening of Glisson's capsule, intracytoplasmic vacuolization in hepatocytes, sinusoidal dilation, vascular and sinusoidal congestion and inflammatory cell infiltration. TCDD administration increased malondialdehyde (MDA), total oxidant status (TOS), alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) levels in rat liver tissue and reduced glutathione (GSH), superoxide dismutase (SOD), catalase (CAT) and total antioxidant status (TAS) levels compared to all other groups. In the TQ treated group, GSH, SOD, CAT and TAS levels increased compared to all other groups. MDA, TOS, ALT, AST, ALP levels decreased compared to all other groups. Our histological findings were consistent with the biochemical findings. The oxidative and histologic effects of TCDD were eliminated by TQ treatment. TCDD administration caused oxidative stress in rat liver and TQ administered with TCDD prevented TCDD induced hepatotoxicity. TQ could be considered an alternative anti-TCDD toxicity agent.


L Amino acids and D-glucose bind stereospecifically to a colloidal clay.
L-Leucine, L-aspartate, and D-glucose bind in a stereospecific manner to a colloidal clay, bentonite. This binding has high-affinity, saturable characteristics. The biologically uncommon enantiomers, D-leucine, D-asparatate, and L-glucose, do not exhibit any selective absorption on bentonite. It is suggested that this difference between stereoisomers could account for the evolution of life forms possessing a great preponderance of L amino acids and D-glucose.


LncRNA BC200 regulates the cell proliferation and cisplatin resistance in non-small cell lung cancer via PI3K/AKT pathway.
Long non-coding RNA (lncRNA) exerts tissue specificity and regulates the occurrence and progression of tumors. Previous bioinformatics showed that lncRNA BC200 is served as an oncogene. However, the specific role of BC200 in lung cancer (LC) is rarely reported. The aim of this study is to elucidate the regulatory effects of BC200 on tumor development and cisplatin resistance in non-small cell lung cancer (NSCLC). The expression level of BC200 in 76 pairs of NSCLC tissues and adjacent normal tissues was detected by quantitative Real Time-Polymerase Chain Reaction (qRT-PCR). Correlation analyses were conducted to investigate the relation between BC200 expression and prognosis of NSCLC patients. Subsequently, BC200 expression in LC cell lines was detected. After construction of si-BC200 and si-NC, the cellular functions of LC cells were detected through colony formation, flow cytometry and transwell assay, respectively. Western blot was performed to detect the protein expressions of key genes in the PI3K/AKT pathway in LC cells. Finally, cell counting kit-8 (CCK-8) assay was carried out to explore the effect of BC200 on cisplatin resistance of LC cells via calculating IC50. Higher expression of BC200 was found in NSCLC tissues than that of adjacent normal tissues. BC200 expression was positively correlated with tumor stage, lymph node metastasis and distant metastasis of NSCLC patients, whereas not correlated to age and sex. Knockdown of BC200 inhibited proliferation, invasion and migration of LC cells. Western blot results showed that protein expressions of PI3K, AKT and STAT3 were downregulated after BC200 knockdown in LC cells. Additionally, the IC50 in H1299/DDP cells transfected with si-BC200 was lower than in those transfected with si-NC. The apoptotic rate in H1299 cells transfected with si-BC200 was remarkably lower than those transfected with si-NC. BC200 is highly expressed in NSCLC, which is positively correlated with tumor stage and metastasis of NSCLC patients. BC200 promotes the malignant progression of NSCLC via regulating cisplatin-induced apoptosis of H1299/DDP cells.


Reproductive and developmental risks from ethylene oxide: a probabilistic characterization of possible regulatory thresholds.
Ethylene oxide is a gas produced in large quantities in the United States that is used primarily as a chemical intermediate in the production of ethylene glycol, propylene glycol, non-ionic surfactants, ethanolamines, glycol ethers, and other chemicals. It has been well established that ethylene oxide can induce cancer, genetic, reproductive and developmental, and acute health effects in animals. The U.S. Environmental Protection Agency is currently developing both a cancer potency factor and a reference concentration (RfC) for ethylene oxide. This study used the rich database on the reproductive and developmental effects of ethylene oxide to develop a probabilistic characterization of possible regulatory thresholds for ethylene oxide. This analysis was based on the standard regulatory approach for noncancer risk assessment, but involved several innovative elements, such as: (1) the use of advanced statistical methods to account for correlations in developmental outcomes among littermates and allow for simultaneous control of covariates (such as litter size); (2) the application of a probabilistic approach for characterizing the uncertainty in extrapolating the animal results to humans; and (3) the use of a quantitative approach to account for the variation in heterogeneity among the human population. This article presents several classes of results, including: (1) probabilistic characterizations of ED10s for two quantal reproductive outcomes-resorption and fetal death, (2) probabilistic characterizations of one developmental outcome-the dose expected to yield a 5% reduction in fetal (or pup) weight, (3) estimates of the RfCs that would result from using these values in the standard regulatory approach for noncancer risk assessment, and (4) a probabilistic characterization of the level of ethylene oxide exposure that would be expected to yield a 1/1,000 increase in the risk of reproductive or developmental outcomes in exposed human populations.


Clinical efficacy and safety of anticholinergic therapies in pediatric patients.
The burden of uncontrolled asthma in children and adolescents is high. Treatment options for pediatric patients (aged under 18 years) with asthma are largely influenced by the Global Initiative for Asthma recommendations. Algorithms for adolescents (12-18 years) and adults are identical, but recommendations for children aged under 6 years and 6-11 years differ. Although the goals of treatment for pediatric patients with asthma are similar to those for adults, relatively few new therapies have been approved for this patient population within the last decade. Designing clinical trials involving children presents several challenges, notably that children are often less able to perform lung function tests, and traditional endpoints used in clinical trials with adults, such as forced expiratory volume in 1 second, asthma exacerbations and questionnaires, have limitations associated with their use in children. There are also ethical considerations related to the performance of longer placebo-controlled exacerbation trials. This review considers additional clinical endpoints to those traditionally reported, including forced expiratory flow at 25%-75% of forced vital capacity, which may help shed light on which treatments are most effective for use in pediatric patients with asthma. The pros and cons of specific and potentially clinically relevant endpoints are considered, along with device considerations and patient preferences that may enhance adherence and quality of life. Recent advances in the management of children and adolescents, including the US Food and Drug Administration and European Medicines Agency approval of tiotropium in patients with asthma aged 6 years and over, are also discussed.


Potassium channel currents in rat mesenchymal stem cells and their possible roles in cell proliferation.
Mesenchymal stem cells (MSC) have shown considerable promise for the regeneration and repair of damaged tissue. However, the electrophysiological properties of K+ channels in MSC are not well established and little is known about the role of K+ channels in the regulation of MSC proliferation. We detected three distinct outward currents in MSC: (i) a delayed rectifier current (IK(DR)); (ii) a Ca2+-activated K+ current (IK(Ca)); and (iii) a transient outward K+ current (Ito). All three were present either alone or in combination in almost all cells (90%) investigated. However, 10% of cells did not express a functional current within physiological potentials. Reverse transcription-polymerase chain reaction was used to identify mRNA associated with functional ionic currents. Kv1.2 and Kv2.1 were associated with IK(DR); Slo and KCNN4 were associated with IK(Ca); and Kv1.4 and Kv4.3 were associated with Ito. The Kv channel blockers amiodarone, tetraethylammonium and verapamil, as well as increased extracellular K+ levels, inhibited proliferation of cultured MSC. In MSC treated with Kv channel blockers or an increased extracellular concentration of K+, the proportion of cells in the S phase decreased significantly and the proportion of cells in the G(0)/G(1) phase tended to increase, indicating that the cells were prevented from entering the S phase of the cell cycle. Our findings suggest that rat MSC heterogeneously express distinct types of K+ current, of which the voltage-gated IK(DR)-like K+ current is most common. Kv channel activity modulates the progression of the cell cycle, affecting the proliferation of MSC.


Should Anthroposophic Medicinal Products Be Regulated in Europe?
European Commission's reports suggest that the European Union should address the status of anthroposophic products, i.e. products that are developed, manufactured and prescribed in accordance with the holistic approach on which anthroposophic medicine is based. Anthroposophic products cannot be placed as such on the European market because they cannot meet the marketing authorisation or even registration requirements set out by European or national pharmaceutical law. Yet, the 95-year European tradition and good safety profile of anthroposophic products justify giving them an easier access to market. Such access can result from specific rules on anthroposophic products, but can be more efficiently achieved by encouraging the Member States to better apply the existing rules on marketing authorisation procedures or on registration of homeopathic and traditional herbal medicinal products, or by including anthroposophic substances, manufacturing methods or uses in monographs.


Discovering Collective Variables of Molecular Transitions via Genetic Algorithms and Neural Networks.
With the continual improvement of computing hardware and algorithms, simulations have become a powerful tool for understanding all sorts of (bio)molecular processes. To handle the large simulation data sets and to accelerate slow, activated transitions, a condensed set of descriptors, or collective variables (CVs), is needed to discern the relevant dynamics that describes the molecular process of interest. However, proposing an adequate set of CVs that can capture the intrinsic reaction coordinate of the molecular transition is often extremely difficult. Here, we present a framework to find an optimal set of CVs from a pool of candidates using a combination of artificial neural networks and genetic algorithms. The approach effectively replaces the encoder of an autoencoder network with genes to represent the latent space, i.e., the CVs. Given a selection of CVs as input, the network is trained to recover the atom coordinates underlying the CV values at points along the transition. The network performance is used as an estimator of the fitness of the input CVs. Two genetic algorithms optimize the CV selection and the neural network architecture. The successful retrieval of optimal CVs by this framework is illustrated at the hand of two case studies: the well-known conformational change in the alanine dipeptide molecule and the more intricate transition of a base pair in B-DNA from the classic Watson-Crick pairing to the alternative Hoogsteen pairing. Key advantages of our framework include the following: optimal interpretable CVs, avoiding costly calculation of committor or time-correlation functions, and automatic hyperparameter optimization. In addition, we show that applying a time-delay between the network input and output allows for enhanced selection of slow variables. Moreover, the network can also be used to generate molecular configurations of unexplored microstates, for example, for augmentation of the simulation data.


FOXP3+ Cells Recruited by CCL22 into Breast Cancer Correlates with Less Tumor Nodal Infiltration.
Regulatory T-cells (Tregs) are a T-cell subpopulation with suppressive capacities, which are specifically attracted by C-C motif chemokine 22 (CCL22). Treg infiltration of tumors is associated with a poor prognosis in many patients. We aimed to investigate whether CCL22 is expressed in human breast cancer and whether its presence is associated with Treg infiltration. Eighty paraffin-embedded human breast cancer samples were stained for CCL22 and for the Treg-specific transcription factor forkhead box P3 (FOXP3). Expression was evaluated in a semi-quantitative manner. FOXP3(+) cells infiltrated 50% of the breast tumors. Moreover, Treg infiltrated 93% of the tertiary lymphoid structures. CCL22 expression positively correlated with FOXP3(+) cell infiltration into the tertiary lymphoid structures. Our results demonstrate that CCL22 expression correlates with infiltration by FOXP3(+) cells. Interestingly, Treg presence negatively correlated with positive nodal status. In addition to their unfavorable role as mediators of evasion from antitumor immune response, Tregs might also have a beneficial role by reducing inflammation thereby limiting early tumor growth and spreading.


[Kinetics of low molecular weight substrate hydrolysis by immobilized trypsin].
The catalytic properties of trypsin immoblized on silochrome were studied in a flow reactor with replacement. The hydrolysis of methyl ester N-n-tosyl-L-arginine obeys the Michaelis--Menten kinetics. The apparent K'm value for the system with immobilized trypsin is considerably lower than for native trypsin. The K'm value was decreased with an increase in the rate of the substrate flow through the reactor or when smaller-sized silochrome granules were used. It is assumed that the apparent K'm value for the immobilized system is due to diffusion. The effects of diffusion on the catalytic properties of the immobilized enzyme were estimated.


Public Health and Medicine's Need to Respond to Cannabis Commercialization in the United States: A Commentary.
Cannabis legalization has resulted in rapid commercialization, making this new market increasingly attractive to tobacco, alcohol and beverage, agricultural, and pharmaceutical multinational corporations, who are well positioned to capitalize on the synergy between cannabis and their products. The fact that cannabis remains a Schedule I drug under the Controlled Substances Act is inhibiting research, which consequently prevents evidence-based regulation of modern, more potent, engineered cannabis products and their use. Without a research exemption for legitimate studies of commercially available products, cannabis' Schedule I classification makes it very difficult to conduct medical and scientific research to inform policymaking and regulation. As corporate commercialization looms large, public health organizations need to engage the issue of rapid commercialization of cannabis products and press for evidence-based policies based on public health best practices.


Relationships between salivary free testosterone and the expression of force and power in elite athletes.
This study examined the predictive relationships between the salivary free testosterone (T) concentrations of elite athletes and the expression of force and power. A group of elite male rugby players (N.=64) were assessed for peak force (PF), peak rate of force development (PRFD), force at 100 milliseconds (F100 ms) and 250 milliseconds (F250 ms) during an isometric mid-thigh pull (IMTP), and/or peak power (PP) and height during a countermovement jump (CMJ). Saliva samples were collected before testing and assayed for free T. Relationships between individual T concentrations and performance were assessed as a pooled group and 4 sub-groups of equal size. As pooled data sets, none of the IMTP and CMJ performance variables were significantly correlated with free T in either the PF or PP groups (r=0.01-0.23). The PF and PP abilities of the 4 sub-groups were significantly different, so that PF1>PF2>PF3>PF4 (P<0.001) and PP1>PP2>PP3>PP4 (P<0.01). When the 4 sub-groups were analysed, the T concentrations of the PF4 group were significantly (P<0.05-0.01) correlated to PRFD (r=0.69) and F100 ms (r=0.55) during the IMTP, as was F100 ms in the PF1 group (r=0.66). In the PP1 group, free T also correlated to CMJ height (r=0.62). The key conclusion is that the expression of force and power in an elite athletic group may be dependent, to some extent, on individual variation in salivary free T concentrations and existing strength or power levels. The current results also confirm that the grouping of elite athletes of mixed strength or power ability may bias predictive results in a manner not reflective of sub-groups within this population.


[Interrelation between the activity of the lytic enzyme producer Actinomyces recifensis var. lyticus 2435 and its population variability].
Spontaneous variability of Actinomyces recifensis var. lyticus 2435 producing a complex of lytic enzymes was studied. A correlation between the strain activity and the content of the variants of the main morphological type in the population was shown. The carbon sources influenced the proportion of different type variants in the population. Strain 2435 was rather stable with respect to the level of the synthesis of yeast-like enzymes and showed a significant variation with respect to the level of the biosynthesis of the bacteriolytic complex. The population variation of strain 2435 with respect to the staphylolytic (synthesis of specific endopeptidases) and muramidase activity was most pronounced. The high activity levels of strain 2435 and wide lytic spectrum were provided by selection of the variants of the first morphological type with respect to the property of high staphylolytic activity.


DNA Methylation and the Potential Role of Methyl-Containing Nutrients in Cardiovascular Diseases.
Patients suffering from cardiovascular diseases (CVDs) experience a low quality of life and increase pressure on healthcare systems both nationally and globally. DNA methylation, which refers to the pathway by which DNA methyltransferase facilitates the addition of a methyl group to DNA, is of critical importance in this respect primarily because the epigenetic modification is implicated in a range of serious conditions including atherosclerosis, CVDs, and cancer. Research findings indicate that the number of epigenetic alterations can be elicited (both in utero and in adults) through the administration of certain nutritional supplements, including folic acid and methionine; this is partly attributable to the effect employed by methyl-containing nutrients in DNA methylation. Thus, for the purpose of illuminating viable therapeutic measures and preventive strategies for CVDs, research should continue to explore the intricate associations that exist between epigenetic regulation and CVD pathogenesis. This review centers on an exposition of the mechanism by which DNA methylation takes place, the impact it has on a range of conditions, and the potential clinical value of nutrition, driven mainly by the observation that nutritional supplements such as folic acid can affect DNA methylation.


Reconstitution of mammalian mitochondrial translation system capable of correct initiation and long polypeptide synthesis from leaderless mRNA.
Mammalian mitochondria have their own dedicated protein synthesis system, which produces 13 essential subunits of the oxidative phosphorylation complexes. We have reconstituted an in vitro translation system from mammalian mitochondria, utilizing purified recombinant mitochondrial translation factors, 55S ribosomes from pig liver mitochondria, and a tRNA mixture from either Escherichia coli or yeast. The system is capable of translating leaderless mRNAs encoding model proteins (DHFR and nanoLuciferase) or some mtDNA-encoded proteins. We show that a leaderless mRNA, encoding nanoLuciferase, is faithfully initiated without the need for any auxiliary factors other than IF-2mt and IF-3mt. We found that the ribosome-dependent GTPase activities of both the translocase EF-G1mt and the recycling factor EF-G2mt are insensitive to fusidic acid (FA), the translation inhibitor that targets bacterial EF-G homologs, and consequently the system is resistant to FA. Moreover, we demonstrate that a polyproline sequence in the protein causes 55S mitochondrial ribosome stalling, yielding ribosome nascent chain complexes. Analyses of the effects of the Mg concentration on the polyproline-mediated ribosome stalling suggested the unique regulation of peptide elongation by the mitoribosome. This system will be useful for analyzing the mechanism of translation initiation, and the interactions between the nascent peptide chain and the mitochondrial ribosome.


A four-cell typology to measure hospital teaching status.
Hospital participation in graduate medical education is of increasing interest in the health policy arena because of its financial and behavioral implications for hospitals. In this attempt to create a more refined method of measuring hospital teaching status, a four-cell classification, or typology, of all nonfederal short-term general teaching hospitals was developed from 11 descriptors of educational output. This typology proved to be both effective in distinguishing different types of teaching institutions and useful in analyzing interhospital variation in scope of services, case mix, and cost.


The allosteric mechanism of bovine liver glutamate dehydrogenase. Evidence from circular-dichroism studies for a conformational change in the ternary complex enzyme-(oxidized nicotinamide-adenine dinucleotide)-glutarate.
1. Computer averaging of multiple scans was used to refine the circular dichroism spectrum of bovine liver glutamate dehydrogenase, revealing well-defined structure in the aromatic region. 2. The circular dichroism of NAD+ bound to glutamate dehydrogenase is strongly negative at 260nm, probably owing to immobilization of the adenosine moiety. Loss of the characteristic adenine-nicotinamide interaction suggests that the coenzyme is bound in an unstacked conformation. 3. Glutarate and succinate, substrate analogues that are both inhibitors competitive with glutamate, do not significantly perturb the circular-dichroism spectrum of the enzyme in the absence of NAD+. 4. In the presence of NAD+, 150nM-succinate decreases the negative circular dichroism corresponding to bound coenzyme, but does not affect the protein circular dichroism. However, ISOmM-glutarate causes profound alternations of the circular-dichroism spectra of the bound NAD+ and of the enzyme, indicative of a protein conformational change. This direct evidence of conformational change specifically promoted by C5 dicarboxylates confirms the previous inference from protection studies. 5. The conformational change is discussed in relation to the allosteric mechanism of glutamate dehydrogenase.


The Dystonia Coalition: A Multicenter Network for Clinical and Translational Studies.
Dystonia is a movement disorder characterized by sustained or intermittent muscle contractions causing abnormal postures, repetitive movements, or both. Research in dystonia has been challenged by several factors. First, dystonia is uncommon. Dystonia is not a single disorder but a family of heterogenous disorders with varied clinical manifestations and different causes. The different subtypes may be seen by providers in different clinical specialties including neurology, ophthalmology, otolaryngology, and others. These issues have made it difficult for any single center to recruit large numbers of subjects with specific types of dystonia for research studies in a timely manner. The Dystonia Coalition is a consortium of investigators that was established to address these challenges. Since 2009, the Dystonia Coalition has encouraged collaboration by engaging 56 sites across North America, Europe, Asia, and Australia. Its emphasis on collaboration has facilitated establishment of international consensus for the definition and classification of all dystonias, diagnostic criteria for specific subtypes of dystonia, standardized evaluation strategies, development of clinimetrically sound measurement tools, and large multicenter studies that document the phenotypic heterogeneity and evolution of specific types of dystonia.


Ketosis and appetite-mediating nutrients and hormones after weight loss.
Diet-induced weight loss is accompanied by compensatory changes, which increase appetite and encourage weight regain. There is some evidence that ketogenic diets suppress appetite. The objective is to examine the effect of ketosis on a number of circulating factors involved in appetite regulation, following diet-induced weight loss. Of 50 non-diabetic overweight or obese subjects who began the study, 39 completed an 8-week ketogenic very-low-energy diet (VLED), followed by 2 weeks of reintroduction of foods. Following weight loss, circulating concentrations of glucose, insulin, non-esterified fatty acids (NEFA), β-hydroxybutyrate (BHB), leptin, gastrointestinal hormones and subjective ratings of appetite were compared when subjects were ketotic, and after refeeding. During the ketogenic VLED, subjects lost 13% of initial weight and fasting BHB increased from (mean±s.e.m.) 0.07±0.00 to 0.48±0.07 mmol/l (P<0.001). BHB fell to 0.19±0.03 mmol/l after 2 weeks of refeeding (P<0.001 compared with week 8). When participants were ketotic, the weight loss induced increase in ghrelin was suppressed. Glucose and NEFA were higher, and amylin, leptin and subjective ratings of appetite were lower at week 8 than after refeeding. The circulating concentrations of several hormones and nutrients which influence appetite were altered after weight loss induced by a ketogenic diet, compared with after refeeding. The increase in circulating ghrelin and subjective appetite which accompany dietary weight reduction were mitigated when weight-reduced participants were ketotic.


Development of a harmonised method for the profiling of amphetamines: III. Development of the gas chromatographic method.
This study focused on gas chromatographic analysis of target compounds found in illicit amphetamine synthesised by the Leuckart reaction, reductive amination of benzyl methyl ketone, and the nitrostyrene route. The analytical method was investigated and optimised with respect to introduction of amphetamine samples into the gas chromatograph and separation and detection of the target substances. Sample introduction using split and splitless injection was tested at different injector temperatures, and their ability to transfer the target compounds to the GC column was evaluated using cold on column injection as a reference. Taking the results from both techniques into consideration a temperature of 250 degrees C was considered to be the best compromise. The most efficient separation was achieved with a DB-35MS capillary column (35% diphenyl 65% dimethyl silicone; 30 m x 0.25 mm, d(f) 0.25 microm) and an oven temperature program that started at 90 degrees C (1 min) and was increased by 8 degrees C/min to 300 degrees C (10 min). Reproducibility, repeatability, linearity, and limits of determination for the flame ionisation detector (FID), nitrogen phosphorous detector (NPD), and mass spectrometry (MS) in scan mode and selected ion monitoring (SIM) mode were evaluated. In addition, selectivity was studied applying FID and MS in both scan and SIM mode. It was found that reproducibility, repeatability, and limits of determination were similar for FID, NPD, and MS in scan mode. Moreover, the linearity was better when applying FID or NPD whereas the selectivity was better when utilising the MS. Finally, the introduction of target compounds to the GC column when applying injection volumes of 0.2 microl, 1 microl, 2 microl, and 4 microl with splitless injection respectively 1 microl with split injection (split ratio, 1:40) were compared. It was demonstrated that splitless injections of 1 microl, 2 microl, and 4 microl could be employed in the developed method, while split injection and splitless injections of 0.2 microl should be avoided.


Persistent collapse of biomass in Amazonian forest edges following deforestation leads to unaccounted carbon losses.
Deforestation is the primary driver of carbon losses in tropical forests, but it does not operate alone. Forest fragmentation, a resulting feature of the deforestation process, promotes indirect carbon losses induced by edge effect. This process is not implicitly considered by policies for reducing carbon emissions in the tropics. Here, we used a remote sensing approach to estimate carbon losses driven by edge effect in Amazonia over the 2001 to 2015 period. We found that carbon losses associated with edge effect (947 Tg C) corresponded to one-third of losses from deforestation (2592 Tg C). Despite a notable negative trend of 7 Tg C year-1 in carbon losses from deforestation, the carbon losses from edge effect remained unchanged, with an average of 63 ± 8 Tg C year-1 Carbon losses caused by edge effect is thus an additional unquantified flux that can counteract carbon emissions avoided by reducing deforestation, compromising the Paris Agreement's bold targets.


Cutaneous mycosis caused by Paecilomyces lilacinus.
A 20-year-old woman had erythematous scaly plaques persistent for 15 years on the left cheek. Cultures from scales and biopsy specimens on Sabouraud's glucose agar repeatedly yielded floccose lilac colonies, and those on a Czapek's solution agar plate developed deep purplish red pigment, which is characteristic of Paecilomyces lilacinus. The PAS stain of the tissue section showed ovoid, divergent, or club-shaped fungal elements among the inflammatory cells or in giant cells. Two months after the patient and a control subject were inoculated with the isolates, P lilacinus could be reisolated from the patient only. Oral administration of griseofulvin significantly reduced erythema and papules. This is the first report, to our knowledge, of deep cutaneous mycosis caused by P lilacinus.


Long-term Effects of Moderate versus High Durations of Aerobic Exercise on Biomarkers of Breast Cancer Risk: Follow-up to a Randomized Controlled Trial.
The optimal lifestyle for breast cancer prevention over the long term is unclear. We aimed to determine whether or not the amount of exercise prescribed in a year-long exercise intervention influences breast cancer biomarker levels 1 year later. We conducted a 24-month follow-up study (2012-2014) to the Breast Cancer and Exercise Trial in Alberta (BETA), a 12-month, two-armed (1:1), two-center randomized controlled trial of exercise in 400 cancer-free, postmenopausal women. The exercise prescription was moderate-vigorous aerobic exercise, 5 days/week (3 days/week supervised) for 30 minutes/session (MODERATE) or 60 minutes/session (HIGH). Participants were asked not to change their usual diet. We used linear mixed models to compare biomarker concentrations (C-reactive protein, insulin, glucose, HOMA-IR, estrone, sex hormone binding globulin, total estradiol, and free estradiol) over time (0, 12, and 24 months) by group (MODERATE, HIGH), using group-time interactions. After 12 months of no intervention, 24-month fasting blood samples were available for 84.0% and 82.5% of MODERATE and HIGH groups, respectively (n = 333/400). We found no evidence that 0 to 24- or 12 to 24-month biomarker changes differed significantly between randomized groups (HIGH:MODERATE ratio of mean biomarker change ranged from 0.97 to 1.06, P values >0.05 for all). We found more favorable biomarker profiles among participants who experienced greater than the median fat loss during the trial. Prescribing aerobic exercise for 300 versus 150 minutes/week for 12 months to inactive, postmenopausal women had no effects on longer-term biomarkers. Exercise may lead to larger improvements in breast cancer biomarkers after intervention among women who also experience fat loss with exercise.


Effects of propiverine and naftopidil on the urinary ATP level and bladder activity after bladder stimulation in rats.
We examined the effects of propiverine hydrochloride and naftopidil on the urinary ATP level and bladder activity after bladder stimulation in rats. Thirty-nine female rats were divided into a control group, a propiverine group, and a naftopidil group. Rats in the propiverine and naftopidil groups were administered 1 ml/day of propiverine or naftopidil dissolved in water at 5mg/ml, while animals in the control group were administered 1 ml of water only. After 2 weeks, 18 rats (6 per group) underwent continuous cystometry with physiological saline or 0.1% acetic acid solution and their bladder activity was recorded. In the remaining 21 rats (7 per group), 0.1% acetic acid solution was infused into the bladder and the urinary ATP level was measured before and after stimulation (days 0-7). During cystometry with acetic acid in the control group, the interval between bladder contractions was shorter and the maximum bladder contraction pressure was higher than the results for cystometry with physiological saline. The maximum bladder contraction pressure was also increased in the naftopidil group, but such a change was not seen in the propiverine group. The urinary ATP level increased significantly in all three groups after the infusion of acetic acid, but the increase of ATP was smaller in the propiverine group (45% of control) and the naftopidil group (62% of control) than in the control group on day 0. Therefore, the inhibitory effect of propiverine and naftopidil on bladder activity may be partly due to blocking ATP release from the bladder epithelium.


Unit costs for non-acute care in Ireland 2016-2019.
Background: This paper presents detailed unit costs for 16 healthcare professionals in community-based non-acute services in Ireland for the years 2016-2019. Unit costs are important data inputs for assessments of health service performance and value for money. Internationally, while some countries have an established database of unit costs for healthcare, there is need for a more coordinated approach to calculating healthcare unit costs. In Ireland, detailed cost analysis of acute care is undertaken by the Healthcare Pricing Office but to date there has been no central database of unit costs for community-based non-acute healthcare services. Methods: Unit costs for publicly employed allied healthcare professionals, Public Health Nurses and Health Care Assistant staff are calculated using a bottom-up micro-costing approach, drawing on methods outlined by the Personal Social Services Research Unit in the UK, and on available Irish and international costing guidelines. Data on salaries, working hours and other parameters are drawn from secondary datasets available from Department of Health, Health Service Executive and other public sources. Unit costs for public and private General Practitioner, dental, and long-term residential care (LTRC) are estimated drawing on available administrative and survey data. Results: The unit costs for the publicly employed non-acute healthcare professionals have changed by 2-6% over the timeframe 2016-2019 while larger percentage changes are observed in the unit costs for public GP visits and public LTRC (14-15%). Conclusions: The costs presented here are a first step towards establishing a central database of unit costs for non-acute healthcare services in Ireland. The database will help ensure consistency across Irish health costing studies and facilitate cross-study and cross-country comparisons. Future work will be required to update and expand on the range of services covered and to incorporate new data and methodological developments in cost estimation as they become available.


Screening for Chronic Infectious Diseases by Serology in Those Presenting with Malaria in London, United Kingdom.
The United Kingdom's cases of malaria infection are primarily acquired in sub-Saharan Africa, with the majority of infections presenting in London.1 When patients go to a hospital with malaria, there is a screening opportunity for other geographically associated chronic infections. We identified patients who were diagnosed with malaria after presenting to our emergency department in London over a 2-year period, to assess whether there may be clinical benefit in screening for chronic viral (hepatitis B, hepatitis C, HIV) or parasitic (schistosomiasis, strongyloidiasis) infection in this cohort. Over this period, 131 patients were diagnosed with malaria. Crude seropositivity rates for HIV, hepatitis B, and strongyloidiasis were higher than expected compared with local population estimates, 7 and 28 times higher for HIV and hepatitis B, respectively. Those patients with previously unidentified cases were offered appropriate treatment. These findings support the potential clinical and public health benefits of screening for other infectious diseases in the context of a malaria diagnosis.


Low mean impedance in 24-hour tracings and esophagitis in children: a strong connection.
Esophageal multiple intraluminal impedance baseline is an additional impedance parameter that was recently related to esophageal integrity. The aim of this study was to assess the relationship between mean esophageal impedance value and endoscopic findings in a large group of children. Children with symptoms of gastroesophageal reflux submitted to both endoscopy and impedance were included. Esophagitis was graded according to the Los Angeles classification. Mean impedance value was automatically calculated over 24-hour tracings. Data were adjusted for age through z-score transformation using percentiles normalized by the LMS (Lambda for the skew, Mu for the median, and Sigma for the generalized coefficient of variation) method. Nonparametric Mann-Whitney and Kruskal-Wallis tests, multiple, and stepwise regression were used. P-value <0.05 was considered as statistically significant. A total of 298 impedance tracings were analyzed. Endoscopic and histological esophagitis were detected in 30 and 29% patients, respectively. Median baseline z-score was significantly decreased both in proximal (P = 0.02) and distal (P = 0.01) esophagus in patients with endoscopic (but not histological) esophagitis. Patients with more severe esophagitis showed the lowest z-score. Bolus exposure index and the number of reflux episodes were the variables that were significantly associated with the baseline z-score. Impedance z-score is significantly decreased in infants and children with endoscopic esophagitis. Severity of esophagitis, bolus exposure index, and number of reflux episodes are factors influencing mean esophageal impedance.


Precautions and strategies in using a commercial flatbed scanner for radiochromic film dosimetry.
The purpose of this study was to investigate the value of a commercially available flatbed scanner for film dosimetry with radiochromic film for external radiotherapy. The EPSON Pro 1680 Expression scanner was examined as a densitometer for two-dimensional film dosimetry with Gafchromic EBT film. An accurate and efficient scanning procedure was established. Possible drift and warm-up effects of the scanner were studied and the direct physical influence of the scanner light on the radiochromic film was assessed. Next, we investigated the scan field uniformity. Also, we examined if the accuracy of radiochromic film was improved by subtracting the optical density of the unirradiated blank film from the optical density of the irradiated film. To assess the accuracy of Gafchromic EBT film when the EPSON scanner was used as a densitometer, the depth dose of a 2 x 15 cm(2) field and the in-plane and cross-plane profiles of a 15 x 15 cm(2) field were measured and compared with diamond detector measurements. When taking consecutive scans, we found that the optical density taken from the first scan was about 1% higher than the optical density taken from subsequent scans. We attribute this to the warming up of the lamp of the scanner. Longer-term drift of the scanner was found to be absent. We found that the use of a correction matrix was necessary to correct for the non-uniform scanner response over the scan field. Subtracting the optical density of the unirradiated blank film from the irradiated film improves the precision of the Gafchromic EBT film. Depth dose and profile measurements with Gafchromic EBT film and the diamond detector are in agreement within 2.5%. The EPSON Pro 1680 Expression scanner is an excellent tool for accurate two-dimensional film dosimetry with Gafchromic EBT film provided that some precautions and corrections are taken into account.


A relation between electrode discrimination and amplitude modulation detection by cochlear implant listeners.
The objective of this study was to examine the relation between measures of spectral and temporal resolutions in cochlear implant listeners at a particular electrode location. The hypothesis was that a common underlying factor, such as the health of local groups of neurons, might partially determine patients' sensitivity to both spectral and temporal cues at specific tonotopic locations. Participants were adult cochlear implant listeners. A significant correlation was found between electrode discrimination measured at soft levels (20% and 30% of the dynamic range) and modulation sensitivity at those levels, for stimulation in bipolar mode and a 100 Hz modulation rate. Correlations between the two measures were weaker under monopolar stimulation, or when the modulation rate was 10 Hz. At a higher stimulation level (40% of the dynamic range), no significant correlations between these measures were observed. It is hypothesized that the more restricted excitation pattern at lower levels and/or with a narrower stimulation mode allows the measurement of locally driven sensitivity to spectral and temporal cues, particularly under more challenging listening conditions. Thus, psychophysical measures obtained under conditions that evoke a narrower excitation pattern may serve as a useful indicator of the functional health of local neural populations.


The mixed lineage kinase-3 inhibitor URMC-099 improves therapeutic outcomes for long-acting antiretroviral therapy.
During studies to extend the half-life of crystalline nanoformulated antiretroviral therapy (nanoART) the mixed lineage kinase-3 inhibitor URMC-099, developed as an adjunctive neuroprotective agent was shown to facilitate antiviral responses. Long-acting ritonavir-boosted atazanavir (nanoATV/r) nanoformulations co-administered with URMC-099 reduced viral load and the numbers of HIV-1 infected CD4+ T-cells in lymphoid tissues more than either drug alone in infected humanized NOD/SCID/IL2Rγc-/- mice. The drug effects were associated with sustained ART depots. Proteomics analyses demonstrated that the antiretroviral responses were linked to affected phagolysosomal storage pathways leading to sequestration of nanoATV/r in Rab-associated recycling and late endosomes; sites associated with viral maturation. URMC-099 administered with nanoATV induced a dose-dependent reduction in HIV-1p24 and reverse transcriptase activity. This drug combination offers a unique chemical marriage for cell-based viral clearance. From the Clinical Editor: Although successful in combating HIV-1 infection, the next improvement in antiretroviral therapy (nanoART) would be to devise long acting therapy, such as intra-cellular depots. In this report, the authors described the use of nanoformulated antiretroviral therapy given together with the mixed lineage kinase-3 inhibitor URMC-099, and showed that this combination not only prolonged drug half-life, but also had better efficacy. The findings are hoped to be translated into the clinical setting in the future.


Outcomes the Ontario Bariatric Network: a cohort study.
Bariatric surgery centres of excellence are relatively new in Canada and were first started in Ontario in 2009. This study presents short-term outcomes of Canada's largest bariatric collaborative, from Ontario, during its first 3 years. We performed a population-based cohort study that included all patients (age ≥ 18) who received a Roux-en-Y gastric bypass or sleeve gastrectomy for the purpose of weight loss from March 2009 to April 2012 within Ontario. Data were derived from the Canadian Institute for Health Information Discharge Abstract and Hospital Morbidity Databases. Primary outcomes included short-term overall complication rate, reoperation rate, anastomotic leak rate and death. Hierarchical logistic regression was used to identify risk factors for overall complications. A median odds ratio (OR) was used to compare risk-adjusted complication rates across centres of excellence. A total of 5007 procedures (91.7% Roux-en-Y gastric bypass, 8.3% sleeve gastrectomy) were performed during the 3-year study period, with an overall complication rate of 11.7% (95% confidence interval [CI] 10.8%-12.6%). The leak rate was 0.84% (95% CI 0.61%-1.13%), the reoperation rate was 4.6% (95% CI 4.0%-5.2%) and mortality was 0.16% (95% CI 0.07%-0.31%). Male sex, chronic kidney disease and osteoarthritis were identified as risk factors for overall complications (p value < 0.05). The median ORs across centres of excellence, calculated for both overall complications and reoperation rate, were 1.76 and 1.49, respectively. Bariatric surgery within Ontario has similar short-term outcomes to those of other major world centres. The variability of outcomes within centres of excellence highlights areas for program quality improvement.


Molecular mechanisms that control expression of the B lymphocyte antigen receptor complex.
The B cell receptor for antigen (BCR) is a complex of membrane immunoglobulin (mIg) and at least two other proteins, Ig alpha (mb-1) and Ig beta (B29). This complex promotes surface expression of the BCR and acts to transduce an activation signal. We have used a system of mu heavy chain constructs transfected into murine B cell lines to probe structure-function relationships in the BCR complex. One mutant mu chain, in which two polar transmembrane residues (Tyr587, Ser588) are replaced with valine, fails to associate with Ig alpha and Ig beta and is incapable of transducing signals as a result of mIg cross-linking. This mutant is expressed on the surface at high levels when transfected into a plasmacytoma line that lacks Ig alpha, whereas wild-type mu is retained in this cell line in the endoplasmic reticulum. Pulse-chase and immunoprecipitation analyses indicate that the mutant is more rapidly released from calnexin than the wild-type mu. Further, transfection of Ig alpha into this Ig alpha-negative cell line allows release of the mu chain from calnexin and surface expression of the BCR. These results identify the transmembrane residues of mu heavy chain that control binding to calnexin and Ig alpha, and suggest that calnexin-dependent intracellular retention is an important control mechanism for expression of the BCR complex.


Gender differences in patterns of HIV service use in a national sample of HIV-positive Australians.
There have been clear gender differences in the experience of living with HIV in Australia since the start of the epidemic. This paper examines the patterns of health service use and experiences at those services over a period of six years. The results reported here are drawn from the HIV Futures surveys, four consecutive national, cross-sectional Australian surveys of the lives of PLWHA. Women were found to use different medical services to men both for non HIV-related and HIV-related treatment, being more likely to use generalist services and hospital-based HIV specialists. Women also reported higher rates of discrimination at health services, however reports of new incidences of discrimination were found to decrease from 2001 onwards. Although women reported higher levels of unwanted disclosure of HIV status than men, particularly by health care workers, new reports of unwanted disclosure decreased between 2003 and 2005. These data indicate that there are long-term gender differences in medical service use by PLWHA in Australia, and that this has been associated with higher rates of discrimination and loss of confidentiality for women. However the decrease in new reports of discrimination over time indicates that improved education of health service providers has been successful.


Factor structure of a male involvement index to increase the effectiveness of prevention of mother-to-child HIV transmission (PMTCT) programs: revised male involvement index.
Male involvement in the prevention of mother to child transmission of HIV (PMTCT) during pregnancy is encouraged, but the accuracy of its measurement has not been established. The purpose of this cross-sectional study was to establish the factor structure of an index of male involvement in PMTCT. Using a structured questionnaire, 1369 HIV positive pregnant women and 522 male partners were recruited in rural Mpumalanga, South Africa. A principal component analysis with varimax rotation yielded two components accounting for 49.9% of the variance. The first factor, named Communication-Based Male Involvement and addressing partner discussions about prenatal, HIV, birth and postnatal issue, accounted for 39.8% of the variance. The second, named Action-Based Male Involvement and addressed partner awareness and actions, and information provided during antenatal visits, financial support, and attendance to visits, accounted for 10.1% of the variance. Given the low rates of male involvement participation in antenatal care, interventions are needed to increase male involvement. However, a method of quantifying male partner participation was needed to assess the effectiveness of such interventions. We hope that the Revised Male Involvement Index will stimulate further research in this area, thus increasing the effectiveness of PMTCT programs aimed at increasing male partner involvement.


[Effect of tranexamic acid on postoperative bleeding in pediatric heart surgery].
To assess the effects of a single dose of tranexamic acid on bleeding and requirement for blood product transfusion in children undergoing cardiac surgery with cardiopulmonary bypass. A prospective study of closed cohorts undergoing pediatric heart surgery was carried out. The children weighed between 4 and 10 kg. Reoperated and cyanotic patients were included in the sample. The treatment group received 50 mg x kg(-1) of tranexamic acid before surgery. Analyzed data collected during the first 24 hours after surgery were biochemical parameters, bleeding, use of blood products, and D-dimer levels. Fifty-three patients, 25 in the treatment group, were enrolled. Patients on treatment had 24.8% less bleeding in the first 24 hours after surgery (P = .02). The transfusion of blood products was 20% less in the treatment group, although the difference was not significant except in the subgroup of patients who were reoperated. In that group the amount of blood products transfused was 72% less than in the control group (P = .05). D-dimer levels were also lower in the treatment group (P = .003). No adverse effects attributable to the treatment were observed. A single preoperative dose of tranexamic acid to inhibit fibrinolysis reduces bleeding 24.8% in pediatric patients undergoing heart surgery with cardiopulmonary bypass. The effect is greater in reoperated patients, leading to a reduction in their requirement for transfusion. The use of this therapy in these patients is therefore highly justified.


Incidence of and Risk Factors for Loss of 1 Blood Volume During Spinal Fusion Surgery in Patients With Cerebral Palsy.
Spinal fusion surgery is associated with greater blood loss in patients with cerebral palsy (CP) than in patients with adolescent idiopathic scoliosis. Risk factors for loss of 1 blood volume (LOBV) in patients with CP have not been well studied. We investigated the incidence of and risk factors for LOBV during spinal fusion surgery in young patients with CP. We queried a multicenter registry of CP patients for all patients 21 years or younger who had undergone spinal fusion from 2008 through 2013; 272 patients met these criteria. We analyzed data on patient characteristics, preoperative laboratory values, radiographic measures, and surgical characteristics. For univariate analysis, we used χ tests and logistic regression models. Factors that were significant in the univariate analysis were used to construct a multivariate logistic regression model. Significance was set at P<0.01. Incidence of LOBV was 39.7%. On multivariate analysis, unit rod construct and coronal curve magnitude were significantly associated with LOBV (P<0.01). The multivariate model accounted for 32.2% of variance in LOBV. Compared with patients with pedicle screw-rod constructs, patients with unit rod constructs had 12.6-fold higher odds of LOBV (P<0.01). For each 1-degree increase in coronal curve magnitude, odds of LOBV increased 1.03-fold (P<0.01). In patients with CP, there is a substantial risk of LOBV during spinal fusion surgery. Use of unit rod constructs and greater preoperative coronal curves were significant risk factors for LOBV during surgery. Level II.


Comparative Evaluation of Two SD-OCT Macular Parameters (GCC, GCL) and RNFL in Chiasmal Compression.
To evaluate the relationship between different macular thickness parameters analyzed by SD-OCT and the central visual field (VF) evaluated with automated kinetic perimetry in a cohort of patients with pituitary tumors. Data from patients with pituitary adenoma treated at Reims University Hospital between October 1st, 2017, and May 31st, 2018 were collected. All patients underwent an automated kinetic perimetry and a SD-OCT to map the ganglion cell complex (GCC), the ganglion cell layer (GCL) thickness and the retinal nerve fiber layer (RNFL) using devices from two different manufacturers. Univariate and multivariate analysis were used to evaluate the correlation between the area of central VF in square degrees (deg2) and the SD-OCT parameters (μm). Eighty-eight eyes were included in the analysis. All the thickness parameters measured in SD-OCT decreased with the visual field alteration. The best correlation was observed between superior thickness parameters (GCC, GCL) and the inferior central visual field. The most pertinent predictive factors for visual field loss were the inferior central GCL and the nasal RNFL (both AUC=0.775) with a sensitivity respectively of 86% and 70%. This study suggests that both GCC, GCL thickness parameters could be reliable predictors of central visual field impairment in patients with pituitary tumors. There was no significative difference between both devices.


Acquired lesions of the corpus callosum: MR imaging.
In this pictorial review, we illustrate acquired diseases or conditions of the corpus callosum that may be found by magnetic resonance (MR) imaging of the brain, including infarction, bleeding, diffuse axonal injury, multiple sclerosis, acute disseminated encephalomyelitis, Marchiafava-Bignami disease, glioblastoma, gliomatosis cerebri, lymphoma, metastasis, germinoma, infections, metabolic diseases, transient splenial lesion, dilated Virchow-Robin spaces, wallerian degeneration after hemispheric damage and focal splenial gliosis. MR imaging is useful for the detection and differential diagnosis of corpus callosal lesions. Due to the anatomical shape and location of the corpus callosum, both coronal and sagittal fluid-attenuated inversion recovery images are most useful for visualizing lesions of this structure.


Asymptotic decay of pair correlations in a Yukawa fluid.
We analyze the r-->infinity asymptotic decay of the total correlation function h (r) for a fluid composed of particles interacting via a (point) Yukawa pair potential. Such a potential provides a simple model for dusty plasmas. The asymptotic decay is determined by the poles of the liquid structure factor in the complex plane. We use the hypernetted-chain closure to the Ornstein-Zernike equation to determine the line in the phase diagram, well removed from the freezing transition line, where crossover occurs in the ultimate decay of h (r) , from monotonic to damped oscillatory. We show that (i) crossover takes place via the same mechanism (coalescence of imaginary poles) as in the classical one-component plasma and in other models of Coulomb fluids and (ii) leading-order pole contributions provide an accurate description of h (r) at intermediate distances r as well as at long range.


Characteristics of brain functional and structural connectivity in alexithymic students.
Alexithymia is a multifaceted personality trait and a risk factor for several mental and physical diseases. In this study, 21 alexithymic students and 21 nonalexithymic students were recruited from the local university and assigned to the alexithymic group and the control group, respectively. Then, the functional connectivity and the structural connectivity among the brain regions of the students were investigated using resting-state functional magnetic resonance imaging (rsfMRI), function connection (FC) analysis, and diffusion tensor imaging (DTI). The rsfMRI results revealed 14 brain regions showing significant differences in the amplitude of low-frequency fluctuations between the two groups. Comparative analysis of the FC and DTI data in these brain regions between the two groups identified altered levels of functional and structural connectivity between the following four pairs of regions in the alexithymic subjects: the right inferior temporal gyrus and the central posterior gyrus, the left temporal gyrus and the insula, and the bilateral superior frontal gyrus and the anterior cingulate gyrus. Compared with single MRI analysis, the multiple MRI analysis identified more precisely the brain regions that could play a key role in the development of alexithymia.


Methodologies to Isolate and Purify Clinical Grade Extracellular Vesicles for Medical Applications.
The use of extracellular vesicles (EV) in nano drug delivery has been demonstrated in many previous studies. In this study, we discuss the sources of extracellular vesicles, including plant, salivary and urinary sources which are easily available but less sought after compared with blood and tissue. Extensive research in the past decade has established that the breadth of EV applications is wide. However, the efforts on standardizing the isolation and purification methods have not brought us to a point that can match the potential of extracellular vesicles for clinical use. The standardization can open doors for many researchers and clinicians alike to experiment with the proposed clinical uses with lesser concerns regarding untraceable side effects. It can make it easier to identify the mechanism of therapeutic benefits and to track the mechanism of any unforeseen effects observed.


Elucidation of immunological response and its regulatory network by P-TUFT-ALT-2: a promising fusion protein vaccine for human lymphatic filariasis.
Human lymphatic filariasis, a mosquito-borne neglected tropical parasitic disease, needs an early development of prophylactic agents such as a vaccine for its successful elimination. Our earlier study suggested the enhanced immunological response by fusion protein (P-TUFT-ALT-2) of Tuftsin and ALT-2 in a mice model. We cultured human peripheral blood mononuclear cells (PBMCs) and treated cells with Escherichia coli-expressed ALT-2 (E-ALT-2) and P-TUFT-ALT-2. Real-time polymerase chain reaction was performed to identify the mRNA copy number of various cytokine and transcription factor genes. The recombinant vaccine candidate was also validated for humans by immunoreactivity with human sera samples of natural infection. In this study, P-TUFT-ALT-2 stimulated 12% higher PBMC proliferation in endemic normal (EN) individuals than E-ALT-2 alone. There was enhanced production of IFN γ, IL-2, IL-5 and IL-12, indicating a balanced Th1/Th2 response. However, higher expression of IL-5 and lower IL-4 validate the humoral response through an IL-5-dependent manner. Also, high level of IL-17 indicates a strong Th/Treg regulation over T-cell activation. The upregulated T-bet might have enhanced IFN-γ production, whereas GATA-3 was supposed to enhance IL-5 expression. The fusion protein also exhibited 15-16% higher reactivity with EN clinical sera, exposing the upregulation of IgG1 and IgM in natural infection. The higher reactivity of P-TUFT-ALT-2 with sera of natural infection (EN) was validated indirectly by B-cell activation through various cytokines and regulatory genes produced from different T cells. Thus, these findings endorse P-TUFT-ALT-2 as a potential vaccine candidate for human lymphatic filariasis.


Evaluation of essential and variable residues of nukacin ISK-1 by NNK scanning.
Nukacin ISK-1, a type-A(II) lantibiotic, comprises 27 amino acids with a distinct linear N-terminal and a globular C-terminal region. To identify the positional importance or redundancy of individual residues responsible for nukacin ISK-1 antimicrobial activity, we replaced the native codons of the parent peptide with NNK triplet oligonucleotides in order to generate a bank of nukacin ISK-1 variants. The bioactivity of each peptide variant was evaluated by colony overlay assay, and hence we identified three Lys residues (Lys1, Lys2 and Lys3) that provided electrostatic interactions with the target membrane and were significantly variable. The ring structure of nukacin ISK-1 was found to be crucially important as replacing the ring-forming residues caused a complete loss of bioactivity. In addition to the ring-forming residues, Gly5, His12, Asp13, Met16, Asn17 and Gln20 residues were found to be essential for antimicrobial activity; Val6, Ile7, Val10, Phe19, Phe21, Val22, Phe23 and Thr24 were relatively variable; and Ser4, Pro8, His15 and Ser27 were extensively variable relative to their positions. We obtained two variants, Asp13Glu and Val22Ile, which exhibited a twofold higher specific activity compared with the wild-type and are the first reported type-A(II) lantibiotic mutant peptides with increased potency.


The thromboprophylactic effect of graded elastic compression stockings in combination with dextran 70.
We studied 80 patients who were older than 50 years of age to determine if graded elastic compression stockings reduced the frequency of postoperative thrombosis in patients undergoing dextran 70 prophylaxis. All of the patients received a total of 2,000 mL of dextran 70 during three days; according to a random table, each of the patients had one leg encased in a graded compression stocking for one week. Thrombosis development was screened with the fibrinogen I 125 test. Eight patients manifested thrombosis-one in the thigh and seven in the calf--localized to the unstockinged leg, a frequency significantly greater than the zero frequency in the stockinged leg. No untoward effects of this combination prophylaxis were noted.


Gamma heavy chain disease: clinical aspects and characterization of a deleted, noncovalently linked gamma1 heavy chain dimer (BAZ).
This report describes the clinical and immunoglobulin features of a patient with gamma heavy chain disease (HCD), who presented with a clinical picture suggestive of an underlying malignancy rather than the usual picture of lymphoma or granulomatous disease. A unique clinical feature was the nearly total replacement of the submaxillary glands by plasma cells. The patient's serum and urine contained a paraprotein, gammaHCD protein BAZ, which belongs to the gamma1 subclass and forms noncovalently linked dimers with a molecular weight of approximately 60,000 daltons. This mutant protein exhibited a deletion which encompassed most of the variable (V) region, the first constant domain (CH 1), and the hinge region. In addition, preliminary structural analyses demonstrated the replacement of alanine by glycine in position 431 of the carboxyterminal octadecapeptide. This substitution may possibly represent another allotypic marker on IgG1 proteins.


The presence or absence of a vimentin-type intermediate filament network affects the shape of the nucleus in human SW-13 cells.
Human SW-13 cells express the intermediate filament protein vimentin in a mosaic pattern (Hedberg, K. K. and Chen, L. B. (1986). Exp. Cell Res. 163, 509-517). We have isolated SW-13 clones that do (vim+) or do not (vim-) synthesize vimentin as analyzed using anti-intermediate filament immunofluorescence, electron microscopy and two-dimensional gel analysis of detergent-extracted preparations. Vimentin is the only cytoplasmic intermediate filament protein present in the vim+ cells, and the vim- cells do not contain any detectable cytoplasmic intermediate filament system. The presence or absence of intermediate filaments did not observably affect the distribution of mitochondria, endoplasmic reticulum, microtubules or actin stress fibers when these structures were visualized by fluorescence microscopy. However, electron microscopy and anti-lamin A/C immunofluorescence studies showed that nuclear morphology in vim- cells was frequently characterized by large folds or invaginations, while vim+ cells had a more regular or smooth nuclear shape. When vim- cells were transfected with a mouse vimentin expression plasmid, the synthesis of a mouse vimentin filament network restored the smooth nuclear morphology characteristic of vim+ cells. Conversely, when vim+ cells were transfected with a carboxy-terminally truncated mutant vimentin, expression of the mutant protein disrupted the organization of the endogenous vimentin filaments and resulted in nuclei with a prominently invaginated morphology. These results indicated that in SW-13 cells the vimentin filament system affects the shape of the nucleus.


Shoulder instability in patients with joint hyperlaxity.
Generalized ligamentous hyperlaxity and glenohumeral joint instability are common conditions that exhibit a spectrum of diverse clinical forms and may coexist in the same patient. No single diagnostic test can confirm the presence of these disorders, and a careful clinical assessment is important. Unlike patients with traumatic shoulder instability, patients with hyperlaxity and instability are more likely to experience episodes of recurrent subluxation than they are to have recurrent dislocation. They are more likely to have instability in more than one anatomic plane, and they usually do not have the soft-tissue and osseous lesions associated with traumatic instability. Shoulder symptoms in a patient with hyperlaxity are not always due to instability; other pathological conditions may coexist, with rotator cuff impingement being the most common. Most patients with hyperlaxity have a reduction in instability symptoms after nonoperative treatment, including physical therapy, activity modification, and additional psychological support when necessary. Operative treatment provides reproducibly good results for patients with hyperlaxity who do not respond to a prolonged program of nonoperative measures. Open inferior capsular shift remains the gold standard of operative treatment, although arthroscopic capsular shift and plication procedures are now producing comparable results. Thermal capsulorrhaphy is associated with unacceptably high failure rates and postoperative complications and cannot be recommended as a treatment.


Changes in respiratory activity induced by mastication in humans.
We studied the influence of mastication on respiratory activity in nine healthy volunteers who were requested to masticate a 5-g chewing gum bolus at a spontaneous rate (SR) for 5 min and "at the maximum possible rate" (MPR) for 1 min. Significant increases in respiratory frequency were induced by SR mastication due to a decrease in both the inspiratory and expiratory time. Tidal volume displayed slight nonsignificant decreases, but minute ventilation and mean inspiratory flow significantly increased. The duty cycle (TI/TT) did not change significantly. Total airway resistance significantly increased. Both peak and rate of rise of the integrated electromyographic activity of inspiratory muscles presented marked increases, accompanied by the appearance of a low level of tonic muscular activity. Similar but more intense effects on respiratory activity were induced by MPR mastication; in addition, a significant decrease in tidal volume and a significant increase in TI/TT were observed. Rhythmic handgrip exercise performed at metabolic rates comparable to those attained during SR or MPR mastication induced similar changes in the drive and time components of the breathing pattern, although accompanied respectively by nonsignificant or significant increases in tidal volume. Furthermore, the frequency of SR mastication significantly entrained the respiratory rhythm. The results suggest that mastication-induced hyperpnea does not merely represent a ventilatory response to exercise but also reflects complex interactions between respiratory and nonrespiratory functions of the upper airway and chest wall muscles.


Functional reserve of the heart and catecholamines in experimental mitral valve incompetence.
In dogs with experimental mitral valve incompetence, by the end of the adaptation stage (2nd week) the cardiac functional reserve decreases; the decrement is correlated with the exhaustion of the reserve of catecholamine synthesis evident from the decrement of their precursors in the myocardium and adrenals as well as from the destruction of plentiful cells of the adrenal medulla, accompanied by development of necrosis, dystrophy, and disturbances of vascular permeability in the adrenal glands. In the initial period of the compensatory stage (1st month) a considerable activation of the catecholamine synthesis takes place, together with their increase in the right ventricular myocardium and in the adrenals.


Adverse outcomes after noncardiac surgery in patients with aortic stenosis.
Whether aortic stenosis (AS) increases perioperative risk in noncardiac surgery remains controversial. Limited information is available regarding adequate anesthetic techniques for patients with AS. Using the reimbursement claims data of Taiwan's National Health Insurance, we performed propensity score matching analyses to evaluate the risk of adverse outcomes in patients with or without AS undergoing noncardiac surgery between 2008 and 2013. We also compared the perioperative risk of AS patients undergoing general anesthesia or neuraxial anesthesia. Multivariable logistic regressions were applied to calculate the adjusted odds ratios (aORs) with 95% confidence intervals (CIs) for postoperative mortality and major complications. The matching procedure generated 9741 matched pairs for analyses. AS was significantly associated with 30-day in-hospital mortality (aOR 1.31, 95% CI 1.03-1.67), acute renal failure (aOR 1.42, 95% CI 1.12-1.79), pneumonia (aOR 1.16, 95% CI 1.02-1.33), stroke (aOR 1.14, 95% CI 1.01-1.29), and intensive care unit stay (aOR 1.38, 95% CI 1.27-1.49). Compared with neuraxial anesthesia, general anesthesia was associated with increased risks of acute myocardial infarction (aOR 3.06, 95% CI 1.22-7.67), pneumonia (aOR 1.80, 95% CI 1.32-2.46), acute renal failure (aOR 1.82, 95% CI 1.11-2.98), and intensive care (aOR 4.05, 95% CI 3.23-5.09). The findings were generally consistent across subgroups. AS was an independent risk factor for adverse events after noncardiac surgery. In addition, general anesthesia was associated with greater postoperative complications in AS patients compared to neuraxial anesthesia. This real-world evidence suggests that neuraxial anesthesia should not be contraindicated in patients with AS.


Clinical potential: angiotensin converting enzyme inhibitor or angiotensin II antagonist?
Blockade of the renin-angiotensin system by angiotensin converting enzyme (ACE) inhibitors has an established role in the management of hypertension, heart failure, patients post-myocardial infarction and renal impairment. The mechanism of action of angiotensin II antagonists offers the potential of more complete blockade of angiotensin II, selective inhibition of the AT1 receptor and specificity for the renin-angiotensin system. Whether these mechanistic differences enhance the clinical potential of these drugs remains to be established. Preliminary evidence suggests that ACE inhibitors and angiotensin II antagonists have similar antihypertensive, haemodynamic and nephroprotective effects. Several major outcome trials with angiotensin II antagonists are underway and these should determine the eventual clinical potential of this class. Early results suggest equivalence with ACE inhibitors but further direct comparisons are needed. Angiotensin II antagonists have one undisputed advantage--excellent tolerability. Given the continuing under-use of ACE inhibitors because of concerns about adverse effects, this property alone may prove decisive in ensuring that angiotensin II antagonists yield the full clinical potential from blockade of the renin-angiotensin system.


Effects of immune complexes on production by human monocytes of interleukin 1 or an interleukin 1 inhibitor.
The objective of these studies was to examine the ability of phorbol myristic acetate (PMA), Fc fragments, and various forms of immune complexes to induce the production by human monocytes of factors stimulatory to chondrocytes or thymocytes. All of these materials were prepared free of detectable contamination with bacterial lipopolysaccharides (LPS) at the level of less than 0.1 ng/ml. Supernatants and lysates from stimulated human monocytes were assayed for their ability to induce collagenase production in cultured rabbit articular chondrocytes or to augment mitogen-induced proliferation of murine thymocytes. The activity detected by these assays exhibited an m.w. of approximately 15,000, and electrophoretic heterogeneity in the pH ranges of 5 to 5.5 and 6.5 to 7.0, characteristics of human interleukin 1 (IL 1) or IL 1-like factors. Monocytes cultured with 2 ng/ml LPS produced chondrocyte and thymocyte stimulatory factors. PMA, Fc fragments, and soluble, precipitated, particulate, or adherent immune complexes were inactive in stimulating the monocytes. However, complement fixation by precipitated immune complexes did generate activity capable of inducing monocytes to synthesize and secrete chondrocyte and thymocyte stimulatory factors. Adherent immune complexes and PMA were biologically active, as evidenced by induction of superoxide generation in the human monocytes. Supernatants from monocytes cultured on adherent immune complexes contained a factor inhibitory to chondrocyte and thymocyte responsiveness. This factor had a m.w. approximately 22,000 and appeared to inhibit specifically IL 1 stimulation, not interleukin 2 stimulation or cell proliferation. It was concluded that PMA, Fc fragments, and various forms of immune complexes in the absence of complement do not induce IL 1 production in human monocytes. However, complement fixation by immune complexes does lead to activation of monocytes to produce IL 1. Monocytes cultured on adherent immune complexes produce an IL 1 inhibitor.


Immunotoxicity of an Electrochemically Fluorinated Aqueous Film-Forming Foam.
Aqueous film-forming foams (AFFFs) are complex per- and polyfluoroalkyl substance (PFAS)-containing mixtures used extensively as fire suppressants. AFFF-impacted groundwater and surface water have contaminated drinking water with PFASs in many communities, raising concerns about health effects from drinking water exposures. As individual PFASs have been identified as immune hazards, the immunotoxicity of complex PFAS mixtures is also a concern. Adult female and male C57BL/6 mice were given a commercial AFFF formulation for 10 days via gavage; administered dose was based on combined content of perfluorooctanoate (PFOA) and perfluorooctane sulfonate (PFOS) measured in the formulation (0, 1.88, 3.75, 7.5, or 10 mg PFOS+PFOA/kg body weight). A PFOA positive control of 7.5 mg/kg body weight was also given. Compared with the 0 mg/kg group, the following changes were noted: Body weights of males exposed to 7.5 and 10 mg PFOS+PFOA/kg were reduced by 15%, on average; female body weights did not differ. Average relative liver weights were increased 50%-200% in males and 37.5%-193% in females and liver peroxisome proliferation was increased 2- to 12-fold in all doses of both sexes. Antigen-specific antibody production was suppressed, on average, by 13% in males and by 12.4% in females across all doses. Spleen cellularity and lymphocyte subpopulations did not differ by dose for either sex. Our data indicate that though this complex PFAS mixture contained fairly low PFOA content, it induced changes in C57BL/6 mice similar to changes induced by PFOA alone, likely due to the presence of PFOS and many other PFASs.


Aerosol exposure to Rift Valley fever virus causes earlier and more severe neuropathology in the murine model, which has important implications for therapeutic development.
Rift Valley fever virus (RVFV) is an important mosquito-borne veterinary and human pathogen that can cause severe disease including acute-onset hepatitis, delayed-onset encephalitis, retinitis and blindness, or a hemorrhagic syndrome. Currently, no licensed vaccine or therapeutics exist to treat this potentially deadly disease. Detailed studies describing the pathogenesis of RVFV following aerosol exposure have not been completed and candidate therapeutics have not been evaluated following an aerosol exposure. These studies are important because while mosquito transmission is the primary means for human infection, it can also be transmitted by aerosol or through mucosal contact. Therefore, we directly compared the pathogenesis of RVFV following aerosol exposure to a subcutaneous (SC) exposure in the murine model by analyzing survival, clinical observations, blood chemistry, hematology, immunohistochemistry, and virus titration of tissues. Additionally, we evaluated the effectiveness of the nucleoside analog ribavirin administered prophylactically to treat mice exposed by aerosol and SC. The route of exposure did not significantly affect the survival, chemistry or hematology results of the mice. Acute hepatitis occurred despite the route of exposure. However, the development of neuropathology occurred much earlier and was more severe in mice exposed by aerosol compared to SC exposed mice. Mice treated with ribavirin and exposed SC were partially protected, whereas treated mice exposed by aerosol were not protected. Early and aggressive viral invasion of brain tissues following aerosol exposure likely played an important role in ribavirin's failure to prevent mortality among these animals. Our results highlight the need for more candidate antivirals to treat RVFV infection, especially in the case of a potential aerosol exposure. Additionally, our study provides an account of the key pathogenetic differences in RVF disease following two potential exposure routes and provides important insights into the development and evaluation of potential vaccines and therapeutics to treat RVFV infection.


Determination of Pb(II), Zn(II), Cd(II), and Co(II) ions by flame atomic absorption spectrometry in food and water samples after preconcentration by coprecipitation with Mo(VI)-diethyldithiocarbamate.
A new, simple, and rapid separation and preconcentration procedure, for determination of Pb(II), Cd(II), Zn(II), and Co(II) ions in environmental real samples, has been developed. The method is based on the combination of coprecipitation of analyte ions by the aid of the Mo(VI)-diethyldithiocarbamate-(Mo(VI)-DDTC) precipitate and flame atomic absorption spectrometric determinations. The effects of experimental conditions like pH of the aqueous solution, amounts of DDTC and Mo(VI), standing time, centrifugation rate and time, sample volume, etc. and also the influences of some foreign ions were investigated in detail on the quantitative recoveries of the analyte ions. The preconcentration factors were found to be 150 for Pb(II), Zn(II) and Co(II), and 200 for Cd(II) ions. The detection limits were in the range of 0.1-2.2 μg L(-1) while the relative standard deviations were found to be lower than 5 % for the studied analyte ions. The accuracy of the method was checked by spiked/recovery tests and the analysis of certified reference material (CRM TMDW-500 Drinking Water). The procedure was successfully applied to seawater and stream water as liquid samples and baby food and dried eggplant as solid samples in order to determine the levels of Pb(II), Cd(II), Zn(II), and Co(II) ions.


Meniere's disease: terminology and data bank acquisition.
It is proposed that the term Meniere's disease be restricted to patients with the classic symptom and sign complex in whom the etiologic factor is unknown (idiopathic). The term Meniere's syndrome is restricted to patients whose etiologic factor is known, who have an incomplete form of the disease, or who are in the process of being evaluated. Vestibular neuronitis and cochlear hydrops are terms that should be retained until the concepts of vestibular and cochlear Meniere's disease are better understood and can be identified prospectively. The classic symptoms and signs, both positive and negative, are outlined and a standard evaluation format is suggested. This must submit to mathematical reduction for pre- and post-treatment comparisons. Until this basic problem has been solved to the satisfaction of the profession, the inferences that may be drawn from otherwise excellent studies will continue to be of very limited clinical value.


Structure of the flavoprotein tryptophan 2-monooxygenase, a key enzyme in the formation of galls in plants.
The flavoprotein tryptophan 2-monooxygenase catalyzes the oxidative decarboxylation of tryptophan to yield indole-3-acetamide. This is the initial step in the biosynthesis of the plant growth hormone indole-acetic acid by bacterial pathogens that cause crown gall and related diseases. The structure of the enzyme from Pseudomonas savastanoi has been determined by X-ray diffraction methods to a resolution of 1.95 Å. The overall structure of the protein shows that it has the same fold as members of the monoamine oxidase family of flavoproteins, with the greatest similarities to the l-amino acid oxidases. The location of bound indole-3-acetamide in the active site allows identification of residues responsible for substrate binding and specificity. Two residues in the enzyme are conserved in all members of the monoamine oxidase family, Lys365 and Trp466. The K365M mutation decreases the kcat and kcat/KTrp values by 60000- and 2 million-fold, respectively. The deuterium kinetic isotope effect increases to 3.2, consistent with carbon-hydrogen bond cleavage becoming rate-limiting in the mutant enzyme. The W466F mutation decreases the kcat value <2-fold and the kcat/KTrp value only 5-fold, while the W466M mutation results in an enzyme lacking flavin and detectable activity. This is consistent with a role for Trp466 in maintaining the structure of the flavin-binding site in the more conserved FAD domain.


Small-fiber sensory neuropathies: clinical course and neuropathology of idiopathic cases.
We describe the clinical features, natural history, and neuropathology of 32 patients presenting with "burning feet," for whom no specific cause was identified. All had neuropathic pain in the feet and morphological abnormalities of cutaneous innervation in skin obtained using punch biopsy. Most (29) had an abnormal sensory examination. All had normal strength, proprioception, tendon reflexes, and nerve conductions. Two clinical patterns were apparent, based on natural history and spatial distribution of cutaneous denervation. Most (28) patients presented with neuropathic pain initially restricted to the feet and toes but extending more proximally to involve the legs and hands with time. Intraepidermal nerve fiber (IENF) density was most severely reduced distally, with more normal IENF densities in skin from proximal sites. In contrast, a minority (4) presented with the abrupt onset of generalized cutaneous burning pain and hyperesthesia. In these patients, IENF densities were reduced in skin from both proximal and distal sites. Absolute IENF densities in calf skin were reduced below the lower limit of normal (5th percentile) in 26 (81%). Of the 6 who underwent sural nerve biopsy, 4 had selective loss of small myelinated and/or unmyelinated axons and 2 had normal histology and fiber densities despite reduced IENF densities in skin biopsy specimens. Punch skin biopsy from proximal and distal sites is a useful means of assessing these distinctive patients and may provide further insight into pathophysiology.


Consensus Paper: Cerebellum and Ageing.
Given the key roles of the cerebellum in motor, cognitive, and affective operations and given the decline of brain functions with aging, cerebellar circuitry is attracting the attention of the scientific community. The cerebellum plays a key role in timing aspects of both motor and cognitive operations, including for complex tasks such as spatial navigation. Anatomically, the cerebellum is connected with the basal ganglia via disynaptic loops, and it receives inputs from nearly every region in the cerebral cortex. The current leading hypothesis is that the cerebellum builds internal models and facilitates automatic behaviors through multiple interactions with the cerebral cortex, basal ganglia and spinal cord. The cerebellum undergoes structural and functional changes with aging, being involved in mobility frailty and related cognitive impairment as observed in the physio-cognitive decline syndrome (PCDS) affecting older, functionally-preserved adults who show slowness and/or weakness. Reductions in cerebellar volume accompany aging and are at least correlated with cognitive decline. There is a strongly negative correlation between cerebellar volume and age in cross-sectional studies, often mirrored by a reduced performance in motor tasks. Still, predictive motor timing scores remain stable over various age groups despite marked cerebellar atrophy. The cerebello-frontal network could play a significant role in processing speed and impaired cerebellar function due to aging might be compensated by increasing frontal activity to optimize processing speed in the elderly. For cognitive operations, decreased functional connectivity of the default mode network (DMN) is correlated with lower performances. Neuroimaging studies highlight that the cerebellum might be involved in the cognitive decline occurring in Alzheimer's disease (AD), independently of contributions of the cerebral cortex. Grey matter volume loss in AD is distinct from that seen in normal aging, occurring initially in cerebellar posterior lobe regions, and is associated with neuronal, synaptic and beta-amyloid neuropathology. Regarding depression, structural imaging studies have identified a relationship between depressive symptoms and cerebellar gray matter volume. In particular, major depressive disorder (MDD) and higher depressive symptom burden are associated with smaller gray matter volumes in the total cerebellum as well as the posterior cerebellum, vermis, and posterior Crus I. From the genetic/epigenetic standpoint, prominent DNA methylation changes in the cerebellum with aging are both in the form of hypo- and hyper-methylation, and the presumably increased/decreased expression of certain genes might impact on motor coordination. Training influences motor skills and lifelong practice might contribute to structural maintenance of the cerebellum in old age, reducing loss of grey matter volume and therefore contributing to the maintenance of cerebellar reserve. Non-invasive cerebellar stimulation techniques are increasingly being applied to enhance cerebellar functions related to motor, cognitive, and affective operations. They might enhance cerebellar reserve in the elderly. In conclusion, macroscopic and microscopic changes occur in the cerebellum during the lifespan, with changes in structural and functional connectivity with both the cerebral cortex and basal ganglia. With the aging of the population and the impact of aging on quality of life, the panel of experts considers that there is a huge need to clarify how the effects of aging on the cerebellar circuitry modify specific motor, cognitive, and affective operations both in normal subjects and in brain disorders such as AD or MDD, with the goal of preventing symptoms or improving the motor, cognitive, and affective symptoms.


HRMS Profile of a Hazelnut Skin Proanthocyanidin-rich Fraction with Antioxidant and Anti-Candida albicans Activities.
Roasted hazelnut skins (RHS) represent a byproduct of kernel industrial processing. In this research, a RHS extract (RHS-M) and its fraction RHS-M-F3 enriched in proanthocyanidins (PAs), with antioxidant activity, were characterized in terms of total phenolic compound and PA contents. RHS-M and RHS-M-F3 showed antifungal properties against Candida albicans SC5314 (MIC2 = 3.00 and 0.10 μg/mL and MIC0 = 5.00 and 0.50 μg/mL, respectively), determined by the microbroth dilution method and Candida albicans morphological analysis. No cytotoxic effect on HEKa and HDFa cell lines was exhibited by RHS-M and RHS-M-F3. The metabolite profiling of RHS-M and RHS-M-F3 was performed by thiolysis followed by HPLC-UV-HRMS analysis and a combination of HRMS-FIA and HPLC-HRMS(n). Extract and fraction contain oligomeric PAs (mDP of 7.3 and 6.0, respectively, and DP up to 10) mainly constituted by B-type oligomers of (epi)-catechin. Also, (epi)-gallocatechin and gallate derivatives were identified as monomer units, and A-type PAs were detected as minor compounds.


Mechanical ventilation in trauma.
The purpose of this review is to evaluate new concepts in mechanical ventilation in trauma. We begin with the keystone of physiology prior to embarking on a discussion of several new modes of mechanical ventilation. We will discuss the use of noninvasive ventilation as a mode to prevent intubation and then go on to airway pressure release ventilation, high-frequency oscillatory ventilation, and computer-based, closed loop ventilation. The importance of preventing further injury in mechanical ventilation lies at the heart of the introduction of several new strategies of mechanical ventilation. New modes of ventilation have been developed to provide lung recruitment and alveolar stabilization at the lowest possible pressure. The old modes of continuous positive airway pressure and bilevel positive airway pressure have been actively introduced in clinical practice in the case of trauma patients. Used with proper pain management protocols, there has been a decrease in the incidence of intubation in blunt thoracic trauma. Airway pressure release ventilation has been gaining a role in the management of thoracic injury and may lead to less incidence of physiologic trauma to mechanically ventilated patients. High-frequency oscillatory ventilation has been shown to be effective in patient care by its ability to open and recruit the lung in trauma patients and in those with acute respiratory distress syndrome but it may not have a role in patients with inhalational injury. Closed loop ventilation is a technology that may better control major pulmonary parameters and lead to more rapid titration from the ventilator to spontaneous breathing.


Surveillance for West Nile virus in wild birds from northern Europe.
A total of 1935 migratory birds from 104 different species were captured in southeastern Sweden in 2005-2006 and tested for antibodies against West Nile virus (WNV). Overall, 46 birds (2.4%; binomial confidence limits, 1.8-3.2) were positive by blocking-ELISA, but only 2 (0.10%; binomial confidence limits, 0.0-0.4) had antibodies detectable by both blocking-ELISA and WNV neutralization test. ELISA-positive birds included long- and short-distance migrants likely exposed to WNV while wintering in or migrating through areas enzootic for WNV. Exposure to a cross-reactive Flavivirus was suspected for short-distance migrants of the Turdidae family, but no cross-neutralization with tick-borne encephalitis and Usutu viruses was observed.


Characterization of smooth lipopolysaccharides and O polysaccharides of Brucella species by competition binding assays with monoclonal antibodies.
Previously, four epitope specificities on the O chain of Brucella species were reported: M, A, C, and C/Y. In this work, according to monoclonal antibody binding to smooth lipopolysaccharides of Yersinia enterocolitica 0:9, Brucella abortus W99 (A-dominant strain), and B. melitensis Rev1 (M-dominant strain), seven O-chain epitope specificities were defined: M, A, C (M > A), C (M = A), C/Y (M > A), C/Y (M = A) and C/Y (A > M). Competitive binding assays between these monoclonal antibodies suggested that these different epitopes are probably overlapping structures.


Reproductive inequality in humans and other mammals.
To address claims of human exceptionalism, we determine where humans fit within the greater mammalian distribution of reproductive inequality. We show that humans exhibit lower reproductive skew (i.e., inequality in the number of surviving offspring) among males and smaller sex differences in reproductive skew than most other mammals, while nevertheless falling within the mammalian range. Additionally, female reproductive skew is higher in polygynous human populations than in polygynous nonhumans mammals on average. This patterning of skew can be attributed in part to the prevalence of monogamy in humans compared to the predominance of polygyny in nonhuman mammals, to the limited degree of polygyny in the human societies that practice it, and to the importance of unequally held rival resources to women's fitness. The muted reproductive inequality observed in humans appears to be linked to several unusual characteristics of our species-including high levels of cooperation among males, high dependence on unequally held rival resources, complementarities between maternal and paternal investment, as well as social and legal institutions that enforce monogamous norms.