Protective effect of Hypericum perforatum in zymosan-induced multiple organ dysfunction syndrome: relationship to its inhibitory effect on nitric oxide production and its peroxynitrite scavenging activity.
Hypericum perforatum is a medicinal plant species containing many polyphenolic compounds, namely flavonoids and phenolic acids. Since polyphenolic compounds have high antioxidant potential, we have investigated the effects of H. perforatum extract on the development of multiple organ dysfunction syndrome caused by zymosan (500 mg/kg, administered i.p. as a suspension in saline) in mice. Organ failure and systemic inflammation in rats was assessed 18 h after administration of zymosan and/or H. perforatum extract and monitored for 12 days (for loss of body weight and mortality). Treatment of mice with H. perforatum extract (30 mg/kg i.p., 1 and 6h after zymosan) attenuated the peritoneal exudation and the migration of polymorphonuclear cells caused by zymosan, pulmonary, intestinal and pancreatic injury, and renal dysfunction as well as the increase in myeloperoxidase in the lung and intestine. Immunohistochemical analysis for inducible nitric oxide synthase (iNOS), nitrotyrosine, and poly(ADP-ribose) (PAR) revealed positive staining in lung and intestine tissues obtained from zymosan-injected mice. The degree of staining for nitrotyrosine, iNOS, and PAR was markedly reduced in tissue sections obtained from zymosan-treated mice, which received H. perforatum extract. In conclusion, this study provides evidence, for the first time, that H. perforatum extract attenuates the degree of zymosan-induced multiple organ dysfunction syndrome in mice.


Beneficial effects of mild stress (hormetic effects): dietary restriction and health.
Hormesis is defined as a dose-response phenomenon characterized by low-dose stimulation and high-dose inhibition, and has been recognized as representing an overcompensation for mild environmental stress. The beneficial effects of mild stress on aging and longevity have been studied for many years. In experimental animals, mild dietary stress (dietary restriction, DR) without malnutrition delays most age-related physiological changes, and extends maximum and average lifespan. Animal studies have also demonstrated that DR can prevent or lessen the severity of cancer, stroke, coronary heart disease, autoimmune disease, allergy, Parkinson's disease and Alzheimer's disease. The effects of DR are considered to result from hormetic mechanisms. These effects were reported by means of various DR regimens, such as caloric restriction, total-nutrient restriction, alternate-day fasting, and short-term fasting. Mild dietary stress, including restriction of amount or frequency of intake, is the essence of DR. For more than 99% of their history, humans lived as hunter-gatherers and adapted to restrictions in their food supply. On the other hand, an oversufficiency of food for many today has resulted in the current global epidemic of obesity and obesity-related diseases. DR may be used, therefore, as a novel approach for therapeutic intervention in several diseases, when detailed information about effects of mild dietary stress on human health is obtained from clinical trials.


An input-output based robust stabilization criterion for neural-network control of nonlinear systems.
A stabilization method based on the input-output conicity criterion is presented. Conventional learning algorithms are applied to adjust the controller dynamics, and robust stability of the closed-loop system is guaranteed by modifying the training patterns which yield unstable behavior. The methodology developed expands the class of nonlinear systems to be controlled using neural control schemes, so that the stabilization of a broad class of neural-network-based control systems, even with unknown dynamics, is assured. Straightforwardness in the application of this method is evident in contrast to the Lyapunov function approach.


Temporal Relation Between Myocardial Fibrosis and Heart Failure With Preserved Ejection Fraction: Association With Baseline Disease Severity and Subsequent Outcome.
Among myriad changes occurring during the evolution of heart failure with preserved ejection fraction (HFpEF), cardiomyocyte-extracellular matrix interactions from excess collagen may affect microvascular, mechanical, and electrical function. To investigate whether myocardial fibrosis (MF) is similarly prevalent both in those with HFpEF and those at risk for HFpEF, similarly associating with disease severity and outcomes. Observational cohort study from June 1, 2010, to September 17, 2015, with follow-up until December 14, 2015, at a cardiovascular magnetic resonance (CMR) center serving an integrated health system. Consecutive patients with preserved systolic function referred for CMR were eligible. Cardiovascular magnetic resonance was used to exclude patients with cardiac amyloidosis (n = 19). Myocardial fibrosis quantified by extracellular volume (ECV) CMR measures. Baseline BNP; subsequent hospitalization for heart failure or death. Of 1174 patients identified (537 [46%] female; median [interquartile range {IQR}] age, 56 [44-66] years), 250 were "at risk" for HFpEF given elevated brain-type natriuretic peptide (BNP) level; 160 had HFpEF by documented clinical diagnosis, and 745 did not have HFpEF. Patients either at risk for HFpEF or with HFpEF demonstrated similarly higher prevalence/extent of MF and worse prognosis compared with patients with no HFpEF. Among those at risk for HFpEF or with HFpEF, the actual diagnosis of HFpEF was not associated with significant differences in MF (median ECV, 28.2%; IQR, 26.2%-30.7% vs 28.3%; IQR, 25.5%-31.4%; P = .60) or prognosis (log-rank 0.8; P = .38). Over a median of 1.9 years, 61 patients at risk for HFpEF or with HFpEF experienced adverse events (19 hospitalization for heart failure, 48 deaths, 6 with both). In those with HFpEF, ECV was associated with baseline log BNP (disease severity surrogate) in multivariable linear regression models, and was associated with outcomes in multivariable Cox regression models (eg, hazard ratio 1.75 per 5% increase in ECV, 95% CI, 1.25-2.45; P = .001 in stepwise model) whether grouped with patients at risk for HFpEF or not. Among myriad changes occurring during the apparent evolution of HFpEF where elevated BNP is prevalent, MF was similarly prevalent in those with or at risk for HFpEF. Conceivably, MF might precede clinical HFpEF diagnosis. Regardless, MF was associated with disease severity (ie, BNP) and outcomes. Whether cells and secretomes mediating MF represent therapeutic targets in HFpEF warrants further evaluation.


Ecologic and geographic distribution of filovirus disease.
We used ecologic niche modeling of outbreaks and sporadic cases of filovirus-associated hemorrhagic fever (HF) to provide a large-scale perspective on the geographic and ecologic distributions of Ebola and Marburg viruses. We predicted that filovirus would occur across the Afrotropics: Ebola HF in the humid rain forests of central and western Africa, and Marburg HF in the drier and more open areas of central and eastern Africa. Most of the predicted geographic extent of Ebola HF appear to have been observed; Marburg HF has the potential to occur farther south and east. Ecologic conditions appropriate for Ebola HF are also present in Southeast Asia and the Philippines, where Ebola Reston is hypothesized to be distributed. This first large-scale ecologic analysis provides a framework for a more informed search for taxa that could constitute the natural reservoir for this virus family.


Geometry of site alignment during int family recombination: antiparallel synapsis by the Flp recombinase.
The Flp site-specific recombinase functions in the copy number amplification of the yeast 2 microm plasmid. The recombination reaction is catalyzed by four monomers of Flp bound to two separate, but identical, recombination sites (FRT sites) and occurs in two sequential pairs of strand exchanges. The relative orientation of the two recombination sites during synapsis was examined. Topoisomerase relaxation and nick ligation were used to detect topological nodes introduced by the synapse prior to the chemical steps of recombination. A single negative supercoil was found to be trapped by Flp in substrates with inverted FRT sites whereas no trapped supercoils were observed with direct repeats. The topology of products resulting from Flp-mediated recombination adjacent to a well characterised synapse, that of Tn3 resolvase/res, was analyzed. The deletion and inversion reactions yielded the four noded catenane and the three noded knot, respectively, as the simplest and the most abundant products. The linking number change introduced by the Flp-mediated inversion reaction was determined to be +/-2. The most parsimonious explanation of these results is that Flp aligns its recombination sites with antiparallel geometry. The majority of synapses appear to occur without entrapment of additional random plectonemic DNA supercoils between the sites and no additional crossings are introduced as a result of the chemical steps of recombination.


Accounting for polarization cost when using fixed charge force fields. II. Method and application for computing effect of polarization cost on free energy of hydration.
Polarization cost is the energy needed to distort the wave function of a molecule from one appropriate to the gas phase to one appropriate for some condensed phase. Although it is not currently standard practice, polarization cost should be considered when deriving improved fixed charge force fields based on fits to certain types of experimental data and when using such force fields to compute observables that involve changes in molecular polarization. Building on earlier work, we present mathematical expressions and a method to estimate the effect of polarization cost on free energy and enthalpy implied by a charge model meant to represent a solvated state. The charge model can be any combination of point charges, higher-order multipoles, or even distributed charge densities, as long as they do not change in response to environment. The method is illustrated by computing the effect of polarization cost on free energies of hydration for the neutral amino acid side chain analogues as predicted using two popular fixed charge force fields and one based on electron densities computed using quantum chemistry techniques that employ an implicit model to represent aqueous solvent. From comparison of the computed and experimental hydration free energies, we find that two commonly used force fields are too underpolarized in their description of the solute-water interaction. On the other hand, a charge model based on the charge density from a hybrid density functional calculation that used an implicit model for aqueous solvent performs well for hydration free energies of these molecules after the correction for dipole polarization is applied. As such, an improved description of the density (e.g., B3LYP, MP2) in conjunction with an implicit solvent (e.g., PCM) or explicit solvent (e.g., QM/MM) approach may offer promise as a starting point for the development of improved fixed charge models for force fields.


Approximate likelihood-based estimation method of multiple-type pathogen interactions: An application to longitudinal pneumococcal carriage data.
While the serotypes of Streptococcus pneumoniae are known to compete during colonization in human hosts, our knowledge of how competition occurs is still incomplete. New insights of pneumococcal between-type competition could be generated from carriage data obtained by molecular-based detection methods, which record more complete sets of serotypes involved in co-carriage than when detection is done by culture. Here, we develop a Bayesian estimation method for inferring between-type interactions from longitudinal data recording the presence/absence of the types at discrete observation times. It allows inference from data containing co-carriage of two or more serotypes, which is often the case when pneumococcal presence is determined by molecular-based methods. The computational burden posed by the increased number of types detected in co-carriage is addressed by approximating the likelihood under a multi-state model with the likelihood of only those trajectories with minimum number of acquisition and clearance events between observation times. The proposed method's performance was validated on simulated data. The estimates of the interaction parameters of acquisition and clearance were unbiased in settings with short sampling intervals between observation times. With less frequent sampling, the estimates of the interaction parameters became more biased, but their ratio, which summarizes the total interaction, remained unbiased. Confounding due to unobserved heterogeneity in exposure could be corrected by including individual-level random effects. In an application to empirical data about pneumococcal carriage in infants, we found new evidence for between-serotype competition in clearance, although the effect size was small.


Relative densities of natural enemy and pest insects within California hedgerows.
Research on hedgerow design for supporting communities of natural enemies for biological control lags behind farmer innovation in California, where assemblages of perennial plant species have been used on crop field margins in the last decade. We compared natural enemy to pest ratios between fields with hedgerows and fields with weedy margins by sampling beneficial insects and key pests of vegetables on sticky cards. We used biweekly vacuum samples to measure the distribution of key insect taxa among native perennial plant species with respect to the timing and intensity of bloom. Sticky cards indicated a trend that field margins with hedgerows support a higher ratio of natural enemies to pests compared with weedy borders. Hedgerow plant species hosted different relative densities of a generally overlapping insect community, and the timing and intensity of bloom only explained a small proportion of the variation in insect abundance at plant species and among hedgerows, with the exception of Orius spp. on Achillea millefolium L. and Baccharis pilularis De Candolle. Indicator Species Analysis showed an affinity of parasitic wasps, especially in the super-family Chalcidoidea, for B. pilularis whether or not it was in flower. A. millefolium was attractive to predatory and herbivorous homopterans; Heteromeles arbutifolia (Lindley) Roemer and B. pilularis to Diabrotica undecimpunctata undecimpunctata Mannerheim; and Rhamnus californica Eschsch to Hemerobiidae. Perennial hedgerows can be designed through species selection to support particular beneficial insect taxa, but plant resources beyond floral availability may be critical in providing structural refuges, alternative prey, and other attractive qualities that are often overlooked.


Influence of postnatal overnutrition and pregnancy on non-insulin dependent diabetes induced in Wistar rats by neonatal streptozotocin.
Wistar rats with non-insulin dependent diabetes induced by neonatal streptozotocin (STZ) administration were raised either in large or in small litters. The STZ-treated rats from small litters showed a higher body weight as well as increased blood glucose levels compared with vehicle- and STZ-treated rats reared in large nests at an age of 8 weeks. The higher body weight of these rats was maintained until an age of 15 weeks, whereas the basal blood glucose was normalized. However, both STZ-treated groups exhibited an impaired glucose tolerance. During pregnancy only the glucose tolerance of the STZ-treated animals from large nests was improved although not normalized. The STZ-treated rats from small nests failed to adapt to pregnancy because the blood glucose levels after glucose load were similar to values found in the virgin state. The body weight of pregnant STZ treated rats raised in small litters was significantly lower than in vehicle- or STZ-terated rats from large nests. The number of fetuses per litter was similar in all groups tested. Compared with the vehicle-treated rats from large litters the fetal body weight of STZ-treated rats from small nests was decreased and that of STZ rats raised in large litters was increased. These results suggest that the rats with the more impaired glucose tolerance produce growth-retarded pups and, conversely, rats with rather mild impairment have bigger fetuses than the vehicle-treated ones. In the present study we have examined for the first time the combined effects of postnatal overnutrition and pregnancy on glucose homeostasis of rats treated neonatally with STZ. Our data demonstrate that postnatal overnutrition is an aggravating factor in the development of a diabetic state in these rats, especially at times when the insulin requirement is higher such as puberty and pregnancy.


Computerized Tomography (CT) Updates and Challenges in Diagnosis of Bone Metastases During Prostate Cancer.
Prostate cancer is one of the most common cancers in men. This cancer is often associated with indolent tumors with little or no lethal potential. Some of the patients with aggressive prostate cancer have increased morbidity and early deaths. A major complication in advanced prostate cancer is bone metastasis that mainly results in pain, pathological fractures, and compression of spinal nerves. These complications in turn cause severe pain radiating to the extremities and possibly sensory as well as motor disturbances. Further, in patients with a high risk of metastases, treatment is limited to palliative therapies. Therefore, accurate methods for the detection of bone metastases are essential. Technical advances such as single-photon emission computed tomography/ computed tomography (SPECT/CT) have emerged after the introduction of bone scans. These advanced methods allow tomographic image acquisition and help in attenuation correction with anatomical co-localization. The use of positron emission tomography/CT (PET/CT) scanners is also on the rise. These PET scanners are mainly utilized with 18F-sodium-fluoride (NaF), in order to visualize the skeleton and possible changes. Moreover, NaF PET/CT is associated with higher tracer uptake, increased target-to-background ratio and has a higher spatial resolution. However, these newer technologies have not been adopted in clinical guidelines due to lack of definite evidence in support of their use in bone metastases cases. The present review article is focused on current perspectives and challenges of computerized tomography (CT) applications in cases of bone metastases during prostate cancer.


Simultaneous leaching of multiple heavy metals from a soil column by extracellular polymeric substances of Aspergillus tubingensis F12.
The use of the biological agents for leaching heavy metals from contaminated soils is a very promising method that is both efficient and eco-friendly. In this study, a fungus Aspergillus tubingensis F12 was reported to possess a strong adsorption capacity for various heavy metal ions and shown to adsorb 90.8% Pb, 68.4% Zn, 64.5% Cr, 13.1% Cu, 12.9% Ni, and 6.9% Cd in aqueous solution. As extracellular polymeric substance (EPS) was found to play a leading role in the adsorption of metal ions, we applied EPS as a leaching agent to simultaneously remove six metals from soil in a column leaching experiment. The flow rate, initial solution pH, initial EPS concentration, and ionic strength were investigated using response surface methodology. The minimum and maximum metal leaching capacities were determined to be 0.089 mg/g and 3.703 mg/g, respectively. Verified by Fourier transform infrared spectroscopy, scanning electron microscope energy dispersive X-ray spectroscopy, and X-ray photoelectron spectroscopy, we made the preliminary deductions that ion exchange determines the leaching capacity limit and that biosorption plays a large role in reaching that limit. Additionally, the redox behaviour of Cu produced more carboxyl groups, which increased the adsorption of heavy metals. The ecological impact of this method was also examined; we found that the influences of leaching with EPS on soil properties and microbial community structure were slight. Therefore, the reported leaching process might have application prospects for metal removal from soil.


Micropatterning neural cell cultures in 3D with a multi-layered scaffold.
Cortical neurons, in their native state, are organized in six different cell layers; and the thickness of the cell layer ranges from 0.12 mm to 0.4 mm. The structure of cell layers plays an important role in neurodegenerative diseases or corticogenesis. We developed a 3D microfluidic device for creating physiologically realistic, micrometer scaled neural cell layers. Using this device, we demonstrated that (1) agarose-alginate mixture can be gelled thermally, thus an excellent candidate for forming multi-layered scaffolds for micropatterning embedded cells; (2) primary cortical neurons were cultured successfully for up to three weeks in the micropatterned multi-layered scaffold; (3) B27 concentration gradient enhanced neurite outgrowth. In addition, this device is compatible with optical microscopy, the dynamic process of neural growth can be imaged, and density and number of neurites can be quantified. This device can potentially be used for drug development, as well as research in basic neural biology.


The roles of active site residues in the catalytic mechanism of methylaspartate ammonia-lyase.
Methylaspartate ammonia-lyase (MAL; EC 188.8.131.52) catalyzes the reversible addition of ammonia to mesaconate to yield l-threo-(2S,3S)-3-methylaspartate and l-erythro-(2S,3R)-3-methylaspartate as products. In the proposed minimal mechanism for MAL of Clostridium tetanomorphum, Lys-331 acts as the (S)-specific base catalyst and abstracts the 3S-proton from l-threo-3-methylaspartate, resulting in an enolate anion intermediate. This enolic intermediate is stabilized by coordination to the essential active site Mg(2+) ion and hydrogen bonding to the Gln-329 residue. Collapse of this intermediate results in the release of ammonia and the formation of mesaconate. His-194 likely acts as the (R)-specific base catalyst and abstracts the 3R-proton from the l-erythro isomer of 3-methylaspartate, yielding the enolic intermediate. In the present study, we have investigated the importance of the residues Gln-73, Phe-170, Gln-172, Tyr-356, Thr-360, Cys-361 and Leu-384 for the catalytic activity of C. tetanomorphum MAL. These residues, which are part of the enzyme surface lining the substrate binding pocket, were subjected to site-directed mutagenesis and the mutant enzymes were characterized for their structural integrity, ability to catalyze the amination of mesaconate, and regio- and diastereoselectivity. Based on the observed properties of the mutant enzymes, combined with previous structural studies and protein engineering work, we propose a detailed catalytic mechanism for the MAL-catalyzed reaction, in which the side chains of Gln-73, Gln-172, Tyr-356, Thr-360, and Leu-384 provide favorable interactions with the substrate, which are important for substrate binding and activation. This detailed knowledge of the catalytic mechanism of MAL can serve as a guide for future protein engineering experiments.


Recent developments in adeno-associated virus vector technology.
Adeno-associated virus (AAV), a single-stranded DNA parvovirus, is emerging as one of the leading gene therapy vectors owing to its nonpathogenicity and low immunogenicity, stability and the potential to integrate site-specifically without known side-effects. A portfolio of recombinant AAV vector types has been developed with the aim of optimizing efficiency, specificity and thereby also the safety of in vitro and in vivo gene transfer. More and more information is now becoming available about the mechanism of AAV/host cell interaction improving the efficacy of recombinant AAV vector (rAAV) mediated gene delivery. This review summarizes the current knowledge of the infectious biology of AAV, provides an overview of the latest developments in the field of AAV vector technology and discusses remaining challenges.


Proteins of the kidney microvillar membrane. Asymmetric labelling of the membrane by lactoperoxidase-catalysed radioiodination and by photolysis of 3,5-di[125I]iodo-4-azidobenzenesulphonate.
Two methods were used to label pig kidney microvillar membrane proteins from the luminal and cytoplasmic surfaces of closed membrane vesicles. The first method was lactoperoxidase-catalysed radioiodination. The enzyme reagents, lactoperoxidase and glucose oxidase, were positioned inside the vesicles before sealing or externally after sealing, iodination being initiated by the subsequent addition of glucose and 125I-. After resolution of the labelled proteins by electrophoresis in the presence of dodecyl sulphate, asymmetric labelling patterns on radioautographs were observed. However, the major disadvantage of this method is the high degree of intramembrane labelling of the fatty acid chains of membrane lipids, a reaction that undermines any conclusions about the location of the label in that region of the protein supposedly exposed at the surface of the membrane. The second method overcame this disadvantage. A new hydrophilic photoreagent, 3,5-di[125I]iodo-4-azidobenzesulphonate, was synthesized via the intermediate, diazotized 3,5-di[125I]iodosulphanilic acid. It was transported by a Na+-dependent system into microvillar vesicles, thus permitting labelling from either side of the membrane when the vesicles were photolysed. The labelling of membrane lipids was less than with the first method and was essentially confined to the polar headgroups. The activity of several microvillar peptidases survived the labelling reaction and they could be identified in the immunoprecipitates after resolution of the detergent-solubilized membrane proteins by crossed-immunoelectrophoresis. Treatment with papain converted the detergent-solubilized form of susceptible enzymes into the proteinase-solubilized form, which lacked the intramembrane domain and any portion exposed at the cytoplasmic surface. Radioautography established that aminopeptidases M and A, dipeptidyl peptidase IV and neutral endopeptidase were transmembrane proteins. This novel approach to the investigation of membrane topology may be applicable to other complex membranes.


Candidate bacterial conditions.
This article provides background information on bacterial diseases and discusses those that are candidates for elimination or eradication. Only one disease, neonatal tetanus, is a strong candidate for elimination. Others, including Haemophilus influenzae b infection, leprosy, diphtheria, pertussis, tuberculosis, meningococcal disease, congenital syphilis, trachoma and syphilis are important causes of morbidity and mortality in industrialized and developing countries. For all these diseases, eradication/elimination is not likely because of the characteristics of the disease and limitations in the interventions.


Adherence, belief, and knowledge about oral anticoagulants in patients with bioprosthetic heart valve replacement: a cross-sectional study.
Aims: To investigate adherence to oral anticoagulants among patients after mechanical heart valve (BHV) replacement and further examine the mediating role of medication belief in the relationship between knowledge and medication adherence. Background: The number of patients who undergo BHV replacement has increased in recent years. Short-term anticoagulant therapy is recommended for patients after BHV replacement. However, little is known about adherence to oral anticoagulant therapy and the underlying mechanisms among patients with BHV replacement. Methods: A cross-sectional study was conducted between September 2022 and November 2022. A convenience sample of 323 patients who underwent BHV replacement was recruited from a tertiary public hospital in Southwest China. Data were collected by using the 8-item Morisky Medication Adherence Scale, Beliefs about Medicines Questionnaire-specific, and the Knowledge of Anticoagulation Questionnaire. The mediation model was tested by Hayes's PROCESS macro. The STROBE checklist was used. Results: Approximately 17.3% of participants had low adherence, 47.1% had medium adherence, and only 35.6% reported high adherence to oral anticoagulants. Knowledge and necessity beliefs were positively related to medication adherence, while concern beliefs were negatively correlated with medication adherence. Medication belief mediated the relationship between knowledge and adherence to oral anticoagulants. Conclusion: Patients with BHV replacement demonstrated relatively low adherence to oral anticoagulant therapy. Efforts to enhance medication adherence should consider improving patients' knowledge and medication beliefs.


The Solution Structure and Dynamics of Cd-Metallothionein from Helix pomatia Reveal Optimization for Binding Cd over Zn.
Metallothioneins (MTs) are cysteine-rich polypeptides that are naturally found coordinated to monovalent and/or divalent transition metal ions. Three metallothionein isoforms from the Roman snail Helix pomatia are known. They differ in their physiological metal load and in their specificity for transition metal ions such as Cd2+ (HpCdMT isoform) and Cu+ (HpCuMT isoform) or in the absence of a defined metal specificity (HpCd/CuMT isoform). We have determined the solution structure of the Cd-specific isoform (HpCdMT) by nuclear magnetic resonance spectroscopy using recombinant isotopically labeled protein loaded with Zn2+ or Cd2+. Both structures display two-domain architectures, where each domain comprises a characteristic three-metal cluster similar to that observed in the β-domains of vertebrate MTs. The polypeptide backbone is well-structured over the entire sequence, including the interdomain linker. Interestingly, the two domains display mutual contacts, as observed before for the metallothionein of the snail Littorina littorea, to which both N- and C-terminal domains are highly similar. Increasing the length of the linker motionally decouples both domains and removes mutual contacts between them without having a strong effect on the stability of the individual domains. The structures of Cd6- and Zn6-HpCdMT are nearly identical. However, 15N relaxation, in particular 15N R2 rates, is accelerated for many residues of Zn6-HpCdMT but not for Cd6-HpCdMT, revealing the presence of conformational exchange effects. We suggest that this snail MT isoform is evolutionarily optimized for binding Cd rather than Zn.


Paradoxical therapy in conversion reaction.
Paradoxical therapy consists of suggesting that the patient intentionally engages in the unwanted behaviour such as performing compulsive ritual or wanting a conversion attack. In this study, the subjects were selected by the emergency unit psychiatrist from patients who were admitted to the emergency unit with pseudoseizure. The diagnoses was based on DSM-IV criteria. Paradoxical intention was applied to half of the 30 patients with conversion disorders; the other half were treated with diazepam in order to examine the efficiency of the paradoxical intention versus diazepam. In both groups the differences of the anxiety scores at the beginning of the study were found to be insignificant (z=1.08, p=0.28). Of the 15 patients who completed paradoxical intention treatment, 14 (93.3%) responded favorably to paradoxical intention. On the other hand of 15 patients who completed diazepam therapy, 9 (60%) responded well to therapy and 6 patients carried on their conversion symptoms at the end of 6 weeks. Paradoxical intention-treated patients appeared to have greater improvements in anxiety scores (z=2.43, p<0.015) and conversion symptoms (t=2.27, p=0.034) than the diazepam-treated patients. The results of the present study are encouraging in that paradoxical intention can be effective in the treatment of conversion disorder.


Advances in the study of nodavirus.
Nodaviruses are small bipartite RNA viruses which belong to the family of Nodaviridae. They are categorized into alpha-nodavirus, which infects insects, and beta-nodavirus, which infects fishes. Another distinct group of nodavirus infects shrimps and prawns, which has been proposed to be categorized as gamma-nodavirus. Our current review focuses mainly on recent studies performed on nodaviruses. Nodavirus can be transmitted vertically and horizontally. Recent outbreaks have been reported in China, Indonesia, Singapore and India, affecting the aquaculture industry. It also decreased mullet stock in the Caspian Sea. Histopathology and transmission electron microscopy (TEM) are used to examine the presence of nodaviruses in infected fishes and prawns. For classification, virus isolation followed by nucleotide sequencing are required. In contrast to partial sequence identification, profiling the whole transcriptome using next generation sequencing (NGS) offers a more comprehensive comparison and characterization of the virus. For rapid diagnosis of nodavirus, assays targeting the viral RNA based on reverse-transcription PCR (RT-PCR) such as microfluidic chips, reverse-transcription loop-mediated isothermal amplification (RT-LAMP) and RT-LAMP coupled with lateral flow dipstick (RT-LAMP-LFD) have been developed. Besides viral RNA detections, diagnosis based on immunological assays such as enzyme-linked immunosorbent assay (ELISA), immunodot and Western blotting have also been reported. In addition, immune responses of fish and prawn are also discussed. Overall, in fish, innate immunity, cellular type I interferon immunity and humoral immunity cooperatively prevent nodavirus infections, whereas prawns and shrimps adopt different immune mechanisms against nodavirus infections, through upregulation of superoxide anion, prophenoloxidase, superoxide dismutase (SOD), crustin, peroxinectin, anti-lipopolysaccharides and heat shock proteins (HSP). Potential vaccines for fishes and prawns based on inactivated viruses, recombinant proteins or DNA, either delivered through injection, oral feeding or immersion, are also discussed in detail. Lastly, a comprehensive review on nodavirus virus-like particles (VLPs) is presented. In recent years, studies on prawn nodavirus are mainly focused on Macrobrachium rosenbergii nodavirus (MrNV). Recombinant MrNV VLPs have been produced in prokaryotic and eukaryotic expression systems. Their roles as a nucleic acid delivery vehicle, a platform for vaccine development, a molecular tool for mechanism study and in solving the structures of MrNV are intensively discussed.


Mycoplasma-induced BALB/c 3T3 collagenase is a mammalian enzyme.
A collagenase previously reported to accumulate in the medium of cultures of BALB/c 3T3 cells on infection with Mycoplasma orale [Kluve, Merrick, Stanbridge & Gershman (1981) Nature (London) 292, 855-857] was partially purified and characterized. With regard to purification properties, activation, sensitivity to inhibitors and relative molecular mass the enzyme was similar to previously reported vertebrate collagenases, but could not be unequivocally distinguished from bacterial collagenases. With regard to substrate-specificity and reaction products, however, the collagenase was typical of vertebrate collagenases and distinct from bacterial collagenases. Specifically, the enzyme displayed a preference for type III collagen and type I collagen, a somewhat decreased ability to degrade type II collagen, and a very limited ability to degrade type IV collagen. The initial products of the action of the collagenase on type I collagen were characterized as fragments one-quarter and three-quarters of the length of the intact collagen molecule. Because the properties of the collagenase produced by cultures of mycoplasma-infected BALB/c 3T3 cells are those of a mammalian-type (vertebrate-type) enzyme, we have concluded that the collagenase is a product of the mouse (BALB/c 3T3) genome, and is not produced by the mycoplasma. Therefore it appears that infection of BALB/c 3T3 mouse fibroblasts with Mycoplasma orale induces the mouse cells to produce and secrete collagenase.


Impact of new hypertension guidelines on target organ damage screening in a Shanghai community-dwelling population.
Recently, the 2017 ACC/AHA released new hypertension guidelines and proposed a redefinition of hypertension from 140/90 to 130/80 mm Hg. This study assesses the impact of the lower threshold for hypertension diagnosis on the association of hypertension with target organ damage (TOD). Health checks were conducted in a community-dwelling population in Shanghai in 2017 (N = 10 826; 43.26% mean, age 62 ± 12 years [range 29-95 years]). Subclinical TOD indices were quantified in terms of left ventricular hypertrophy (LVH) by electrocardiogram (Sokolow-Lyon standard), estimated glomerular filtration rate (eGFR), and presence of proteinuria. Information on clinical TOD was obtained by questionnaire. Arteriosclerotic cardiovascular disease (ASCVD) was determined by the 2013 ACC/ AHA recommended guidelines. Compared to the higher threshold (140/90 mm Hg), the lower threshold (130/80 mm Hg) was associated with variable rates of increased detection of hypertension and TOD: (a) Hypertension: incidence of hypertension, 29.5% (51.8%-81.5%) increase in persons with hypertension if the threshold of 130/80 mm Hg is used; (b) Subclinical TOD: LVH, 20.8%; eGFR (30-60 mL/min per 1.73 m2 ), 23.7%; proteinuria, 23.5%; (c) Clinical TOD: chronic kidney disease (CKD) IV (eGFR<30 mL/min per 1.73 m2 ), 3.1%; diabetes (fasting glucose ≥7.0 mmol/L or HbA1C>7.0%), 24.3%; stroke, 26.4%; chronic heart disease, 28.1%; acute myocardial infarction, 19.5% (69.4% to 88.9% of total of 36); ASCVD ≥10%, 29.3%. The lower threshold was associated with a significantly higher detection rate of clinical and subclinical TOD of approximately 20% compared to the higher threshold. 15%-20% of TOD and 29% of ASCVD were also found below the lower threshold of hypertension.


Functioning of identified snail neurones in electric fields.
In both silent and spontaneously active neurones of the snail Helix lucorum, depolarization and spikes were elicited by low-frequency (0.1 Hz) sinusoidal currents applied to the bath solution. Threshold voltage gradients had a range of 1-10 V m-1, which is less than gradients in the nervous tissue during synchronous activation of the neurones. It is shown that the same neurone can generate spikes in response to opposite directions of polarizing currents. Thresholds of spontaneously active neurones to extracellular currents were significantly lower than thresholds of silent cells. A simple quantitative method for evaluation of the transmembrane voltage drop evoked by an electric field is presented. The role of neuronal branches in the response was studied by electrophysiological and morphological methods.


Immunisation coverage in the rural Eastern Cape - are we getting the basics of primary care right? Results from a longitudinal prospective cohort study.
Immunisations are one of the most cost-effective public health interventions available and South Africa (SA) has implemented a comprehensive immunisation schedule. However, there is disagreement about the level of immunisation coverage in the country and few studies document the immunisation coverage in rural areas. To examine the successful and timely delivery of immunisations to children during the first 2 years of life in a deeply rural part of the Eastern Cape Province of SA. From January to April 2013, a cohort of sequential births (N=470) in the area surrounding Zithulele Hospital in the OR Tambo District of the Eastern Cape was recruited and followed up at home at 3, 6, 9, 12 and 24 months post birth, up to May 2015. Immunisation coverage was determined using Road-to-Health cards. The percentages of children with all immunisations up to date at the time of interview were: 48.6% at 3 months, 73.3% at 6 months, 83.9% at 9 months, 73.3% at 12 months and 73.2% at 24 months. Incomplete immunisations were attributed to stock-outs (56%), lack of awareness of the immunisation schedule or of missed immunisations by the mother (16%) and lack of clinic attendance by the mother (19%). Of the mothers who had visited the clinic for baby immunisations, 49.8% had to make multiple visits because of stock-outs. Measles coverage (of at least one dose) was 85.2% at 1 year and 96.3% by 2 years, but 20.6% of babies had not received a second measles dose (due at 18 months) by 2 years. Immunisations were often given late, particularly the 14-week immunisations. Immunisation rates in the rural Eastern Cape are well below government targets and indicate inadequate provision of basic primary care. Stock-outs of basic childhood immunisations are common and are, according to mothers, the main reason for their children's immunisations not being up to date. There is still much work to be done to ensure that the basics of disease prevention are being delivered at rural clinics in the Eastern Cape, despite attempts to re-engineer primary healthcare in SA.


Sternal osteosarcoma in a blue crane (Anthropoides paradiseus).
A previously healthy, adult male blue crane (Anthropoides paradiseus) became peracutely distressed and ataxic. Examination revealed hemoptysis and a large mass associated with the cranial aspect of the sternum (keel). The patient died before treatment could be initiated. Gross necropsy revealed a large, hemorrhagic mass originating from the cranial aspect of the keel and extending into the cranial coelomic cavity. Histopathology confirmed the mass as an osteosarcoma. This is the first known report of an osteosarcoma in any crane species.


Long-Term Treatment With Raltegravir is Associated with Lower Triglycerides and Platelets Count in the Older HIV+ Population: Results from the Ral-Age Study.
Raltegravir (RAL) is considered one of the better-tolerated antiretroviral medications, due to limited side effects and minimal drug-drug interactions. Matherials and Methods: We retrospectively evaluated 96 HIV+, over 60 years old, experienced patients who had switched from any antiretroviral drug to raltegravir-based nuc-sparing or standard nucleoside-backbone regimens. A control group with patients aged under 60 years old was included. The median age of the patients was 66 years (IQR 10.5) (77 M, 19 F); the median time horizon of follow-up was 4 years (IQR 5). HIV-RNA at baseline was undetectable for more than 6 months in most of the patients. Median CD4+ count was 453 cells/mmc (IQR 379). 49 patients had AIDS history. All the patients were assuming concomitant medications. No adverse effect attributed to the use of raltegravir was reported in the medical records. Only 2 patients presented virological failure, whereas viremic blips were observed in 10 patients. After switching to RAL-containing regimens triglycerides values showed a statistically significant reduction from a median value of 172 (IQR 105.5) mg/dl to 129 mg/dl (IQR 73) (p=0,0001). Switching to a standard regimens was associated with a marked reduction of triglycerides. Cholesterol levels were reduced at the time of follow-up (T2) but no significant modifications were observed when patients which had introduced drugs to treat dislypidemia were removed from the analysis; in contrast, triglycerides reduction was also confirmed in this sub-group. Patients presented higher levels of CD4+ at T2 and reduced platelet count [from 230 300/mmc (SD 123 527) to 197 125/mmc (SD 66 377), p=0,04]. Similar trends were observed in younger patients. RAL-containing regimens are safe and highly effective in the older population. RALtreatment is associated with the reduction of triglycerides and platelets count in the older population.


Anthropogenic disturbance reduces seed-dispersal services for myrmecochorous plants in the Brazilian Caatinga.
Anthropogenic disturbance can have important indirect effects on ecosystems by disrupting species interactions. Here we examine the effects of anthropogenic disturbance on distance dispersal by ants for the diaspores of myrmecochorous Euphorbiaceae in Brazilian Caatinga. Rates of diaspore removal and distances removed of Croton sonderianus and Jatropha mollissima were observed at 24 sites ranging from low to very high disturbance (primarily grazing by livestock, hunting and firewood collection). Despite a large number of seed-disperser ant species, there were only two species providing high-quality distance-dispersal services, Dinoponera quadriceps (40% of all observed seed removals) and Ectatomma muticum (33%). D. quadriceps was responsible for 97% of all removals >2 m, and 100% of all removals >5 m. Removal rates did not vary with disturbance for C. sonderianus (small elaiosome), but declined with increasing disturbance for J. mollissima (large elaiosome). The number of removals by Ectatomma was highest at intermediate levels of disturbance, whereas those by Dinoponera decreased systematically with increasing levels of disturbance. Mean dispersal distance was four times higher at sites experiencing low disturbance, where removals >5 m represented a third of all removal events, compared with very highly disturbed sites, where no removals >5 m were observed. Despite high overall diversity there is very limited functional redundancy in disperser ant species, resulting in low disperser resilience in relation to disturbance. This is likely to have important implications for recruitment by myrmecochorous plants, and therefore on vegetation composition and structure, at sites subject to high anthropogenic disturbance.


Controlled tests of fenbendazole against migrating Strongylus vulgaris in ponies.
Sixteen pony foals were reared worm-free and inoculated with Strongylus vulgaris. On day 7 after inoculation, 12 ponies were given a fenbendazole 10% suspension at dose rate of 50 mg/kg of body weight by stomach tube. On day 8 after inoculation, 8 of these ponies were given the 2nd treatment of the anthelmintic and on day 9, 4 of these ponies were given the 3rd treatment. (The other 4 of the 16 ponies were given only tap water, as controls.) The ponies were necropsied at death or on day 28 after inoculation. Fenbendazole was effective in minimizing the appearance of clinical signs associated with acute arteritis and was highly efficacious in eliminating early 4th-stage S vulgaris larvae in ponies treated for 3 consecutive days (ie, days 7, 8, and 9). After administration of the anthelmintic, clinical signs of toxicosis were not observed.


Fluid resuscitation: past, present, and the future.
Hemorrhage remains a major cause of preventable death following both civilian and military trauma. The goals of resuscitation in the face of hemorrhagic shock are restoring end-organ perfusion and maintaining tissue oxygenation while attempting definitive control of bleeding. However, if not performed properly, resuscitation can actually exacerbate cellular injury caused by hemorrhagic shock, and the type of fluid used for resuscitation plays an important role in this injury pattern. This article reviews the historical development and scientific underpinnings of modern resuscitation techniques. We summarized data from a number of studies to illustrate the differential effects of commonly used resuscitation fluids, including isotonic crystalloids, natural and artificial colloids, hypertonic and hyperoncotic solutions, and artificial oxygen carriers, on cellular injury and how these relate to clinical practice. The data reveal that a uniformly safe, effective, and practical resuscitation fluid when blood products are unavailable and direct hemorrhage control is delayed has been elusive. Yet, it is logical to prevent this cellular injury through wiser resuscitation strategies than attempting immunomodulation after the damage has already occurred. Thus, we describe how some novel resuscitation strategies aimed at preventing or ameliorating cellular injury may become clinically available in the future.


Potential for bias in case-crossover studies with shared exposures analyzed using SAS.
The case-crossover method is an efficient study design for evaluating associations between transient exposures and the onset of acute events. In one common implementation of this design, odds ratios are estimated using conditional logistic or stratified Cox proportional hazards models, with data stratified on each individual event. In environmental epidemiology, where aggregate time-series data are often used, combining strata with identical exposure histories may be computationally convenient. However, when the SAS software package (SAS Institute Inc., Cary, North Carolina) is used for analysis, users can obtain biased results if care is not taken to properly account for multiple cases observed at the same time. The authors show that fitting a stratified Cox model with the "Breslow" option for handling tied failure times (i.e., ties = Breslow) provides unbiased health-effects estimates in case-crossover studies with shared exposures. The authors' simulations showed that using conditional logistic regression-or equivalently a stratified Cox model with the "ties = discrete" option-in this setting leads to health-effect estimates which can be biased away from the null hypothesis of no association by 22%-39%, even for small simulated relative risks. All methods tested by the authors yielded unbiased results under a simulated scenario with a relative risk of 1.0. This potential bias does not arise in R (R Foundation for Statistical Computing, Vienna, Austria) or Stata (Stata Corporation, College Station, Texas).


Can your children drive you to drink? Stress and parenting in adults interacting with children with ADHD.
Several publications in the psychological literature support the theory that children are a major source of stress for their parents. Not surprisingly, parents of children with behavior problems--particularly children with attention deficit hyperactivity disorder (ADHD)--experience highly elevated levels of daily child-rearing stresses. Children with ADHD disregard parental requests, commands, and rules; fight with siblings; disturb neighbors; and have frequent negative encounters with schoolteachers and principals. Although may investigations have dealt with parenting stress caused by disruptive children, only a handful of studies have addressed the question of how parents cope with this stress. Those findings are presented, including a series of studies assessing parental distress and alcohol consumption among parents of normal children and ADHD children after the parents interacted with either normal- or deviant-behaving children. Those studies strongly support the assumption that the deviant child behaviors that represent major chronic interpersonal stressors for parents of ADHD children are associated with increased parental alcohol consumption. Studies also have demonstrated that parenting hassles may result in increased alcohol consumption in parents of "normal" children. Given these findings, the stress associated with parenting and its influence on parental alcohol consumption should occupy a salient position among the variables that are examined in the study of stress and alcohol problems.


[New approaches in correcting disorders of higher integrative brain functions in the pharmacotherapy of arterial hypertension with propranolol].
In experiments on rats it is found that propranolol in a dose of 2 mg/kg has a negative effect on higher integrative functions of the brain. Nootropics--pyracetam (200 mg/kg), AKF-94 (20 mg/kg), PIR-87-6-O (50 mg/kg) and actoprotector bemityl (40 mg/kg)--normalized orientative-trying behavior, memory, and emotionality of the animals. A possible mechanism of the drug action and prospects of their clinical application are discussed.


Age-related differences in pulmonary and cardiovascular responses to SiO2 nanoparticle inhalation: nanotoxicity has susceptible population.
Epidemiologic studies have revealed that pollution by ambient particulates is associated with respiratory and cardiovascular diseases, particularly in older people. Toxicologic sensitivity of nanoparticles in different ages was investigated for the first time to demonstrate and explain an age-related difference in response to manufactured nanoparticles. Young, adult, and old rats physiologically inhaled air containing aerosol of manufactured SiO2 nanoparticles (24.1 mg/m3; 40 min/day) for four weeks. Changes in serum biomarkers, hemorheologic, pulmonary inflammation, heart injury, and pathology in rats of different ages and their corresponding controls were compared. Inhalation of SiO2 nanoparticles under identical conditions caused pulmonary and cardiovascular alterations in old rats, yet less change in young and adult rats, including pulmonary inflammation, myocardial ischemic damage, atrio-ventricular blockage, and increase in fibrinogen concentration and blood viscosity. Old individuals were more sensitive to nanoparticle exposure than the young and adult rats. The risk of causing pulmonary damages was: old > young > adult The risk of cardiovascular disorder was observed only in old age. Our results suggest that different ages may require different biomarkers for identifying pulmonary toxicity during inhalation of nanoparticles.


Improving digit span assessment of short-term verbal memory.
We measured digit span (DS) in two experiments that used computerized presentation of randomized auditory digits with performance-adapted list length adjustment. A new mean span (MS) metric of DS was developed that showed reduced variance, improved test-retest reliability, and higher correlations with the results of other neuropsychological test results when compared to traditional DS measures. The MS metric also enhanced the sensitivity of forward versus backward span comparisons, enabled the development of normative performance criteria with subdigit precision, and elucidated changes in DS performance with age and education level. Computerized stimulus delivery and improved scoring metrics significantly enhance the precision of DS assessments of short-term verbal memory.


[Occurrence of carbon monoxide, carbon dioxide and nitrogen oxides during the use of gas stoves].
The concentrations of carbon monoxide, carbon dioxide, nitrogen monoxide and nitrogen dioxide arising from gas burning have been measured under experimental and field conditions. In the test room propane, butane and town-gas have been burned, whereas in the apartments investigated only town-gas has been used. The most important influence on the concentration of the four substances arises from the changes in the burning conditions of the flame. Laboratory experiments have been carried out in the test room with open flames and with an aluminum block or a kettle on the flame. The following results have been obtained: (a) for CO the lowest concentration is obtained with open flames irrespective of the type of gas burned. Higher concentrations have been found with aluminum blocks, whereas the highest concentrations were associated with the use of kettles and pots, (b) the experimental conditions have only a small influence on the CO2 concentration, (c) NO concentrations are influenced by the gas type and by the experimental conditions. They are low with kettles but high with open flames, (d) NO2 concentrations are less influenced by the experimental conditions than are NO concentrations. The results of more than 1000 paired determinations of NO2 in kitchen and other rooms are presented. The concentrations which have been measured using diffusion tubes according to Palmes which were exposed for 48 h, were highest in kitchens of dwellings fully equipped with gas devices (heating, cooking, warming water). The mean value of the concentrations was about 50 micrograms/m3, whereas the mean for dwellings without any gas device has been found to be lower than 20 micrograms/m3.


Development and evaluation of addiction treatment programs in Latin America.
The aim of this article is to present a state-of-the-art review of the scientific studies that have evaluated healthcare systems, services and programs for addiction treatment in Latin America. As a secondary aim, this article presents a brief description and analysis of the addiction prevention and treatment resources and programs available in Latin America, based on information from the ATLAS on Substance Use (ATLAS-SU) project led by the WHO. Substance use disorders (SUDs) are among the main causes associated with global burden of disease. Around the world, many initiatives have been proposed to promote policies to reduce substance use and reduce the impact of SUD, including integrating treatments into healthcare systems, increasing access to treatment programs and impacting outcome measures. In Latin America, multiple efforts have been implemented to improve addiction services and programs, although little is known about the impact they have generated. International studies report the availability of strategies and public inicitatives on prevention and treatment of addiction in Latin America. These studies also report established networks of public and private services that include prevention and detoxification programs, outpatient and residential treatment, and also social reintegration initiatives. However, despite these advances, information on the evaluation of the progress, results and impact of these programs is limited.


Self-rated health compared with objectively measured health status as a tool for mortality risk screening in older adults: 10-year follow-up of the Bambuí Cohort Study of Aging.
Interest in self-rated health (SRH) as a tool for use in disease and mortality risk screening is increasing. The authors assessed the discriminatory ability of baseline SRH to predict 10-year mortality rates compared with objectively measured health status. Principal component analysis was used to create a health score that included systolic blood pressure, presence of diabetes mellitus, body mass index, electrocardiographic parameters, B-type natriuretic peptide, and other biochemical and hematologic measures. From 1997 to 2007, a total of 474 of the 1,388 baseline participants died and 81 were lost to follow-up, yielding 11,833 person-years of observation. The adjusted hazard ratio for death was 1.74 (95% confidence interval (CI): 1.32, 2.29) for persons reporting poor health versus those reporting good health. When combined with age and sex, SRH had a C statistic to predict death equal to 0.69 (95% CI: 0.67, 0.71), which was comparable to that of the inclusive health score (C = 0.69, 95% CI: 0.67, 0.72). The addition of other parameters, such as lifestyle, physical functioning, mental symptoms, and physical symptoms, had little effect on these 2 predictive models (C = 0.71 (95% CI: 0.69, 0.73) and C = 0.71 (95% CI: 0.69, 0.74), respectively). The abilities of the SRH and the health score models to predict death decreased in parallel fashion over time. These results suggest that older adults who report poor health warrant particular attention as persons who have accumulated biologic markers of disease.


Combined Conjunctival Limbal Autografts and Living-Related Conjunctival Limbal Allografts for Severe Unilateral Ocular Surface Failure.
To describe the technique and present 2 cases of a combined conjunctival limbal autograft (CLAU) and living-related conjunctival limbal allograft (lr-CLAL) procedure for treatment of severe unilateral ocular surface failure. Interventional case series of 2 eyes of 2 patients sustaining severe thermal/chemical injuries from firework explosions. They both underwent the combined CLAU/lr-CLAL procedure followed by penetrating keratoplasty. Systemic immunosuppression consisted of oral tacrolimus and mycophenolate mofetil. Preoperative vision was counting fingers for both patients, whereas visual acuity at last follow-up ranged between 20/40 and 20/50. Both patients maintained a stable surface at last follow-up without any episodes of rejection. Patients tolerated systemic immunosuppression well without any persistent adverse reactions. Certain etiologies of limbal stem cell deficiency also lead to significant conjunctival (and goblet cell) deficiency. Combined CLAU and lr-CLAL procedures maximize the amount of healthy limbal stem cells with conjunctiva while also minimizing the antigenic burden as all transplanted tissue potentially can be a complete (or near-complete), compatible HLA and crossmatch.


Humans actively sample evidence to support prior beliefs.
No one likes to be wrong. Previous research has shown that participants may underweight information incompatible with previous choices, a phenomenon called confirmation bias. In this paper, we argue that a similar bias exists in the way information is actively sought. We investigate how choice influences information gathering using a perceptual choice task and find that participants sample more information from a previously chosen alternative. Furthermore, the higher the confidence in the initial choice, the more biased information sampling becomes. As a consequence, when faced with the possibility of revising an earlier decision, participants are more likely to stick with their original choice, even when incorrect. Critically, we show that agency controls this phenomenon. The effect disappears in a fixed sampling condition where presentation of evidence is controlled by the experimenter, suggesting that the way in which confirmatory evidence is acquired critically impacts the decision process. These results suggest active information acquisition plays a critical role in the propagation of strongly held beliefs over time.


Early weight loss as a predictor of 3-year weight loss and weight regain in patients with good compliance after sleeve gastrectomy.
Sleeve gastrectomy (SG) is the most common surgery for severe obesity. Patients lose weight post SG and regain some weight in the following years. Early weight loss predicts weight loss after SG. However, etiologies of weight loss and regain after SG remain unclear. To investigate the effects of early weight loss on medium-term weight regain post SG. Two university hospitals in Taiwan. Patients with records within 1 and at 3 years after SG were enrolled retrospectively. Preoperative clinical variables and percentage of total weight loss (%TWL) were analyzed. Weight regain was defined as a weight increase from 1 year postoperatively of >25% of the lost weight. Linear and multiple logistic regression were applied to examine the associations of early weight loss, weight loss, and weight regain. A total of 363 patients were included. Body mass indexes before and 1, 3, 6, 12, and 36 months postoperatively were 40.7 ± 6.8 kg/m2, 36.6 ± 6.2 kg/m2, 33.5 ± 5.8 kg/m2, 30.9 ± 5.5 kg/m2, 28.4 ± 5.2, and 29.3 ± 5.4 kg/m2, respectively. At 3 years after SG, 73 patients (20.1%) had weight regain. In multivariate linear analyses, initial age, waist circumference, type 2 diabetes, and %TWL at 1 or 3 months were associated with either 1-year or 3-year %TWL. Multiple logistic regression revealed %TWL at 3 months to be a predictor for 3-year weight regain after SG (odds ratio, .927; P = .02). Early weight loss predicted weight loss and regain 3 years after SG. Early lifestyle and behavioral interventions are suggested in patients at high risk of poor weight loss and weight regain outcomes after SG.


Validation of a quantitative food frequency questionnaire for Inuit population in Nunavut, Canada.
Validation of a quantitative food frequency questionnaire (QFFQ) developed specifically for Inuit is necessary to determine its usefulness in assessing dietary intake and adequacy and in identifying dietary risk factors for chronic disease in this population. Seventy-five randomly selected Inuit adults in Nunavut, Canada, were recruited. Mean daily intake of nutrients from one to three 24-h recalls was used as the reference to measure QFFQ validity. Crude and energy-adjusted Spearman rank correlations (ρ), cross classification and weighted kappa were computed as measures of concordance. Bland-Altman plotting was used for additional assessment. Excluding four participants with daily energy intake of >25.1 MJ, 71 participants were included in the analysis. For all nutrients, mean daily intake from the QFFQ was higher than the recall. ρ's for macronutrients were in the range 0.71 for carbohydrate to 0.25 for protein. The best ρ amongst micronutrients was observed for vitamin C (0.66). Overall correlation between the two dietary tools improved after correction for within-person variance (from 0.46 to 0.49), although adjusting for energy did not improve the overall coefficient. When nutrient intakes were categorised into quartiles, the QFFQ and 24-h recalls indicated relative agreement proportion (same or adjacent quartiles) of 83% for energy, 94% for total sugar, 83% for macronutrients and 77% for micronutrients. Bland-Altman plots showed a tendency for increased scatter of the differences in nutrients at higher intakes. The QFFQ developed is valid and can be used to assess usual dietary intake and dietary adequacy, determine the contribution of foods to specific nutrient intakes, and identify dietary risk factors for chronic disease amongst this population.


Coding regions affect mRNA stability in human cells.
A new paradigm has emerged that coding regions can regulate mRNA stability in model organisms. Here, due to differences in cognate tRNA abundance, synonymous codons are translated at different speeds, and slow codons then stimulate mRNA decay. To ask if this phenomenon also occurs in humans, we isolated RNA stability effects due to coding regions using the human ORFeome collection. We find that many open reading frame (ORF) characteristics, such as length and secondary structure, fail to provide explanations for how coding regions alter mRNA stability, and, instead, that the ORF relies on translation to impact mRNA stability. Consistent with what has been seen in other organisms, codon use is related to the effects of ORFs on transcript stability. Importantly, we found instability-associated codons have longer A-site dwell times, suggesting for the first time in humans a connection between elongation speed and mRNA decay. Thus, we propose that codon usage alters decoding speeds and so affects human mRNA stability.


Adherence to colposcopy among women with HIV infection.
In the general population, nonadherence to the recommendation to have colposcopy in women with abnormal cytologic smears is estimated at 30% to 80%, but studies have failed to identify consistent risk factors for nonadherence. The purpose of this analysis is to assess adherence to colposcopy in a subset of participants in the Women's Interagency HIV Study (WIHS), an ongoing multisite longitudinal study of HIV infection in women in the United States and determine factors associated with nonadherence. Identification of such predictors would be useful in designing strategies to improve adherence in this group. Adherence to colposcopy was examined in a cohort of 462 women with, or at risk for, HIV infection with abnormal cervical cytology on entry into WIHS. Adherence was defined as having colposcopy done within 6 months of an abnormal cytology result. Overall adherence to colposcopy was 65% (302 of 462). A multivariate logistic regression model revealed that the odds of adherence were significantly lower for the women who were HIV-infected (p = .011), current crack/cocaine users (p = .040), ever too ill to get medical care (p = .033), not recruited by WIHS study staff (p = .004), and less concerned about the care of their children (p = .037). Among HIV-seropositive women, low CD4 counts, high viral loads, and presence of AIDS-defining illness were not predictive of nonadherence. Adherence to colposcopy among WIHS participants was at the upper limit of the reported range in the United States. Chemical dependency and domestic violence may negatively impact on colposcopy adherence whereas supportive study personnel, having health insurance, and concerns about raising one's children appear to be motivators for adherence to colposcopy in this study. HIV infection was a risk factor for nonadherence, but markers of advanced disease were not predictive of nonadherence.


Organic chloramines in drinking water: An assessment of formation, stability, reactivity and risk.
Although organic chloramines are known to form during the disinfection of drinking water with chlorine, little information is currently available on their occurrence or toxicity. In a recent in vitro study, some organic chloramines (e.g. N-chloroglycine) were found to be cytotoxic and genotoxic even at micromolar concentrations. In this paper, the formation and stability of 21 different organic chloramines, from chlorination of simple amines and amino acids, were studied, and the competition between 20 amino acids during chlorination was also investigated. For comparison, chlorination of two amides was also conducted. The formation and degradation of selected organic chloramines were measured using either direct UV spectroscopic or colorimetric detection. Although cysteine, methionine and tryptophan were the most reactive amino acids towards chlorination, they did not form organic chloramines at the chlorine to precursor molar ratios that were tested. Only 6 out of the 21 organic chloramines formed had a half-life of more than 3 h, although this group included all organic chloramines formed from amines. A health risk assessment relating stability and reactivity data from this study to toxicity and precursor abundance data from the literature indicated that only N-chloroglycine is likely to be of concern due to its stability, toxicity and abundance in water. However, given the stability of organic chloramines formed from amines, more information about the toxicity and precursor abundance for these chloramines is desirable.


Drug-induced liver injury and drug development: industry perspective.
Despite intensive ongoing research, drug-induced live injury (DILI) remains a serious issue for care providers and patients, and has been a major cause of drug withdrawal and non-approval by regulatory authorities in the past 50 years. Consequently, DILI remains a major concern for the pharmaceutical industry and a leading cause for attrition during drug development. In most instances, severe DILI is an uncommon idiosyncratic reaction, which typically does not present during preclinical phases or early clinical phases of drug development. In the majority of cases, drugs that caused severe DILI in humans have not shown clear and consistent hepatotoxic signals in preclinical assessment including animal studies, cell cultures, or other methods. Despite intensive efforts to develop better biomarkers that would help in predicting DILI risk in earlier phases of drug development, such biomarkers are currently not supported by sufficient evidence and are not yet available for routine use by drug makers. Due to the lack of effective and accurate methods for prediction of idiosyncratic DILI during preclinical phases of drug development, different drug makers have adopted different approaches, which are often not supported by strong systematic evidence. Based on growing experience, it is becoming increasingly evident that milder forms of liver injury occurring during clinical development, when assessed correctly, may significantly enhance our ability to predict the drug's potential to cause more severe liver injury postmarketing. Strategies based on this concept have been adopted by many drug makers, and are being increasingly implemented during drug development. Meticulous causality assessment of individual hepatic cases and adherence to strict hepatic discontinuation rules are critical components of this approach and have to rely on thorough clinical evaluation and occasionally on assessment by liver experts experienced with DILI and drug development.


[Therapeutic effectiveness of intra-knee-articular injection of platelet-rich plasma on knee articular cartilage degeneration].
Platelet-rich plasma (PRP) can enhance the chondrocyte proliferation and repair of cartilage defects. To explore the safety and efficacy of intra-knee-articular injection of PRP to treat knee articular cartilage degeneration by comparing with injecting sodium hyaluronate (SH). Thirty consecutive patients (30 knees) with knee articular cartilage degeneration were selected between January 2010 and June 2010. According to different injections, 30 patients were randomly divided into PRP group (test group, n = 15) and SH group (control group, n = 15). There was no significant difference in gender, age, body mass index, and Kellgren-Lawrence grade between 2 groups (P > 0.05). Test group received 3.5 mL of PRP intra-knee-articular injections while control group received 2 mL of SH during the same time period. Both treatments were administered in series of 3 intra-knee-articular injections at 3-week intervals. Then, adverse reactions were recorded. International Knee Documentation Committee (IKDC) score, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score, and Lequesne index were used for evaluation of treatment results. The patients of 2 groups were followed up 6 months. There were significant differences in IKDC score, WOMAC score, and Lequesne index between pre- and post-injection in 2 groups (P < 0.05); no significant difference was found between different time points (3, 4, and 6 months) in test group (P > 0.05), while significant differences were found between the postoperative 6th month and the postoperative 3rd and 4th months in control group (P < 0.05). There was no significant difference in IKDC score, WOMAC score, and Lequesne index between 2 groups within 4 months (P > 0.05), but the effectiveness of test group was significantly better than that of control group at 6 months after injection (P < 0.05). Adverse reactions occurred in 12 patients (31 injections) of test group and in 12 patients (30 injections) of control group. No significant difference in onset time, termination time, and duration of adverse reactions were found between 2 groups (P > 0.05). Intra-knee-articular injection of PRP to treat knee articular cartilage degeneration is safe, which can alleviate symptoms of pain and swelling and improve the quality of life of patients; however, further data of large samples and long-term follow-up are needed to confirm the safety and effectiveness.


Insulin-stimulated endothelial nitric oxide release is calcium independent and mediated via protein kinase B.
Insulin exerts a vasodilator effect by stimulating endothelial nitric oxide (NO) production. Studies in cultured cells suggest that insulin might activate endothelial nitric oxide synthase (eNOS) by an atypical, calcium-independent mechanism. This study investigates the mechanism of insulin-stimulated endothelial NO production in intact aortic wall. Real time fluorescence imaging with 4,5-diaminofluorescin diacetate (DAF-2 DA) or 4-amino-5-methylamino-2',7'-difluorofluorescein diacetate (DAF-FM DA) and FURA 2-AM was used to simultaneously visualise NO and intracellular calcium concentrations at multiple locations in the endothelium and vascular smooth muscle of isolated rat and mouse aorta after exposure to insulin. Inhibitors of intracellular insulin signalling were used to determine the pathway for insulin-stimulated NO production. Unlike acetylcholine, which stimulated endothelial NO production with a typical increase in free intracellular calcium, insulin (10(-8) to 10(-6)M) stimulated endothelial NO production without elevating intracellular calcium levels. Insulin-stimulated NO production was concentration dependent and detected within 30s of application. Peak increases in NO occurred between 60 and 120 s and declined slowly thereafter. Separate measurements of NO production by fluorescence of 2,3-diaminonaphthalene (DAN) noted that selective inhibitors of phosphatidylinositol 3-kinase (PI3K) and protein kinase B (PKB) inhibited insulin-stimulated NO production, whereas these inhibitors alone did not alter NO production or acetylcholine-stimulated NO production. Insulin-stimulated NO production by endothelium is an acute calcium-independent effect mediated via the PI3K-PKB signalling pathway.


Oral Tolerance Induction by Bothrops jararaca Venom in a Murine Model and Cross-Reactivity with Toxins of Other Snake Venoms.
Oral tolerance is defined as a specific suppression of cellular and humoral immune responses to a particular antigen through prior oral administration of an antigen. It has unique immunological importance since it is a natural and continuous event driven by external antigens. It is characterized by low levels of IgG in the serum of animals after immunization with the antigen. There is no report of induction of oral tolerance to Bothrops jararaca venom. Here, we induced oral tolerance to B. jararaca venom in BALB/c mice and evaluated the specific tolerance and cross-reactivity with the toxins of other Bothrops species after immunization with the snake venoms adsorbed to/encapsulated in nanostructured SBA-15 silica. Animals that received a high dose of B. jararaca venom (1.8 mg) orally responded by showing antibody titers similar to those of immunized animals. On the other hand, mice tolerized orally with three doses of 1 µg of B. jararaca venom showed low antibody titers. In animals that received a low dose of B. jararaca venom and were immunized with B. atrox or B. jararacussu venom, tolerance was null or only partial. Immunoblot analysis against the venom of different Bothrops species provided details about the main tolerogenic epitopes and clearly showed a difference compared to antiserum of immunized animals.


Parsimonious model for blood glucose level monitoring in type 2 diabetes patients.
To establish the parsimonious model for blood glucose monitoring in patients with type 2 diabetes receiving oral hypoglycemic agent treatment. One hundred and fifty-nine adult Chinese type 2 diabetes patients were randomized to receive rapid-acting or sustained-release gliclazide therapy for 12 weeks. Their blood glucose levels were measured at 10 time points in a 24 h period before and after treatment, and the 24 h mean blood glucose levels were measured. Contribution of blood glucose levels to the mean blood glucose level and HbA1c was assessed by multiple regression analysis. The correlation coefficients of blood glucose level measured at 10 time points to the daily MBG were 0.58-0.74 and 0.59-0.79, respectively, before and after treatment (P<0.0001). The multiple stepwise regression analysis showed that the blood glucose levels measured at 6 of the 10 time points could explain 95% and 97% of the changes in MBG before and after treatment. The three blood glucose levels, which were measured at fasting, 2 h after breakfast and before dinner, of the 10 time points could explain 84% and 86% of the changes in MBG before and after treatment, but could only explain 36% and 26% of the changes in HbA1c before and after treatment, and they had a poorer correlation with the HbA1c than with the 24 h MBG. The blood glucose levels measured at fasting, 2 h after breakfast and before dinner truly reflected the change 24 h blood glucose level, suggesting that they are appropriate for the self-monitoring of blood glucose levels in diabetes patients receiving oral anti-diabetes therapy.


Operculoinsular cortectomy for refractory epilepsy. Part 1: Is it effective?
Patients with refractory epilepsy of operculoinsular origin are often denied potentially effective surgical treatment with operculoinsular cortectomy (also termed operculoinsulectomy) because of feared complications and the paucity of surgical series with a significant number of cases documenting seizure control outcome. The goal of this study was to document seizure control outcome after operculoinsular cortectomy in a group of patients investigated and treated by an epilepsy team with 20 years of experience with this specific technique. Clinical, imaging, surgical, and seizure control outcome data of all patients who underwent surgery for refractory epilepsy requiring an operculoinsular cortectomy were retrospectively reviewed. Tumors and progressive encephalitis cases were excluded. Descriptive and uni- and multivariate analyses were done to determine seizure control outcome and predictors. Forty-three patients with 44 operculoinsular cortectomies were studied. Kaplan-Meier estimates of complete seizure freedom (first seizure recurrence excluding auras) for years 0.5, 1, 2, and 5 were 70.2%, 70.2%, 65.0%, and 65.0%, respectively. With patients with more than 1 year of follow-up, seizure control outcome Engel class I was achieved in 76.9% (mean follow-up duration 5.8 years; range 1.25-20 years). With multivariate analysis, unfavorable seizure outcome predictors were frontal lobe-like seizure semiology, shorter duration of epilepsy, and the use of intracranial electrodes for invasive monitoring. Suspected causes of recurrent seizures were sparing of the language cortex part of the focus, subtotal resection of cortical dysplasia/polymicrogyria, bilateral epilepsy, and residual epileptic cortex with normal preoperative MRI studies (insula, frontal lobe, posterior parieto-temporal, orbitofrontal). The surgical treatment of operculoinsular refractory epilepsy is as effective as epilepsy surgeries in other brain areas. These patients should be referred to centers with appropriate experience. A frontal lobe-like seizure semiology should command more sampling with invasive monitoring. Recordings with intracranial electrodes are not always required if the noninvasive investigation is conclusive. The complete resection of the epileptic zone is crucial to achieve good seizure control outcome.


Investigation of MicroRNA-134 as a Target against Seizures and SUDEP in a Mouse Model of Dravet Syndrome.
Dravet syndrome (DS) is a catastrophic form of pediatric epilepsy mainly caused by noninherited mutations in the SCN1A gene. DS patients suffer severe and life-threatening focal and generalized seizures which are often refractory to available anti-seizure medication. Antisense oligonucleotides (ASOs) based approaches may offer treatment opportunities in DS. MicroRNAs are short noncoding RNAs that play a key role in brain structure and function by post-transcriptionally regulating gene expression, including ion channels. Inhibiting miRNA-134 (miR-134) using an antimiR ASO (Ant-134) has been shown to reduce evoked seizures in juvenile and adult mice and reduce epilepsy development in models of focal epilepsy. The present study investigated the levels of miR-134 and whether Ant-134 could protect against hyperthermia-induced seizures, spontaneous seizures and mortality (SUDEP) in F1.Scn1a(+/-)tm1kea mice. At P17, animals were intracerebroventricular injected with 0.1-1 nmol of Ant-134 and subject to a hyperthermia challenge at postnatal day (P)18. A second cohort of P21 F1.Scn1a(+/-)tm1kea mice received Ant-134 and were followed by video and EEG monitoring until P28 to track the incidence of spontaneous seizures and SUDEP. Hippocampal and cortical levels of miR-134 were similar between wild-type (WT) and F1.Scn1a(+/-)tm1kea mice. Moreover, Ant-134 had no effect on hyperthermia-induced seizures, spontaneous seizures and SUDEP incidence were unchanged in Ant-134-treated DS mice. These findings suggest that targeting miR-134 does not have therapeutic applications in DS.


Epidermal growth factor negatively regulates chondrogenesis of mesenchymal cells by modulating the protein kinase C-alpha, Erk-1, and p38 MAPK signaling pathways.
During limb development, epithelial cells in the apical ectodermal ridge keep the underlying mesenchymal cells in a proliferative state preventing differentiation by secreting signaling molecules such as epidermal growth factor (EGF). We investigated the molecular mechanism of the EGF effect on the regulation of micromass culture-induced chondrogenesis of chick limb bud mesenchymal cells as a model system. We found that expression and tyrosine phosphorylation of the EGF receptor was increased transiently during chondrogenesis. Exogenous EGF inhibited chondrogenic differentiation of mesenchymal cells, and this effect was reversed by the EGF receptor inhibitor AG1478. EGF treatment also inhibited the expression and activation of protein kinase C-alpha, whereas it activated Erk-1 and inhibited p38 mitogen-activated protein kinase, all of which appeared to be involved in the EGF-induced inhibition of chondrogenesis. Stimulation of the EGF receptor blocked precartilage condensation and altered the expression of cell adhesion molecules such as N-cadherin and integrins alpha(5) and beta(1). All these EGF effects were reversible by AG1478. The data indicate that EGF negatively regulate chondrogenesis of chick limb bud mesenchymal cells by inhibiting precartilage condensation and by modulating signaling pathways including those of protein kinase C-alpha, Erk-1, and p38 mitogen-activated protein kinase.


Intelligence quotient pattern over age: comparisons among siblings and parent-child pairs.
Comparisons between sibling and parent-child pairs with unrelated control pairs matched for year of birth and parental education were made to determine the relative heritability of the general level of intelligence quotient as opposed to that of the sequential pattern of IQ change over age (3 to 12 years). There was greater similarity among related siblings relative to matched controls for general level than for pattern of IQ over age. Relationships between the IQ's of children and that of their parents as children were not consistent across age.


Prophylactic treatment with miconazole in patients highly predisposed to fungal infection. A placebo-controlled double-blind study.
In a placebo-controlled double-blind study the prophylactic value of oral systemic treatment with the antimycotic agent miconazole was assessed in 30 highly predisposed patients receiving intensive cytostatic chemotherapy because of haematological malignancies. Patients colonized with Candida before treatment were not freed from this micro-organism by miconazole treatment. However, only 3 out of 6 initially non-colonized miconazole-treated patients became colonized during the study, against 10 out of 10 placebo-treated patients (p = 0.036). Seven out of 15 patients in the placebo group developed clinical mycosis, against only two out of 15 in the miconazole group. The miconazole-treated patients remained clinically free of mycosis for 252 out of 264 treatment days, while the placebo-treated patients remained free of mycosis for only 263 out or 338 treatment days (p = 0.0001). The results indicate that systemic miconazole treatment protects highly predisposed patients from colonization with Candida and prevents or postpones clinically established candidosis.


Characterizing the phenotype and genotype of a family with occult macular dystrophy.
To characterize the phenotype of a white patient with occult macular dystrophy (OMD) and her clinically unaffected family members and to determine whether similar mutations were present in the RP1L1 gene in this family. Occult macular dystrophy is a rare macular dystrophy with central cone dysfunction hidden behind a normal fundus appearance that has been attributed to a mutation in the retinitis pigmentosa 1-like 1 (RP1L1) gene in 4 Japanese families. In this observational cross-sectional study of 1 white family with OMD, patients meeting the clinical criteria for OMD and their family members were evaluated by use of multifocal electroretinography, the Farnsworth D-15 color vision test, automated perimetry, spectral-domain optical coherence tomography (SD-OCT), fundus autofluorescence, and fundus photography. Fluorescein angiography was performed only on the proband. Members of this family were screened for genetic mutations in the RP1L1 gene. In the family studied, the clinically affected proband was noted to have loss of the foveal outer segments and absence of bowing of the inner segment/outer segment junction on SD-OCT scans. In addition, 1 clinically unaffected family member also demonstrated loss of the foveal photoreceptor outer segments and, therefore, decreased bowing of the inner segment/outer segment junction on SD-OCT scans. The fundus autofluorescence images of the eyes of the proband and her family members were normal. Although mutations in the RP1L1 gene have been identified in sporadic and autosomal dominant OMD pedigrees, no mutations in the RP1L1 gene were found in any of the participants. Loss of the outer segments of foveal photoreceptors can be detected and quantified by use of SD-OCT in patients with OMD. Similar findings are present in some clinically unaffected family members and may represent subclinical manifestations of the disease. Although mutations in the RP1L1 gene have been described in several Japanese families with OMD, there were no such mutations in this white family of European descent, which suggests that inherited OMD is a genetically heterogeneous disorder.


Crosstalk between gut microbiota and host lipid metabolism in a mouse model of alcoholic liver injury by chronic baijiu or ethanol feeding.
A growing body of evidence highlights the important role of gut microbiota and host metabolism, particularly for lipid metabolism, in the development and progression of alcoholic liver disease (ALD). However, the effects of fermented alcoholic beverages on gut microbiota and host lipid metabolism remain under-investigated. Moreover, the crosstalk between gut microbiota and host lipid metabolism is still unclear in experimental ALD. Baijiu is a traditional Chinese alcoholic beverage. It contains large amounts of small molecule bioactive compounds in addition to a significant amount of ethanol (EtOH). In this study, we showed that baijiu caused lower degrees of liver injury than pure EtOH as revealed by phenotypic, biochemical and histologic analyses. Furthermore, baijiu and EtOH gavage resulted in different gut microbiota structures. Specifically, the baijiu group had a significantly higher abundance of Ruminococcus, Oscillospira, Mucispirillum, Bilophila, Parabacteroides and Odoribacter and a lower abundance of Helicobacter and Prevotella than that of the EtOH group. Using a targeted metabolomics approach, we also observed a greater than 19% increase of total hepatic free fatty acids (FFAs) after baijiu feeding and a 33% increase of hepatic FFAs after EtOH feeding. Baijiu feeding significantly increased total hepatic mono-unsaturated FAs (MUFAs). In contrast, polyunsaturated fatty acids (PUFAs), MUFAs and saturated FAs were significantly increased by EtOH feeding. Finally, Spearman's rank correlation showed that the increased levels of FFAs (mainly C20 and C22 unsaturated FAs) significantly correlated with key different gut microbiota, including a positive correlation with Desulfovibrio, Maihella, Helicobacter, Acholeplasma, Parasutterella, Prevotella, AF12 and Alistipes, and a negative correlation with Dorea, Olsenella, Adlercreutzia and Akkermansia. Our results suggest that compounds in baijiu attenuated the development of ALD and thus provided supporting evidence that the host-gut microbiota metabolic interactions play an important role in the development of ALD.


The morning after the night before: Alcohol-induced blackouts impair next day recall in sober young adults.
Binge-drinking in adolescents and young adults is a widespread problem, however, an often unreported consequence of binge-drinking behaviour is an alcohol-induced memory blackout (MBO). An MBO is a transient amnesic event resulting from rapid, excessive alcohol consumption. Here, we examine the short-term impact of an alcohol-induced MBO event (testing < 20 hours after blackout) on memory performance in people who have experienced a high volume of MBOs. In addition, we aimed to test the hypothesis that people who experience a high volume of MBOs may have poorer recall than non-blackout controls in either sober or intoxicated states. Three episodic memory paradigms consisting of free recall, serial recall, and depth of encoding tasks, were conducted by a group of alcohol drinkers who had never experienced a memory blackout, and those who reported at least 9 in the preceding 12-months. Studies were completed sober and after alcohol by all participants, and sober but after blackout by the experimental group. Accuracy of recall was assessed with linear mixed effects modelling for all experiments and conditions. Recall rate both before and after alcohol consumption was similar between groups, with poorer recall after drinking alcohol by all participants in all three studies. After blackout, MBO participants showed no significant improvement from their intoxicated state in serial recall and depth of encoding tasks, but an improvement in free recall. Further analysis of these findings revealed that 10 out of 23 participants showed significantly impaired performance after blackout during free recall, extending up to 17 participants in serial recall. In general, alcohol reduced recall rate in both blackout and control participants similarly, but recall following MBO remained poor. Our evidence suggests that alcohol-induced blackouts impair memory functioning the next day, and future research should establish the duration of deficits after an acute alcohol-induced blackout episode.


PERFORMANCE OPTIMIZATION AND INJURY PREVENTION STRATEGIES FOR THE ARMY PHYSICAL FITNESS TEST: TECHNIQUE MATTERS.
The Army Physical Fitness Test (APFT) is a biannual training requirement for all soldiers. The Army has made significant overall fitness gains by developing functional and comprehensive Physical Readiness Training (PRT) programs, but more emphasis on individualized physical fitness test taking technique is warranted in order to optimize performance. The purpose of this clinical commentary is to provide clinicians with several examples of APFT performance enhancement techniques that can potentially be applied not only in the Army, but throughout the military and in the sports community where general fitness assessments are routinely administered. 5.


Retrospective review of 707 cases of spinal cord stimulation: indications and complications.
Appropriate patient selection and minimizing complications are critical for successful spinal cord stimulation (SCS) therapy in managing intractable pain. We thus reviewed electronic medical records of 707 consecutive cases of patients who received SCS therapy in the Cleveland Clinic from 2000 to 2005 with an emphasis on indications and complications. SCS was used to treat complex regional pain syndrome (CRPS) (345 cases), failed back surgery syndrome (235 cases), peripheral vascular disease (20 cases), visceral pain in the chest, abdomen, and pelvis (37 cases), and peripheral neuropathy (70 cases). CRPS and failed back surgery syndrome accounted for 82% of the cases. The implant-to-trial ratio was 75% on average, with the highest for CRPS type 2 (83%) and the lowest for peripheral vascular diseases (65%). The only documented complication associated with SCS trials was lead migration in 5 of 707 patients (0.7%). There were no permanent neurological deficits or deaths as a result of SCS implant or its complications. Hardware-related complications were common (38%) and included lead migration (22.6%), lead connection failure (9.5%), and lead breakage (6%). Revisions or replacements were required in these cases. Biologically related complications included pain at the generator site (12%) and clinical infection (4.5%; 2.5% with positive culture). The rates of infection varied among the different diagnoses with the highest in failed back surgery syndrome (6.3%). Patients with diabetes had an infection rate of 9%, over the 4% in non-diabetics. Infections were managed successfully with explantation and antibiotic therapy without permanent sequela.


Influence of serotonin 3A and 3B receptor genes on clozapine treatment response in schizophrenia.
Earlier results suggest a minor role of variants in the serotonin 3 receptor (HTR3) subunit genes on antipsychotic treatment outcome of schizophrenia patients. In this study, we further investigated the role of the subunits A and B of the HTR3 receptor using 140 schizophrenia patients taking clozapine for 6 months. We have found significant allelic association of clozapine response with three variants in the HTR3A receptor (rs2276302, rs1062613, rs1150226) although only rs1062613 association remained significant after permutations (permutated P=0.041). Moreover, rs2276302 and rs1062613 have shown nominally significant genotypic association. The two haplotypes composed of rs2276302-rs1062613-rs1150226 were also nominally significant. Taken together, our results suggest that variants in the HTR3A receptor gene can play a role in the treatment outcome of clozapine in schizophrenia patients that are refractory or intolerant of typical antipsychotic therapy. Further studies are necessary to confirm the reported associations.


Impact of parental smoking on diabetes, hypertension and the metabolic syndrome in adult men and women in the San Antonio Heart Study.
In the San Antonio Heart Study (SAHS) we investigated the effects of exposure to parental smoking on diabetes, hypertension and the metabolic syndrome in adult offspring aged 25-64 years. In a retrospective cohort study the parental smoking status during childhood, obtained through a postal questionnaire, determined a person's exposure status. Logistic regression models were used to calculate odds ratios for diabetes, hypertension and the metabolic syndrome at the baseline SAHS examination in relation to parental smoking status. All models were adjusted for age, sex, ethnicity, education years, personal smoking status (current, former or never-smoker), BMI and, in the case of diabetes, a family history of diabetes. Of the 2,371 participants who returned the mailing, 44.5, 5.4, 20.0 and 30.1% reported that their father, mother, both or neither parent smoked, respectively. Participants reporting that both parents smoked were 1.60 (95% CI: 0.95-2.69) times more likely to have diabetes, 1.55 (95% CI: 1.05-2.28) times more likely to have hypertension, and 1.46 (95% CI: 1.01-2.10) times more likely to have the metabolic syndrome than participants reporting that neither parent smoked during their childhood. Odds ratios, after limiting the population to younger participants (i.e. <or=50 years) to reduce survivor bias, were 2.53 (95% CI: 1.21-5.31), 1.29 (95% CI: 0.78-2.16), and 1.41 (95% CI: 0.89-2.22) for diabetes, hypertension and the metabolic syndrome, respectively. These results provide evidence that early exposure to parental smoking may be associated with an increased risk of diabetes and perhaps hypertension and the metabolic syndrome.