A Hybrid Metaheuristic Based on Neurocomputing for Analysis of Unipolar Electrohydrodynamic Pump Flow.
A unipolar electrohydrodynamic (UP-EHD) pump flow is studied with known electric potential at the emitter and zero electric potential at the collector. The model is designed for electric potential, charge density, and electric field. The dimensionless parameters, namely the electrical source number (Es), the electrical Reynolds number (ReE), and electrical slip number (Esl), are considered with wide ranges of variation to analyze the UP-EHD pump flow. To interpret the pump flow of the UP-EHD model, a hybrid metaheuristic solver is designed, consisting of the recently developed technique sine-cosine algorithm (SCA) and sequential quadratic programming (SQP) under the influence of an artificial neural network. The method is abbreviated as ANN-SCA-SQP. The superiority of the technique is shown by comparing the solution with reference solutions. For a large data set, the technique is executed for one hundred independent experiments. The performance is evaluated through performance operators and convergence plots.


[Use of behavioral scales in the diagnosis of dementia in the aged].
The authors present their own experience with the use of the behavioural scale elaborated by Blessed, Tomlinson and Roth usually called Blessed Dementia Scale-BS. They examined 76 patients (59 dementia, 17 with major depression, aged 57 - 87 years (mean age 70.3 +/- 7.2 years). The results obtained by BS were compared with WAIS-R, Wechsler's memory scale (WMS) and the MSE cognitive scale (Knopman et al., 1985). They found that BS differentiates satisfactorily patients with dementia and major depression (dementia X = 8.16 +/- 5.4, depression X = 4.41 +/- 2.41, t = 4.07, p < 0,001). The results of examinations by means of BS correlate significantly inversely with the results of examinations of cognitive functions. The closest correlation is between the total BS score and MSE (r = -0.705, p < 0,001). It was confirmed that BS can be used in the diagnosis of dementia for the differential diagnosis of dementia and depressions. Evaluation of partial BS scores (associated with instrumental ADL, basic ADL and personality changes, drives and interests) provides information important for evaluation of the functional capacity of the patient and for the procedure after termination of in-patient treatment. It is important that the total BS score and the partial BS score is not influenced by the patients' age.


G protein signaling from activated rat frizzled-1 to the beta-catenin-Lef-Tcf pathway.
The frizzled receptors, which mediate development and display seven hydrophobic, membrane-spanning segments, are cell membrane-localized. We constructed a chimeric receptor with the ligand-binding and transmembrane segments from the beta2-adrenergic receptor (beta2AR) and the cytoplasmic domains from rat Frizzled-1 (Rfz1). Stimulation of mouse F9 clones expressing the chimera (beta2AR-Rfz1) with the beta-adrenergic agonist isoproterenol stimulated stabilization of beta-catenin, activation of a beta-catenin-sensitive promoter, and formation of primitive endoderm. The response was blocked by inactivation of pertussis toxin-sensitive, heterotrimeric guanine nucleotide-binding proteins (G proteins) and by depletion of Galphaq and Galphao. Thus, G proteins are elements of Wnt/Frizzled-1 signaling to the beta-catenin-lymphoid-enhancer factor (LEF)-T cell factor (Tcf) pathway.


Older adults' preferences for informal, formal, and mixed support for future care needs: a comparison of Germany and the United States.
Based on the complementary model of support use, we investigated older adults' preferences for short-term and long-term future care needs in a U.S. and a German sample (65+ years). A greater preference for the exclusive use of informal support and for mixed support (a combination of informal and formal support) was found with regard to short-term care needs whereas a greater preference for the exclusive use of formal support was reported for long-term care needs. German seniors were more likely than U.S. seniors to report a preference for informal support. U.S. seniors, however, were more likely than German seniors to prefer mixed support. Being male, and having more contact with relatives predicted stronger preferences for informal and mixed support. In addition, age, the number of adult children, previous receipt of support, education, and income were associated with preferences for future support.


Intrafamilial outbreak of Mediterranean spotted fever.
The existence of intrafamilial outbreaks of spotted-fever group rickettsioses has seldom been reported, and their true incidence is not known. We here report the occurrence of Mediterranean spotted fever (MSF) in three members of a family: a boy, his grandmother and his grandfather. The infection resolved uneventfully in the boy, and followed a more protracted course in the two older patients, who suffered complications including drowsiness, clotting defects and acute renal failure. This finding highlights the importance of conditioning factors such as age and associated illnesses in the prognosis of infection due to Rickettsia conorii, and suggests that strict surveillance of individuals at risk of infection is necessary for prompt recognition of the onset of the illness and initiation of antibiotic treatment without delay.


The effect of fMRI (noise) on cognitive control.
Stressful situations, the aversiveness of events, or increases in task difficulty (e.g., conflict) have repeatedly been shown to be capable of triggering attentional control adjustments. In the present study we tested whether the particularity of an fMRI testing environment (i.e., EPI noise) might result in such increases of the cognitive control exerted. We found that participants were more effective in controlling episodic retrieval of previous stimulus-response bindings (Experiment 1), in switching to a new task (Experiment 2), and shielding a current goal from distracting response tendencies (Experiment 3) if they were exposed to challenging task situations, such as 70 dB echo planar imaging noise sampled from an fMRI scanner. These findings have considerable theoretical implications in questioning the widespread assumption that people are equally devoted to easy and more challenging tasks, and methodological implications in raising the possibility that experiments carried out in fMRI scanners or under otherwise challenging conditions systematically overestimate contributions from cognitive control processes.


Analysis of homeobox gene HOXA10 mutations in cryptorchidism.
Cryptorchidism is the most common congenital abnormality of the genitalia. However, its exact etiology remains to be defined. Homeobox (HOX) containing genes have a key role in the morphogenesis of segmental structures along the primary body axis, including the urogenital mesenchyma. In male mice with a targeted deletion of the HOXA10 gene cryptorchidism manifests in the absence of other major defects. Because to our knowledge this gene has never been examined for alterations in humans, we evaluated whether mutations of HOXA10 are associated with cryptorchidism in humans. Genomic deoxyribonucleic acid (DNA) was extracted from human blood or tissue samples from 16 noncryptorchid control subjects and 45 cryptorchid boys. To screen for mutations exons 1 and 2 of the HOXA10 gene were amplified individually by polymerase chain reaction using 6 overlapping oligonucleotide primer pairs. Single strand conformational polymorphism (SSCP) analysis of the amplified radiolabeled DNA fragments was performed. Variant band shifts were detected due to abnormal migration of the denatured DNA fragment compared to controls, suggesting an alteration in the DNA sequence. Sequence analysis of these variant bands was then done to define any mutations. SSCP analysis revealed variants in 2 controls. Of the 45 samples from cryptorchid patients 30 had SSCP variants in exon 1. No variants were found in other regions of the gene. Sequence analysis revealed several DNA polymorphisms in exon 1 in controls and boys with cryptorchidism. Other nucleotide changes (point mutations) were noted only in exon 1 in the DNA of 5 cryptorchid patients, of whom 1 had a 24 nucleotide deletion. Our initial analysis of the HOXA10 gene in humans demonstrates that genetic alterations of this gene may be present in some boys with cryptorchidism. HOXA10 polymorphisms exist in normal control subjects as well as in cryptorchid patients. Further analysis of the function of the mutated protein will elucidate the role of this gene as a potential causative factor of testicular descent.


Mediators of meningitis: therapeutic implications.
Despite the availability of potent antibiotics, bacterial meningitis is still a major clinical problem. Mortality is high, and up to a third of survivors are left with neurologic sequelae that may range from mild behavioral disorders to mental retardation or deafness. New therapeutic approaches to meningeal inflammation, however, are reducing the neurologic risks.


Exogenous application and interaction of biochar with environmental factors for improving functional diversity of rhizosphere's microbial community and health.
The usage of fertilizer with high nitrogen content in many countries, as well as its enormous surplus, has a negative impact on the soil ecological environment in agricultural system. This consumption of nitrogen fertilizer can be minimized by applying biochar to maintain the sufficient supply of nitrogen as nutrient to the near-root zone. This study investigated the effects of various amounts of biochar application (450, 900, 1350, and 1800 kg/hm2) and reduction of nitrogen fertilizer amount (10, 15, 20, and 25%) on the nutrients and microorganism community structure in rhizosphere growing tobacco plant. The microorganism community was found essential in improving nitrogen retention. Compared with conventional treatment, an application of biochar in rhizosphere soil increased the content of soil available phosphorus, organic matter and total nitrogen by 21.47%, 26.34%, and 9.52%, respectively. It also increased the abundance of microorganisms that are capable of degrading and utilizing organic matter and cellulose, such as Actinobacteria and Acidobacteria. The relative abundance of Chloroflexi was also increased by 49.67-78.61%, and the Acidobacteria increased by 14.79-39.13%. Overall, the application of biochar with reduced nitrogen fertilizer amount can regulate the rhizosphere microecological environment of tobacco plants and their microbial population structure, thereby promoting soil health for tobacco plant growth while reducing soil acidification and environmental pollution caused by excessive nitrogen fertilizer.


Is there a typical conflict in gastric complaints? An epidemiologic-psychoanalytic contribution to the question of conflict specificity in psychosomatic medicine.
The question of conflict specificity for subjects with gastric complaints was investigated in the context of a representative, epidemiologic-psychoanalytic field study. Out of a population of 600 adults probands with dyspepsia were compared with individuals with musculoskeletal symptoms and 'healthy' subjects. Using interview protocols 2 'blinded' raters judged whether a dependency-independency conflict was present in different aspects of life. Findings supported the higher prevalence of the conflict among subjects with dyspepsia. Therefore, the conflict was considered typical, but not specific for the experimental group.


In situ Fourier transform infrared spectroscopy as an efficient tool for determination of reaction kinetics.
The performance of new FTIR-based monitoring technology to representatively determine reaction kinetics has been demonstrated on an example of homogeneously catalyzed liquid-phase sucrose hydrolysis to fructose and glucose. The reaction kinetics were investigated by using the ReactIR 1000 reaction analysis system, which enables determination of the component concentration from its characteristic FTIR spectrum. During the sucrose inversion, the ReactIR 1000 instrument connected to a computer controlled standard glass batch reactor provided the required operating conditions and information about the component concentration in real-time. We have studied the influence of hydrogen ion concentration, temperature and initial concentration of sucrose on the sucrose disappearance rate. It was found out that the inversion of sucrose is an irreversible reaction, which is not affected by the formation of fructose and glucose in the liquid-phase. Then, the parameters of the kinetic model (i.e., reaction rate constant and activation energy) were calculated. A comparison of the model output and the measured data showed that the kinetics of the sucrose inversion could be well described by means of the pseudo first-order kinetic model. Finally, the method of determining the kinetic model by FTIR spectroscopy was verified by comparing the results obtained in the batch reactor with the results obtained in the continuously stirred tank reactor.


Comparison of Epidermal Gene Expression Profiles in Mice Aged 1 to 20 Months.
Although it is well known that epidermal function changes with aging, the transcriptomic basis and possible signaling pathways for aging-associated functional changes remain largely unknown. Here, we employed RNA sequencing techniques to assess epidermal gene expression profiles in the epidermis of mice aged 1, 2, 6, 12 and 20 months. A total of 132 genes displayed reductions in expression levels with aging, while expression levels of 406 genes increased with aging. Epidermal gene expression was prominently upregulated in 2-month-old vs 1-month-old mice, while more genes were downregulated in 12-month-old mice. Upregulation of genes associated with immune/inflammatory responses was observed in the epidermis of aged mice in comparison to that of young mice, whereas downregulated signaling pathways in the epidermis of aged mice were primarily involved in metabolism, such as fatty acid elongation, glutathione metabolism and biosynthesis of antibiotics. Some signaling pathways, such as chemokine signaling, cytokine/cytokine receptor interaction signaling and IL-17 signaling pathways, were remarkably upregulated in 12-month-old mice. Steroid synthesis, metabolic pathway, thermogenesis and proteasome pathways were steadily downregulated, starting at 2 months old. These results indicate that the epidermis of aged mice displays an upregulation of genes associated with inflammatory signaling pathways, and downregulation of genes related to metabolic signaling pathways.


Photosynthetic control of Arabidopsis leaf cytoplasmic translation initiation by protein phosphorylation.
Photosynthetic CO2 assimilation is the carbon source for plant anabolism, including amino acid production and protein synthesis. The biosynthesis of leaf proteins is known for decades to correlate with photosynthetic activity but the mechanisms controlling this effect are not documented. The cornerstone of the regulation of protein synthesis is believed to be translation initiation, which involves multiple phosphorylation events in Eukaryotes. We took advantage of phosphoproteomic methods applied to Arabidopsis thaliana rosettes harvested under controlled photosynthetic gas-exchange conditions to characterize the phosphorylation pattern of ribosomal proteins (RPs) and eukaryotic initiation factors (eIFs). The analyses detected 14 and 11 new RP and eIF phosphorylation sites, respectively, revealed significant CO2-dependent and/or light/dark phosphorylation patterns and showed concerted changes in 13 eIF phosphorylation sites and 9 ribosomal phosphorylation sites. In addition to the well-recognized role of the ribosomal small subunit protein RPS6, our data indicate the involvement of eIF3, eIF4A, eIF4B, eIF4G and eIF5 phosphorylation in controlling translation initiation when photosynthesis varies. The response of protein biosynthesis to the photosynthetic input thus appears to be the result of a complex regulation network involving both stimulating (e.g. RPS6, eIF4B phosphorylation) and inhibiting (e.g. eIF4G phosphorylation) molecular events.


Responses of an aphidophagous ladybird beetle, Anegleis cardoni, to varying densities of Aphis gossypii.
Laboratory experiments were conducted to determine the functional and numerical responses of fourth instar larvae, adult male, and adult female ladybird beetles, Anegleis cardoni Weise (Coleoptera: Coccinellidae), to different densities of aphids, Aphis gossypii Glover (Hemiptera: Aphididae), on the bottle gourd, Lagenaria vulgaris Seringe (Cucurbitales: Cucurbitaceae). The results revealed a density dependent, Type II functional response of A. cardoni. Prey consumption increased curvilinearly with an increase in prey density for all three predatory stages. Numerical responses revealed significant increases in oviposition with increases in prey density. The food exploitation efficiency and the efficiency of conversion of ingested food decreased with increases in prey density. The attack rate was highest for adult females, followed by fourth instar larvae and adult males. Prey consumption was highest and handling time lowest in fourth instar larvae, followed by adult females and males. Therefore, fourth instar larvae of A. cardoni may be considered the most efficient predatory stage in aphid management strategies.


An improved global model for air-sea exchange of mercury: high concentrations over the North Atlantic.
We develop an improved treatment of the surface ocean in the GEOS-Chem global 3-D biogeochemical model for mercury (Hg). We replace the globally uniform subsurface ocean Hg concentrations used in the original model with basin-specific values based on measurements. Updated chemical mechanisms for Hg⁰/Hg(II) redox reactions in the surface ocean include both photochemical and biological processes, and we improved the parametrization of particle-associated Hg scavenging. Modeled aqueous Hg concentrations are consistent with limited surface water observations. Results more accurately reproduce high-observed MBL concentrations over the North Atlantic (NA) and the associated seasonal trends. High seasonal evasion in the NA is driven by inputs from Hg enriched subsurface waters through entrainment and Ekman pumping. Globally, subsurface waters account for 40% of Hg inputs to the ocean mixed layer, and 60% is from atmospheric deposition. Although globally the ocean is a net sink for 3.8 Mmol Hg y⁻¹, the NA is a net source to the atmosphere, potentially due to enrichment of subsurface waters with legacy Hg from historical anthropogenic sources.


Mice show circadian rhythms of blood pressure during each wake-sleep state.
A daily rhythm of blood pressure (BP), with maximum values in the activity period, carries important prognostic information. The extent to which this rhythm depends on behavioral factors remains debated. Mice are the species of choice for functional genomics. In mice, episodes of wakefulness and sleep are not restricted to particular daily periods, allowing BP in each wake-sleep state to be measured at each time of day. The aim of this study was to investigate whether a circadian rhythm of BP is manifest in each wake-sleep state in mice. Mice with B6 genetic background (n = 26) were implanted with a telemetric BP transducer and electrodes to discriminate wake-sleep states and recorded while housed under a 12:12 h light-dark period. For each mouse, 8 values of BP were obtained in each wake-sleep state (wakefulness, non-rapid-eye-movement sleep, and rapid-eye-movement sleep) by averaging over successive 3-h time bins. Analysis of variance evidenced a significant time effect in each wake-sleep state as well as a significant wake-sleep state × time interaction effect. In an additional group of mice (n = 3) recorded in constant darkness, the Lomb-Scargle periodogram also revealed a significant circadian rhythm of BP in each wake-sleep state. These findings demonstrate that during each wake-sleep state, mice show daily and circadian rhythms of BP in conditions of entrainment to the light-dark cycle and in free-running conditions of constant darkness, respectively.


Metabolic Syndrome Prevalence in Students Attending West Virginia University.
Metabolic Syndrome (MetS) contributes to the development of cardiovascular disease (CVD) and type II diabetes mellitus (T2DM). Few studies have investigated the MetS risk of young adults (18⁻24 years old). This study aims to determine the prevalence of MetS in Appalachian and non-Appalachian students attending West Virginia University. The prevalence of MetS in this population was 15%. There was no difference in MetS prevalence between male students and female students (18.8% males and 11.1% females, p-value = 0.30), or between Appalachian students and non-Appalachian students (17.7% Appalachian and 10.0% non-Appalachian, p-value = 0.33). Identification of MetS early in life is needed in order to reduce the onset of chronic disease. Therefore, implementing a screening process to identify at-risk young adults will help tailor more effective behavioral interventions.


Acute hydrocephalus following cervical spinal cord injury.
We present a case of acute hydrocephalus secondary to cervical spinal cord injury in a patient with diffuse ossification of the posterior longitudinal ligament (OPLL). A 75-year-old male patient visited the emergency department with tetraparesis and spinal shock. Imaging studies showed cervical spinal cord injury with hemorrhage and diffuse OPLL from C1 to C4. We performed decompressive laminectomy and occipitocervical fusion. Two days after surgery, his mental status had deteriorated to drowsiness with dilatation of the right pupil. Findings on brain computed tomography revealed acute hydrocephalus and subarachnoid hemorrhage in the cerebellomedullary cistern, therefore, extraventricular drainage was performed immediately. Acute hydrocephalus as a complication of cervical spine trauma is rare, however, it should be considered if the patient shows deterioration of neurologic symptoms.


Extended exposure to a discriminated, limited-hold temporal schedule does not produce stimulus control.
Four rats were exposed to two different stimuli (either lights or tones), each stimulus being correlated with independent probabilities of water delivery in a temporally defined schedule. The schedule consisted of a 60 s T cycle with 30 s t(D) and t(-) successive subcycles; t(D) was correlated with a probability of water delivery of 1.0 and t(-) was correlated with a probability of water delivery of 0.0. The schedule was maintained during 180 sessions and extended for 25 extra sessions omitting the stimulus in t(-). The four rats showed low frequencies of responding, response frequency being slightly higher in t(-) than in t(D). The percentage of lost reinforcers was independent of response frequency. The rats which lost less reinforcers were those which obtained more water deliveries during the first 15 cycles of each session. These results show that stimulus control does not develop in limited-hold temporal schedules, and that response-reinforcer effectiveness may depend on the initial contact with reinforcers in the first cycles of the session.


Peri-implant mucosal recession: Clinical significance and therapeutic opportunities.
Peri-implant mucosal recessions can be a major esthetic problem in the anterior zone, whereas in the functional zone the coverage of exposed implants is not of primary significance, as methods to clean these structures are more important. In these situations free gingival grafts are often used to deepen the vestibule and increase the amount of attached keratinized mucosa. Complete coverage of mucosal recessions around dental implants is still a challenging procedure, but it seems that recessions up to 2 mm can be successfully grafted with subepithelial connective tissue grafts.


Facing Back Pain with Wine and Physical Activity.
Intervertebral disc disease (IVDD) refers to degenerative processes of the spine resulting in reduced shock-absorbing ability, which may ultimately lead to disc herniation and spinal cord compression. Back pain is associated with this condition, representing the clinical feature mostly frequently referred by the patients. In this contribution, we analysed a recent review published in the Journal of Investigative Surgery, which discusses the mechanisms of the ROS production in IVDD with respect to resveratrol activity.


The Molecular Recognition Paradigm of Environmental Chemicals with Biomacromolecules.
The interactions of ligands with biomacromolecules play a fundamental role in almost all bioprocesses occuring in living organisms. The binding of ligands can cause the conformational changes of biomacromolecules, possibly affecting their physiological functions. The interactions of ligands with biomacromolecules are thus becoming a research hotspot. However, till now, there still lacks a systematic compilation of review with the focus on the interactions between environmental chemicals and biomacromolecules. In this review, we focus on the molecular recognition paradigm of environmental chemicals with biomacromolecules and chemical basis for driving the complex formation. The state-of-the-art review on in vitro and in silico studies on interaction of organic chemicals with transport proteins, nuclear receptors and CYP450 enzymes was provided, and the enantioselective interactions of chiral environmental chemicals was also mentioned.


Isolation of Mycobacterium malmoense in the island of Crete, Greece.
Mycobacterium malmoense was isolated from a broncho-alveolar lavage sample of a 73-year-old cancer (small cell lung carcinoma) patient in Crete, representing the first reported case of this pathogen in Greece. The isolate was considered to be a colonizer and the patient did not receive any antimycobacterial treatment while he received chemotherapy to which he responded favourably. No signs of pulmonary infection were noted during the course of his disease. This case provides evidence of the ubiquitous nature of this mycobacterial species, believed until recently to favour cooler climates. We, therefore, propose that the index of suspicion for this pathogen should be raised particularly in patients with underlying immunodeficiency, cancer and chronic lung disease, irrespective of the geographic location.


Wnt/beta-catenin signaling regulates cytokine-induced human inducible nitric oxide synthase expression by inhibiting nuclear factor-kappaB activation in cancer cells.
The human inducible nitric oxide synthase (hiNOS) gene is regulated by nuclear factor kappaB (NF-kappaB) and has recently been shown to be a target of the Wnt/beta-catenin pathway. In this study, we tested the hypothesis that Wnt/beta-catenin signaling might regulate cytokine- or tumor necrosis factor alpha (TNFalpha)-induced hiNOS expression through interaction with NF-kappaB. A cytokine mixture of TNFalpha + interleukin (IL)-1beta + IFNgamma induced a 2- to 3-fold increase in hiNOS promoter activity in HCT116 and DLD1 colon cells, but produced a 2-fold decrease in SW480 colon cancer cells. A similar differential activity was seen in liver cancer cells (HepG2, Huh7, and Hep3B). Overexpression of beta-catenin produced a dose-dependent decrease in NF-kappaB reporter activity and decreased cytokine mixture-induced hiNOS promoter activity. Gel shift for TNFalpha-induced hiNOS NF-kappaB activation showed decreased p50 binding and decreased NF-kappaB reporter activity in the beta-catenin-mutant HAbeta18 cells. Conversely, enhanced p50 binding and increased NF-kappaB reporter activity were seen in HAbeta85 cells, which lack beta-catenin signaling. Coimmunoprecipitation confirmed that beta-catenin complexed with both p65 and p50 NF-kappaB proteins. NF-kappaB-dependent Traf1 protein expression also inversely correlated with the level of beta-catenin. Furthermore, SW480 cells stably transformed with wild-type adenomatous polyposis coli showed decreased beta-catenin protein and increased TNFalpha-induced p65 NF-kappaB binding as well as iNOS and Traf1 expression. Finally, beta-catenin inversely correlated with iNOS and Fas expression in vivo in hepatocellular carcinoma tumor samples. Our in vitro and in vivo data show that beta-catenin signaling inversely correlates with cytokine-induced hiNOS and other NF-kappaB-dependent gene expression. These findings underscore the complex role of Wnt/beta-catenin, NF-kappaB, and iNOS signaling in the pathophysiology of inflammation-associated carcinogenesis.


Activity of disulfiram (bis(diethylthiocarbamoyl)disulphide) and ditiocarb (diethyldithiocarbamate) against metronidazole-sensitive and -resistant Trichomonas vaginalis and Tritrichomonas foetus.
Clinical resistance of Trichomonas vaginalis to metronidazole is best correlated with MIC values measured under aerobic conditions. Under these conditions both disulfiram (bis(diethylthiocarbamoyl)disulphide), and its first mammalian metabolite, ditiocarb (diethyldithiocarbamate), showed high levels of activity against metronidazole-sensitive (disulfiram MIC, 0.1-0.7 microM; ditiocarb MIC, 0.3-9 microM) and -resistant (MICs 0.2-1.3 microM and 1.2-9 microM respectively) isolates. Tritrichomonas foetus was also sensitive-the MICs for seven metronidazole-sensitive isolates were 0.1-1.0 microM for disulfiram and 1.0-6.9 microM for ditiocarb; those for two highly metronidazole-resistant strains were 0.3-1.3 microM and 0.6-6 microM respectively. Under anerobic conditions most strains became highly resistant to both compounds. Surprisingly, disulfiram was consistently more active than ditiocarb.


[Clinical manifestations of atopy in children up to two years of age].
Atopic diseases such as atopic dermatitis, allergic rhinitis and asthma have had increased prevalence during the past decade and nowadays occur in every third child in developed countries. The aim of the study was to determine frequency and type of atopic diseases at the age of two, as well as the importance the total IgE antibodies concentrations have in diagnosis and prognosis of the disease. The study involved 175 children up to two years of age. Allergy-like symptoms were found after surveying their parents and pediatric medical records. Using the fluorescence immunossay (FIA) method, total IgE antibodies concentrations and specific IgE antibodies (Phadiatop infant) were determined on an Immunocap 100 Dyagnostic System. One or more allergy-like symptoms accounted for 57.7% of findings in children under the age of two, whilst in 19.4% the existence of IgE-related allergic diseases was found. Atopic diseases usually have clinical manifestations of atopic dermatitis (11.4%), IgE-bound wheezing/asthma (10.8%) and food allergies (7.4%), and to much lesser extent those of allergic rhinitis (3.4%) and urticaria (1.7%). The significantly higher total IgE antibodies concentrations were found in children with allergy-like symptoms (p < 0.0005) (cut-off 15.15 kU/L, sensitivity 76.5% specificity 71.6%). Almost 20% of two-year-old children have any of clinically manifested allergic diseases, with atopic dermatitis and IgE wheeze/asthma being predominant. The higher total IgE antibodies concentration is a good marker for sensitization in children with allergy-like symptoms.


Monitoring the real-time kinetics of the hydrolysis reaction of guanine nucleotide-binding proteins.
The conversion of guanosine triphosphate (GTP) to guanosine diphosphate (GDP) and inorganic phosphate (Pi) by guanine nucleotide-binding proteins (GNBPs) is a fundamental enzyme reaction in living cells that acts as an important timer in a variety of biological processes. This reaction is intrinsically slow but can be stimulated by GTPase-activating proteins (GAPs) by several orders of magnitude. In the present study, we synthesized and characterized a new fluorescent nucleotide, 2'(3')-O-(N-ethylcarbamoyl-(5''-carboxytetramethylrhodamine) amide)-GTP, or tamraGTP, which is sensitive towards conformational changes of certain GNBPs induced by GTP hydrolysis. Unlike other fluorescent nucleotides, tamra-GTP allows real-time monitoring of the kinetics of the intrinsic and GAP-catalyzed GTP hydrolysis reactions of small GNBPs from the Rho family.


Novel Design of Neuropeptide-Based Drugs with β-Sheet Breaking Potential in Amyloid-Beta Cascade: Molecular and Structural Deciphers.
Our work discusses the investigation of 75 peptide-based drugs with the potential ability to break the β-sheet structures of amyloid-beta peptides from senile plaques. Hence, this study offers a unique insight into the design of neuropeptide-based drugs with β-sheet breaker potential in the amyloid-beta cascade for Alzheimer's disease (AD). We started with five peptides (15QKLVFF20, 16KLVFF20, 17LVFF20, 16KLVF19 and 15QKLV18), to which 14 different organic acids were attached at the N-terminal. It was necessary to evaluate the physiochemical features of these sequences due to the biological correlation with our proposal. Hence, the preliminary analysis of different pharmacological features provided the necessary data to select the peptides with the best biocompatibility for administration purposes. Our approaches demonstrated that the peptides 17LVFF20, NA-17LVFF20, 16KLVF19 and NA-16KLVF19 (NA-nicotinic acid) have the ability to interfere with fibril formation and hence improve the neuro and cognitive functions. Moreover, the peptide conjugate NA-16KLVF19 possesses attractive pharmacological properties, demonstrated by in silico and in vitro studies. Tandem mass spectrometry showed no fragmentation for the spectra of 16KLVF19. Such important results suggest that under the action of protease, the peptide cleavage does not occur at all. Additionally, circular dichroism confirmed docking simulations and showed that NA-16KLVF19 may improve the β-sheet breaker mechanism, and thus the entanglement process of amyloid-beta peptides can be more effective.


Measuring progressive independence with the resident supervision index: theoretical approach.
Graduate medical education is based on an on-the-job training model in which residents provide clinical care under supervision. The traditional method is to offer residents graduated levels of responsibility that will prepare them for independent practice. However, if progressive independence from supervision exceeds residents' progressive professional development, patient outcomes may be at risk. Leaders in graduate medical education have called for "optimal" supervision, yet few studies have conceptually defined what optimal supervision means and whether optimal care is theoretically compatible with progressive independence, nor have they developed a test for progressive independence. This research develops theory and analytic models as part of the Resident Supervision Index to quantify the intensity of supervision. We introduce an explicit set of assumptions for an ideal patient-centered theory of optimal supervision of resident-provided care. A critical assumption is that informed attending staff will use available resources to optimize patient outcomes first and foremost, with residents gaining clinical competencies by contributing to optimal care. Next, we derive mathematically the consequences of these assumptions as theoretical results. Under optimal supervision, (1) patient outcome is expected to be no worse than if residents were not involved, (2) supervisors will avoid undersupervising residents (when patients are at increased risk for poor outcomes) or oversupervising residents (when residents miss clinical opportunities to practice care), (3) optimal patient outcomes will be compatible with progressive independence, (4) progressive development can be inferred from progressive independence whenever residents contribute to patient care, and (5) analytic models that test for progressive independence will emphasize adjusting the association between length of graduate medical education training and supervision for case complexity and clinic workload, but not patient health outcomes. An explicit theoretical framework is critical to measure scientifically progressive independence from supervision using graduate medical education data.


Mutations in COX15 produce a defect in the mitochondrial heme biosynthetic pathway, causing early-onset fatal hypertrophic cardiomyopathy.
Deficiencies in the activity of cytochrome c oxidase (COX), the terminal enzyme in the respiratory chain, are a frequent cause of autosomal recessive mitochondrial disease in infants. These patients are clinically and genetically heterogeneous, and all defects so far identified in this group have been found in genes coding for accessory proteins that play important roles in the assembly of the COX holoenzyme complex. Many patients, however, remain without a molecular diagnosis. We have used a panel of retroviral vectors expressing human COX assembly factors in these patients to identify the molecular basis for the COX deficiency by functional complementation. Here we show that overexpression of COX15, a protein involved in the synthesis of heme A, the heme prosthetic group for COX, can functionally complement the isolated COX deficiency in fibroblasts from a patient with fatal, infantile hypertrophic cardiomyopathy. Mutation analysis of COX15 in the patient identified a missense mutation (C700T) on one allele, changing a conserved arginine to tryptophan (R217W), and a splice-site mutation in intron 3 on the other allele (C447-3G), resulting in a deletion of exon 4. This splicing error introduces a frameshift and a premature stop codon, resulting in an unstable mRNA and, likely, a null allele. Mitochondrial heme A content was reduced in the patient's heart and fibroblast mitochondria, and levels of heme O were increased in the patient's heart. COX activity and the total amount of fully assembled enzyme were reduced by 50%-70% in patient fibroblasts. Expression of COX15 increased heme A content and rescued COX activity. These results suggest that reduced availability of heme A stalls the assembly of COX. This study establishes COX15 as an additional cause, along with SCO2, of fatal infantile, hypertrophic cardiomyopathy associated with isolated COX deficiency.


Single-fraction radiation: A promising adjuvant therapy to prevent keloid recurrence.
Keloids are characterized by collection of atypical fibroblasts with excessive deposition of extracellular matrix components. Keloids are prone to high recurrence (50%-80%) with unimodality treatment. Radiation is a promising approach among the adjuvant modalities in vogue though consensus is lacking on dose-fractionation schedule. The present study aimed to analyze the efficacy of single-fraction high-dose adjuvant radiotherapy to prevent keloid recurrence. Details of patients treated for keloids using external beam radiation therapy from January 2011 to December 2016 were retrieved from electronic medical records and radiation therapy charts and analyzed. Thirty-seven keloid lesions in thirty patients were analyzed. Keloids received radiation within 24-72 h postsurgery using 6 MeV electron beam. 45.9% of keloids were in the chest wall. Dose ranged between 5 Gy and 12 Gy in 1-3 fractions. Eight Gy was used in 78.4%. The single fraction was preferred in 91.9%. Good cosmesis was achieved in all except three who had wound dehiscence. Median follow-up was 32.67 months. 16.2% had recurrence. Median time to recur was 13.6 months, and median recurrence-free interval 21.23 months. Among those who received 8 Gy single fraction, 73.4% remained recurrence-free at 5 years. Albeit a retrospective analysis, ours is the only study in literature offering 8 Gy single dose, using electrons, as a postoperative adjuvant treatment to prevent recurrence in keloids. Our recurrence rates were similar to that quoted in published series. This hence can be validated in further studies as it is cosmetically acceptable, safe, painless, and cost-effective with good patient compliance.


PARP Inhibitor Protects Against Chronic Hypoxia/Reoxygenation-Induced Retinal Injury by Regulation of MAPKs, HIF1α, Nrf2, and NFκB.
In the eye, chronic hypoxia/reoxygenation (H/R) contributes to the development of a number of ocular disorders. H/R induces the production of reactive oxygen species (ROS), leading to poly(ADP-ribose) polymerase-1 (PARP1) activation that promotes inflammation, cell death, and disease progression. Here, we analyzed the protective effects of the PARP1 inhibitor olaparib in H/R-induced retina injury and investigated the signaling mechanisms involved. A rat retinal H/R model was used to detect histologic and biochemical changes in the retina. H/R induced reductions in the thickness of most retinal layers, which were prevented by olaparib. Furthermore, H/R caused increased levels of Akt and glycogen synthase kinase-3β phosphorylation, which were further increased by olaparib, contributing to retina protection. By contrast, H/R-induced c-Jun N-terminal kinase and p38 mitogen-activated protein kinases (MAPK) phosphorylation and activation were reduced by olaparib, via mitogen-activated protein kinase phosphatase 1 (MKP-1) expression. In addition, H/R-induced hypoxia-inducible factor 1α (HIF1α) levels were decreased by olaparib, which possibly contributed to reduced VEGF expression. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) expression was slightly increased by H/R and was further activated by olaparib. Nuclear factor-κB (NFκB) was also activated by H/R through phosphorylation (Ser536) and acetylation (Lys310) of the p65 subunit, although this was significantly reduced by olaparib. Olaparib reduced H/R-induced degenerative changes in retinal morphology. The protective mechanisms of olaparib most probably involved Nrf2 activation and ROS reduction, as well as normalization of HIF1α and related VEGF expression. In addition, olaparib reduced inflammation by NFκB dephosphorylation/inactivation, possibly via the PARP1 inhibition-MKP-1 activation-p38 MAPK inhibition pathway. PARP inhibitors represent potential therapeutics in H/R-induced retinal disease.


Mild chronic exposure to pesticides alters physiological markers of honey bee health without perturbing the core gut microbiota.
Recent studies highlighted that exposure to glyphosate can affect specific members of the core gut microbiota of honey bee workers. However, in this study, bees were exposed to relatively high glyphosate concentrations. Here, we chronically exposed newly emerged honey bees to imidacloprid, glyphosate and difenoconazole, individually and in a ternary mixture, at an environmental concentration of 0.1 µg/L. We studied the effects of these exposures on the establishment of the gut microbiota, the physiological status, the longevity, and food consumption of the host. The core bacterial species were not affected by the exposure to the three pesticides. Negative effects were observed but they were restricted to few transient non-core bacterial species. However, in the absence of the core microbiota, the pesticides induced physiological disruption by directly altering the detoxification system, the antioxidant defenses, and the metabolism of the host. Our study indicates that even mild exposure to pesticides can directly alter the physiological homeostasis of newly emerged honey bees and particularly if the individuals exhibit a dysbiosis (i.e. mostly lack the core microbiota). This highlights the importance of an early establishment of a healthy gut bacterial community to strengthen the natural defenses of the honey bee against xenobiotic stressors.


Survival, growth, and thermal resistance of Listeria monocytogenes in products containing peanut and chocolate.
Outbreaks of listeriosis associated with the consumption of ready-to-eat foods have raised interest in determining growth, survival, and inactivation characteristics of Listeria monocytogenes in a wide range of products. A study was undertaken to determine the thermal tolerance of L. monocytogenes in a peanut-based beverage (3.1% fat), whole-fat (3.5%) milk, wholefat (4.0%) and reduced-fat (1.0%) chocolate milk, a chocolate-peanut spread (39% fat), and peanut butter (53% fat). The D60 degrees C value (decimal reduction time at 60 degrees C) in peanut beverage (3.2 min) was not significantly different (P > 0.05) than the D60 degrees C value in whole-fat milk (3.3 min) or whole-fat chocolate milk (4.5 min) but significantly lower (P < or = 0.05) than the D60 degrees C value in reduced-fat chocolate milk (5.9 min). The pathogen was significantly more resistant to heat when enmeshed in chocolate-peanut spread (water activity [aw] of 0.46; D60 degrees C = 37.5 min) and peanut butter (aw of 0.32; D60 degrees C = 26.0 min) than in liquid products. At 10 degrees C, the pathogen grew most rapidly in whole-fat chocolate milk and slowest in peanut beverage. At 22 degrees C, populations increased significantly within 12 and 16 h in whole-fat milk and reduced-fat chocolate milk, respectively, and within 8 h in whole-fat chocolate milk and peanut beverage. Initial populations (3.37 to 4.42 log CFU/g) of L. monocytogenes in chocolate-peanut spread and peanut butter adjusted to an aw of 0.33 and 0.65 declined, but the pathogen was not eliminated during a 24-week period at 20 degrees C. Survival was enhanced at reduced aw. Results indicate that a pasteurization process similar to that used for full-fat milk would be adequate to ensure the destruction of L. monocytogenes in peanut beverage. The pathogen survives for at least 24 weeks in chocolate-peanut spread and peanut butter at an aw range that encompasses that found in these products.


Headache in United States emergency departments: demographics, work-up and frequency of pathological diagnoses.
Headache is a common complaint in the emergency department (ED). In order to examine headache work-ups and diagnoses across the USA, we queried a representative sample of adult ED visits (the National Hospital Ambulatory Medical Care Survey) for the years 1992-2001. Headache accounted for 2.1 million ED visits per year (2.2% of visits). Of the 14% of patients who underwent neuroimaging, 5.5% received a pathological diagnosis. Of the 2% of patients who underwent lumbar puncture, 11% received a pathological diagnosis. On multivariable analysis, a decreased rate of imaging was noted for patients without private insurance [odds ratio (OR) 0.61, confidence interval (CI) 0.44, 0.86] and for those presenting off-hours (OR 0.55, CI 0.39, 0.77). Patients over 50 were more likely to receive a pathological diagnosis (OR 3.3, CI 1.2, 9.3). In conclusion, clinicians should ensure that appropriate work-ups are performed regardless of presentation time or insurance status, and be vigilant in the evaluation of older patients.


Multi-tailoring of a modified MOF-derived CuxO electrochemical transducer for enhanced hydrogen peroxide sensing.
Reasonable control of the redox states within the catalytic units together with the interconnection degrees of the substrate is of great significance in the modulation of a well-performing transducer. Herein, a novel carbon black (CB)-modified copper metal-organic framework nanomaterial (CB@Cu-MOF) prepared at room temperature was utilized as a precursor to synthesize mixed-valent copper-oxide composite catalysts (NC/CuxO-T). By tuning the carbonization process of the precursor at different temperatures (T = 100 °C, 200 °C, 300 °C and 400 °C), the different ratio configurations of the redox-alternated CuxO portions were successfully controlled with the simultaneous effective tailoring of the defect abundance in the N-doped carbon substrate. As a result, an optimized NC/CuxO-300 electrochemical H2O2 sensor was able to present a low detection limit (0.26 μM) and decent linear ranges (0.02-1.79 mM and 2.29-9.29 mM). Our strategy using easily available initial materials with mild preparation conditions is expected to promote the practical application of the star materials in laboratories.


rAAV vector-mediated gene therapy for experimental ischemic stroke.
The safest viral vector system for gene therapy is based on recombinant adeno-associated virus (rAAV) up to date in Phase I clinical trials, which has been developed rapidly and applied for ischemic stroke gene therapy in animal experiments since the past seven years. rAAV vector has made great progress in improving gene delivery by modification of the capsid and increasing transgene expression by encapsidation of double-stranded rAAV genome. And in all, nine therapeutic genes in 12 animal studies were successfully delivered using rAAV vector to ischemic brain via different approaches in rat or mice stroke models for gene therapy and the results suggested that rAAV could mediate genes' expression efficiently; most of them displayed evidently therapeutic efficacy with satisfactory biological safety. Gene therapy involving rAAV vector seems effective in attenuation of ischemic damage in stroke and has greatly promising potential use for patients in the future. In this review, we will focus on the basic biology and development of rAAV vector itself as well as the recent progress in the use of this vector for ischemic stroke gene therapy in animal experiments.


Hypofractionated vs. standard radiotherapy for locally advanced limited-stage small cell lung cancer.
Hypofractionated radiotherapy in locally advanced limited-stage small cell lung cancer is preferred in many Western countries but not used regularly in the United States. We examined practice patterns and overall survival with definitive hypofractionated radiotherapy and chemotherapy vs. standard radiotherapy in this setting. We included patients in the National Cancer Database with unresected primary stage II-III small cell lung cancer in 2008-2016 who underwent chemotherapy within six months of either hypofractionated radiotherapy (40-45 Gy/15 fractions) or standard radiotherapy (45 Gy/30 fractions or 60-70 Gy/30-35 fractions) in this retrospective cohort study. Patient characteristics were assessed with univariable and multivariable logistic regression. Kaplan-Meier estimator, log-rank test, and multivariable Cox regression were used to evaluate overall survival. Propensity score matching (PSM) was performed as a sensitivity analysis. Early concurrent chemotherapy consisted of radiotherapy and chemotherapy initiated within 30 days of each other. Seven thousand and one hundred forty-three patients were included: 97.9% received standard radiotherapy and 2.1% hypofractionated radiotherapy. Multivariable analysis on the whole cohort yielded comparable overall survival (HR for hypofractionated radiotherapy 1.09, CI: 0.90-1.32, P=0.37). On PSM (N=292), median overall survival was similar between standard radiotherapy [22.9 months (95% CI: 18.2-30.4 months)] vs. hypofractionated radiotherapy [21.2 months (CI: 16.3-24.7 months); P=0.13]. Overall survival was shorter with hypofractionated radiotherapy in the early concurrent chemotherapy subset (15.8 vs. 22.1 months, P=0.007) and longer with hypofractionated radiotherapy in the non-early concurrent chemotherapy subset (29.5 vs. 18.5 months, P=0.027). Overall survival with hypofractionated radiotherapy appears similar to standard radiotherapy in locally advanced limited-stage small cell lung cancer. Chemotherapy timing may modify the effect of fractionation on overall survival, though larger numbers must confirm. Hypofractionated radiotherapy may be considered in those unable to receive early concurrent chemotherapy.


Meta-analysis of outcomes related to the quality of life after orthodontic-surgical treatment.
Orthognathic surgery causes functional and aesthetic changes, which could affect patients' quality of life (QOL). The current analysis assessed the impact of orthodontic-surgical treatment on the parameters affecting the QOL using different scoring systems. The criteria for inclusion were studies written in various languages that compared the effects of the intervention on patients' QOL before surgery and at various periods after surgery (3 weeks to several months), which resulted in including 19 studies into this meta-analysis. The outcomes of these studies underwent random-effect modeling to calculate the mean difference (MD) and 95% confidence intervals (95% CIs) of the impact of different surgical techniques on clinical parameters, and publication bias was analyzed with Begg's test. According to the total score of the Orthognathic Quality of Life Questionnaire (OQLQ), surgery significantly affected patients' QOL after 2 months or less (p = 0.049), up to 6 months (p < 0.001), and when comparing 2 months or less with up to 6 months (2-6 months) (p < 0.001). In addition, the total Oral Health Impact Profile-14 (OHIP-14) score showed a significant difference in the QOL after 6 months (p = 0.003) and up to 12 months (p = 0.002) after surgery. Therefore, orthodontic-surgical treatment significantly improves patients' QOL after surgery compared to before surgery.


Adolescent vulnerability to PTSD and effects of community-based intervention: Longitudinal study among adolescent survivors of the Ehime Maru sea accident.
The aim of the present study was to examine the psychological impact on adolescent survivors of a maritime disaster that resulted in the deaths of nine people, including four high school students, and the effects of psychiatric intervention for the survivors. Long-term multidimensional intervention consisting of psychoeducation, hospital treatment, family support and day care, was provided for nine adolescent survivors. To evaluate these effects, the survivors were also assessed using self-rating scales (Impact of Event Scale, General Health Questionnaire and Self-rating Depression Scale) and psychiatric structured interviews (Clinician-Administered Post-Traumatic Stress Disorder [PTSD] Scale) at 2, 8, 14, 26, and 38 months after the accident. Prevalence of PTSD among adolescent survivors was much higher than in adult survivors at the 2-month examination (78% vs 12%, respectively). Although the observed prevalence remained high until the 14-month examination, remarkable improvement occurred thereafter and none was diagnosed with PTSD at the 38-month examination. Adolescents may have a specific vulnerability to PTSD and community-based intervention is effective for adolescents with serious symptoms of PTSD.


Family involvement in the gynecologic care of adolescents.
The purpose of this paper is to address the issues of family involvement in gynecologic care for adolescent girls. This is accomplished by reviewing pertinent literature and its implication for health-care delivery. Specific aspects of adolescent development including changes in cognitive development and relationships are reviewed. In addition, the implications of communication between parent and adolescent, degree of parental monitoring, and the type of parenting style are discussed. Using this information as a background, recommendations for family involvement in gynecologic care are given. Methods for handling appointments are addressed; including the structure and content of the appointment and also the follow-up appointment, especially for high-risk families. Issues of confidentiality for both adolescent and parent are discussed. This information should aid clinicians in supporting those features of families that promote positive growth in adolescent girls.


Traffic Vehicle Counting in Jam Flow Conditions Using Low-Cost and Energy-Efficient Wireless Magnetic Sensors.
The jam flow condition is one of the main traffic states in traffic flow theory and the most difficult state for sectional traffic information acquisition. Since traffic information acquisition is the basis for the application of an intelligent transportation system, research on traffic vehicle counting methods for the jam flow conditions has been worthwhile. A low-cost and energy-efficient type of multi-function wireless traffic magnetic sensor was designed and developed. Several advantages of the traffic magnetic sensor are that it is suitable for large-scale deployment and time-sustainable detection for traffic information acquisition. Based on the traffic magnetic sensor, a basic vehicle detection algorithm (DWVDA) with less computational complexity was introduced for vehicle counting in low traffic volume conditions. To improve the detection performance in jam flow conditions with a "tailgating effect" between front vehicles and rear vehicles, an improved vehicle detection algorithm (SA-DWVDA) was proposed and applied in field traffic environments. By deploying traffic magnetic sensor nodes in field traffic scenarios, two field experiments were conducted to test and verify the DWVDA and the SA-DWVDA algorithms. The experimental results have shown that both DWVDA and the SA-DWVDA algorithms yield a satisfactory performance in low traffic volume conditions (scenario I) and both of their mean absolute percent errors are less than 1% in this scenario. However, for jam flow conditions with heavy traffic volumes (scenario II), the SA-DWVDA was proven to achieve better results, and the mean absolute percent error of the SA-DWVDA is 2.54% with corresponding results of the DWVDA 7.07%. The results conclude that the proposed SA-DWVDA can implement efficient and accurate vehicle detection in jam flow conditions and can be employed in field traffic environments.


The direction and role of phenotypic transition between podocytes and parietal epithelial cells in focal segmental glomerulosclerosis.
Focal segmental glomerulosclerosis (FSGS) is a podocyte disease. Among the various histologies of FSGS, active epithelial changes, hyperplasia, as typically seen in the collapsing variant, indicates disease progression. Using a podocyte-specific injury model of FSGS carrying a genetic podocyte tag combined with double immunostaining by different sets of podocytes and parietal epithelial cell (PEC) markers [nestin/Pax8, Wilms' tumor-1 (WT1)/claudin1, and podocalyxin/Pax2], we investigated the direction of epithelial phenotypic transition and its role in FSGS. FSGS mice showed progressive proteinuria and renal dysfunction often accompanied by epithelial hyperplasia, wherein 5-bromo-4-chloro-3-indoyl β-d-galactoside (X-gal)-positive podocyte-tagged cells were markedly decreased. The average numbers of double-positive cells in all sets of markers were significantly increased in the FSGS mice compared with the controls. In addition, the average numbers of double-positive cells for X-gal/Pax8, nestin/Pax8 and podocalyxin/Pax2 staining in the FSGS mice were comparable, whereas those of WT1/claudin1 were significantly increased. When we divided glomeruli from FSGS mice into those with FSGS lesions and those without, double-positive cells tended to be more closely associated with glomeruli without FSGS lesions compared with those with FSGS lesions. Moreover, the majority of double-positive cells appeared to be isolated and very rarely associated with FSGS lesions (1/1,997 glomeruli). This study is the first to show the incidence and localization of epithelial cells with phenotypical changes in FSGS using a genetic tag. The results suggest that the major direction of epithelial phenotypic transition in cellular FSGS is from podocytes to PECs and that these cells were less represented in the active lesions of FSGS.


Small molecule c-Met kinase inhibitors: a review of recent patents.
c-Met kinase is the receptor for hepatocyte growth factor. Primarily expressed on epithelial and mesenchymal cells its normal function is associated with wound healing, liver regeneration and embryo development. However, dysregulation of c-Met through overexpression, gene amplification, mutation or a ligand-dependent autocrine/paracrine loop is associated with tumorigenesis. c-Met dysregulation in human cancer patients is typically associated with a poor prognosis, aggressive disease, increased metastasis and shortened patient survival. Targeting the hepatocyte growth factor/c-Met signalling pathway as a means of cancer therapy has, therefore, become increasingly popular with a number of different therapeutic approaches undergoing clinical trials. AREAS COVERED BY THIS REVIEW: This review covers the patent applications for small molecule c-Met kinase inhibitors since 2007, attempts to place them in context from a structural point of view and examines their potential applications in cancer therapy. Readers will gain an overview of the structural types of c-Met inhibitors, the major players in the field and an insight into what is progressing into the clinic. This area is developing rapidly and the results of the various ongoing clinical trials will generate an increased understanding of the potential benefits and pitfalls of c-Met inhibitors as therapeutic agents.


Recognition of ten base pairs of DNA by head-to-head hairpin dimers.
Hairpin polyamides coupled head-to head with alkyl linkers of varying lengths were synthesized, and their DNA binding properties were determined. The DNA binding affinities of six-ring hairpin dimers Im-Im-Py-(R)[Im-Im-Py-(R)(HNCO(CH))(n)(CO)gamma-Py-Py-Py-beta-Dp](NH)gamma-Im-Py-Py-beta-Dp (1-4) (where n = 1-4) for their 10-bp, 11-bp, and 12-bp match sites 5'-TGGCATACCA-3', 5'-TGGCATTACCA-3', and 5'-TGGCATATACCA-3' were determined by quantitative DNase I footprint titrations. The most selective dimer Im-Im-Py-(R)[Im-Im-Py-(R)(HNCO(CH)(2))(2)(CO)gamma-Py-Py-Py-beta-Dp](NH)gamma-Im-Py-Py-beta-Dp (2) binds the 10-bp site match site with an equilibrium association constant of K(a) = 7.5 x 10(10) M(-1) and displays 25- and 140-fold selectivity over the 11-bp and 12-bp match sites, respectively. The affinity toward single base pair mismatched sequences is 4- to 8-fold lower if one hairpin module of the dimer is affected, but close to 200-fold lower if both hairpin modules face a single mismatch base pair. The head-to-head hairpin dimer motif expands the binding site size of DNA sequences targetable with polyamides.


Tanshinone IIA increases mRNA expression of efflux transporters in cultured human intestinal cell.
Tanshinone IIA (TSNIIA) is the major active component of Salvia miltorrhiza, which is used in treatment of cardiovascular and cerebrovascular diseases traditionally in China. However, the low bioavailability of TSNIIA limits its clinical usage. To reveal the mechanism relating the absorption of TSNIIA, we detected the expression of efflux transporters in Caco-2 cells under the stimulation of TSNIIA. TSNIIA was purified and above 98% purity was confirmed by high-performance liquid chromatography. The expression of nine efflux transporters including BCRP, hPepT1, MCT and MRP1-6 in Caco-2 were verified by reverse transcription polymerase chain reaction, and the up-regulation of TSNIIA on the expression of these transporters was found by reverse transcription real-time polymerase chain reaction. These results indicate that the low bioavailability of TSNIIA is partially due to its up-regulation on efflux transporters.


Extraction of maxillary first molars improves second and third molar inclinations in Class II Division 1 malocclusion.
The aim of this study was to assess the changes in inclination of the maxillary second (M2) and third (M3) molars after orthodontic treatment of Class II Division 1 malocclusion with extraction of maxillary first molars. Two groups of subjects were studied. The experimental group consisted of 37 subjects, 18 boys and 19 girls (mean age, 13.2 ± 1.62 years). The inclusion criteria were white origin, Class II Division 1 malocclusion, overjet ≥4 mm, no missing teeth or agenesis, and maxillary M3 present. All patients were treated with extraction of the maxillary first molars and the Begg technique. Standardized lateral cephalometric radiographs were taken at the start of active treatment (T1) and at least 3.7 years posttreatment (T2). The control group was drawn from the archives of the Nittedal Growth Material (Oslo University, Oslo, Norway) and included 54 untreated Class I and Class II subjects,18 boys and 36 girls (mean age, 13.4 ± 1.99 years) followed up for a minimum of 3.6 years. M2 and M3 inclinations relative to the palatal plane (PP) and functional occlusal plane (FOP) were measured and compared between groups and time periods. M2 to PP inclination improved significantly in both the control group (M2-PP at T1, 17.7° ± 5.81°, and at T2, 11.9° ± 4.61°) and the experimental group (M2-PP at T1, 26.7° ± 5.75°, and at T2, 6.9° ± 6.76°). There were also significant increases of the mesial inclination of M3 in the control group (M3-PP at T1, 30.1° ± 8.54°, and at T2, 19.6° ± 9.01°) and extraction group (M3-PP at T1, 32.2° ± 7.90°, and at T2, 12.8° ± 7.36°). By using the FOP as the reference system, no significant change in the inclination of M2 was observed in the control group, whereas, in the extraction group, although more distally inclined at T1, M2 ended up mesially inclined at T2 (M2-FOP at T1, 14.2° ± 4.62°, and at T2, -6.2° ± 6.10°; P <0.0001). M3 inclinations were similar between the groups at T1 (M3-FOP control, 17.3° ± 9.35°; M3-FOP experimental, 19.6° ± 7.37°), and these improved significantly in both groups. However, M3 uprighting was almost 4 times greater in the extraction group (M3-FOP from T2-T1, 5.6° vs 19.9°). The greatest distal inclination of M3 at T2 in the extraction group was 9.4°, a value attained by only 43% of the control group. Extraction of the maxillary first molars in Class II Division 1 patients results in significant uprighting of M2 and M3 and facilitates the normal eruption of M3.


Therapeutic implications of macrolide resistance in pneumococcal community-acquired lower respiratory tract infections.
Macrolide anti-bacterials are widely used for the empirical treatment of lower respiratory tract infections (RTIs) due to their activity against Streptococcus pneumoniae and other common respiratory pathogens and good safety/tolerability profile. However, the prevalence of macrolide resistance, particularly pneumococcal macrolide resistance, is increasing all around the world. The mechanisms underlying macrolide resistance include efflux pump, methylase activity and, less commonly, ribosomal mutation, which produce differing levels of resistance. Growth in macrolide resistance has been linked to the increased use of these agents, and several risk factors for the development of resistance have been identified. There are emerging data to suggest that in vitro macrolide resistance may increase the likelihood of treatment failure in patients with lower RTIs. However, at present, treatment failure is rare and randomised; intervention-based trials investigating the impact of anti-bacterial resistance on clinical outcomes are lacking. Strategies to promote appropriate use of macrolides and other anti-bacterials are needed, both to maximise therapeutic impact and to minimise the development of resistance. Furthermore, there is a need for alternative anti-bacterial agents which have high efficacy against respiratory pathogens (including resistant strains) and a low potential to induce resistance.


Arm reduced robotic-assisted laparoscopic hysterectomy with transvaginal cuff closure.
The use of robotics for benign etiology in gynecology has not proven to be more beneficial when compared to traditional laparoscopy. The major concern regarding robotic hysterectomy stems from its high cost. To evaluate the clinical utility and effectiveness of one-arm reduced robotic-assisted laparoscopic hysterectomy as a cost-effective surgical option for total robotic hysterectomy. A sample population of 54 women who underwent robotic-assisted laparoscopic surgery for benign gynecologic indications was evaluated, and two groups were identified: (1) the two-armed robotic-assisted laparoscopic surgery group (n = 38 patients), and (2) the three-armed robotic-assisted laparoscopic surgery group (n = 16 patients). An increased cost was observed when three-armed robotic surgery was employed for benign gynecologic surgery (p < 0.001). The cost reduction observed in the study group was primarily derived from one robotic arm reduction and vaginal closure of the cuff. This cost reduction was achieved without an increase in complication rates or undesirable postoperative outcomes. An estimated profit between $399.5 and $421.5 was made for each patient depending on the suture material chosen for cuff closure. Two-armed surgery resulted in an 18.6% reduction in procedure-specific costs for robotic hysterectomy. Two-armed robotic-assisted laparoscopic hysterectomy appears to be a cost-effective solution for robotic gynecologic surgery. This surgical solution can be performed as effectively as classical three-armed robotic hysterectomies for benign indications without the risk of increased surgical-related morbidities. This approach has the potential to be a widely preferred surgical approach in medical communities where cost reduction is one of the primary determinants of surgery type.


Methylation-sensitive restriction enzyme nested real time PCR, a potential approach for sperm DNA identification.
Mammal H19 gene is an imprinting gene in which the paternal allele is silenced. On H19 imprinting control region (ICR), one of the mechanisms regulating the paternal allelic specific silence is DNA methylation in somatic cells throughout the individual's whole life. Nevertheless, this pattern of DNA methylation is erased and re-established in germline. As results, in mature sperm H19 ICR shows biallelic methylation instead of paternal specific methylation in somatic cells. Although the data were mainly from experiments on mice the same mechanisms are believed existing in human germline. We designed an experiment to probe the sperm DNA by methylation sensitive restriction enzyme based nested qPCR (MSRE-nested-qPCR). The genomic DNA digested/undigested by HhaI was amplified by outer primers encompassing four HhaI sites on H19 ICR. These PCR products were used as templates for second round real-time PCR to quantify the DNA methylation level. The results showed that DNA methylation level at H19 ICR were 55.27 ± 8.36% in 32 blood samples and 101.94 ± 11.66% in 31 semen samples. Based on our data sperm DNA could be identified if H19 ICR methylation level is over 78.62%.


Detecting signs of decline.
Congenital heart disease (CHD) is a leading cause of mortality in infancy in the UK and parents must be able to recognise early signs of deterioration if they are to access timely care.


Neuroimmunophysiology of the gastrointestinal mucosa: implications for inflammatory diseases.
In conclusion, studies of the neuroimmunophysiology of the intestinal mucosa of the past 5-8 years have demonstrated an important role for the immune system in modulating water and electrolyte transport as well as intestinal motility in the gut. Activation of mast cells and phagocytes leads to heightened Cl- and water secretion, as well as changes in intestinal motility which leads to diarrheal states. These diarrheal responses are self-protective; they rid the intestine of offending microorganisms and antigens. Our investigation of this response has uncovered a new immune accessory cell Cz, the intestinal myofibroblast. This cell seems to play an important role in amplifying the immune signal. This cell is probably also important for the secretion of growth factors onto the epithelium and also the secretion of collagen which results in fibrosis under diseased states. These intestinal myofibroblasts are prolific prostaglandin producers, an important finding because prostaglandin synthesis inhibition has been shown to decrease the development of neoplasia in the gut. Thus, these intestinal myofibroblasts may have other important roles in addition to just modulating water and electrolyte secretion or gut motility. Our laboratory is now engaged in studying these intestinal myofibroblasts in some detail hoping to better understand the biology of these interesting cells.


Pros and cons of causative association between periodontitis and rheumatoid arthritis.
Research in recent decades has brought significant advancements in understanding of the molecular basis of the etiology of autoimmune diseases, including rheumatoid arthritis, a common systemic disease in which an inappropriate or inadequate immune response to environmental challenges leads to joint destruction. Recent studies have indicated that the classical viewpoint of the immunological processes underpinning the pathobiology of rheumatoid arthritis is restricted and needs to be expanded to include a more holistic and interdisciplinary approach incorporating bacteria-induced inflammatory reactions as an important pathway in rheumatoid arthritis etiology. Here, we discuss in detail data showing the clinical and molecular association of rheumatoid arthritis development with periodontal diseases. We also describe the unique role of periopathogens, which have been proposed to be crucial in the initiation and progression of this autoimmune pathological disorder.


Gender differences of mental health consumers accessing integrated primary and behavioral care.
Persons with severe mental illness and addiction are at higher risk for early morbidity and mortality than the general population, and are less likely to receive primary care and preventive health services. Primary and behavioral integrated care programs aim to reduce these health disparities by providing comprehensive health and wellness services. Gender in particular may play a significant role in individuals' engagement and outcomes in such programs. Hence, this study examines the salient characteristics of behavioral health consumers accessing an integrated care program at a large community mental health center. Baseline gender differences in consumer demographics, substance use, psychological distress and functioning, physical health indicators, and risk factors for serious medical conditions are examined. Our results demonstrate that key gender differences exist and may warrant distinct treatment needs for men and women receiving integrated care.


Excess entropy and long-time diffusion in colloidal fluids with short-range interparticle attraction.
Liquid structure and dynamics are experimentally investigated in colloidal suspensions with short-range depletion attraction. The colloidal fluid samples consist of hard-sphere colloidal particles suspended along with rodlike depletants based on surfactant micelles. The spheres have a range of surface chemistries, diameters, and packing fractions, and the rodlike micelle length depends on the temperature. Thus, the combination of hard-spheres and depletants generates a sample wherein short-range interparticle attraction can be temperature-tuned in situ. Video optical microscopy and particle tracking techniques are employed to measure particle trajectories from which structural and dynamical quantities are derived, including the particle pair correlation function [g(r)], mean square displacement, long-time diffusion coefficient, and the sample two-body excess entropy (S2). The samples with stronger short-range attractions exhibit more order, as characterized by g(r) and S2. The stronger short-range attractions are also observed to lead to slower long-time diffusion and more heterogeneous dynamics at intermediate time scales. Finally, the excess entropy scaling law prediction, i.e., the exponential relationship between two-body excess entropy and long-time diffusivity, is observed across the full range of samples.


Statins and vulnerable plaque.
Atherosclerosis is a systemic, progressive lipid-driven inflammatory disease of the arterial vascular wall leading progressively to plaque development. The vulnerable plaque, the one considered to be the leading cause of cardiovascular events seems to exhibit a large and soft lipid-rich necrotic core covered by a thin and inflamed fibrous cap. Statin treatment is considered as one of the most effective methods for vulnerable plaque stabilization, currently being the principal drug in primary and secondary prevention of cardiovascular disease. We sought to evaluate the beneficial effect of statins on biological processes involved in the evolution of vulnerable plaques Method: We performed a systematic review of the literature searching MEDLINE via Pubmed for all experimental and human studies implementing statins in vulnerable plaque. Statins seem to have a beneficial role in plaque stabilization and patient outcome. It seems that this effect is mediated by improving endothelial function, decreasing oxidative stress and inflammation, reducing inflammatory activation and inhibiting thrombogenic response. Although these data are quite promising, it remains to be determined the extent of a potent benefit of the pleiotropic effects of statin therapy in clinical setting. Prospective randomized trials should be conducted in order to further elucidate differences among type and dose of statin therapy, duration of treatment and association with LDL levels and clinical outcome.


Plantar pressure distribution in a hyperpronated foot before and after intervention with an extraosseous talotarsal stabilization device-a retrospective study.
Plantar pressure measurements have long been used by clinicians to provide information regarding potential impairments and disorders of the foot and ankle. Elevations in peak plantar pressures or a poor distribution of these pressures can be an indication of pathomechanics in the foot. Lower extremity deficits such as sensory impairment, foot deformities, limited joint mobility, and reduced plantar tissue thickness have been associated with high plantar pressures. The total pressures, pressure distribution, and peak pressures provide useful information to evaluate the abnormal functioning of the talotarsal joint. Instability of the talotarsal joint can result in excessive forces exerted on the joints and surrounding tissues in the foot that can then lead to dysfunction of the proximal musculoskeletal kinetic chain. In the present study, we performed a retrograde analysis of the pre- and postoperative measurements of the peak plantar pressures, peak forces, and area of contact between the foot and the ground during each phase of the gait cycle for 6 patients (12 feet) who had undergone a bilateral extraosseous talotarsal stabilization procedure using a type II extraosseous talotarsal stabilization device. After the procedure, a significant reduction was seen in the peak pressures (42%) over the entire foot and a significant increase in the contact area (19.7%) between the foot and the floor. This could imply that the extraosseous talotarsal stabilization procedure was effective in stabilizing the talotarsal joint complex, thus eliminating abnormal hindfoot motion and restoring the normal biomechanics of the foot and ankle complex, as indicated by a reduction and realignment of the peak plantar pressures and forces.


Texture orientation-based algorithm for detecting infrared maritime targets.
Infrared maritime target detection is a key technology for maritime target searching systems. However, in infrared maritime images (IMIs) taken under complicated sea conditions, background clutters, such as ocean waves, clouds or sea fog, usually have high intensity that can easily overwhelm the brightness of real targets, which is difficult for traditional target detection algorithms to deal with. To mitigate this problem, this paper proposes a novel target detection algorithm based on texture orientation. This algorithm first extracts suspected targets by analyzing the intersubband correlation between horizontal and vertical wavelet subbands of the original IMI on the first scale. Then the self-adaptive wavelet threshold denoising and local singularity analysis of the original IMI is combined to remove false alarms further. Experiments show that compared with traditional algorithms, this algorithm can suppress background clutter much better and realize better single-frame detection for infrared maritime targets. Besides, in order to guarantee accurate target extraction further, the pipeline-filtering algorithm is adopted to eliminate residual false alarms. The high practical value and applicability of this proposed strategy is backed strongly by experimental data acquired under different environmental conditions.


Cardiovascular health and sleep disturbances in two population-based cohort studies.
We aimed to investigate the association between cardiovascular health (CVH), as defined by the American Heart Association, and several sleep disturbances. Two community-based cohorts, the Paris Prospective Study 3 (PPS3, France, n=6441) and the CoLaus study (Switzerland, n=2989) were analysed. CVH includes 7 metrics which all can be classified as poor, intermediate and ideal. Global CVH score was categorised into poor (0-2 ideal metrics), intermediate (3-4 ideal metrics) and ideal (≥5 ideal metrics). Associations between global CVH and self-reported sleep disturbances (proxy of sleep-disordered breathing [SDB], excessive daytime sleepiness, insomnia symptoms and short/long sleep duration) and SDB severity measured by polysomnography (PSG) were investigated. Adjusted OR/relative risk ratio (RRR) and 95% CIs were estimated. Subjects with previous cardiovascular disease were excluded. Compared with poor CVH, subjects with intermediate and ideal global CVH had lower odds of self-reported SDB in both cohorts (ORs 0.55; 95% CI 0.44 to 0.68 and 0.35; 95% CI 0.22 to 0.53, respectively) and had lower SDB severity measured by PSG (RRR 0.07; 95% CI 0.02 to 0.20) in CoLaus. Subjects with intermediate and ideal global CVH had lower odds of excessive daytime sleepiness in PPS3 (ORs 0.82; 0.72 to 0.95 and 0.80; 0.82 to 1.02, respectively). No consistent associations were found between CVH and sleep duration or insomnia symptoms. Higher levels of CVH are associated with lower odds of SDB and excessive daytime sleepiness. However, causal interpretation cannot be made and associations might be bidirectional.


Is growth without IGF1 possible? A case report.
According to the growth hormone - insulin-like growth factor 1 axis (GH/IGF1 axis) theory, the actions of GH on promoting growth are mediated by IGF1. In the blood, IGF1, insulin-like growth factor 1 binding protein 3 (IGFBP3) and acid-labile subunit (ALS) form ternary complexes, hence the accumulation of IGF1. We report a case of 10-year-old male with short stature due to GH deficiency diagnosed with hypopituitarism. Therapy with recombinant human GH (rhGH) was initiated at 11 years and 4 months. After twenty three months on treatment clinical effects were as follows: increase in the patient's height by 19.2 cm (initial height 12.4 cm vs. 140.6 cm; hSDS -4.35 vs. -2.7; predicted adult height 176 cm vs. 182 cm, respectively). Despite good clinical response to the therapy, serum levels of IGF1 and IGFBP3 remained diminished: IGF1 - 28 ng/ml initially, vs. 23 ng/ml 19 months on therapy and IGFBP3 - 1116 ng/ml initially, vs. 1888 ng/ml after 11 months on therapy. We attempt to justify this phenomenon by reconsidering the IGF1-independent GH actions, assessing the endocrine role of hepatic IGF1 in comparison to the autocrine/paracrine role of its bone tissue fraction, and evaluating the functions of ALS. The exact explanation for the positive response to rhGH treatment without the expected increase in IGF1 in our patient remains unknown. Serum levels of IGF1 and IGFBP3 seem not always to be reliable markers of the response to rhGH treatment in GH-deficient patients.


Cloning of the human MCCA and MCCB genes and mutations therein reveal the molecular cause of 3-methylcrotonyl-CoA: carboxylase deficiency.
3-Methylcrotonyl-CoA: carboxylase (EC 184.108.40.206; MCC) deficiency is an inborn error of the leucine degradation pathway (MIM *210200) characterized by increased urinary excretion of 3-hydroxyisovaleric acid and 3-methylcrotonylglycine. The clinical phenotypes are highly variable ranging from asymptomatic to profound metabolic acidosis and death in infancy. Sequence similarity with Glycine max and Arabidopsis thaliana genes encoding the two subunits of MCC permitted us to clone the cDNAs encoding the alpha- and beta-subunits of human MCC. The 2580 bp MCCA cDNA encodes the 725 amino acid biotin-containing alpha-subunit. The MCCA gene is located on chromosome 3q26-q28 and consists of 19 exons. The 2304 bp MCCB cDNA encodes the non-biotin-containing beta-subunit of 563 amino acids. The MCCB gene is located on chromosome 5q13 and consists of 17 exons. We have sequenced both genes in four patients with isolated biotin-unresponsive deficiency of MCC. In two of them we found mutations in the MCCA gene. Compound heterozygosity for a missense mutation (S535F) and a nonsense mutation (V694X) were identified in one patient. One heterozygous mutation (S535F) was found in another patient. The remaining two patients had mutations in the MCCB gene. One consanguineous patient was homozygous for a missense mutation (R268T). In the other we identified a missense mutation in one allele (E99Q) and allelic loss of the other. Mutations were correlated with an almost total lack of enzyme activity in fibroblasts. These data provide evidence that human MCC deficiency is caused by mutations in either the MCCA or MCCB gene.


Immunolocalization of a Na-K-2Cl cotransporter in human tracheobronchial smooth muscle.
Inhibition of the Na-K-2Cl (NKCC) cotransporter by loop diuretics is associated with airway relaxation, but there has been no direct evidence for the expression of this protein in airway smooth muscle. Thus we hypothesized that a NKCC cotransporter is present and functional in airway smooth muscle cells. Monoclonal and polyclonal antibodies were used first to demonstrate the presence of a NKCC cotransporter protein in isolated human fetal trachea and normal human bronchial smooth muscle cells (BSMC) by Western blotting. The cotransporter protein was then localized by immunohistochemical staining to airway smooth muscle cells in culture and in situ. The localization was confirmed by indirect immunofluorescence and laser confocal microscopy in the BSMC. Cotransporter function in BSMC was also confirmed in vitro by bumetanide-mediated inhibition of rubidium uptake. Our present findings thus document the presence of a functional NKCC cotransporter in human airway smooth muscle, providing a basis for defining the role of this ion cotransporter in airway smooth muscle function.


Activation mechanism of calcium-activated neutral protease. Evidence for the existence of intramolecular and intermolecular autolyses.
The activation mechanism through limited autolysis of a calcium-activated neutral protease (CANP) with a high sensitivity to calcium ions (microCANP) was analyzed. The rate of autolysis was dependent on microCANP concentration. The reaction was inhibited by high concentrations of digestible substrates but not by a nondigestible substrate. Incubation of microCANP inactivated by N-ethylmaleimide with a small amount of activated microCANP caused the degradation of the former in a manner similar to the autolysis of native microCANP. Immobilized microCANP bound to an anti-microCANP immunoglobulin G column autolyzed on addition of calcium ions. These results show that activation of microCANP through limited autolysis involves both intramolecular and intermolecular reactions.


Multinational cholera outbreak after wedding in the Dominican Republic.
We conducted a case–control study of a cholera outbreak after a wedding in the Dominican Republic, January 22, 2011. Ill persons were more likely to report having consumed shrimp on ice (odds ratio 8.50) and ice cubes in beverages (odds ratio 3.62). Travelers to cholera affected areas should avoid consuming uncooked seafood and untreated water.


Replication of African swine fever virus DNA in infected cells.
We have examined the ultrastructural localization of African swine fever virus DNA in thin-sections of infected cells by in situ hybridization and autoradiography. Virus-specific DNA sequences were found in the nucleus of infected Vero cells at early times in the synthesis of the viral DNA, forming dense foci localized in proximity to the nuclear membrane. At later times, the viral DNA was found exclusively in the cytoplasm. Electron microscopic autoradiography of African swine fever virus-infected macrophages showed that the nucleus is also a site of viral DNA replication at early times. These results provide further evidence of the existence of nuclear and cytoplasmic stages in the synthesis of African swine fever virus DNA. On the other hand, alkaline sucrose sedimentation analysis of the replicative intermediates synthesized in the nucleus and cytoplasm of infected macrophages showed that small DNA fragments ( approximately 6-12S) were synthesized in the nucleus at an early time, whereas at later times, larger fragments of approximately 37-49S were labeled in the cytoplasm. Pulse-chase experiments demonstrated that these fragments are precursors of the mature cross-linked viral DNA. The formation of dimeric concatemers, which are predominantly head-to-head linked, was observed by pulsed-field electrophoresis and restriction enzyme analysis at intermediate and late times in the replication of African swine fever virus DNA. Our findings suggest that the replication of African swine fever virus DNA proceeds by a de novo start mechanism with the synthesis of small DNA fragments, which are then converted into larger size molecules. Ligation or further elongation of these molecules would originate a two-unit concatemer with dimeric ends that could be resolved to generate the genomic DNA by site-specific nicking, rearrangement, and ligation as has been proposed in the de novo start model of Baroudy et al. (B. M. Baroudy, S. Venkatesam, and B. Moss, 1982, Cold Spring Harbor Symp. Quant. Biol. 47, 723-729) for the replication of vaccinia virus DNA.


Unilateral withholding and withdrawal of potentially life-sustaining treatment: a violation of dignity under the law in Canada.
In this paper, I review Canadian law in relation to the unilateral withholding or withdrawal of potentially life-sustaining treatment, and I look at such questions as whether physicians are legally permitted to unilaterally put a do-not-resuscitate (DNR) order on a patient's chart. I explore who has the legal authority in Canada to decide on withholding and withdrawal of potentially life-sustaining treatment, and I conclude that unilateral withholding and withdrawal is a violation of the strong social commitment to dignity as it is understood and reflected in the law by the Supreme Court of Canada. I then offer a concrete proposal for institutional policy with respect to unilateral withholding and withdrawal of treatment in light of the law.


Z-Scheme Heterojunction of 3-Dimensional Hierarchical Bi3O4Cl/Bi5O7I for a Significant Enhancement in the Photocatalytic Degradation of Organic Pollutants (RhB and BPA).
In this study, we report the synthesis of a 3-dimensional (3D) hierarchical Bi3O4Cl/Bi5O7I (BOC/BOI) heterostructure for the photocatalytic degradation of Rhodamine-B (RhB) dye and colorless Bisphenol-A (BPA) pollutant under visible light. The heterostructure was prepared using in situ solvothermal and calcination methods. BOC/BOI exhibits a 3D hierarchical structure constructed with thin nano-platelets. The photocatalytic performance of the BOC/BOI photocatalyst demonstrated that the degradation efficiencies of RhB and BPA were 97% and 92% after light illumination within 90 and 30 min, respectively. In comparison, bare BOC and BOI efficiencies were only 20% and 10% for RhB dye, respectively, and 2.3% and 37% for BPA aqueous pollutants, respectively. Moreover, radical trapping measurements indicated that •O2- and •OH radicals played prominent roles in RhB and BPA degradation into mineralization. Analysis of band structures and photochemical redox reactions of BOC/BOI revealed a Z-scheme charge transfer between BOC and BOI by an internal electric field formed at the interface. Therefore, the highly improved photocatalytic performance of the BOC/BOI heterostructure is attributed to the synergetic effects of large surface area, high visible-light absorption, and the enhanced separation and transport of photo-excited electron-hole pairs induced by the hierarchical and Z-scheme heterojunction of the BOC/BOI.


Regulation of reaction forces during the golf swing.
During the golf swing, the reaction forces applied at the feet control translation and rotation of the body-club system. In this study, we hypothesized that skilled players using a 6-iron would regulate shot distance by scaling the magnitude of the resultant horizontal reaction force applied to the each foot with minimal modifications in force direction. Skilled players (n = 12) hit golf balls using a 6-iron. Shot distance was varied by hitting the ball as they would normally and when reducing shot distance using the same club. During each swing, reaction forces were measured using dual force plates (1200 Hz) and three-dimensional kinematics were simultaneously captured (110 Hz). The results indicate that, on average, the peak resultant horizontal reaction forces of the target leg were significantly less than normal (5%, p < 0.05) when reducing shot distance. No significant differences in the orientation of the peak resultant horizontal reaction forces were observed. Resultant horizontal reaction force-angle relationships within leg and temporal relationships between target and rear legs during the swing were consistent within player across shot conditions. Regulation of force magnitude with minimal modification in force direction is expected to provide advantages from muscle activation, coordination, and performance points of view.


Long-term video-EEG monitoring and interictal epileptiform abnormalities.
In the appropriate clinical setting, the presence of interictal epileptiform abnormalities (IEAs) on EEG supports the diagnosis of epilepsy. However, the absence of epileptiform abnormalities on EEG cannot exclude a diagnosis of epilepsy. The goal of our study is to determine the prevalence of IEAs in patients with confirmed epilepsy, determined by having at least one epileptic seizure recorded during video-EEG monitoring. In addition, we aimed to analyze the time to recording IEAs and seizures in correlation with patient age, duration of epilepsy, and seizure focus localization. We retrospectively evaluate EEG data for all patients admitted to the epilepsy monitoring unit over a 2-year period. Of the 151 patients included, 129 (86%) patients had IEAs and 22 (14%) patients had no IEAs. Age and duration of epilepsy were not independent predictors of whether IEAs were present on EEG. The duration of EEG monitoring and time to first seizure did not influence IEA detection. In patients with IEAs, the mean time to the first IEA was 1.57 days. By day 5, IEAs were observed in 95% of the patients who had IEAs present on EEG (82% of total patients). The majority (75%) of patients also had their first seizure by day 5. We concluded that five days of EEG recording is optimal to detect IEAs and seizures, and that more prolonged recording has a low yield. Failure to detect IEAs should be interpreted with caution, and is not useful for diagnostic purposes.


A Novel Staging System to Forecast the Cancer-Specific Survival of Patients With Resected Gallbladder Cancer.
Objective: Gallbladder cancer (GBC) is one of the most aggressive malignant tumors, and there is no effective and convenient method for predicting cancer-specific survival (CSS). We aim to develop a novel nomogram staging system based on the positive lymph node ratio (pLNR) for GBC patients. Methods:A total of 1,356 patients enrolled in the study. We evaluated the prognostic value of the pLNR and built a prognostic nomogram staging system based on the pLNR in the training cohort. The concordance index and calibration plots were used to evaluate model discrimination. The predictive accuracy and clinical value of the nomograms were measured by decision curve analysis (DCA). The CSS nomogram was further validated in an internal validation cohort. Results:The pLNR was an independent prognostic factor for CSS based on Cox regression analyses. A prognostic nomogram that combined T classification, pLNR, M classification, histologic grade, live metastasis, and tumor size was formulated with a c-index of 0.763 (95% CI, 0.728-0.798), while the c-indexes for the staging system of AJCC 8th, 7th, and 6th for CSS prediction were 0.718, 0.718, and 0.717, respectively. The calibration curves showed perfect agreement. The DCA showed that the nomogram provided substantial clinical value. The nomogram (the AUCs for 1, 3, and 5 years were 0.693, 0.716, and 0.726, respectively,) showed high prognostic accuracy. Conclusion:We have developed a formulated nomogram staging system based on the pLNR that allows more accurate individualized predictions of CSS for resected GBC patients than the AJCC staging systems.


In-Flight Medical Emergencies Management by Anesthetist-Intensivists and Emergency Physicians.
BACKGROUND: In-flight medical emergencies (IME) are challenging situations: aircraft cabins are noisy and narrow, medical supplies are scarce, and high-altitude related physiological changes may worsen chronic respiratory or cardiac conditions. The aim of this study was to assess the extent to which anesthetist-intensivists and emergency physicians are aware of IME specificities.METHODS: A questionnaire containing 21 items was distributed to French anesthetist-intensivists and emergency physicians between January and May 2020 using the mailing list of the French Society of Anesthesia and Intensive Care Medicine and the French Society of Emergency Medicine. The following topics were evaluated: high-altitude related physiological changes, medical and human resources available inside commercial aircraft, common medical incidents likely to happen on board, and previous personal experiences.RESULTS: The questionnaire was completed by 1064 physicians. The items corresponding to alterations in the arterial oxygen saturation, respiratory rate, and heart rate at cruising altitude were answered correctly by less than half of the participants (respectively, 3%, 42%, and 44% of the participants). Most responders (83%) were interested in a complementary training on IME management.DISCUSSION: The present study illustrates the poor knowledge in the medical community of the physiological changes induced by altitude and their consequences. In addition to offering specific theoretical courses to the medical community, placing sheets in commercial aircraft summarizing the optimal management of the main emergencies likely to happen on board might be an interesting tool.Diop S, Birnbaum R, Cook F, Mounier R. In-flight medical emergencies management by anesthetist-intensivists and emergency physicians. Aerosp Med Hum Perform. 2022; 93(8):633-636.