Drug-resistant malaria - an insight.
Despite intensive research extending back to the 1930s, when the first synthetic antimalarial drugs made their appearance, the repertoire of clinically licensed formulations remains very limited. Moreover, widespread and increasing resistance to these drugs contributes enormously to the difficulties in controlling malaria, posing considerable intellectual, technical and humanitarian challenges. A detailed understanding of the molecular mechanisms underlying resistance to these agents is emerging that should permit new drugs to be rationally developed and older ones to be engineered to regain their efficacy. This review summarizes recent progress in analysing the causes of resistance to the major antimalarial drugs and its spread.


Emotion processing in schizophrenia: fMRI study of patients treated with risperidone long-acting injections or conventional depot medication.
We employed two event-related functional magnetic resonance imaging tasks using the pictures of mild and intense facial emotions of fear or happiness. The sample comprised 16 chronic schizophrenia patients treated with risperidone long-acting injections (RLAI), 16 patients treated with conventional antipsychotic depots (CONV) and 16 healthy controls (HC). The HC and RLAI groups demonstrated greater activation in the left amygdala in response to intensively fearful faces, and in right cerebellum to intensively happy faces compared with CONV patients. The CONV group demonstrated under-activation in the right temporal pole in response to intensively happy faces (compared with HC) and over-activation in ventro-medial prefrontal cortex (VMPFC) in response to both intensively happy and fearful expressions, compared with HC and RLAI groups. Our results suggest that networks implicated in the allocation of attentional resources (VMPFC) and emotion processing (amygdala, cerebellum) are differentially affected in patients on CONV versus RLAI.


Nutrient-driven O-GlcNAc cycling influences autophagic flux and neurodegenerative proteotoxicity.
O-GlcNAcylation is an abundant post-translational modification implicated in human neurodegenerative diseases. We showed that loss-of-function of OGT (O-linked GlcNAc transferase) alleviated, while loss of OGA (O-GlcNAc selective β-N-acetyl-D-glucosaminidase) enhanced, the proteotoxicity of C. elegans neurodegenerative disease models including tauopathy, β-amyloid peptide and polyglutamine expansion. The O-GlcNAc cycling mutants act, in part, by altering insulin signaling, proteasome activity and autophagy. In mutants lacking either of these enzymes of O-GlcNAc cycling, there is a striking accumulation of GFP::LGG-1 (C. elegans homolog of Atg8 and LC3) and increased phosphatidylethanolamine (PE)-modified GFP::LGG-1 upon starvation. We speculate that O-GlcNAc cycling is a key nutrient-responsive regulator of autophagic flux acting at multiple levels including direct modification of BECN1 and BCL2.


Sensor positioning for a human activity recognition system using a double layer classifier.
This paper describes the development of a human gait activity recognition system. A multi-sensor recognition system, which has been developed for this purpose, was reduced to a single sensor-based recognition system. A sensor election method was devised based on the maximum relevance minimum redundancy feature selector to determine the sensor's optimum position regarding activity recognition. The election method proved that the thigh has the highest contribution to recognize walking, stairs and ramp ascending, and descending activities. A recognition algorithm (which depends mainly on features that are classified by random forest, and selected by a combined feature selector using the maximum relevance minimum redundancy and genetic algorithm) has been modified to compensate the degradation that occurs in the prediction accuracy due to the reduction in the number of sensors. The first modification was implementing a double layer classifier in order to discriminate between the interfered activities. The second modification was adding physical features to the features dictionary used. These modifications succeeded to improve the prediction accuracy to allow a single sensor recognition system to behave in the same manner as a multi-sensor activity recognition system.


Electro-elastocapillary Rayleigh-plateau instability in dielectric elastomer films.
We demonstrate, using both finite element simulations and a linear stability analysis, the emergence of an electro-elastocapillary Rayleigh-plateau instability in dielectric elastomer (DE) films under 2D, plane strain conditions. When subject to an electric field, the DEs exhibit a buckling instability for small elastocapillary numbers. For larger elastocapillary numbers, the DEs instead exhibit the Rayleigh-plateau instability. The stability analysis demonstrates the critical effect of the electric field in causing the Rayleigh-plateau instability, which cannot be induced solely by surface tension in DE films. Overall, this work demonstrates the effects of geometry, boundary conditions, and multi-physical coupling on a new example of Rayleigh-plateau instability in soft solids.


False-positive results from cultures of Mycobacterium tuberculosis due to laboratory cross-contamination confirmed by restriction fragment length polymorphism.
During 1994, a cross-contamination problem leading to false-positive cultures of Mycobacterium tuberculosis was revealed in a mycobacteriology laboratory processing 30,000 to 35,000 samples per year. Molecular strain typing based on restriction fragment length polymorphism confirmed the contaminations. Out of 1,439 positive cultures of Mycobacterium tuberculosis, 49 samples from 48 patients were suspected to be cross-contaminated. In 37 cases, growth was observed both in BACTEC vials and on solid media, indicating that the contamination took place during the processing of the samples. The majority of the contaminated samples had been handled by the same technician.


IL-17 produced by Th17 cells alleviates the severity of fungal keratitis by suppressing CX43 expression in corneal peripheral vascular endothelial cells.
Fungal keratitis is a relatively common ocular disease requiring positive medical management combined with surgical intervention. Interleukin-17 (IL-17) was reported to promote the activation and mobilization of neutrophile granulocyte to foci of inflammation. This study investigated the effect of IL-17 production from Th17 cells on the progression of fungal keratitis. A mouse model of fungal keratitis induced by Candida albicans was successfully constructed to detect infiltration of inflammatory cells in corneal tissues by hematoxylin-eosin (HE) staining and immunohistochemistry. Fungal load capacity of mouse cornea was also detected. The regulatory role of IL-17 in fungal keratitis with the involvement of CX43 was investigated with the relevant expression of inflammatory factors detected and activation of vascular endothelial cells assessed. Furthermore, in vivo experiment was also performed to confirm the role of CX43 in keratitis. Mice with fungal keratitis showed increased level of inflammatory cytokines and infiltration of inflammatory cells. Silencing IL-17 in Th17 cells and overexpressing CX43 could inhibit the activation of vascular endothelial cells. Besides, CX43 knockdown in vivo alleviated fungal keratitis in mice. The possible mechanism of the above findings could be IL-17 inhibiting the level of CX43 through the AKT signaling pathway. Taken together, IL-17 could inhibit the occurrence and development of fungal keratitis by suppressing CX43 expression through the AKT signaling pathway. Therefore, this study provides a potential target for the treatment of fungal keratitis.


Human T-cell responses to secreted antigen fractions of Mycobacterium tuberculosis.
The T-cell response of human donors to secreted antigen fractions of Mycobacterium tuberculosis was investigated. The donors were divided into five groups: active pulmonary tuberculosis (TB) patients with minimal and with advanced disease, Mycobacterium bovis BCG-vaccinated donors with and without contact with TB patients, and nonvaccinated individuals. We found that patients with active minimal TB responded powerfully to secreted antigens contained in a short-term culture filtrate. The response to secreted antigens was mediated by CD4+ Th-1-like lymphocytes, and the gamma interferon release by these cells was markedly higher in patients with active minimal TB than in healthy BCG-vaccinated donors. Patients with active advanced disease exhibited depressed responses to all preparations tested. The specificity of the response to secreted antigens was investigated by stimulating lymphocytes with narrow-molecular-mass fractions of short-term culture filtrate obtained by the multielution technique. Considerable heterogeneity was found within the donor groups. Patients with active minimal TB recognized multiple secreted targets, but interestingly, six of eight patients demonstrated a predominant recognition of a low-mass (< 10-kDa) protein fraction which induced high levels of gamma interferon release in vitro. Only a few of 12 previously characterized secreted antigens were recognized by T cells isolated from TB patients, suggesting the existence of a number of as yet undefined antigenic targets among secreted antigens.


Health in the Neighborhood and Household Contexts Among Older Chinese Americans.
This study examined the associations of neighborhood characteristics and living arrangements with physical and mental health among older Chinese Americans. A sample of 3,159 community-dwelling Chinese older adults in the Greater Chicago area provided reports of health, socio-demographic characteristics, living arrangements, social cohesion, and neighborhood disorder. We used multinomial logistic, Poisson, and negative binominal regression analyses. Neighborhood disorder was consistently associated with negative health indicators, including poor self-reported health, more chronic conditions, depressive symptoms, and anxiety symptoms. Findings about the relationships between social cohesion and health indicators were mixed. Social cohesion was more salient to mental health for those living with spouse, children, and/or grandchildren relative to those living with spouse only. Policies and interventions are needed to improve the physical and social environments of neighborhoods and to promote healthy aging among Chinese older adults and in the general population as well.


Photoelectrochemical performance of birnessite films and photoelectrocatalytic activity toward oxidation of phenol.
Birnessite films on fluorine-doped tin oxide (FTO) coated glass were prepared by cathodic reduction of aqueous KMnO4. The deposited birnessite films were characterized with X-ray diffraction, Raman spectroscopy, scanning electron microscopy and atomic force microscopy. The photoelectrochemical activity of birnessite films was investigated and a remarkable photocurrent in response to visible light was observed in the presence of phenol, resulting from localized manganese d-d transitions. Based on this result, the photoelectrocatalytic oxidation of phenol was investigated. Compared with phenol degradation by the electrochemical oxidation process or photocatalysis separately, a synergetic photoelectrocatalytic degradation effect was observed in the presence of the birnessite film coated FTO electrode. Photoelectrocatalytic degradation ratios were influenced by film thickness and initial phenol concentrations. Phenol degradation with the thinnest birnessite film and initial phenol concentration of 10mg/L showed the highest efficiency of 91.4% after 8hr. Meanwhile, the kinetics of phenol removal was fit well by the pseudofirst-order kinetic model.


Immobilization of Enzymes in Mesoporous Silica Particles: Protein Concentration and Rotational Mobility in the Pores.
Enzyme immobilization in porous silica particles is used to improve enzyme function in biocatalytic applications. Here, we study the effective protein concentration and rotational mobility of lipase and bovine serum albumin in the pores, when confined in five types of mesoporous silica particles with different pore and particle sizes, exploiting the intrinsic UV-vis absorption and fluorescence anisotropy of the tryptophan residues. For all investigated combinations of proteins and particles, the steady-state anisotropy is higher than for the same protein in free solution, indicating a slower protein rotation inside the pores. The retardation is stronger in more narrow pores, but the proteins can still move, and there is no dependence on the particle size. The average number of proteins per particle, Nprot, varies with the particle diameter, D, as Nprot ∼ D2.95±0.02 for both proteins, which is close to the scaling D3.0±0.1 for the available pore volume. This observation indicates that both proteins are distributed evenly throughout the particles and rules out that the proteins are only externally bound to the particle surface. Secondly, the concentration of the protein in the pores depends on the pore and protein size but not on the particle size and corresponds to volume fractions in the range of 20-60%.


Restoring grassland savannas from degraded pinyon-juniper woodlands: effects of mechanical overstory reduction and slash treatment alternatives.
Although the distribution and structure of pinyon-juiper woodlands in the southwestern United States are thought to be the result of historic fluctuations in regional climatic conditions, more recent increases in the areal extent, tree density, soil erosion rates and loss of understory plant diversity are attributed to heavy grazing by domestic livestock and interruption of the natural fire regime. Prior to 1850, many areas currently occupied by high-density pinyon-juniper woodlands, with their degraded soils and depauperate understories, were very likely savannas dominated by native grasses and forbs and containing sparse tree cover scattered across the landscape. The purpose of this study was to evaluate the effectiveness of mechanical overstory reduction and three slash treatment alternatives (removal, clustering and scattering) followed by prescribed fire as techniques for restoring grassland savannas from degraded woodlands. Plant cover, diversity, biomass and nutrient status, litter cover and soil chemistry and erosion rates were measured prior to and for two years following experimental treatment in a degraded pinyon-juniper woodland in central New Mexico. Treatment resulted in a significant increase in the cover of native grasses and, to a lesser degree, forbs and shrubs. Plant species richness and diversity increased most on sites where slash was either completely removed or scattered to serve as a mulch. Although no changes in soil chemistry or plant nutrient status were observed, understory biomass increased over 200% for all harvest treatments and was significantly greater than controls. While treatment increased litter cover and decreased soil exposure, this improvement did not significantly affect soil loss rates. Even though all slash treatment alternatives increased the cover and biomass of native grasses, scattering slash across the site to serve as a mulch appears most beneficial to improving plant species diversity and conserving site resources.


Evaluation of a labeling system to indicate the presence of an advance directive in a hospital medical record.
To investigate the accuracy of one hospital's system to indicate whether an advance directive exists within a patient's medical record. Medical record review while patients were hospitalized. Internal medicine residency program within a tertiary care hospital. Patients admitted to four internal medicine services between 25 October 2000 and 6 December 2000. Presence of an advance directive and a label in medical records were recorded, along with patient demographics, and sensitivity, specificity, and accuracy were calculated. Four of 125 medical records (3%) contained advance directives. Sensitivity of a label for an advance directive was 25% [95% confidence interval (CI) 1-81%], specificity was 62% (95% CI 53-71%), and accuracy was 61% (95% CI 52-69%). Use of the hospital's labeling system to indicate the presence of advance directives was found to be highly inaccurate. Failure to correctly follow or understand the intended labeling procedure was the most likely source of error. Hospitals should include plans to check the accuracy of protocols when they are adopted to ensure that they are performing as intended.


Optimization of dynamic-microwave assisted enzymatic hydrolysis extraction of total ginsenosides from stems and leaves of panax ginseng by response surface methodology.
Ginseng stems and leaves (GSAL) are abundant in ginsenosides compounds. For efficient utilization of GSAL and the enhancement of total ginsenosides (TG) compound yields in GSAL, TG from GSAL were extracted, using dynamic-microwave assisted extraction coupled with enzymatic hydrolysis (DMAE-EH) method. The extraction process has been simulated and its main influencing factors such as ethanol concentration, microwave temperature, microwave time and pump flow rate have been optimized by response surface methodology coupled with a Box-Behnken design(BBD). The experimental results indicated that optimal extraction conditions of TG from GSAL were as follows: ethanol concentration of 75%, microwave temperature of 60°C, microwave time of 20 min and pump flow rate of 38 r/min. After experimental verification, the experimental yields of TG was 60.62 ± 0.85 mg g-1, which were well agreement with the predicted by the model. In general, the present results demonstrated that DMAE-EH method was successfully used to extract total ginsenosides in GSAL.


Phytofabricated gold nanoparticles and their biomedical applications.
In a couple of decades, nanotechnology has become a trending technology owing to its integrated science collection that incorporates variety of fields such as chemistry, physics, medicine, catalytic processes, food processing industries, electronics and energy sectors. One of the emerging fields of nanotechnology that has gained momentous admiration is nano-biotechnology. Nano-biotechnology is an integrated combination of biology with nanotechnology that encompasses the tailoring, and synthesis of small particles that are less than 100nm in size and subsequent exploitation of these particles for their biological applications. Though the variety of physical techniques and chemical procedures are known for the nanoparticles synthesis, biological approach is considered to be the preferred one. Environmental hazards and concerns associated with the physical and chemical approaches of nanoparticles synthesis has added impetus and zenith to the biological approach involving the use of plants and microorganisms. The current review article is focused on the synthesis of plant-derived (phytochemical) gold nanoparticles alongside their scope in biomedical applications.


Effects of the LPA1 Receptor Deficiency and Stress on the Hippocampal LPA Species in Mice.
Lysophosphatidic acid (LPA) is an important bioactive lipid species that functions in intracellular signaling through six characterized G protein-coupled receptors (LPA1-6). Among these receptors, LPA1 is a strong candidate to mediate the central effects of LPA on emotion and may be involved in promoting normal emotional behaviors. Alterations in this receptor may induce vulnerability to stress and predispose an individual to a psychopathological disease. In fact, mice lacking the LPA1 receptor exhibit emotional dysregulation and cognitive alterations in hippocampus-dependent tasks. Moreover, the loss of this receptor results in a phenotype of low resilience with dysfunctional coping in response to stress and induces anxiety and several behavioral and neurobiological changes that are strongly correlated with mood disorders. In fact, our group proposes that maLPA1-null mice represent an animal model of anxious depression. However, despite the key role of the LPA-LPA1-pathway in emotion and stress coping behaviors, the available information describing the mechanisms by which the LPA-LPA1-pathway regulates emotion is currently insufficient. Because activation of LPA1 requires LPA, here, we used a Matrix-Assisted Laser Desorption/ Ionization mass spectrometry-based approach to evaluate the effects of an LPA1 receptor deficiency on the hippocampal levels of LPA species. Additionally, the impact of stress on the LPA profile was also examined in both wild-type (WT) and the Malaga variant of LPA1-null mice (maLPA1-null mice). Mice lacking LPA1 did not exhibit gross perturbations in the hippocampal LPA species, but the LPA profile was modified, showing an altered relative abundance of 18:0 LPA. Regardless of the genotype, restraint stress produced profound changes in all LPA species examined, revealing that hippocampal LPA species are a key target of stress. Finally, the relationship between the hippocampal levels of LPA species and performance in the elevated plus maze was established. To our knowledge, this study is the first to detect, identify and profile LPA species in the hippocampus of both LPA1-receptor null mice and WT mice at baseline and after acute stress, as well as to link these LPA species with anxiety-like behaviors. In conclusion, the hippocampal LPA species are a key target of stress and may be involved in psychopathological conditions.


Antiepileptic drugs and neuroprotection: current status and future roles.
There has been a growing interest in the use of antiepileptic drugs (AEDs) for neuroprotection, and in the possible role of AEDs in disease modification (i.e., antiepileptogenesis). Increased understanding of the mechanisms underlying brain injury has led to advances in the study of neuroprotection. However, defining the clinical paradigm and selecting appropriate outcomes to detect neuroprotective effects present challenges to clinicians studying the neuroprotective properties of drugs. Established AEDs, such as phenytoin, phenobarbital, and carbamazepine, have shown neuroprotective activity in an ischemic/hypoxic model of neuronal injury. Animal model studies also have suggested that newer AEDs, such as levetiracetam, topiramate, and zonisamide, may have neuroprotective or antiepileptogenic properties. However, the prevention of epileptogenesis by an AED has yet to be demonstrated in clinical trials. The future of neuroprotection may involve established and newer AEDs, as well as other compounds, such as immunophilins, caspase inhibitors, endocannabinoids, and antioxidants.


Chloroquine-induced QTc prolongation in COVID-19 patients.
In the battle against the SARS-CoV‑2 pandemic, chloroquine has emerged as a new potential therapeutic option for the treatment of infected patients. A safety consideration for the application of chloroquine is its QTc-prolonging potential. Thus far, no data are available on the QTc-prolonging potential of chloroquine in COVID-19 patients. To assess the degree of chloroquine-induced QTc prolongation in hospitalised COVID-19 patients. A baseline electrocardiogram (ECG) and ECGs recorded during chloroquine treatment were retrospectively collected in patients suspected of having COVID-19. The QTc interval was calculated by computerised and manual interpretation. Baseline and follow-up QTc intervals were compared using the paired samples t-test. A total of 95 patients had a baseline ECG recording and at least one ECG recording during chloroquine therapy. Chloroquine treatment resulted in a mean QTc prolongation of 35 ms (95% CI 28-43 ms) using computerised interpretation and 34 ms (95% CI 25-43 ms) using manual interpretation. No torsade de pointes was observed during chloroquine treatment. After manual review, 22 patients (23%) had a QTc interval exceeding 500 ms during chloroquine treatment. None of these patients had a prolonged QTc interval prior to the initiation of chloroquine treatment. Chloroquine significantly prolongs the QTc interval in a clinically relevant matter. This highlights the need for ECG monitoring when prescribing chloroquine to COVID-19 patients.


Microsurgical tubal anastomosis: a controlled trial in four Asian centers.
An international program to determine the reversibility of female sterilization in Asia using microsurgical technique was established in 1980. One hundred eleven of 219 patients (51%) conceived following tubal anastomosis; of these, 79 delivered living children. The overall cumulative probability of conception at the end of follow-up, as determined by life-table analysis, was 63%. A decreased pregnancy rate was associated with anastomosis of tubes sterilized by electrocautery methods.


Clinical Phenotype of Diabetic Peripheral Neuropathy and Relation to Symptom Patterns: Cluster and Factor Analysis in Patients with Type 2 Diabetes in Korea.
Patients with diabetic peripheral neuropathy (DPN) is the most common complication. However, patients are usually suffering from not only diverse sensory deficit but also neuropathy-related discomforts. The aim of this study is to identify distinct groups of patients with DPN with respect to its clinical impacts on symptom patterns and comorbidities. A hierarchical cluster analysis and factor analysis were performed to identify relevant subgroups of patients with DPN (n = 1338) and symptom patterns. Patients with DPN were divided into three clusters: asymptomatic (cluster 1, n = 448, 33.5%), moderate symptoms with disturbed sleep (cluster 2, n = 562, 42.0%), and severe symptoms with decreased quality of life (cluster 3, n = 328, 24.5%). Patients in cluster 3, compared with clusters 1 and 2, were characterized by higher levels of HbA1c and more severe pain and physical impairments. Patients in cluster 2 had moderate pain levels but disturbed sleep patterns comparable to those in cluster 3. The frequency of symptoms on each item of MNSI by "painful" symptom pattern showed a similar distribution pattern with increasing intensities along the three clusters. Cluster and factor analysis endorsed the use of comprehensive and symptomatic subgrouping to individualize the evaluation of patients with DPN.


Modeling and optimization of heterogeneous photo-Fenton process with response surface methodology and artificial neural networks.
In this study, estimation capacities of response surface methodology (RSM) and artificial neural network (ANN) in a heterogeneous photo-Fenton process were investigated. The zeolite Fe-ZSM5 was used as heterogeneous catalyst of the process for degradation of C.I. Acid Red 14 azo dye. The efficiency of the process was studied as a function of four independent variables, concentration of the catalyst, molar ratio of initial concentration of H2O2 to that of the dye (H value), initial concentration of the dye and initial pH of the solution. First, a central composite design (CCD) and response surface methodology were used to evaluate simple and combined effects of these parameters and to optimize process efficiency. Satisfactory prediction second-order regression was derived by RSM. Then, the independent parameters were fed as inputs to an artificial neural network while the output of the network was the degradation efficiency of the process. The multilayer feed-forward networks were trained by the sets of input-output patterns using a backpropagation algorithm. Comparable results were achieved for data fitting by using ANN and RSM. In both methods, the dye mineralization process was mainly influenced by pH and the initial concentration of the dye, whereas the other factors showed lower effects.


Modulation of cell rounding and apoptosis in trigeminal neurinoma cells by protein phosphatase inhibitors.
Exposure of trigeminal neurinoma 476-16 cells to C2-ceramide in a serum-deprived medium induces cell rounding followed by cell death characterized by cytoplasmic shrinkage and nuclear condensation. The induction of cell rounding and death occurs in proliferating cells but not in essentially quiescent cells of confluent cultures. Trypan blue-unpermeable round cells formed as a result of ceramide treatment undergo apoptosis without ceramide in a serum-containing medium, suggesting that they are irreversibly committed to cell death. The induction of cell rounding by ceramide is inhibited by low doses of the protein-tyrosine phosphatase inhibitors, orthovanadate and pervandate, and stimulated by high doses of pervanadate. The inhibition of protein-tyrosine phosphatases interfers the induction of cell death by ceramide. The protein-serine/threonine phosphatase inhibitor calyculin A induces cell rounding in proliferating cells. This cell rounding does not lead to cell death, thus calyculin A inhibits the induction of cell death by ceramide. While orthovanadate inhibits the induction of cell rounding by calyculin A, the latter is potentiated by ceramide. A combination of ceramide and calyculin A induces cell rounding and cell death in confluent cultures. These results demonstrate that modulation of phosphorylation of the serine/threonine and tyrosine of cellular proteins is intimately involved in the process of cell rounding and apoptosis in anchorage-dependent cells.


Complications of laparoscopic inguinal hernia repair.
Laparoscopic herniorrhaphy has been gaining popularity along with other minimally invasive surgical techniques. With the sophistication of instruments, evaluation of techniques and longer follow-up of patients, the outcome of such repairs is changing. Many authors are reporting a variety of techniques, complications, and results compared to conventional surgery.


[Cloning and expression of gynecophoral canal protein gene of Schistosoma japonicum (Chinese strain)].
A 1949 bp cDNA fragment was amplified by RT-PCR from adult Schistosoma japonicum (Chinese strain) mRNA with 3 pair of primers that were designed according to published SmGCP gene encoding gynecophoral canal protein of Schistosoma mansoni and SjGCP1 gene encoding the conservative region of gynecophoral canal protein of Schistosoma japonicum. Sequence analysis indicated that this fragment, named SjGCP, with 85% identity to SmGCP, contained a complete open reading frame (ORF) of gynecophoral canal protein gene of Schistosoma japonicum (Chinese strain). The amino acid sequence shared 83.7% identity with gynecophoral canal protein of Schistosoma mansoni. This fragment was cloned into the expression vector pET28c(+) and subsequently expressed in Escherichia coli. SDS-PAGE revealed that the molecular weight of this expressed product was 80 kD. Western blotting showed that the recombinant protein reacted well with the rabbit serum immunized with Sj worm antigen, indicating that this expressed product had good antigenicity.


Manganese-Catalyzed and Mediated Synthesis of Arylphosphinates and Related Compounds.
The free-radical arylation of H-phosphinates and related compounds was examined. A practical catalytic process with the air as the oxidant could not be found. However, an inexpensive and robust methodology was developed, using catalytic Mn(II) as the radical initiator and excess Mn(IV) as the stoichiometric oxidant. Using these conditions, the inter- and intramolecular arylation of phosphinylidene compounds has a broad scope, including application to the synthesis of P-heterocycles. A full account of this methodology is presented including a discussion of its limitations.


Anchor-based whole genome phylogeny (ABWGP): a tool for inferring evolutionary relationship among closely related microorganisms [corrected].
Phenotypic behavior of a group of organisms can be studied using a range of molecular evolutionary tools that help to determine evolutionary relationships. Traditionally a gene or a set of gene sequences was used for generating phylogenetic trees. Incomplete evolutionary information in few selected genes causes problems in phylogenetic tree construction. Whole genomes are used as remedy. Now, the task is to identify the suitable parameters to extract the hidden information from whole genome sequences that truly represent evolutionary information. In this study we explored a random anchor (a stretch of 100 nucleotides) based approach (ABWGP) for finding distance between any two genomes, and used the distance estimates to compute evolutionary trees. A number of strains and species of Mycobacteria were used for this study. Anchor-derived parameters, such as cumulative normalized score, anchor order and indels were computed in a pair-wise manner, and the scores were used to compute distance/phylogenetic trees. The strength of branching was determined by bootstrap analysis. The terminal branches are clearly discernable using the distance estimates described here. In general, different measures gave similar trees except the trees based on indels. Overall the tree topology reflected the known biology of the organisms. This was also true for different strains of Escherichia coli. A new whole genome-based approach has been described here for studying evolutionary relationships among bacterial strains and species.


The Potential for Community-Directed Interventions: Reaching Underserved Populations in Africa.
Community-directed interventions (CDIs) have the potential for fulfilling the promise of primary health care by reaching underserved populations in various settings. CDI has been successfully tested by expanding access to additional health services like malaria case management through local effort in communities where ivermectin distribution is ongoing. The question remains whether the CDI approach has potential in communities that do not have a foundation of community-directed treatment with ivermectin. The UNICEF/UNDP/World Bank/WHO Special Program of Research and Training in Tropical Diseases commissioned three sets of formative studies to explore the potential for introducing CDI among nomads, urban poor, and rural areas with no community-directed treatment with ivermectin. This article reviews their findings. Community and health system respondents identified a set of mainly communicable diseases that could be adapted to CDI as well as participatory mechanisms like community-based organizations and leaders that could form a foundation for local organizing and participation. It is hoped that the results of these formative studies will spur further research on CDI among peoples with poor health-care access.


B-Site Cation Ordered Double Perovskites as Efficient and Stable Electrocatalysts for Oxygen Evolution Reaction.
Simple disordered perovskite oxides have been intensively exploited as promising electrocatalysts for the oxygen evolution reaction (OER) towards their application in water splitting, reversible fuel cells, and rechargeable metal-air batteries. Here, the B-site cation-ordered double perovskites Ba2 Bix Sc0.2 Co1.8-x O6-δ , with two types of cobalt local environments, are demonstrated to be superior electrocatalysts for OER in alkaline solution, demonstrating ultrahigh catalytic activity. In addition, no obvious performance degradation is observed for the Ba2 Bi0.1 Sc0.2 Co1.7 O6-δ sample after a continuous chronopotentiometry test. The critical role of the ordered [Co2+ ] and [Sc3+ , Bi5+ , Co3+ ] dual environments in improving OER activity is exhibited. These results indicate that B-site cation-ordered double perovskite oxides may represent a new class of promising electrocatalysts for the OER in sustainable energy storage and conversion systems.


Effect of Steroids on Gonadal Growth and Gametogenesis in the Juvenile Red Sea Urchin Pseudocentrotus depressus.
Red sea urchins, 10 months old, were fed for 30 days on a casein-based diet containing progesterone, androstenedione, testosterone, estrone, or estradiol-17{beta}. The mean gonad indices of male animals in the androstenedione-and the estrone-treated groups were significantly higher than those in the control group, suggesting that these steroids promote gonadal growth in male animals. Histological observations indicated that spermatogenesis in the estrone-treated group was also promoted compared to that in the control group. In contrast, female urchins were not obviously affected by the steroid-treated diets, probably because yearling female P. depressus are not otherwise ready to carry out gametogenesis. We conclude that androstenedione, estrone, and possibly their derivatives, are involved in the reproduction of male P. depressus.


Biodiesel Production Using Palm Oil with a MOF-Lipase B Biocatalyst from Candida Antarctica: A Kinetic and Thermodynamic Study.
This research presents the results of the immobilization of Candida Antarctica Lipase B (CALB) on MOF-199 and ZIF-8 and its use in the production of biodiesel through the transesterification reaction using African Palm Oil (APO). The results show that the highest adsorption capacity, the 26.9 mg·g-1 Lipase, was achieved using ZIF-8 at 45 °C and an initial protein concentration of 1.20 mg·mL-1. The results obtained for the adsorption equilibrium studies allow us to infer that CALB was physically adsorbed on ZIF-8 while chemically adsorbed with MOF-199. It was determined that the adsorption between Lipase and the MOFs under study better fit the Sips isotherm model. The results of the kinetic studies show that adsorption kinetics follow the Elovich model for the two synthesized biocatalysts. This research shows that under the experimental conditions in which the studies were carried out, the adsorption processes are a function of the intraparticle and film diffusion models. According to the results, the prepared biocatalysts showed a high efficiency in the transesterification reaction to produce biodiesel, with methanol as a co-solvent medium. In this work, the catalytic studies for the imidazolate, ZIF-8, presented more catalytic activity when used with CALB. This system presented 95% biodiesel conversion, while the biocatalyst formed by MOF-199 and CALB generated a catalytic conversion percentage of 90%. Although both percentages are high, it should be noted that CALB-MOF-199 presented better reusability, which is due to chemical interactions.


Prediction of severe toxicity in adult patients under treatment with 5-fluorouracil: a prospective cohort study.
5-Fluorouracil (5-FU) has long been used for the treatment of gastrointestinal tumors harboring interindividual variability in both the pharmacokinetic and the pharmacogenetic profiles, which in turn may lead to life-threatening toxicities. We carried out a prospective cohort study of adult patients initiating treatment with 5-FU between 2013 and 2015. Primary exposures of interest were the methylenetetrahydrofolate reductase single nucleotide polymorphism in exons 4 and 7 and 5'-untranslated region-thymidylate synthase VNTR genotypes, in addition to baseline clinical and demographic variables. The primary outcome was the time to the occurrence of severe toxicity. We used a Cox regression model to evaluate patients' survival and toxicity experience and its association with baseline characteristics and a priori determined genetic polymorphisms. A total of 197 patients were included, 40.1% developed severe toxicity during follow-up. Variables that were significantly associated with developing severe toxicity were the European Organization for Research and Treatment of Cancer functional score [hazard ratio (HR): 0.98; 95% confidence interval (CI): 0.97-0.99]; type of tumor [anus (HR: 2.50; 95% CI: 1.07-5.82), head and neck/esophagus/stomach (HR: 2.95; 95% CI: 1.64-5.33)] and 5-FU continuous infusion regimens over 4-5 days (HR: 9.35; 95% CI: 2.68-32.59). We found a significant association between baseline functional status, type of tumor and continuous infusion regimens and the occurrence of severe toxicity during the follow-up of patients receiving 5-FU. No association was found with the genotypic variants evaluated. Future validation and modeling of an everyday easy-to-use score to predict toxicity among these subgroup of patients remains warranted.


Repeated administration of recombinant human serum albumin caused no serious allergic reactions in patients with liver cirrhosis: a multicenter clinical study.
We carried out a multicenter study to evaluate the safety of recombinant human serum albumin (rHSA), developed using the methylotrophic yeast Pichia pastoris, during and after repeated administration in patients with liver cirrhosis. rHSA was administered to 423 cirrhosis patients with ascites or edema. rHSA was administered three times over 3 days, and each 3-day treatment course was repeated at least three times with an interval of at least 2 weeks between courses. Adverse drug reactions (ADRs) were monitored during and after repeated rHSA administration. Specific antibody titers against Pichia yeast components were measured before and after treatment. Efficacy was evaluated on the basis of changes in serum albumin level, colloid osmotic pressure, and body weight. ADRs were observed in 96 of 423 patients (22.7%), with no serious allergy or difference in the incidence of ADRs observed among the first, second, and third administrations. Specific IgE and IgG antibodies were detected before treatment in 19 and 422 patients, respectively. However, allergic ADRs were observed in 14 patients in whom specific IgE antibodies were not detected. No obvious relationship between allergic ADRs and specific IgE or IgG titers was identified. Serum albumin levels and colloid osmotic pressure increased significantly (P < 0.0001), and body weight decreased significantly (P < 0.0001) after rHSA administration. rHSA caused no serious allergic reactions even when three treatment courses were administered at intervals of at least 2 weeks.


Trend Analysis of Betel Nut-associated Oral Cancer and Health Burden in China.
To forecast the future trend of betel nut-associated oral cancer and the resulting burden on health based on historical oral cancer patient data in Hunan province, China. Oral cancer patient data in five hospitals in Changsha (the capital city of Hunan province) were collected for the past 12 years. Three methods were used to analyse the data; Microsoft Excel Forecast Sheet, Excel Trendline, and the Logistic growth model. A combination of these three methods was used to forecast the future trend of betel nut-associated oral cancer and the resulting burden on health. Betel nut-associated oral cancer cases have been increasing rapidly in the past 12 years in Changsha. As of 2016, betel nuts had caused 8,222 cases of oral cancer in Changsha and close to 25,000 cases in Hunan, resulting in about ¥5 billion in accumulated financial loss. The combined trend analysis predicts that by 2030, betel nuts will cause more than 100,000 cases of oral cancer in Changsha and more than 300,000 cases in Hunan, and more than ¥64 billion in accumulated financial loss in medical expenses. The trend analysis of oral cancer patient data predicts that the growing betel nut industry in Hunan province will cause a humanitarian catastrophe with massive loss of human life and national resources. To prevent this catastrophe, China should ban betel nuts and provide early oral cancer screening for betel nut consumers as soon as possible.


Stabilization of growth factors relevant to wound healing by a plant cell wall biomaterial.
Stabilization of growth factors in a wound environment is critical to the wound healing process. Here we report on the stabilization of key growth factors by a unique plant cell wall biomaterial. MicroSheets are clear cell wall fragments isolated from the non-living water storage cells in the pulp or inner gel of Aloe vera L., which has widely been used for wound healing. It was found that MicroSheets bind to a subset of heparin binding growth factors including basic fibroblast growth factor (bFGF) and keratinocyte growth factor (KGF), two key growth factors in the wound healing process. The binding of bFGF and KGF to MicroSheets was inhibited by heparin and also by a pectic substance isolated from the MicroSheets, indicating that the binding was mediated by this pectic component of the MicroSheet. The binding protected the growth factors against protease digestion. Furthermore, the protective effect was also demonstrated with KGF against digestion by wound fluids and by measuring the biological activity. Thus, these results showed that MicroSheets can stabilize certain critical growth factors in wounds and thereby promote the healing process. Incorporation of a material like MicroSheets provides an important functional element in wound dressings, i. e., growth factor stabilization.


Obesity, adipokines, and C-peptide are associated with distinct plasma phospholipid profiles in adult males, an untargeted lipidomic approach.
Obesity is associated with dysregulated lipid metabolism and adipokine secretion. Our group has previously reported obesity and adipokines are associated with % total fatty acid (FA) differences in plasma phospholipids. The objective of our current study was to identify in which complex lipid species (i.e., phosphatidylcholine, sphingolipids, etc) these FA differences occur. Plasma lipidomic profiling (n = 126, >95% Caucasian, 48-65 years) was performed using chromatographic separation and high resolution tandem mass spectrometry. The responses used in the statistical analyses were body mass index (BMI), waist circumference (WC), serum adipokines, cytokines, and a glycemic marker. High-dimensional statistical analyses were performed, all models were adjusted for age and smoking, and p-values were adjusted for false discovery. In Bayesian models, the lipidomic profiles (over 1,700 lipids) accounted for >60% of the inter-individual variation of BMI, WC, and leptin in our population. Across statistical analyses, we report 51 individual plasma lipids were significantly associated with obesity. Obesity was inversely associated lysophospholipids and ether linked phosphatidylcholines. In addition, we identify several unreported lipids associated with obesity that are not present in lipid databases. Taken together, these results provide new insights into the underlying biology associated with obesity and reveal new potential pathways for therapeutic targeting.


LbL fabricated poly(styrene sulfonate)/TiO(2) multilayer thin films for environmental applications.
Fabrication of multilayer ultrathin composite films composed of nanosized titanium dioxide particles (P25, Degussa) and polyelectrolytes (PELs), such as poly(allyl amine hydrochloride) (PAH) and poly(styrene sulfonate sodium salt) (PSS), on glass substrates using the layer-by-layer (LbL) assembly technique and its potential application for the photodegradation of rhodamine B under ultraviolet (UV) irradiation has been reported. The polyelectrolytes and TiO(2) were deposited on glass substrates at pH 2.5 and the growth of the multilayers was studied using UV/vis spectrophotometer. Thickness measurements of the films showed a linear increase in film thickness with increase in number of bilayers. The surface microstructure of the thin films was characterized by field emission scanning electron microscope. The ability of the catalysts immobilized by this technique was compared with TiO(2) films prepared by drop casting and spin coating methods. Comparison has been made in terms of film stability and photodegradation of rhodamine B. Process variables such as the effect of surface area of the multilayers, number of bilayers, and initial dye concentration on photodegradation of rhodamine B were studied. Degradation efficiency increased with increase in number of catalysts (total surface area) and bilayers. Kinetics analysis indicated that the photodegradation rates follow first order kinetics. Under maximum loading of TiO(2), with five catalyst slides having 20 bilayers of polyelectrolyte/TiO(2) on each, 100 mL of 10 mg/L dye solution could be degraded completely in 4 h. The same slides could be reused with the same efficiency for several cycles. This study demonstrates that nanoparticles can be used in wastewater treatment using a simple immobilization technique. This makes the process an attractive option for scale up.


Some aspects of erythrocyte metabolism in insulin-treated diabetic dogs.
Insulin-dependent diabetes mellitus (IDDM) is a common metabolic disease often complicated by a number of pathological conditions among which are haematological changes and alterations in blood cell function. Human and feline diabetes mellitus patients have been reported to be associated with oxidative stress that can lead to membrane alterations and to reduced erythrocyte life-span. Erythrocyte function in dogs affected by IDDM has been investigated during insulin therapy, paying attention to antioxidant status, membrane resistance, enzyme activities and 2,3-diphosphoglycerate (2,3DPG) concentration. Thirteen diabetic and 36 healthy dogs were bled and haematology and blood chemistry assays were performed to evaluate the degree of compensation. Osmotic fragility, the activities of the enzymes glucose-6-phosphate dehydrogenase (G6PD) and pyruvate-kinase (PK) and the concentrations of reduced glutathione (GSH) and 2,3DPG were evaluated in the erythrocytes. Diabetic dogs did not differ from controls in terms of haematological parameters, except for higher numbers of platelets. Higher values of fructosamine, glucose, protein, plasma potassium and calculated osmolality were detected in the plasma from diabetic dogs. No differences were detected in osmotic fragility, GSH concentration and PK activity between the two groups but 2,3DPG concentration and G6PD activity were statistically significantly higher in the diabetic group. The results indicate minimal alterations in erythrocyte functions occur in insulin-treated diabetic dogs. This contrasts with what has been reported for IDDM humans and cats.


First Report of Clostridium lavalense Isolated in Human Blood Cultures.
An 88-year-old man was admitted to the hospital with worsening malaise, fever, and weakness. Anaerobic blood culture bottles revealed the presence of an anaerobic, Gram-positive sporulated bacillus. Empirical antibiotherapy with intravenous piperacillin-tazobactam was initiated. The patient defervesced after four days and was switched to oral amoxicillin on his 6th day of antibiotic therapy and later discharged from the hospital. Four months later, he had recovered. The bacterium was initially identified as Clostridium butyricum using anaerobic manual identification panel. 16S rRNA gene sequence and phylogenetic analysis showed the bacterium to be Clostridium lavalense, a recently described species with no previously published case of isolation in human diagnostic samples so far. This is the first report of Clostridium lavalense isolation from human blood cultures. Further studies are needed in order to elucidate the role of Clostridium lavalense in human disease and its virulence factors.


Immediate interpersonal and intermanual referral of sensations following anesthetic block of one arm.
To explore whether interpersonal and intermanual sensory referral occurs following anesthetic block of a limb and to test theories of disinhibition of mirror neuron activity and transcallosal referral. Case series. Outpatient surgery at the University of California San Diego Medical Center. Six patients who underwent orthopedic surgery. Patient verbal ratings. Patients with brachial plexus blocks experienced touch sensations in the anesthetized arm when watching another person's arm being touched or when the contralateral intact hand was touched. To our knowledge, this is the first demonstration of rapid reorganization of functional connectivity in the adult human brain, most likely in S2 neurons. This finding suggests that conscious perception of touch results from fluctuating mosaics of cortical excitation and inhibition between different regions within the patient's own S2 neurons and, more remarkably, from viewing others' sensations.


A low affinity ground state conformation for the Dynein microtubule binding domain.
Dynein interacts with microtubules through a dedicated binding domain that is dynamically controlled to achieve high or low affinity, depending on the state of nucleotide bound in a distant catalytic pocket. The active sites for microtubule binding and ATP hydrolysis communicate via conformational changes transduced through a approximately 10-nm length antiparallel coiled-coil stalk, which connects the binding domain to the roughly 300-kDa motor core. Recently, an x-ray structure of the murine cytoplasmic dynein microtubule binding domain (MTBD) in a weak affinity conformation was published, containing a covalently constrained beta(+) registry for the coiled-coil stalk segment (Carter, A. P., Garbarino, J. E., Wilson-Kubalek, E. M., Shipley, W. E., Cho, C., Milligan, R. A., Vale, R. D., and Gibbons, I. R. (2008) Science 322, 1691-1695). We here present an NMR analysis of the isolated MTBD from Dictyostelium discoideum that demonstrates the coiled-coil beta(+) registry corresponds to the low energy conformation for this functional region of dynein. Addition of sequence encoding roughly half of the coiled-coil stalk proximal to the binding tip results in a decreased affinity of the MTBD for microtubules. In contrast, addition of the complete coiled-coil sequence drives the MTBD to the conformationally unstable, high affinity binding state. These results suggest a thermodynamic coupling between conformational free energy differences in the alpha and beta(+) registries of the coiled-coil stalk that acts as a switch between high and low affinity conformations of the MTBD. A balancing of opposing conformations in the stalk and MTBD enables potentially modest long-range interactions arising from ATP binding in the motor core to induce a relaxation of the MTBD into the stable low affinity state.


Exploring the free energy gain of phase separation via Markov state modeling.
The gain of free energy upon unmixing is determined via application of Markov state modeling (MSM), using an Ising model with a fixed number of up- and down-spins. MSM yields reasonable estimates of the free energies. However, a closer look reveals significant differences that point to residual non-Markovian effects. These non-Markovian effects are rather unexpected since the typical criteria to study the quality of Markovianity indicate complete Markovian behavior. We identify the sparse connectivity between different Markov states as a likely reason for the observed bias. By studying a simple five state model system, we can analytically elucidate different sources of the bias and thus explain the different deviations that were observed for the Ising model. Based on this insight, we can modify the determination of the count matrix in the MSM approach. In this way, the estimation of the free energy is significantly improved.


Tissue Renin-Angiotensin System (tRAS) Induce Intervertebral Disc Degeneration by Activating Oxidative Stress and Inflammatory Reaction.
Lumbar intervertebral disc degeneration (IDD) has been the major contributor to low back pain (LBP). IDD is an chronic inflammation process, with the activation of plentiful inflammation-related cytokines and ECM degradation-related enzymes. In the past few years, hypertension has been reported to correlate with LBP. In addition, the local tissue renin-angiotensin system (tRAS) has been identified in multiple tissues, including the spinal cord, skin, kidney, heart, and bone. Recently, tRAS has also been established in both bovine and human intervertebral disc tissues, especially in the degenerated disc tissue. However, the exact of tRAS and IDD remains unknown. In this present study, proteomic analysis, molecular biology analysis, and animal model were all used. Firstly, we revealed that tRAS was excessively activated in the human degenerated intervertebral disc tissue via proteomic analysis and molecular biology analysis. Then, in vitro experiment suggested that Ang II could decrease the cell viability of human NP cells and promote NP cell apoptosis, senescence, oxidative stress, and NLRP3 activation in human NP cells. In addition, Ang II could also trigger degeneration and fibrosis phenotype in human NP cells. Finally, the animal model demonstrated that the local activated ACE/Ang II axis in the NP tissue could accelerate IDD in aging spontaneously hypertensive rats (SHR). Collectively, the degenerated intervertebral disc tissue showed excessively activated tRAS, and local activated tRAS could induce NP cell senescence, apoptosis, oxidative stress, and inflammatory reaction to promote IDD. These biological effects of Ang II on human NP cells may provide novel insight into further treatment of IDD.


Results of the 2006 National Resident Matching Program: family medicine.
The results of the 2006 National Resident Matching Program (NRMP) reflect a currently stable level of student interest in family medicine residency training in the United States. Compared with the 2005 Match, 26 more positions (with the same number of US seniors) were filled in family medicine residency programs through the NRMP in 2006, at the same time as four more (five fewer US seniors) in primary care internal medicine, one fewer in pediatrics-primary care (12 more US seniors), and four more (19 more US seniors) in internal medicine-pediatric programs. Many different forces, including student perspectives of the demands, rewards, and prestige of the specialty; the turbulence and uncertainty of the health care environment; lifestyle issues; and the impact of faculty role models continue to influence medical student career choices. Two more positions (nine more US seniors) were filled in categorical internal medicine. Two fewer positions (11 fewer US seniors) were filled in categorical pediatrics programs. The 2006 NRMP results suggest that interest in family medicine and primary care careers continues to be stable. With the needs of the nation calling for the roles and services of family physicians, family medicine matched too few graduates through the 2006 NRMP to meet the nation's needs for primary care physicians.


Prevalence of the number of pre-gestational diagnoses and trends in the United States in 2006 and 2016.
There is a trend in reproductive-aged women to live with more chronic conditions, likely resulting in pregnancies complicated by one or more pre-gestational diagnoses. The objective of this study is to determine the prevalence of women with pre-gestational diagnoses and pregnancy-related complications, and assess the trends of pre-gestational diagnoses between two time-points, ten-years apart from 2006 to 2016. We abstracted pregnant patients from the Healthcare Cost and Utilization Project's National Inpatient Sample by the Agency for Healthcare Research and Quality in 2006 and 2016. We classified diagnosis codes, ICD 9 for 2006 and ICD 10 for 2016, as pre-gestational diagnoses or as pregnancy-related complications. Descriptive statistics were presented as frequencies and proportions for categorical variables. Chi-square analysis was performed. All statistical analyses were two-sided and p-value < .05 was considered to be statistically significant. Between 2006 and 2016, the percentage of patients with at least one pre-gestational diagnoses increased from 35.3% in 2006 to 53.8% in 2016 (p < .0001) and the percentage of patients with at least one pregnancy-related complication increased from 62.6% to 69.1% (p < .0001). We found a trend of increasing pregnancy-related complications with an increasing number of pre-gestational diagnoses. The prevalence of asthma and obesity, either alone or in combination were found to rise over the ten-year time span. The percent of patients entering pregnancy with any pre-gestational diagnosis has increased, along with the number of pregnancy-related complications. Future research is needed to understand the effects of these diagnoses in combination and the possible impact on pregnancy outcomes.


Transient helicity in intrinsically disordered Axin-1 studied by NMR spectroscopy and molecular dynamics simulations.
Many natural proteins are, as a whole or in part, intrinsically disordered. Frequently, such intrinsically disordered regions (IDRs) undergo a transition to a defined and often helical conformation upon binding to partner molecules. The intrinsic propensity of an IDR sequence to fold into a helical conformation already in the absence of a binding partner can have a decisive influence on the binding process and affinity. Using a combination of NMR spectroscopy and molecular dynamics (MD) simulations we have investigated the tendency of regions of Axin-1, an intrinsically disordered scaffolding protein of the WNT signaling pathway, to form helices in segments interacting with binding partners. Secondary chemical shifts from NMR measurements show an increased helical population in these regions. Systematic application of MD advanced sampling approaches on peptide segments of Axin-1 reproduces the experimentally observed tendency and allows insights into the distribution of segment conformations and free energies of helix formation. The results, however, were found to dependent on the force field water model. Recent water models specifically designed for IDRs significantly reduce the predicted helical content and do not improve the agreement with experiment.


Spinal proteins in patients with acoustic neuromas.
The values of total spinal protein in cerebrospinal fluid (CSF), used as normal material, from 98 persons are presented. These values showed that the previously used reference limits (0.20-0.40 g/l) for total protein in CSF were too low, and consequently the new reference values 0.20-0.85 g/l are used. 77 patients with surgically verified acoustic neuromas had total protein determined in CSF prior to operation, and 63% of patients with tumours less than 25 mm in diameter had normal total protein values, while only 3% of patients with tumours larger than 25 mm had normal values. Since the large tumours can be easily diagnosed by the non-invasive computer tomography, it is concluded that CSF total protein determination is only of limited value in the search for acoustic neuromas. A more quantitated examination of CSF proteins (albumin, alpha 2-macroglobulin, IgA, IgG and IgM) showed significantly increased values among the tumour patients, but the findings were not of any significant clinical value in the diagnosis of tumours.


Transforming growth factor-beta stimulates intestinal epithelial focal adhesion kinase synthesis via Smad- and p38-dependent mechanisms.
Focal adhesion kinase (FAK) regulates cell migration, proliferation, and apoptosis. FAK protein is reduced at the edge of migrating gut epithelial sheets in vitro, but it has not been characterized in restitutive gut mucosa in vivo. Here we show that FAK and activated phospho-FAK (FAK(397)) immunoreactivity was lower in epithelial cells immediately adjacent to human gastric and colonic ulcers in vivo, but dramatically increased in epithelia near the ulcers, possibly reflecting stimulation by growth factors absent in vitro. Transforming growth factor (TGF)-beta, but not fibroblast growth factor, platelet-derived growth factor, or vascular endothelial growth factor, increased FAK levels in Caco-2 and IEC-6 cells. Epithelial immunoreactivity to TGF-beta and phospho-Smad3 was also higher near the ulcers, varying in parallel with FAK. The TGF-beta receptor antagonist SB431542 completely blocked TGF-beta-induced Smad2/3 and p38 activation in IEC-6 cells. SB431542, the p38 antagonist SB203580, and siRNA-mediated reduction of Smad2 and p38alpha prevented TGF-beta stimulation of both FAK transcription and translation (as measured via a FAK promoter-luciferase construct). FAK(397) levels were directly related to total FAK protein expression. Although gut epithelial motility is associated with direct inhibition of FAK protein adjacent to mucosal wounds, TGF-beta may increase FAK protein near but not bordering mucosal ulcers via Smad2/3 and p38 signals. Our results show that regulation of FAK expression may be as important as FAK phosphorylation in critically influencing gut epithelial cell migration after mucosal injury.


Effects of various radiation doses on induced T-helper cell differentiation and related cytokine secretion.
Exposure to ionizing radiation often induces T helper (Th) cell differentiation, resulting in an imbalance of Th1 and Th2 cellular subtypes, which can affect the efficacy of cancer radiotherapy. The aim of this study was to analyze differential expression of Th1, Th2 and Th3/Type 1 regulatory T cell (Tr1) subtype-related genes and cytokines in mouse thymocytes after high- and low-dose systemic radiation, using functional classification gene arrays and Elisa assays, and to explore the molecular mechanisms underlying radiation's immune effects and their relationship with Th1/Th2 immunity. We found that expression of 8 genes was upregulated after LDR, while expression of 5 genes was downregulated. After HDR, 54 genes were upregulated and 3 genes were downregulated, including genes related to Th1, Th2 and Th3/Tr1 cellular subtypes, Th1/Th2-type immune response genes and transcription factor-related genes. In the foregoing results, LDR and HDR in the thymus induced opposite patterns of expression for Th1-, Th2- and Th3-type related cytokines TGF-β, C/EBP-β and TNF-α. We also found that expression of Interferon-γ (IFN-γ) and Interleukin-2 (IL-2), which have a moderating effect on immune function, was upregulated after LDR. Furthermore, the secretion of negative regulatory factors Interleukin-1β (IL-1β), Interleukin-4 (IL-4), transforming growth factor-β (TGF-β) and Interleukin-21 (IL-21) was reduced after LDR, but HDR produced the opposite effect and stimulated their expression. These findings suggest that LDR may induce a Th1-type immune response, while HDR may lead to a Th2-type immune response.


Subacute constrictive uremic pericarditis. Survival after pericardiectomy.
Uremic pericarditis progressed to subacute constriction despite intensive medical treatment in two patients with concomitant metabolic stress of surgery and infection. Total pericardiectomy was successful and should be done as soon as medical measures fail to resolve the pericarditis.


Ellagic acid ameliorates learning and memory deficits in a rat model of Alzheimer's disease: an exploration of underlying mechanisms.
Alzheimer's disease (AD) is a neurodegenerative disorder with irreversible loss of intellectual abilities. Current therapies for AD are still insufficient. In this study, the effect of ellagic acid on learning and memory deficits was evaluated in intrahippocampal amyloid beta (Aβ25-35)-microinjected rats and its modes of action were also explored. AD rat model was induced by bilateral intrahippocampal microinjection of Aβ25-35 and ellagic acid was daily administered (10, 50, and 100 mg/kg), and learning, recognition memory, and spatial memory were evaluated in addition to histochemical assessment, oxidative stress, cholinesterases activity, and level of nuclear factor-kappaB (NF-κB), Toll-like receptor 4 (TLR4), and nuclear factor (erythroid-derived 2)-like 2 (Nrf2). The amyloid beta-microinjected rats showed a lower discrimination ratio in novel object and alternation score in Y maze tasks and exhibited an impairment of retention and recall capability in passive avoidance paradigm and higher working and reference memory errors in radial arm maze (RAM). In addition, amyloid beta group showed a lower number of Nissl-stained neurons in CA1 area in addition to enhanced oxidative stress, higher activity of cholinesterases, greater level of NF-κB and TLR4, and lower level of nuclear/cytoplasmic ratio for Nrf2 and ellagic acid at a dose of 100 mg/kg significantly prevented most of these abnormal alterations. Ellagic acid pretreatment of intrahippocampal amyloid beta-microinjected rats could dose-dependently improve learning and memory deficits via neuronal protection and at molecular level through mitigation of oxidative stress and acetylcholinesterase (AChE) activity and modulation of NF-κB/Nrf2/TLR4 signaling pathway.


Phylogenetic analysis of pbp genes in treponemes.
β-Lactamases are the main cause of bacterial resistance to penicillin, cephalosporins, and related β-lactam compounds. The presence of the novel penicillin-binding protein (pbp) Tp47 in Treponema pallidum has been reported to be a well-known mechanism for turnover of b-lactam antibiotics. Although, T. pallidum remains sensitive to penicillin, clinically significant resistance to macrolides has emerged in many developing countries. The genome sequence of T. pallidum has shown the presence of genes encoding pbp, but there are no current reports of the presence of mobile plasmids. The phylogenetic analysis is used to study the diversity of chromosomal pbp genes and its relatedness to Tp47 in Treponema species. In our study, genes encoding penicillin-binding proteins that showed significant similarity to each other appeared in separate clusters. Tp47 showed no substantial similarity to other β-lactamases in treponemes. The relatedness of Treponema denticola to other treponemes, including T. pallidum, and the reported presence of natural mobile antibiotic determinants highlight the importance of investigating the diversity of pbp genes in Treponema species. This will lead to a greater understanding of its potential to develop additional antibiotic resistance via horizontal gene transfer that could seriously compromise the treatment and control of syphilis.


Long-term Cognitive Implications of Intrauterine Hyperglycemia in Adolescent Offspring of Women With Type 1 Diabetes (the EPICOM Study).
Exposure to maternal diabetes in utero may have a negative impact on the developing brain. The objective was to examine long-term cognitive consequences of intrauterine hyperglycemia in adolescent offspring of women with type 1 diabetes and to ascertain a possible association with maternal HbA1c. Offspring of a prospectively followed cohort of women with type 1 diabetes (n = 277) participated in a follow-up examination at the age of 13-19 years. A control group from the background population was identified (n = 301). Cognitive function was evaluated using Reynolds Intellectual Assessment Scales and classified into indices of composite intelligence, verbal and nonverbal intelligence, and composite memory. Frequencies of reading and writing problems and attendance to classes for children with learning difficulties were assessed. Offspring of women with type 1 diabetes scored lower in all normalized and standardized intelligence indices compared with controls: composite intelligence (95.7 vs. 100, P = 0.001), verbal intelligence (96.2 vs. 100, P = 0.004), nonverbal intelligence (96.4 vs. 100, P = 0.008), and composite memory (95.7 vs. 100, P = 0.001). A higher frequency of diabetes-exposed offspring had parent-reported learning difficulties in primary school. Differences between groups remained after adjustment for confounders and potential mediators. We found no direct association between maternal HbA1c and offspring cognitive function in the exposed group. Adolescent offspring of women with type 1 diabetes had lower cognitive function compared with a control group, also after adjustment for confounders and potential mediators. These differences may reflect direct harmful effects of maternal diabetes on neurodevelopment in the offspring.


Correlation study on chromogranin A genetic polymorphism and prognosis of critically ill patients.
The objective was to investigate the correlation between single nucleotide polymorphism (SNP) of chromogranin A (CHGA) and prognosis of critically ill patients. We screened 357 critically ill patients consecutively admitted to our intensive care unit. The -89/-415/-462 SNP locus in the promoter region and the +9559/+9578/+9590/+9611 SNP locus in exon 7 coding of CHGA were genotyped by polymerase chain reaction and DNA sequencing technology. Subsequently, the correlation between genotype and prognosis of patients was analyzed. (1) Three hundred critically ill Chinese Han patients were enrolled in the study. CHGA-415/-462/+9559/+9611 SNPs were polymorphically distributed. Phenotypes of the 4 SNPs were shown not to be in linkage disequilibrium, and there were no significant differences in the minor allele frequencies (MAFs) of the 4 SNPs between participants of this study and healthy people in Asia. (2) The CHGA-415 T/C MAF of the nonsurvival group was significantly higher than that of the survival group (MAF 0.3813 and 0.2864, respectively; P=.026). Survival analysis showed that there were significant differences between the CHGA-415 T/C mutation group (including TC and CC genotypes) and the wild-type group (TT genotype) (log rank=8.887, P=.003). The mortality in the mutant group was significantly higher than that in the wild-type group (0.3333 and 0.1852, respectively; P=.004). (3) Binary logistic analysis showed that CHGA-415 T/C polymorphism was an independent risk factor for the mortality of critically ill patients (odds ratio, 2.286; 95% confidence interval, 1.165-4.484; P=.016). Critically ill patients with CHGA-415 T/C mutant genotype display higher 30-day mortality than those with the wild-type group. CHGA-415 T/C polymorphism is an independent risk factor of poor prognosis in critically ill Chinese Han patients.


Unusual anatomical features of the right atrioventricular valve.
Despite the great interest taken in the tricuspid valve, the anatomical literature on the subject still leaves much open to question. The aim of this study was to describe the natural foramina which are present in the leaflets of the tricuspid valve, as well as, well -- founded onto -- and phylogenetically lack of continuity of its attachment and the frenula of the tricuspid valve. We studied the frequency of occurrence and morphology of these features of the tricuspid valve in 107 adult hearts.


Localized bursting of mesocarp cells triggers catastrophic fruit cracking.
The so-called rain-cracking of sweet cherry fruit severely threatens commercial production. Simple observation tells us that cuticular microcracking (invisible) always precedes skin macrocracking (visible). The objective here was to investigate how a macrocrack develops. Incubating detached sweet cherry fruit in deionized water induces microcracking. Incubating fruit in D2O and concurrent magnetic resonance imaging demonstrates that water penetration occurs only (principally) through the microcracks, with nondetectable amounts penetrating the intact cuticle. Optical coherence tomography of detached, whole fruit incubated in deionized water, allowed generation of virtual cross-sections through the zone of a developing macrocrack. Outer mesocarp cell volume increased before macrocracks developed but increased at a markedly higher rate thereafter. Little change in mesocarp cell volume occurred in a control zone distant from the crack. As water incubation continued, the cell volume in the crack zone decreased, indicating leaking/bursting of individual mesocarp cells. As incubation continued still longer, the crack propagated between cells both to form a long, deep macrocrack. Outer mesocarp cell turgor did not differ significantly before and after incubation between fruit with or without macrocracks; nor between cells within the crack zone and those in a control zone distant from the macrocrack. The cumulative frequency distribution of the log-transformed turgor pressure of a population of outer mesocarp cells reveals all cell turgor data followed a normal distribution. The results demonstrate that microcracks develop into macrocracks following the volume increase of a few outer mesocarp cells and is soon accompanied by cell bursting.


Restructuring and Hydrogen Evolution on Pt Nanoparticle.
The restructuring of nanoparticles at the in situ condition is a common but complex phenomenon in nanoscience. Here, we present the first systematic survey on the structure dynamics and its catalytic consequence for hydrogen evolution reaction (HER) on Pt nanoparticles, as represented by a magic number Pt44 octahedron (∼1 nm size). Using a first principles calculation based global structure search method, we stepwise follow the significant nanoparticle restructuring under HER conditions as driven by thermodynamics to expose {100} facets, and reveal the consequent large activity enhancement due to the marked increase of the concentration of the active site, being identified to be apex atoms. The enhanced kinetics is thus a "byproduct" of the thermodynamical restructuring. Based on the results, the best Pt catalyst for HER is predicted to be ultrasmall Pt particles without core atoms, a size below ∼20 atoms.


Centrifugal partition chromatography in a biorefinery context: Optimisation and scale-up of monosaccharide fractionation from hydrolysed sugar beet pulp.
The isolation of component sugars from biomass represents an important step in the bioprocessing of sustainable feedstocks such as sugar beet pulp. Centrifugal partition chromatography (CPC) is used here, as an alternative to multiple resin chromatography steps, to fractionate component monosaccharides from crude hydrolysed sugar beet pulp pectin. CPC separation of samples, prepared in the stationary phase, was carried out using an ethanol: ammonium sulphate (300gL-1) phase system (0.8:1.8v:v) in ascending mode. This enabled removal of crude feedstream impurities and separation of monosaccharides into three fractions (l-rhamnose, l-arabinose and d-galactose, and d-galacturonic acid) in a single step. Throughput was improved three-fold by increasing sample injection volume, from 4 to 16% of column volume, with similar separation performance maintained in all cases. Extrusion of the final galacturonic acid fraction increased the eluted solute concentration, reduced the total separation time by 24% and removed the need for further column regeneration. Reproducibility of the separation after extrusion was validated by using multiple stacked injections. Scale-up was performed linearly from a semi-preparative 250mL column to a preparative 950mL column with a scale-up ratio of 3.8 applied to mobile phase flow rate and sample injection volume. Throughputs of 9.4gL-1h-1 of total dissolved solids were achieved at the preparative scale with a throughput of 1.9gL-1h-1 of component monosaccharides. These results demonstrate the potential of CPC for both impurity removal and target fractionation within biorefinery separations.


Adjudicating entitlements: the emerging discourses of research ethics boards.
Research ethics boards adjudicate between competing sacred discourses in the knowledge industries. The traditional rights of researchers to initiate and conduct enquiry, the rights of research subjects to have stewardship over their own experiential knowledge and the legal responsibilities of universities and other institutions often compete in the process of adjudication. The justification narrative leading to the establishment of boards is reviewed along with the governmental and institutional actions that have led to the ethics codes in existence. Also discussed is divisiveness between researchers and boards, changes brought about by shifting moral bases, trust and confidentiality, privacy, informed consent, the creation of cultures of research ethics and the unresolved issues awaiting future discussion.


Two sisters with growth failure, microcephaly, peculiar facies and apical dystrophy: the presentation of brachymorphism-onychodysplasia-dysphalangism syndrome?
We report two sisters with growth failure, relative microcephaly, peculiar facies and apical dystrophy (brachydactyly type B). They had shortness and clinodactyly of the 5th fingers, aplasia or hypoplasia of the distal phalanges of 5th fingers, short medial phalanges of the 2nd and 5th fingers, hypoplasia or aplasia of distal phalanges of 2-5th toes, with tiny toenails, and aplasia or nails of 5th fingers and right 5th toe in the younger sister. Dysmorphic facial features included high forehead, sparse hair, blepharophimosis, telecanthus, epicanthic folds, a low nasal bridge, a broad nasal tip and micrognathia. Their ears were low-set and malformed. The older sister additionally had a high-pitched voice and eczema on the face and limbs. In the younger sister a cardiac defect was diagnosed--ventricular and atrial septal defect, patent ductus arteriosus. They had some clinical features of Coffin-Siris syndrome, but with a milder phenotype and much less severe mental handicap. Their clinical picture resembles more the brachymorphism-onychodysplasia-dysphalangism (BOD) syndrome.


Cushing's syndrome in pregnancy.
A 22-year-old G(1)P(0) was admitted at 26 weeks gestation for preeclampsia, hyperglycaemia and cushingoid features. Elevated 24-h urine free cortisol (UFC) and suppressed plasma adrenocorticotrophic hormone (ACTH) suggested ACTH-independent Cushing's syndrome. Ultrasound showed left adrenal mass. She delivered preterm at 28 weeks due to severe preeclampsia and fetal distress. The infant expired after 4 days. Blood pressure was controlled after delivery and the patient was discharged on ketoconazole. Adrenalectomy was planned postpartum; however, she withdrew consent and was lost to follow-up. A 33-year-old G(1)P(1) presented with gestational diabetes. Pregnancy was complicated by premature delivery at 31 weeks for fetal distress. The baby improved and survived. Three months postpartum, she was evaluated for osteoporosis after sustaining a fracture from a fall. Cushingoid facies, elevated 24-h UFC, suppressed ACTH and a right adrenal mass on MRI confirmed an ACTH-independent Cushing's syndrome. She underwent adrenalectomy and improved.


Factitious posttraumatic stress disorder: the veteran who never got to Vietnam.
The historical uniqueness of the Vietnam War produced an unusually high rate of psychiatric dysfunction among veterans, particularly in the form of posttraumatic stress disorder (PTSD). Now, in the wake of unprecedented media coverage of PTSD and the growth of veteran outreach centers documenting and publicizing the difficulties of some veterans, a heretofore unrecognized variant of PTSD-factitious PTSD--has arisen. The authors present seven cases of factitious PTSD, a classic example of clinical deception found among veterans who were never in combat and, in some cases, were never in Vietnam. The authors discuss the etiologies of the disorder and the underlying psychopathology, which suggests either factitious syndromes, such as Munchausen's, or malingering. They conclude with recommendations for diagnosis and treatment.


Fuzzy temporal logic based railway passenger flow forecast model.
Passenger flow forecast is of essential importance to the organization of railway transportation and is one of the most important basics for the decision-making on transportation pattern and train operation planning. Passenger flow of high-speed railway features the quasi-periodic variations in a short time and complex nonlinear fluctuation because of existence of many influencing factors. In this study, a fuzzy temporal logic based passenger flow forecast model (FTLPFFM) is presented based on fuzzy logic relationship recognition techniques that predicts the short-term passenger flow for high-speed railway, and the forecast accuracy is also significantly improved. An applied case that uses the real-world data illustrates the precision and accuracy of FTLPFFM. For this applied case, the proposed model performs better than the k-nearest neighbor (KNN) and autoregressive integrated moving average (ARIMA) models.


Intersecting pentagons as surrogate for identifying the use of mini mental state examination in assessment of dementia in a largely illiterate population.
The mini-mental state evaluation (MMSE) is often used to identify patients with dementia. One component of the MMSE is the intersecting pentagon copying (IPC) test, which may be difficult to be used in an illiterate population. A post hoc analysis on an elderly population (60 years and above) from Himachal Pradesh was carried out. The data of only 1,513 elderly individuals out of a total of 2,000 participants with a score of more than 26 (nondemented) out of a possible score of 30 on cognitive battery available were used. The scores on the IPC were evaluated and their association with some demographic variables was also assessed. Illiterate participants, female participants, those with greater age, and the rural/tribal population groups faced the most difficulty in drawing the intersecting pentagons and even greater difficulty in drawing them correctly. The IPC presents challenges for people who are illiterate and the scoring method needs to be addressed and changed particularly when the test is used in largely illiterate populations.


Melatonin Regulates Differentiation of Sheep Brown Adipocyte Precursor Cells Via AMP-Activated Protein Kinase.
In sheep industry, hypothermia caused by insufficient brown adipose tissue (BAT) deposits is one of the major causes of lamb deaths. Enhancing the formation and function of BAT in neonatal lamb increases thermogenesis and hence reduces economic losses. The aim of the present study was to explore the effect and mechanism of melatonin on sheep brown adipocyte formation and function. Sheep brown adipocyte precursor cells (SBACs) isolated from perirenal BAT were treated with melatonin (1 and 10 nM). The SBACs subjected to melatonin exhibited a decreased proliferation ability, accompanied by down-regulated proliferating cell nuclear antigen, cyclin D1, and CDK4 protein contents in a melatonin dose-dependent manner. Melatonin promoted brown adipocyte formation and induced the expression of brown adipogenic markers, including uncoupling protein 1 and PR domain-containing 16 during differentiation of SBAC. Moreover, the AMP-activated protein kinase α1 (AMPKα1) activity was positively correlated with brown adipocyte formation potential. Importantly, melatonin effectively activated AMPKα1. Furthermore, promotional effects of melatonin were abolished by AMPKα1 knockout, suggesting the involvement of AMPKα1 in this process. Collectively, these results suggested that melatonin enhanced brown adipocyte formation in SBACs in vitro through activation of AMPKα1.


Changes in subendocardial viability ratio with acute high-altitude exposure and protective role of acetazolamide.
High-altitude tourism is increasingly frequent, involving also subjects with manifest or subclinical coronary artery disease. Little is known, however, on the effects of altitude exposure on factors affecting coronary perfusion. The aim of our study was to assess myocardial oxygen supply/demand ratio in healthy subjects during acute exposure at high altitude and to evaluate the effect of acetazolamide on this parameter. Forty-four subjects (21 men, age range: 24-59 years) were randomized to double-blind acetazolamide 250 mg bid or placebo. Subendocardial viability ratio and oxygen supply/demand ratio were estimated on carotid artery by means of a validated PulsePen tonometer, at sea level, before and after treatment, and after acute and more prolonged exposure to high altitude (4559 m). On arrival at high altitude, subendocardial viability ratio was reduced in both placebo (from 1.63±0.15 to 1.18±0.17; P<0.001) and acetazolamide (from 1.68±0.25 to 1.35±0.18; P<0.001) groups. Subendocardial viability ratio returned to sea level values (1.65±0.24) after 3 days at high altitude under acetazolamide but remained lower than at sea level under placebo (1.42±0.22; P<0.005 versus baseline). At high altitude, oxygen supply/demand ratio fell both under placebo (from 29.6±4.0 to 17.3±3.0; P<0.001) and acetazolamide (from 32.1±7.0 to 22.3±4.6; P<0.001), its values remaining always higher (P<0.001) on acetazolamide. Administration of acetazolamide may, thus, antagonize the reduction in subendocardial oxygen supply triggered by exposure to hypobaric hypoxia. Further studies involving also subjects with known or subclinical coronary artery disease are needed to confirm a protective action of acetazolamide on myocardial viability under high-altitude exposure.


Severity of Illness in Bronchiolitis Amid Unusual Seasonal Pattern During the COVID-19 Pandemic.
We aimed to characterize recent trends in bronchiolitis at US children's hospitals and to compare severity of illness in bronchiolitis in the most recent year to the previous seasonal epidemics. This is a cross-sectional study of visits for bronchiolitis in infants <24 months old from October 2016 to September 2021 at 46 US children's hospitals participating in the Pediatric Health Information Systems database. Study years were defined by 12-month periods beginning in October to account for typical winter epidemics that crossover calendar years. We used logistic and Fourier Poisson regression models to examine trends in outcomes and compare seasonality, respectively. The study included 389 411 emergency visits for bronchiolitis. Median age of infants with bronchiolitis was higher in October 2020 to September 2021 compared to previous epidemics (8 and 6 months, respectively, P < .001) The odds of hospitalization, ICU admission, invasive mechanical ventilation, and noninvasive ventilation did not differ in October 2020 to September 2021 compared to previous epidemics from October 2016 to September 2020 (all P > .05 for unadjusted models and models adjusted for age). Seasonality varied significantly among these 2 periods (P < .001). Although the seasonality of bronchiolitis differed in October 2020 to September 2021, severity of illness in infants with bronchiolitis was consistent with previous epidemics.


Improved naïve Bayesian modeling of numerical data for absorption, distribution, metabolism and excretion (ADME) property prediction.
We have implemented a naïve Bayesian classifier which models continuous numerical data using a Gaussian distribution. Several cases of interest in the area of absorption, distribution, metabolism, and excretion prediction are presented which demonstrate that this approach is superior to the implementation of naïve Bayesian classifiers in which continuous chemical descriptors are modeled as binary data. We demonstrate that this enhanced performance, upon comparison with other implementations, is independent of the descriptor sets chosen. We also compare the performance of three implementations of naïve Bayesian classifiers with other previously described models.


Guidelines for the interpretation of analytical toxicology results and unit of measurement conversion factors.
A data compilation has been published on the World Wide Web [http:// www.leeds.ac.uk/acb/annals] which aims to assist in the interpretation of analytical toxicology results in individual patients. 'Therapeutic' or 'normal' plasma/whole blood/urine concentrations, as well as the concentrations associated with serious toxicity (if known), for some 700 analytes of toxicological interest are given together with (when possible) relative atomic or formula masses, and mass/amount and amount/mass concentration conversion factors. This paper gives background and supplementary information which should be borne in mind when providing interpretation or using the Web table. Supplementary tables listing (i) common therapeutic drug monitoring assays and guidelines for interpretation of results, (ii) emergency toxicology analyses which may influence active treatment, (iii) blood carboxyhaemoglobin saturation and clinical features of toxicity, (iv) information important when interpreting the results of toxicology investigations, (v) factors which may affect interpretation of analytical toxicology results, and (vi) conversion factors for volatile compounds are included.


Paradoxical response to carbonic anhydrase inhibitors in patients with intraretinal cystoid spaces.
Background: Intraretinal cystoid spaces (IRCS) are fluid-filled spaces seen in some retinal dystrophies and often treated with carbonic anhydrase inhibitors. The purpose of this study is to report an unexpected bilateral improvement in the IRCS after discontinuation of therapy. Material and Methods: We identified from our records 23 patients with retinal dystrophy and IRCS who had been treated with topical and/or oral carbonic anhydrase inhibitors. All subjects had regular follow-up with OCT and previous genetic testing. Results: We identified four (17%) patients who experienced a bilateral and symmetrical paradoxical improvement in IRCS size and visual acuity after discontinuation of carbonic anhydrase inhibitors. Two were mutations in RS1, one in CLN3 and another in NR2E3. All patients were followed for at least three years (range 39-63 months). None had systemic abnormalities. Conclusions: Patients with IRCS may exhibit a paradoxical response after discontinuation of carbonic anhydrase inhibitors. Although the pathophysiology of these phenomena is unclear, stopping treatment may be an option in patients who cease to improve or get worse on treatment.


Classification of Attentional Tunneling Through Behavioral Indices.
The objective of this study was to develop a machine learning classifier to infer attentional tunneling through behavioral indices. This research serves as a proof of concept for a method for inferring operator state to trigger adaptations to user interfaces. Adaptive user interfaces adapt their information content or configuration to changes in operating context. Operator attentional states represent a promising class of triggers for these adaptations. Behavioral indices may be a viable alternative to physiological correlates for triggering interface adaptations based on attentional state. A visual search task sought to induce attentional tunneling in participants. We analyzed user interaction under tunnel and non-tunnel conditions to determine whether the paradigm was successful. We then examined the performance trade-offs stemming from attentional tunnels. Finally, we developed a machine learning classifier to identify patterns of interaction characteristics associated with attentional tunnels. The experimental paradigm successfully induced attentional tunnels. Attentional tunnels were shown to improve performance when information appeared within them, but to hinder performance when it appeared outside. Participants were found to be more tunneled in their second tunnel trial relative to their first. Our classifier achieved a classification accuracy similar to comparable studies (area under curve = 0.74). Behavioral indices can be used to infer attentional tunneling. There is a performance trade-off from attentional tunneling, suggesting the opportunity for adaptive systems. This research applies to adaptive automation aimed at managing operator attention in information-dense work domains.


Regulation of centriolar satellite integrity and its physiology.
Centriolar satellites comprise cytoplasmic granules that are located around the centrosome. Their molecular identification was first reported more than a quarter of a century ago. These particles are not static in the cell but instead constantly move around the centrosome. Over the last decade, significant advances in their molecular compositions and biological functions have been achieved due to comprehensive proteomics and genomics, super-resolution microscopy analyses and elegant genetic manipulations. Centriolar satellites play pivotal roles in centrosome assembly and primary cilium formation through the delivery of centriolar/centrosomal components from the cytoplasm to the centrosome. Their importance is further underscored by the fact that mutations in genes encoding satellite components and regulators lead to various human disorders such as ciliopathies. Moreover, the most recent findings highlight dynamic structural remodelling in response to internal and external cues and unexpected positive feedback control that is exerted from the centrosome for centriolar satellite integrity.


[Attention deficit hyperactivity disorder and epilepsy].
Attention deficit hyperactivity disorder (ADHD) is currently one of the morbid clinical pictures in childhood and adolescence that is most frequently diagnosed in the Neuropaediatric clinic. ADHD is sometimes associated to other important neurological problems, such as behavioural disorders, tics or headaches, and may occasionally be related to epilepsy, although in this particular case the epileptic syndromes often involve disorders affecting behaviour and attention. Due to the frequent association of these disorders (epilepsy and ADHD) it is wise to perform an electroencephalographic study in patients who visit because of symptoms of disattention. Likewise, the neuropsychological assessment of epileptic children must not be neglected. We analyse the therapeutic options regarding the use of stimulants when both disorders coexist and we endorse the association of antiepileptic and psychostimulant drugs when necessary.


Effects of Combining Caffeine and Sodium Bicarbonate on Exercise Performance: A Review with Suggestions for Future Research.
This paper aimed to: (a) critically review studies that explored the isolated and combined effects of caffeine and sodium bicarbonate ingestion on exercise performance; (b) discuss some of the possible reasons for the discrepancy in findings; and, (c) provide suggestions for future studies. Out of the eight studies that examined this topic, only one study found that the combined ingestion of both supplements provided additive effects. In other studies, the following findings were observed: (a) only caffeine was ergogenic; (b) isolated and combined ingestion of both supplements was comparably ergogenic; (c) neither isolated nor combined ingestion of caffeine and sodium bicarbonate provided a performance-enhancing effect; and, (d) caffeine and caffeine plus sodium bicarbonate improved performance compared to sodium bicarbonate (but not as compared to placebo). Even though studies used currently recommended protocols of caffeine supplementation and exercise tasks for which the isolated ergogenic effects of caffeine and sodium bicarbonate are already established, the response to sodium bicarbonate supplementation was very variable, which might largely explain the discrepancies in the findings. The protocols of sodium bicarbonate ingestion generally resulted in high incidence and severity of side-effects, which might have had a negative effect on exercise performance. Future studies that optimize protocols of sodium bicarbonate supplementation are needed to fully explore if combining caffeine and sodium bicarbonate indeed provides any additive effects on exercise performance.