Challenges in the Diagnosis and Assessment in Patients with Tourette Syndrome and Comorbid Obsessive-Compulsive Disorder.
Tourette syndrome (TS) is characterized by the presence of vocal and motor tics with an onset in childhood. In almost 80% of patients psychiatric comorbidities coexist, particularly, attention deficit/hyperactivity disorder (ADHD), obsessive-compulsive disorder (OCD) or behavior (OCB), depression, anxiety, rage attacks, and self-injurious behaviour (SIB). In this review, we discuss current state of the art regarding diagnosis and assessment of tics and OCD in patients with TS as well as challenges related to differential diagnosis between tics and OCD-related phenomena based on a systematic literature search. While in most cases clinical symptoms can be easily classified as either tics or OCB/OCD, some phenomena lay on the frontier between tics and compulsions/obsessions. For example, compulsions may resemble tics and, vice versa, sequences of motor tics may be misdiagnosed as compulsions. Accordingly, the terms "compulsive tics" and "cognitive tics" have been introduced. The most common and typical OCD symptom in patients with TS are "just right" phenomena, which also may show an overlap with tics, since patients may perform tics repeatedly until this feeling is achieved. Similarly, repetitive behaviors in patients with TS may manifest in a more "tic-like" or a more "OCD-like" type. Furthermore, SIB shows similarities with both tics and OCD. Until today, it is unclear how to classify this symptom best, although from most recent research a closer relationship between SIB and tics is suggested. In this review, in addition, we illustrate differences of the clinical spectrum of OCD in patients with TS compared to those with "pure OCD" without tics. To assess tics, the revised version of the Yale Global Tic Severity Scale (YGTSS-R) should be used, while for the assessment of OCD, the Yale Brown Obsessive Compulsive Disorder Scale (Y-BOCS) is recommended. Finally, we briefly summarize treatment strategies for tics and OCB/OCD in patients with TS.


[Chromatographic mass-spectrometric determination of the air content of styrene, phenol, and naphthalene].
A selective chromatographic mass-spectrometric procedure was developed to determine of air styrene, phenol, and naphthalene in the concentration range of 0.001-0.05 mg/m3, Analysis used preconcentration of the compounds on a solid sorbent, followed by thermal desorption into the capillary column of a chromatograph. Qualitative and quantitative measurements of concentrations were carried out by the characteristics chosen for each compound. The maximum relative measurement error in 1-2-liter air sampling was +/- 23% at a 0.95 significant confidence. The analytic procedure was tested on real objects.


Droplet-based immunoassay on a 'sticky' nanofibrous surface for multiplexed and dual detection of bacteria using smartphones.
We have developed a rapid, sensitive, and specific droplet-based immunoassay for the detection of Escherichia coli and Salmonella within a single-pipetted sample. Polycaprolactone (PCL) electrospun fibers on indium-tin-oxide (ITO) glass provide a sufficient surface to render a non-slip droplet condition, and while the PCL fibers lend a local hydrophilicity (contact angle θ=74°) for sufficient sub-micron particle adhesion, air pockets within the fibers lend an apparent hydrophobicity. Overall, the contact angle of water on this electrospun surface is 119°, and the air pockets cause the droplet to be completely immobile and resistant to movement, protecting it from external vibration. By using both anti-E. coli conjugated, 510 nm diameter green fluorescent particles (480 nm excitation and 520 nm emission) and anti-Salmonella conjugated, 400 nm diameter red fluorescent particles (640 nm excitation and 690 nm emission), we can detect multiple targets in a single droplet. Using appropriate light sources guided by fiber optics, we determined a detection limit of 10(2) CFU mL(-1). Immunoagglutination can be observed under a fluorescence microscope. Fluorescence detection (at the emission wavelength) of immunoagglutination was maximum at 90° from the incident light, while light scattering (at the excitation wavelength) was still present and behaved similarly, indicating the ability of double detection, greatly improving credibility and reproducibility of the assay. A power function (light intensity) simulation of elastic Mie scatter confirmed that both fluorescence and light scattering were present. Due to the size of the fluorescent particles relative to their incident excitation wavelengths, Mie scatter conditions were observed, and fluorescence signals show a similar trend to light scattering signals. Smartphone detection was included for true portable detection, in which the high contact angle pinning of the droplet makes this format re-usable and re-configurable.


Suppression of glypican 3 inhibits growth of hepatocellular carcinoma cells through up-regulation of TGF-β2.
Glypican 3 (GPC3) is a valuable diagnostic marker and a potential therapeutic target in hepatocellular carcinoma (HCC). To evaluate the efficacy of targeting GPC3 at the translational level, we used RNA interference to examine the biologic and molecular effects of GPC3 suppression in HCC cells in vitro and in vivo. Transfection of Huh7 and HepG2 cells with GPC3-specific small interfering RNA (siRNA) inhibited cell proliferation (P < .001) together with cell cycle arrest at the G(1) phase, down-regulation of antiapoptotic protein (Bcl-2, Bcl-xL, and Mcl-1), and replicative senescence. Gene expression analysis revealed that GPC3 suppression significantly correlated with transforming growth factor beta receptor (TGFBR) pathway (P = 4.57e-5) and upregulated TGF-β2 at both RNA and protein levels. The effects of GPC3 suppression by siRNA can be recapitulated by addition of human recombinant TGF-β2 to HCC cells in culture, suggesting the possible involvement of TGF-β2 in growth inhibition of HCC cells. Cotransfection of siRNA-GPC3 with siRNA-TGF-β2 partially attenuated the effects of GPC3 suppression on cell proliferation, cell cycle progression, apoptosis, and replicative senescence, confirming the involvement of TGF-β2 in siRNA-GPC3-mediated growth suppression. In vivo, GPC3 suppression significantly inhibited the growth of orthotopic xenografts of Huh7 and HepG2 cells (P < .05), accompanied by increased TGF-β2 expression, reduced cell proliferation (observed by proliferating cell nuclear antigen staining), and enhanced apoptosis (by TUNEL staining). In conclusion, molecular targeting of GPC3 at the translational level offers an effective option for the clinical management of GPC3-positive HCC patients.


Deep eutectic solvents: syntheses, properties and applications.
Within the framework of green chemistry, solvents occupy a strategic place. To be qualified as a green medium, these solvents have to meet different criteria such as availability, non-toxicity, biodegradability, recyclability, flammability, and low price among others. Up to now, the number of available green solvents are rather limited. Here we wish to discuss a new family of ionic fluids, so-called Deep Eutectic Solvents (DES), that are now rapidly emerging in the current literature. A DES is a fluid generally composed of two or three cheap and safe components that are capable of self-association, often through hydrogen bond interactions, to form a eutectic mixture with a melting point lower than that of each individual component. DESs are generally liquid at temperatures lower than 100 °C. These DESs exhibit similar physico-chemical properties to the traditionally used ionic liquids, while being much cheaper and environmentally friendlier. Owing to these remarkable advantages, DESs are now of growing interest in many fields of research. In this review, we report the major contributions of DESs in catalysis, organic synthesis, dissolution and extraction processes, electrochemistry and material chemistry. All works discussed in this review aim at demonstrating that DESs not only allow the design of eco-efficient processes but also open a straightforward access to new chemicals and materials.


Early diagnosis of pancreatic necrosis based on perfusion CT to predict the severity of acute pancreatitis.
Perfusion CT can diagnose pancreatic necrosis in early stage of severe acute pancreatitis, accurately. However, no study to date has examined whether early diagnosis of pancreatic necrosis is useful in predicting persistent organ failure (POF). We performed a multi-center prospective observational cohort study to investigate whether perfusion CT can predict the development of POF in the early stage of AP, based on early diagnosis of the development of pancreatic necrosis (PN). From 2009 to 2012, we examined patients showing potential early signs of severe AP (n = 78) on admission. Diagnoses for the development of PN were made prospectively by on-site physicians on the admission based on perfusion CT (diagnosis 1). Blinded retrospective reviews were performed by radiologists A and B, having 8 and 13 years of experience as radiologists (diagnosis 2 and 3), respectively. Positive diagnosis for the development of PN were assumed equivalent to positive predictions for the development of POF. We then calculated the area under the curve (AUC) of the receiver operating characteristic for POF predictions. Fourteen (17.9%) and 23 patients (29.5%) developed PN and POF, respectively. For diagnoses 1, 2, and 3, AUCs for POF predictions were 74, 68, and 73, respectively. Perfusion CT diagnoses pancreatic necrosis and on that basis predicts the development of POF; http://www.umin.ac.jp/ctr/index-j.htm,UMIN000001926 .


One session of exercise or endurance training does not influence serum levels of irisin in rats.
Irisin induces the browning of adipose tissue. The goal of this study was to investigate the influence of acute exercise in untrained and trained rats and endurance training on FNDC5 mRNA and irisin levels in white and red skeletal muscle and serum. Rats (n=60) were randomly divided into two groups: untrained and trained (subjected to 6-week endurance training with increasing load). Subgroups of rats from each group were sacrificed before (controls), immediately after, or 3 hours following acute exercise with the same work load. Muscle samples (red and white) and serum were collected. FNDC5 mRNA was evaluated using RT-PCR. Irisin levels were measured using an immunoenzymatic method. Muscle FNDC5 mRNA decreased immediately after acute exercise compared with baseline levels, but not in red muscle in trained rats. Atrend toward a return to baseline appeared 3 hours after the exercise, but only in white muscle in untrained group. Irisin protein levels increased after acute exercise in red muscle 3 hours post-exercise compared with samples taken immediately after exercise, and decreased 3 hours post-exercise compared to pre-exercise level in white muscles. FNDC5 mRNA did not change following training, whereas irisin protein levels increased in red muscle and decreased in white muscle. Serum irisin levels remained unchanged following acute exercise and training. We concluded that changes in irisin mRNA and protein levels in rat muscle after acute exercise are limited and depend on training status and the muscle type. Irisin serum levels remained stable after acute exercise or endurance training.


Respiratory effects in relation to estimated tar exposure from current and cumulative cigarette consumption.
Relationships between estimated "tar" exposure from current and past cigarette consumption, were related to respiratory symptoms and function during the seventh survey (1981-1983) of the Tucson epidemiologic study of airways obstructive diseases. Smokers (n = 582; 280 males and 302 females) and exsmokers (n = 621; 345 males and 276 females), answered detailed questions on current and past smoking, and performed flow-volume maneuvers. Cough and phlegm were significantly associated with estimated "tar" exposure from current cigarette consumption. Cough, phlegm, and dyspnea were associated with reported deep inhalation in both sexes, while wheeze was so associated in females. In young smokers (less than 35 years), symptoms were more prevalent in those who had predominantly smoked cigarettes with estimated high "tar." Total exposure was more important in older smokers. Generally, exsmokers showed a lower prevalence of symptoms than smokers. Cross-sectional lung function measurements were significantly related to total estimated "tar" exposure and age. Multiple logistic regressions provided models which helped predict symptoms and lung function impairment in smokers and exsmokers on the basis of estimated "tar" exposure and pack-years of smoking.


Lack of an antibacterial response defect in Drosophila Toll-9 mutant.
Toll and Toll-like receptors represent families of receptors involved in mediating innate immunity response in insects and mammals. Although Drosophila proteome contains multiple Toll paralogs, Toll-1 is, so far, the only receptor to which an immune role has been attributed. In contrast, every single mammalian TLR is a key membrane receptor upstream of the vertebrate immune signaling cascades. The prevailing view is that TLR-mediated immunity is ancient. Structural analysis reveals that Drosophila Toll-9 is the most closely related to vertebrate TLRs and utilizes similar signaling components as Toll-1. This suggests that Toll-9 could be an ancestor of TLR-like receptors and could have immune function. Consistently, it has been reported that over-expression of Toll-9 in immune tissues is sufficient to induce the expression of some antimicrobial peptides in flies. These results have led to the idea that Toll-9 could be a constitutively active receptor that maintain significant levels of antimicrobial molecules and therefore provide constant basal protection against micro-organisms. To test theses hypotheses, we generated and analyzed phenotypes associated with a complete loss-of-function allele of Toll-9. Our results suggest that Toll-9 is neither required to maintain a basal anti-microbial response nor to mount an efficient immune response to bacterial infection.


[Treatment of patients with respiratory papillomatosis: experience analysis].
The authors of the article analyze clinical observations of 240 patients with respiratory papillomatosis (aged 7 months to 56 years), treated in the ETN clinic of Moscow Regional Research Clinical Institute in 1984-2003 using endolaringeal microsurgical techniques, such as ultrasound desintegration and laser photodestruction of papillomas. Additional therapy included immunocorrection with T-activin and leukomax, discrete plasmopheresis, antiviral therapy with zovirax, and photodynamic therapy. Having compared various methods and their combinations, the authors conclude that "clinical recovery" (no relapses within more than 2.5 years), was achieved in 41.4 +/- 0.5% - 77.8 +/- 0.2% patients.


Regulating the Regulators: The Control of Transcription Factors in Plant Defense Signaling.
Being sessile, plants rely on intricate signaling pathways to mount an efficient defense against external threats while maintaining the cost balance for growth. Transcription factors (TFs) form a repertoire of master regulators in controlling various processes of plant development and responses against external stimuli. There are about 58 families of TFs in plants and among them, six major TF families (AP2/ERF (APETALA2/ethylene responsive factor), bHLH (basic helix-loop-helix), MYB (myeloblastosis related), NAC (no apical meristem (NAM), Arabidopsis transcription activation factor (ATAF1/2), and cup-shaped cotyledon (CUC2)), WRKY, and bZIP (basic leucine zipper)) are found to be involved in biotic and abiotic stress responses. As master regulators of plant defense, the expression and activities of these TFs are subjected to various transcriptional and post-transcriptional controls, as well as post-translational modifications. Many excellent reviews have discussed the importance of these TFs families in mediating their downstream target signaling pathways in plant defense. In this review, we summarize the molecular regulatory mechanisms determining the expression and activities of these master regulators themselves, providing insights for studying their variation and regulation in crop wild relatives (CWR). With the advance of genome sequencing and the growing collection of re-sequencing data of CWR, now is the time to re-examine and discover CWR for the lost or alternative alleles of TFs. Such approach will facilitate molecular breeding and genetic improvement of domesticated crops, especially in stress tolerance and defense responses, with the aim to address the growing concern of climate change and its impact on agriculture crop production.


An active ribonucleotide reductase from Arabidopsis thaliana cloning, expression and characterization of the large subunit.
In all living organisms, deoxyribonucleotides, the DNA precursors, are produced by reduction of the corresponding ribonucleotides catalyzed by ribonucleotide reductase. In mammals as in Escherichia coli, the enzyme consists of two proteins. Protein R1 is the proper reductase as it contains, in the substrate binding site, the reducing active cysteine pair. Protein R2 provides a catalytically essential organic radical. Here we report the cloning, expression, purification and characterization of protein R1 from Arabidopsis thaliana. Expression in E. coli was made possible by coexpression of tRNAArg4 which is required for the utilization of AGA and AGG as codons for arginines. Protein R1 shows extensive similarities with protein R1 from mammals: (a) it shows 69% amino-acid sequence identity to human and mouse R1 protein; (b) it is active during CDP reduction by dithiothreitol, in the presence of protein R2 [Sauge-Merle, S., Laulhère, J.-P., Coves, J., Ménage, S., Le Pape, L. & Fontecave, M. (1997) J. Biol. Inorg. Chem. 2, 586-594]; (c) activity is stimulated by thioredoxin and ATP and is inhibited by dATP, showing that as in the mammalian enzyme, the plant ribonucleotide reductase seems to be allosterically regulated by positive (ATP) and negative (dATP) effectors.


Compound glycyrrhizin injection for improving liver function in children with acute icteric hepatitis: A systematic review and meta-analysis.
Compound glycyrrhizin injection (CGI) is a preparation with glycyrrhizin as the main active ingredient extracted from licorice. As clinical trials suggest that CGI is effective in improving liver function for acute icteric hepatitis in children (AIHC), this systematic review aimed to evaluate and verify its therapeutic effects and safety. Six electronic databases were searched from their inception to 15 May 2021. Randomized controlled trials (RCTs) assessing therapeutic effects and safety of CGI for AIHC were included. The risk of bias for each trial was assessed using the Cochrane Risk of Bias Tool 2.0. Primary outcomes were indexes related to liver function, including total bilirubin (TBiL), alanine aminotransferase (ALT) and aspartate transaminase (AST). RevMan 5.4 software was used for data analyses. The certainty of the evidence was assessed using the online GRADEpro tool. Six RCTs involving 608 children were included. The overall bias was assessed as having "high risk of bias" in all trials. All trials compared the combination of CGI and conventional western medicine (CWM) with CWM alone. Regarding the effects of CGI for AIHC, results showed that CGI plus CWM was superior to CWM alone in reducing the levels of TBiL (mean difference (MD) = -8.19 mmol/L, 95% CI -9.86 to -6.53), ALT (MD = -24.09 U/L, 95% CI -30.83 to -17.34) and AST (MD = -18.67 U/L, 95% CI -21.88 to -15.45). No trial reported adverse events. The certainty of the evidence for outcomes were all evaluated as low or very low. CGI may have adjuvant therapeutic effects on improving the liver function of children with AIHC. There is no evidence to determine the safety of CGI for AIHC. As current evidence is weak, further well-designed RCTs are required for verification of the therapeutic effects of CGI.


Estimating the global incidence of traumatic spinal cord injury.
Population modelling--forecasting. To estimate the global incidence of traumatic spinal cord injury (TSCI). An initiative of the International Spinal Cord Society (ISCoS) Prevention Committee. Regression techniques were used to derive regional and global estimates of TSCI incidence. Using the findings of 31 published studies, a regression model was fitted using a known number of TSCI cases as the dependent variable and the population at risk as the single independent variable. In the process of deriving TSCI incidence, an alternative TSCI model was specified in an attempt to arrive at an optimal way of estimating the global incidence of TSCI. The global incidence of TSCI was estimated to be 23 cases per 1,000,000 persons in 2007 (179,312 cases per annum). World Health Organization's regional results are provided. Understanding the incidence of TSCI is important for health service planning and for the determination of injury prevention priorities. In the absence of high-quality epidemiological studies of TSCI in each country, the estimation of TSCI obtained through population modelling can be used to overcome known deficits in global spinal cord injury (SCI) data. The incidence of TSCI is context specific, and an alternative regression model demonstrated how TSCI incidence estimates could be improved with additional data. The results highlight the need for data standardisation and comprehensive reporting of national level TSCI data. A step-wise approach from the collation of conventional epidemiological data through to population modelling is suggested.


Total Synthesis of Aspergillomarasmine A and Related Compounds: A Sulfamidate Approach Enables Exploration of Structure-Activity Relationships.
The fungal secondary metabolite aspergillomarasmine A (AMA) has recently been identified as an inhibitor of metallo-β-lactamases NDM-1 and VIM-2. Described herein is an efficient and practical route to AMA and its related compounds by a sulfamidate approach. In addition, a series of derivatives has been prepared and tested for biological activity in an effort to explore preliminary structure activity relationships. While it was determined that natural LLL isomer of AMA remains the most effective inactivator of NDM-1 enzyme activity both in vitro and in cells, the structure is highly tolerant of the changes in the stereochemistry at positions 3, 6, and 9.


Regulated copper uptake in Chlamydomonas reinhardtii in response to copper availability.
A saturable and temperature-dependent copper uptake pathway has been identified in Chlamydomonas reinhardtii. The uptake system has a high affinity for copper ions (Km approximately 0.2 microM) and is more active in cells that are adapted to copper deficiency than to cells grown in a medium containing physiological (submicromolar to micromolar) copper ion concentrations. The maximum velocity of copper uptake by copper-deficient cells (169 pmol h-1 10(6) cells-1 or 62 ng min-1 mg-1 chlorophyll) is up to 20-fold greater than that of fully copper-supplemented cells, and the Km (approximately 2 x 10(2) nM) is unaffected. Thus, the same uptake system appears to operate in both copper-replete and copper-deficient cells, but its expression or activity must be induced under copper-deficient conditions. A cupric reductase activity is also increased in copper-deficient compared with copper-sufficient cells. The physiological characteristics of the regulation of this cupric reductase are compatible with its involvement in the uptake pathway. Despite the operation of the uptake pathway under both copper-replete and copper-deficient conditions, C. reinhardtii cells maintained in fully copper-supplemented cells do not accumulate copper in excess of their metabolic need. These results provide evidence for a homeostatic mechanism for copper metabolism in C. reinhardtii.


Low-Rankness Transfer for Realistic Denoising.
Current state-of-the-art denoising methods, such as non-local low-rank approaches, have shown to give impressive results. They are, however, mainly tuned to work with uniform Gaussian noise corruption and known variance, which is far from the real noise scenario. In fact, noise level estimation is already a challenging problem and denoising methods are quite sensitive to this parameter. Moreover, these methods are based on shrinkage models that are too simple to reflect reality, which results in over-smoothing of important structures, such as small-scale text and textures. We propose in this paper a new approach for more realistic image restoration based on the concept of low-rankness transfer. Given a training clean/noisy image pair, our method learns a mapping between the non-local noisy singular values and the optimal values for denoising to be transfered to a new noisy input. One single image is enough for training the model and can be adapted to the noisy input by taking a correlated image. Experiments conducted on synthetic and real camera noise show that the proposed method leads to an important improvement both visually and in terms of PSNR/SSIM.


How to increase proximal adenoma detection rate: a meta-analysis comparing water exchange, water immersion and air/CO2 insufflation methods for colonoscopy.
Recent meta-analyses have demonstrated a higher adenoma detection rate using the water exchange method (WE), compared to water immersion (WI) and air/CO2 insufflation (ACI). Proximal adenomas have a high miss rate owing to their location and appearance. We performed a systematic review and meta-analysis of studies comparing the WE and WI methods to the ACI method, with a primary focus on proximal adenoma detection rate. The following databases were searched for our systematic review: Medline, Embase, Cochrane Library, CINAHL, and Web of Sciences. We included both randomized controlled trials and cohort studies. The primary outcome was proximal adenoma detection rate, and secondary outcomes were right adenoma detection rate and cecal intubation rate. A total of 12 studies (17 arms) with 5660 patients (2260 ACI, 2281 WE, and 1119 WI) were included. A higher proximal adenoma detection rate (risk ratio [RR] 1.30, 95% confidence interval [CI] 1.11-1.53; P=0.001) and right adenoma detection rate (RR 1.43, 95%CI 1.19-1.71; P≤0.001; I 2=0%) were noted for the WE group compared to the ACI group. The WI group did not demonstrate a better detection rate of proximal or right adenomas. The water exchange method for colonoscopy holds promise and should be encouraged in the clinical setting to increase proximal and right adenoma detection rates. This will in turn decrease the incidence of colorectal cancer.


Influence of H-2 and non-H-2 genes on resistance to murine cytomegalovirus infection.
The resistance of adult mice to acute lethal infection with murine cytomegalovirus is controlled by genes linked to the H-2 complex. The k haplotype is approximately 10 times more resistant than the b or d haplotypes. Susceptibility is inherited as a completely dominant trait. At least two genes within the H-2 complex are involved, one mapping to the K/IA subregion and the other to the D subregion. The data suggest that interactions may occur between these K- and D-end genes which further affect resistance to the virus. The precise mechanism of H-2 gene control of resistance to murine cytomegalovirus remains to be elucidated. Non-H-2 linked genes also affect resistance to the virus, particularly in the C57BL genetic background, which is associated with an increased resistance to murine cytomegalovirus. Newborn mice of all strains are equally susceptible: both the H-2- and the non-H-2-associated resistances develop in the first few weeks of life and are retained up to at least 18 months of age.


Pediatric Sepsis: New Strategies for Reducing Sepsis Related Mortality.
Sepsis is one of the leading causes of morbidity and mortality in children. Timely recognition and management of sepsis with fluid resuscitation and antibiotic administration leads to better clinical outcomes. However, clinical recognition of sepsis in children is challenging given its rare occurrence, the overlap of clinical features with other common febrile illness, lack of specific diagnostic biomarkers and the ability of children to compensate until the late stages of shock. Despite updating of pediatric sepsis definition and implementation of screening tools to facilitate early recognition, mortality from sepsis continues to be high. Continued education, research and advocacy efforts are needed to improve patient outcomes in pediatric sepsis.


Identification of a novel gene, fimV, involved in twitching motility in Pseudomonas aeruginosa.
Transposon mutagenesis was used to identify a new locus required for twitching motility in Pseudomonas aeruginosa. Four Tn5-B21 mutants which lacked twitching motility and a fifth which exhibited impaired motility were found to map to the same KPN:I restriction fragment at approximately 40 min on the P. aeruginosa genome. Cloning and sequencing studies showed that all five transposon insertions occurred within the same 2.8 kb ORF, which was termed fimV. The product of this gene has a putative peptidoglycan-binding domain, predicted transmembrane domains, a highly acidic C terminus and anomalous electrophoretic migration, indicating unusual primary or secondary structure. The P. aeruginosa genome also possesses a paralogue of fimV. Homologues of fimV were also found in the sequenced genomes of the other type-IV-fimbriated bacteria Neisseria gonorrhoeae, Neisseria meningitidis, Legionella pneumophila and Vibrio cholerae, but not in those of other bacteria which lack type IV fimbriae. A fimV homologue was also found in the genome sequence of Shewanella putrefaciens, along with many other homologues of type IV fimbrial genes, indicating that this bacterium is also likely to produce type IV fimbriae. Wild-type twitching motility was restored to fimV mutants by complementation in a dosage-dependent manner. Overexpression of fimV resulted in an unusual phenotype where the cells were massively elongated and migrated in large convoys at the periphery of the colony. It is suggested that FimV may be involved in remodelling of the peptidoglycan layer to enable assembly of the type IV fimbrial structure and machinery.


Epidemiological surveys revealed the risk of TAMV spill-over from ticks to hosts.
Tick-borne viral diseases have become an increasingly important public health concern. Tamdy virus (TAMV) is a tick-borne virus of the genus Orthonairovirus in the family Nairoviridae. While some studies have suggested that TAMV is a pathogen associated with human febrile illness, its epidemiology and the risk of TAMV spill-over remain poorly understood. Ticks were collected in Xinjiang, China, and grouped into pools. RT-PCR assays were used to detect TAMV RNA in these pools. The seroprevalence of TAMV was investigated using Immunofluorescence assays, Western blotting, and Luciferase immunoprecipitation system (LIPS) assays. TAMV RNA was detected in 17 out of 363 tick pools, resulting in a minimum infection rate (MIR) of 4.7%. Hyalomma asiaticum and Dermacentor nuttalli were identified as major tick vectors of TAMV. Phylogenetic analysis demonstrated that TAMV strains from Xinjiang are closely related to strains from other countries. Seroprevalence studies showed that TAMV exposure has been occurring in Xinjiang since at least 2006. Antibody responses to TAMV were detected in 1.1% (26/2296) of animals, including domestic animals and wild rodents. The seropositivity rates were as follows: sheep (1.7%), dog (2.3%), Marmota monax (0.8%), Meriones meridianus (3.5%). The research findings reveal that TAMV can be transmitted by ticks to various animal species, posing a significant public health risk. The wide distribution of TAMV and its tick vectors emphasise the importance of early preparedness and control measures. This study highlights the necessity for maintaining vigilance in addressing emerging zoonotic diseases transmitted by ticks.


New insights into the mechanism of the Schiff base hydrolysis catalyzed by type I dehydroquinate dehydratase from S. enterica: a theoretical study.
The reaction pathway of Schiff base hydrolysis catalyzed by type I dehydroquinate dehydratase (DHQD) from S. enterica has been studied by performing molecular dynamics (MD) simulations and density functional theory (DFT) calculations and the corresponding potential energy profile has also been identified. On the basis of the results, the catalytic hydrolysis process for the wild-type enzyme consists of three major reaction steps, including nucleophilic attack on the carbon atom involved in the carbon-nitrogen double bond of the Schiff base intermediate by a water molecule, deprotonation of the His143 residue, and dissociation between the product and the Lys170 residue of the enzyme. The remarkable difference between this and the previously proposed reaction mechanism is that the second step here, absent in the previously proposed reaction mechanism, plays an important role in facilitating the reaction through a key proton transfer by the His143 residue, resulting in a lower energy barrier. Comparison with our recently reported results on the Schiff base formation and dehydration processes clearly shows that the Schiff base hydrolysis is rate-determining in the overall reaction catalyzed by type I DHQD, consistent with the experimental prediction, and the calculated energy barrier of ∼16.0 kcal mol(-1) is in good agreement with the experimentally derived activation free energy of ∼14.3 kcal mol(-1). When the imidazole group of His143 residue is missing, the Schiff base hydrolysis is initiated by a hydroxide ion in the solution, rather than a water molecule, and both the reaction mechanism and the kinetics of Schiff base hydrolysis have been remarkably changed, clearly elucidating the catalytic role of the His143 residue in the reaction. The new mechanistic insights obtained here will be valuable for the rational design of high-activity inhibitors of type I DHQD as non-toxic antimicrobials, anti-fungals, and herbicides.


mRNPs meet stress granules.
Stress granules are cytoplasmic structures that form in response to a variety of cellular stresses. They contain mRNAs and many proteins including numerous types of RNA-binding proteins, and have been studied in connection to major cellular events such as protein synthesis as well as disease. Despite the well-known fact that stress granules encapsulate mRNPs (mRNA-protein complexes), much of the research has naturally focused on the protein components of stress granules. The specific details of mRNP entry into and exit from stress granules and the functional reasons for these dynamics are not fully understood. Here, we review studies that have concentrated on the aspects of mRNP accumulation in stress granules and produced quantitative data concerning mRNP/stress granule interactions.


[Intensive care medicine today].
Physicians, nurses and many other allied health professions join in intensive care as a team for the treatment of patients whose vital functions are either endangered or impaired. Apart from continuous monitoring, which represents the smallest common denominator of all types of intensive-care treatment, intensive-care therapy also encompasses continuous treatment and support of failing organ functions and likewise continuous intensive nursing. The complexity of intensive-care medicine is a strong argument against intensive-care becoming a medical specialty of its own. Nevertheless, the coordination of intensive care-medicine by an experienced intensive care physician is of utmost importance. The present situation in intensive-care medicine is characterised by an increasing tension between new and fascinating medical possibilities (such as right and left ventricular assistance device systems, liver support, pharmacologic treatment of sepsis, avoidance of the complications of critical illness) on the one hand, and limited budgets on the other hand. This conflict is reflected by two basic fears within the population: firstly, the fear that not everything medically possible is being done for the patient due to economic reasons, secondly, a fear of futile treatment at the end of life, merely prolonging inevitable death. Accordingly, ethical questions regarding intensive-care are emerging at all levels of the health system.


Intrinsic Regression Models for Positive-Definite Matrices With Applications to Diffusion Tensor Imaging.
The aim of this paper is to develop an intrinsic regression model for the analysis of positive-definite matrices as responses in a Riemannian manifold and their association with a set of covariates, such as age and gender, in a Euclidean space. The primary motivation and application of the proposed methodology is in medical imaging. Because the set of positive-definite matrices do not form a vector space, directly applying classical multivariate regression may be inadequate in establishing the relationship between positive-definite matrices and covariates of interest, such as age and gender, in real applications. Our intrinsic regression model, which is a semiparametric model, uses a link function to map from the Euclidean space of covariates to the Riemannian manifold of positive-definite matrices. We develop an estimation procedure to calculate parameter estimates and establish their limiting distributions. We develop score statistics to test linear hypotheses on unknown parameters and develop a test procedure based on a resampling method to simultaneously assess the statistical significance of linear hypotheses across a large region of interest. Simulation studies are used to demonstrate the methodology and examine the finite sample performance of the test procedure for controlling the family-wise error rate. We apply our methods to the detection of statistical significance of diagnostic effects on the integrity of white matter in a diffusion tensor study of human immunodeficiency virus. Supplemental materials for this article are available online.


Persistent opioid use after radiation therapy in opioid-naive cervical cancer survivors.
Opioids are first-line therapy for cancer-related pain, but their use should be minimized in disease-free survivors. We sought to describe rates and identify predictors of persistent opioid use among previously opioid-naive cervical cancer survivors treated with radiation. Opioid-naive cervical cancer patients treated primarily with radiation and chemosensitization at a single institution, between January 2011 and December 2015, were identified. Charts were reviewed for demographics, disease, and treatment characteristics, and opioid prescriptions. Primary outcome was persistent opioid use, defined as continued opioid prescription use, 6 months after radiation; patients recurring within 6 months were excluded. Groups were compared using χ2 or Fisher's exact test. Multivariable logistic regression identified predictors of persistent opioid use. A total of 96 patients were included, with a median age of 49 years (range 27-84). Most patients (59%) at diagnosis had International Federation of Gynecology and Obstetrics (FIGO) stage I or II cervical cancer. The most common histology was squamous cell carcinoma (72%) and most (94.7%) patients received radiation with chemosensitization. Rates of persistent opioid use at 3 and 6 months after treatment were 29% and 25%, respectively. Persistent users were more likely to be <40 years old, have disease outside the pelvis at diagnosis, and have had a history of substance abuse, depression or anxiety (p<0.05). In multivariable analysis, a history of substance abuse (adjusted OR 6.21, 95% CI 1.08 to 35.67) and depression or anxiety (aOR 6.28, 95% CI 1.70 to 23.30) were independently associated with persistent opioid use. Our study showed that 25% of patients with cervical cancer were still using opioids 6 months after radiation. History of substance abuse and depression or anxiety, all known risk factors for opioid misuse, were associated with persistent use. The goal in the disease-free survivor population should be opioid independence.


MRI findings after successful vertebroplasty.
Recurrent or residual back pain after vertebroplasty (VP) is common, and many patients with these symptoms are evaluated by MRI. The purpose of this report is to describe post-treatment MRI findings after successful VP. We identified all patients who underwent VP at our institution and later presented with back pain and had a spine MRI. From these patients, we identified a cohort with uncomplicated procedures, in whom back pain at the site of the VP was not the dominant pain source at follow-up. Using the pre- and postoperative MRIs and the VP conventional radiographs, we assessed such features as interval height loss and changes in marrow edema in treated vertebrae. Thirty patients (51 treated vertebrae) met our clinical criteria for uncomplicated VP. Nine (18%) of 51 vertebrae lost additional height after the procedure. Neither patient demographics nor variables associated with the procedure itself, including volume of cement injected, correlated with additional height loss after VP. Moderate or severe marrow edema was demonstrated in 62% of vertebrae on preoperative MRI and in 33% of vertebrae on follow-up MRI. Twenty-one percent of vertebrae had new areas of marrow edema on follow-up. Twenty-two percent of vertebrae imaged >6 months after VP had moderate or severe edema. Progressive and persistent edema and interval height loss after successful VP are common and should not be interpreted as sufficient evidence of ongoing pathology at the treated vertebral level.


Effect of RhD and RhE sample phenotypic blood transfusion on the prognosis of hepatocellular carcinoma.
This study aimed to analyze the therapeutic effects and clinical outcomes of HCC patients, who received both RhD and RhE same phenotypic blood transfusion during perioperative period. Microcolumn gel technology (MGT) was used to detect Rh blood group phenotyping in 98 HCC patients. Patients received RhD and RhE same phenotypic transfusion were defined experimental group, and those received only RhD same phenotypic but RhE different phenotypic transfusion were included in control group. Hemoglobin (Hb) and hematocrit (HCT) before and after perioperative transfusion were analyzed. The occurrence of adverse transfusion reactions were observed. Survival analysis was performed using the Kaplan-Meier method. After the transfusion treatment, the Hb (118.9 ± 34.8 g/L vs 99.6 ± 26.9 g/L) and HCT [(34.0 ± 7.6)% vs (29.9 ± 8.8)%] of experimental group and the Hb (104.3 ± 36.2 g/L vs 94.8 ± 25.0 g/L) of control group were significantly higher than those before blood transfusion, respectively (all P < .05). In addition, Hb and HCT in experimental group were significantly higher than those in the control group after transfusion (P < .05). For the adverse blood transfusion reactions, the incidence of backache was reduced in the patients received Rh same phenotypic transfusion compared with those in control group (1.9% vs 15.2%, P = .024). The overall survival of patients in experimental group was better than that in control group (log-rank P = .036). Our study indicated that both RhD and RhE same phenotypic transfusion significantly increased Hb and HCT and reduced backache incidence than RhE different phenotypic transfusion in HCC patients. The overall survival of patients was improved by RhD and RhE same phenotypic transfusion.


Protein and site specificity of fucosylation in liver-secreted glycoproteins.
Chronic liver diseases are a serious health problem worldwide. One of the frequently reported glycan alterations in liver disease is aberrant fucosylation, which was suggested as a marker for noninvasive serologic monitoring. We present a case study that compares site specific glycoforms of four proteins including haptoglobin, complement factor H, kininogen-1, and hemopexin isolated from the same patient. Our exoglycosidase-assisted LC-MS/MS analysis confirms the high degree of fucosylation of some of the proteins but shows that microheterogeneity is protein- and site-specific. MSn analysis of permethylated detached glycans confirms the presence of LeY glycoforms on haptoglobin, which cannot be detected in hemopexin or complement factor H; all three proteins carry Lewis and H epitopes. Core fucosylation is detectable in only trace amounts in haptoglobin but with confidence on hemopexin and complement factor H, where core fucosylation of the bi-antennary glycans on select glycopeptides reaches 15-20% intensity. These protein-specific differences in fucosylation, observed in proteins isolated from the same patient source, suggest that factors other than up-regulation of enzymatic activity regulate the microheterogeneity of glycoforms. This has implications for selection of candidate proteins for disease monitoring and suggests that site-specific glycoforms have structural determinants, which could lead to functional consequences for specific subsets of proteins or their domains.


Aggregation of subclinical autonomic nervous system dysfunction and autoantibodies in families with type I diabetes.
The purpose of our study was to evaluate the occurrence of autonomic nervous system autoantibodies (ANS) in the nondiabetic family members of insulin-dependent (type I) diabetic subjects. We studied 24 families, including 45 nondiabetic parents and 53 nondiabetic siblings of a type I diabetic proband. One hundred one nondiabetic population control subjects were also studied. Stored sera from nondiabetic family members and control subjects were evaluated for the presence of complement-fixing (CF) adrenal medullary antibodies (CF-ADM), sympathetic ganglia antibodies (CF-SG), and vagus nerve antibodies (CF-V) by indirect immunofluorescence. HLA-DR3 and -DR4 typing was performed on 42 nondiabetic family members and 104 diabetic subjects. One or more CF-ANS were in 45 of 93 (40%) nondiabetic family members compared to 2 of 70 (2.8%) control subjects. CF-SG were in 28 of 92 (30%) family members compared to 0 of 101 control subjects (P = 0.0001). CF-V were in 25 of 95 (26%) family members compared to 0 of 76 control subjects (P = 0.0001). CF-ADM were in 10 of 83 (12%) family members compared to 2 of 70 (2.8%) control subjects (P = 0.056). There was no HLA-DR3 or HLA-DR4 association with ANS. Subclinical autonomic dysfunction was demonstrated in 3 of 4 family members with autoantibodies compared to 0 of 4 family members without autoantibodies.


Elimination of infectious human immunodeficiency virus from human T-cell cultures by synergistic action of CD4-Pseudomonas exotoxin and reverse transcriptase inhibitors.
We have previously described a recombinant protein, designated CD4(178)-PE40, consisting of the human immunodeficiency virus (HIV) envelope glycoprotein-binding region of human CD4 linked to the translocation and ADP-ribosylation domains of Pseudomonas aeruginosa exotoxin A. By virtue of its affinity for gp120 (the external subunit of the HIV envelope glycoprotein), the hybrid toxin selectively binds to and kills HIV-1-infected human T cells expressing surface envelope glycoprotein and also inhibits HIV-1 spread in mixed cultures of infected and uninfected cells. We now report that CD4(178)-PE40 and reverse transcriptase inhibitors exert highly synergistic effects against HIV-1 spread in cultured human primary T cells. Furthermore, combination treatment can completely eliminate infectious HIV-1 from cultures of human T-cell lines. This conclusion is based on protection of a susceptible cell population from HIV-induced killing, complete inhibition of virus protein accumulation, and elimination of HIV DNA (as judged by quantitative polymerase chain reaction analysis). The results highlight the therapeutic potential of treatment regimens involving combination of a virostatic drug that inhibits virus replication plus an agent that selectively kills HIV-infected cells.


A gradual decrease in nucleolar size with the maturation of columnar epithelial cells in the adult rat intestine under normal and various experimental conditions.
The columnar cells, which form over 90% of the epithelium in the small intestine, undergo rapid and continuous renewal and maturation. Samples from duodenum, jejunum, upper, mid- and terminal ileum of young male rats were processed for histology. The average maximal nucleolar area was determined in 10-cell-wide bands of the basal, mid and upper levels of crypts and villi, respectively, by image analysis; in the duodenum, it was 2.8, 2.1, 1.7, 1.5, 1.3 and 0.8 (in micron2) in the respective epithelial levels from crypt base to villus top. Although villus size decreased by 68% from duodenum to terminal ileum, nucleolar area was similar at each respective epithelial level along the intestine. This indicated that nucleolar size was related to cell maturity, rather than to the size of epithelium. In other groups of rats, the duodenum was examined after administering specific inhibitors. Methotrexate (within a day) and cycloheximide (within 3 h) did not significantly affect nucleolar size, indicating that the decrease in size was not under the influence of immediate synthesis of nucleic acid or protein. On the other hand, tunicamycin (within a day) delayed the decrease and actinomycin D (within 3 h) caused a maximal decrease in all nucleoli. This implied that a glycoprotein factor and some changes in DNA were involved in the decrease in nucleolar size. The rate of protein synthesis in duodenum was then measured by grain count per cell area in autoradiographs made after 1 h of injection of [3H]leucine. From crypt base to villus base, the grain count doubled while the nucleoli decreased to nearly half of their size in the crypt base. When actinomycin D injection preceded the [3H]leucine administration, all nucleoli decreased markedly and the grain counts increased by about 30% in all epithelial levels. It thus appears that the decrease in nucleolar size stimulates protein synthesis, possibly by the release of ribosomal material or some other factor. Protein synthesis in turn has been shown to be related to cell maturation. It is concluded that the nucleolus is involved in some manner in the regulation of the maturation and renewal of the epithelial cells.


Neurocysticercosis as a probable risk factor for hippocampal sclerosis.
Neurocysticercosis is one of the most common risk factors for epilepsy but its association with drug-resistant epilepsy remains uncertain. Conjectures of an association with drug-resistant epilepsy have been fueled by reports of an association between calcific neurocysticercosis lesions (CNL) and hippocampal sclerosis (HS) from specialized epilepsy centers in Taenia solium-endemic regions. The debate arising from these reports is whether the association is causal. Evidence for the association is not high quality but sufficiently persuasive to merit further investigation with longitudinal imaging studies in population-based samples from geographically-diverse regions. The other controversial point is the choice of a surgical approach for drug-resistant epilepsy associated with CNL-HS. Three approaches have been described: standard anteromesial temporal lobectomy, lesionectomy involving a CNL alone and lesionectomy with anteromesial temporal lobectomy (for dual pathology); reports of the latter two approaches are limited. Presurgical evaluation should consider possibilities of delineating the epileptogenic zone/s in accordance with all three approaches.


Comparison of the effectiveness of three manual physical therapy techniques in a subgroup of patients with low back pain who satisfy a clinical prediction rule: a randomized clinical trial.
Randomized clinical trial. The purpose of this randomized clinical trial was to examine the generalizability of 3 different manual therapy techniques in a patient population with low back pain that satisfy a clinical prediction rule (CPR). Recently a CPR that identifies patients with LBP who are likely to respond rapidly and dramatically to thrust manipulation has been developed and validated. The generalizability of the CPR requires further investigation. A total of 112 patients were enrolled in the trial and provided demographic information and completed a number of self-report questionnaires including the Oswestry Disability Questionnaire (ODQ) and the Numerical Pain Rating Scale (NPRS) at baseline, 1-week, 4-weeks, and 6-months. Patients were randomly assigned to receive 1 of the 3 manual therapy techniques for 2 consecutive treatment sessions followed by exercise regimen for an additional 3 sessions. We examined the primary aim using a linear mixed model for repeated measures, using the ODQ and NPRS as dependent variables. The hypothesis of interest was the group by time interaction, which was further explored with pair-wise comparisons of the estimated marginal means. There was a significant group x time interaction for the ODQ (P < 0.001) and NPRS scores (P = 0.001). Pair-wise comparisons revealed no differences between the supine thrust manipulation and side-lying thrust manipulation at any follow-up period. Significant differences in the ODQ and NPRS existed at each follow-up between the thrust manipulation and the nonthrust manipulation groups at 1-week and 4-weeks. There was also a significant difference in ODQ scores at 6-months in favor of the thrust groups. The results of the study support the generalizability of the CPR to another thrust manipulation technique, but not to the nonthrust manipulation technique that was used in this study. In general, our results also provided support that the CPR can be generalized to different settings from which it was derived and validated. However, additional research is needed to examine this issue.


[Experimental evaluation of the pathogenicity of Lassa virus variants].
Pathogenicity for guinea pigs and white mice of various Lassa virus variants: native, having had 1 passage in Vero cell culture and 4 passages in newborn white mouse brain; a virus having gone through 10 passages in Vero cells and 8 mouse brain passages (variant No. 10); a small-plaque clone derived from variant No. 10 by the method of plaque-to-plaque cloning (variant No. 11k), was studied. Both the native virus and variant No. 10 were found to be similarly pathogenic for susceptible laboratory animals, while the small-plaque variant of Lassa virus became non-fatal for guinea pigs and white mice. The decline of pathogenic properties in variant No. 11k was shown not to be associated with the presence of temperature-sensitive mutants or defective interfering particles.


Half-Life of Sulfur-35.
A new determination has been made of the half-life of the beta emitter sulfur-35. Approximately 400 measurements were taken over a period of a year and a half. These data were corrected for the dead time of the counter and then treated statistically. The half-life was found to be 86.35 +/- 0.17 days.


Student productivity in a comprehensive care program without numeric requirements.
As the dental students of the Class of 2000 entered the Comprehensive Care Clinic at the University of Colorado School of Dentistry in the spring of their second year (spring of 1998), a different, competency-based set of clinical expectations was communicated to them. These students were presented a list of "Recommended Core Experiences" and told that the "requirements" for completion of the Comprehensive Care Program were 1) successful performance on all departmental competency examinations, and 2) timely completion of the comprehensive dental treatment appropriate to each assigned patient. This study examined the number of procedures completed during the six semesters in the Comprehensive Care Clinic for the Class of 2000, as compared to the clinical activity for the Class of 1999 during the same stage of their career. The overall mean number of clinical procedures performed per student was 7 percent greater for the students in the Class of 2000 than for those in the Class of 1999. These results suggest that numerical requirements are not necessary to ensure dental student productivity and that, in fact, students can complete more clinical procedures in a comprehensive care clinical environment without numerical requirements.


[Serum level of digoxin and digitoxin and glomerular filtration rate in hyper- and hypothyroidism].
In a comparative prospective study the serum levels of digoxin and digitoxin and the glomerular filtration of the kidneys were determined radioimmunologically in thyroid function disorders using the endogenous creatinine clearance and the 51Cr-EDTA clearance. Compared to a euthyroid control group 17 patients with hyperthyroidism showed a decreased and 5 patients with hypothyroidism showed a largely toxic digoxin level, both groups being on a maintenance therapy of 0.25 mg digoxin b. i. d. During an oral maintenance therapy of daily 0.1 mg digitoxin unchanged therapeutic serum levels were found in 35 hyperthyroid and 18 hypothyroid patients when compared to a euthyroid control group. Assessment of clearances showed that glomerular filtration rates were clearly increased in the hyperthyroid and lowered in the hypothyroid patients. Renewed assessment of the clearance in four hyperthyroid patients and three with hypothyroidism after thyroid recompensation showed a marked decrease of clearance values in hyperthyroidism and an increase in hypothyroidism. Increased clearance values in hyperthyroidism were associated with lowered digoxin serum levels. In contrast, lowered clearance values in hypothyroidism were accompanied by increased serum digoxin levels. There was no such association detectable for digitoxin.


Mimicking Cartilage Tissue Zonal Organization by Engineering Tissue-Scale Gradient Hydrogels as 3D Cell Niche.
Zonal organization plays an important role in cartilage structure and function, whereas most tissue-engineering strategies developed to date have only allowed the regeneration of cartilage with homogeneous biochemical and mechanical cues. To better restore tissue structure and function, there is a strong need to engineer materials with biomimetic gradient niche cues that recapitulate native tissue organization. To address this critical unmet need, in this study, we report a method for rapid formation of tissue-scale gradient hydrogels as a three-dimensional (3D) cell niche with tunable biochemical and physical properties. When encapsulated in stiffness gradient hydrogels, both chondrocytes and mesenchymal stem cells demonstrated zone-specific response and extracellular deposition that mimics zonal organization of articular cartilage. Blocking cell mechanosensing using blebbistatin abolished the zonal response of chondrocytes in 3D hydrogels with a stiffness gradient. Such tissue-scale gradient hydrogels can provide a 3D artificial cell niche to enable tissue engineering of various tissue types with zonal organizations or tissue interfaces.


Optimal imaging protocol after intraocular silicone oil tamponade.
Our purpose was to define the optimal protocol for imaging of the orbits after vitreous humor replacement with silicone oil. Eleven eyes in 10 patients with tractional and/or rhegmatogenous retinal detachment were studied. Five CT scans and 18 high-field (1.5 T) MR images were obtained. Standard T1-weighted, T1-weighted with fat and silicone saturation, fast spin density-weighted, and T2-weighted orbital MR sequences were performed. Unique pulse sequences included fast spin density-weighted and T2-weighted imaging with and without fat saturation or silicone saturation, gradient-echo imaging, and short-tau inversion recovery imaging. The T1-weighted MR and CT studies were comparable in displaying the silicone. However, the fat- or silicone-saturated fast T2-weighted sequences always showed the fibrous bands and subretinal fluid to best advantage. In one case, the eye also contained inadvertently retained perfluorocarbon liquid, which blended with silicone oil on both saturated images, requiring companion T1-weighted sequences without saturation to demonstrate its presence. Simple, commonly available fat-saturated fast T2-weighted MR images supplemented by standard T1-weighted images are all that are needed to evaluate the eye efficiently after vitrectomy and tamponade.


Role of CuZn superoxide dismutase in regulating lymphocyte apoptosis during sepsis.
The lymphocyte is a principal mediator of the inflammatory response, and lymphocyte depletion via apoptosis may be an important mechanism of modulating inflammation. Increased oxygen consumption occurs during sepsis and results in the generation of reactive oxygen species. Although reactive oxygen species initiate apoptosis in many biological systems, their role in controlling lymphocyte apoptosis during sepsis is unclear. The objective of this study was to better characterize the role of oxidative stress in precipitating lymphocyte apoptosis during sepsis and to specifically define the role of the CuZn superoxide dismutase (SOD) enzyme complex, a major antioxidant defense, in modulating this process. Prospective, randomized, controlled study. Research laboratory at an academic medical center. Mice that were either genetically normal or that were deficient in or overexpressed the enzyme CuZn SOD. Mice from each genetic group were randomized to no manipulation (control), sham surgery, or cecal ligation and puncture. Mice were killed 18-24 hrs after study entry, and the thymi and spleen were removed for analysis of apoptosis. Lymphocyte apoptosis was assessed by three independent methods: light microscopy, fluorescent terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling, and DNA gel electrophoresis. Comparisons were performed using standard parametric statistical tests. Lymphocyte apoptosis was present in mice after CLP but not in control mice or in mice after sham surgery (p < .05). Mice completely lacking CuZn SOD developed significantly more lymphocyte apoptosis than did either partially CuZn SOD-deficient or genetically normal mice (p < .05). This apoptosis was more pronounced in the thymus than the spleen and, within the thymus, more prominent in the cortex than medulla (p < .05 for all). In contrast, mice that overexpressed CuZn SOD did not differ in the amount of apoptosis after CLP compared with genetically normal mice (p = NS for all). Oxidative stress occurs in sepsis and appears to be one stimulus for the development of lymphocyte apoptosis, a process that is partly regulated by CuZn SOD. However, we were unable to demonstrate that overexpression of this enzyme suppressed lymphocyte apoptosis, suggesting that either other antioxidant defenses or other pathways independent of oxidative stress may mediate lymphocyte elimination in this syndrome.


Some ecological mechanisms to generate habitability in planetary subsurface areas by chemolithotrophic communities: the Río Tinto subsurface ecosystem as a model system.
Chemolithotrophic communities that colonize subsurface habitats have great relevance for the astrobiological exploration of our Solar System. We hypothesize that the chemical and thermal stabilization of an environment through microbial activity could make a given planetary region habitable. The MARTE project ground-truth drilling campaigns that sampled cryptic subsurface microbial communities in the basement of the Río Tinto headwaters have shown that acidic surficial habitats are the result of the microbial oxidation of pyritic ores. The oxidation process is exothermic and releases heat under both aerobic and anaerobic conditions. These microbial communities can maintain the subsurface habitat temperature through storage heat if the subsurface temperature does not exceed their maximum growth temperature. In the acidic solutions of the Río Tinto, ferric iron acts as an effective buffer for controlling water pH. Under anaerobic conditions, ferric iron is the oxidant used by microbes to decompose pyrite through the production of sulfate, ferrous iron, and protons. The integration between the physical and chemical processes mediated by microorganisms with those driven by the local geology and hydrology have led us to hypothesize that thermal and chemical regulation mechanisms exist in this environment and that these homeostatic mechanisms could play an essential role in creating habitable areas for other types of microorganisms. Therefore, searching for the physicochemical expression of extinct and extant homeostatic mechanisms through physical and chemical anomalies in the Mars crust (i.e., local thermal gradient or high concentration of unusual products such as ferric sulfates precipitated out from acidic solutions produced by hypothetical microbial communities) could be a first step in the search for biological traces of a putative extant or extinct Mars biosphere.


Direct detection of Mycobacterium avium in environmental water and scale samples by loop-mediated isothermal amplification.
We previously demonstrated the colonization of Mycobacterium avium complex in bathrooms by the conventional culture method. In the present study, we aimed to directly detect M. avium organisms in the environment using loop-mediated isothermal amplification (LAMP), and to demonstrate the efficacy of LAMP by comparing the results with those obtained by culture. Our data showed that LAMP analysis has detection limits of 100 fg DNA/reaction for M. avium. Using an FTA(®) elute card, DNA templates were extracted from environmental samples from bathrooms in the residences of 29 patients with pulmonary M. avium disease. Of the 162 environmental samples examined, 143 (88%) showed identical results by both methods; 20 (12%) and 123 (76%) samples were positive and negative, respectively, for M. avium. Of the remaining 19 samples (12%), seven (5%) and 12 (7%) samples were positive by the LAMP and culture methods, respectively. All samples that contained over 20 colony forming units/primary isolation plate, as measured by the culture method, were also positive by the LAMP method. Our data demonstrate that the combination of the FTA elute card and LAMP can facilitate prompt detection of M. avium in the environment.


[Suprascapular nerve entrapment].
Isolated compression of the suprascapular nerve is a rare entity, that is seldom considered in differential diagnosis of shoulder pain. Usually atrophy of supraspinatus and infraspinatus muscles is present, resulting in weakened abduction and external rotation of the shoulder. Mostly the patients do not note the paresis, but complain about a dull and burning pain over the dorsal shoulder region. In a proximal lesion (at level of the superior transverse scapular ligament) electromyography reveals changes in both muscles, while in a distal lesion (spinoglenoidal notch) only the infraspinatus shows a pathology. From 1996 to 2001 we diagnosed an isolated suprascapular entrapment in nine patients. Seven patients were operated: The ligament was removed and the nerve was neurolysed. The average age was 36 years. All patients showed pathological findings in electrophysiological and clinical examination. Five patients had an atrophy of both scapula muscles, two showed only infraspinatus muscle atrophy (one with a ganglion in the distal course of the nerve). Six patients were followed up. All showed an improvement. Pain disappeared and all patients were able to return to work and sport activities. Electrophysiological examination one year after operation revealed normal nerve conduction velocity. The number of motor units, however, showed a reduction by half compared to the healthy side. Lesions without history of trauma are usually caused by repetitive motion or posture. Weight lifting, volley ball and tennis promote the entrapment. Rarely a lesion (either idiopathic or due to external compression) is described for patients who underwent surgery. Patients with a ganglion or a defined cause of compression should be operated, patients who present without a distinct reason for compression should firstly be treated conservatively. Physiotherapy, antiphlogistic medication and avoiding of the pain triggering motion can improve the symptoms. However, if muscle atrophy is evident, an operation is indicated from our experience.


Sodium channels amplify spine potentials.
Dendritic spines mediate most excitatory synapses in the brain. Past theoretical work and recent experimental evidence have suggested that spines could contain sodium channels. We tested this by measuring the effect of the sodium channel blocker tetrodotoxin (TTX) on depolarizations generated by two-photon uncaging of glutamate on spines from mouse neocortical pyramidal neurons. In practically all spines examined, uncaging potentials were significantly reduced by TTX. This effect was postsynaptic and spatially localized to the spine and occurred with uncaging potentials of different amplitudes and in spines of different neck lengths. Our data confirm that spines from neocortical pyramidal neurons are electrically isolated from the dendrite and indicate that they have sodium channels and are therefore excitable structures. Spine sodium channels could boost synaptic potentials and facilitate action potential backpropagation.


Public fear of vaccination: separating fact from fiction.
During the last two centuries, the world has seen a substantial increase in the number and availability of vaccines for the prevention of infectious disease. Smallpox vaccine remains the most celebrated vaccine-related achievement in human history, but worldwide reductions in many other diseases including measles, mumps, rubella, polio, diphtheria, and whooping cough (Bordetella pertussis) also illustrate the power of vaccination in controlling outbreaks of contagious diseases. Ironically, as advances in vaccination successfully limit disease outbreaks, the impact that these infectious agents once had on society becomes marginalized. Public confidence in vaccination may erode because of real or perceived risks associated with immunization, and this in turn may lead to lower vaccination coverage and loss of herd immunity. Here, we will discuss some of the elements associated with public perceptions and fear of vaccination and place these into the context of how deadly several vaccine-preventable childhood diseases can be if vaccination coverage is insufficient.


Cortical recruitment of nonmuscle myosin II in early syncytial Drosophila embryos: its role in nuclear axial expansion and its regulation by Cdc2 activity.
The nuclei of early syncytial Drosophila embryos migrate dramatically toward the poles. The cellular mechanisms driving this process, called axial expansion, are unclear, but myosin II activity is required. By following regulatory myosin light chain (RLC)-green fluorescent protein dynamics in living embryos, we observed cycles of myosin recruitment to the cortex synchronized with mitotic cycles. Cortical myosin is first seen in a patch at the anterocentral part of the embryo at cycle 4. With each succeeding cycle, the patch expands poleward, dispersing at the beginning of each mitosis and reassembling at the end of telophase. Each cycle of actin and myosin recruitment is accompanied by a cortical contraction. The cortical myosin cycle does not require microtubules but correlates inversely with Cdc2/cyclinB (mitosis-promoting factor) activity. A mutant RLC lacking inhibitory phosphorylation sites was fully functional with no effect on the cortical myosin cycle, indicating that Cdc2 must be modulating myosin activity by some other mechanism. An inhibitor of Rho kinase blocks the cortical myosin recruitment cycles and provokes a concomitant failure of axial expansion. These studies suggest a model in which cycles of myosin-mediated contraction and relaxation, tightly linked to Cdc2 and Rho kinase activity, are directly responsible for the axial expansion of the syncytial nuclei.


Infrared and electron paramagnetic resonance study of nitrosyl(protoporphyrin IX dimethyl ester)iron(II) and its complexes with nitrogenous bases as model systems for nitrosylhemoproteins: effect of solvent polarity.
Infrared and electron paramagnetic resonance spectra of nitrosyl(protoporphyrin IX dimethyl ester)iron(II)(Fe(PPDME)(NO)) and its complexes with nitrogenous bases (N bases) such as imidazoles, pyridines, aliphatic amines, and anilines have been measured in various solvents. At room temperature, giso, Aiso, and nu NO values of five-coordinate Fe(PPDME)(NO) decreased with an increase in solvent polarity parameter ET, indicating the interaction between the solvent and the vacant axial coordination position. It has been found that the nu NO value of six-coordinate species is very sensitive to the solvent polarity, while the giso value is less sensitive. The solvent effect on the equilibrium constants, which are evaluated from the intensity change of the NO stretching band for five- and six-coordinate species, is discussed.


Double bilayers and transmembrane gradients: a molecular dynamics study of a highly charged peptide.
The position and extent of movement of a charged peptide within a membrane bilayer provides much controversy. In our study, we have examined the nature of the highly charged helix-turn-helix motif (S3b and S4) to address how a highly charged peptide is stabilized within a bilayer in the presence of various transmembrane electrical potentials. Our double-bilayer simulation results show how the variation of the salt concentrations between the inner and outer bath establishes a transmembrane potential. Our results also show that important features of the peptide affected by changes in electrical potential are the center of mass depth, the swivel/kink degrees of conformation, and the hydrogen-bonding patterns. As the voltage gradient across the bilayer increased, the center of mass of the peptide shifted in a direction toward the outer bath. The peptide also has a higher percent helical content and the swivel/kink conformation is more rigid for nonpolarized systems where no voltage drop occurred between salt baths. Our results also provide some suggestions for how this domain may be affected by environmental changes as part of the voltage sensor in a K-channel.


Morphine and clonidine combination therapy improves therapeutic window in mice: synergy in antinociceptive but not in sedative or cardiovascular effects.
Opioids are used to manage all types of pain including acute, cancer, chronic neuropathic and inflammatory pain. Unfortunately, opioid-related adverse effects such as respiratory depression, tolerance, physical dependence and addiction have led to an underutilization of these compounds for adequate pain relief. One strategy to improve the therapeutic utility of opioids is to co-administer them with other analgesic agents such as agonists acting at α2-adrenergic receptors (α2ARs). Analgesics acting at α2ARs and opioid receptors (ORs) frequently synergize when co-administered in vivo. Multimodal analgesic techniques offer advantages over single drug treatments as synergistic combination therapies produce analgesia at lower doses, thus reducing undesired side effects. This inference presumes, however, that the synergistic interaction is limited to the analgesic effects. In order to test this hypothesis, we examined the effects of α2AR/OR combination therapy in acute antinociception and in the often-undesired side effects of sedation and cardiovascular depression in awake unrestrained mice. Morphine, clonidine or their combination was administered by spinal or systemic injection in awake mice. Antinociception was determined using the warm water tail flick assay (52.5°C). Sedation/motor impairment was evaluated using the accelerating rotarod assay and cardiovascular function was monitored by pulse oximetry. Data were converted to percent maximum possible effect and isobolographic analysis was performed to determine if an interaction was subadditive, additive or synergistic. Synergistic interactions between morphine and clonidine were observed in the antinociceptive but not in the sedative/motor or cardiovascular effects. As a result, the therapeutic window was improved ∼200-fold and antinociception was achieved at non-sedating doses with little to no cardiovascular depression. In addition, combination therapy resulted in greater maximum analgesic efficacy over either drug alone. These data support the utility of combination adrenergic/opioid therapy in pain management for antinociceptive efficacy with reduced side-effect liability.


Trends in incidence of skin basal cell carcinoma. Additional evidence from a UK primary care database study.
We determined the trends in incidence of skin basal cell carcinoma (BCC) using a primary care population-based cohort study in the UK. 11,113 adults with a BCC diagnosis were identified from a total of 7.22 million person-years of data between 1996 and 2003 from the Health Improvement Network database. From a random subsample of BCC cases identified from the database, 93% were confirmed by hospital letter and/or pathology report. The incidence of BCC was 153.9 per 100,000 person-years (95% CI 151.1, 156.8) and was slightly higher in men as compared to women (Incidence Rate Ratio 1.10, 95% CI 1.06, 1.14). There was a 3% increase year on year across the study period (IRR 1.03, 95% CI 1.01, 1.04), with the largest increase in incidence seen in the 30-39 year age groups, although this did not reach statistical significance. Our study indicates 53,000 new cases of BCC are estimated every year in the UK and figures are continuing to rise on a yearly basis. Incidence rates are highest for men and in particular in the older age categories. These findings are consistent with those reported for various other populations. We have also found an increase in incidence in ages 30-39, which may suggest a cohort effect of increasing ultraviolet exposure in successive younger generations. This may have a huge public and service impact in future years in countries such as the UK, with predominantly fair-skinned population, with high leisure exposure to ultraviolet light. Our findings underline the need for more elaborate preventive measures.


Glycosylation of resveratrol protects it from enzymic oxidation.
Plant polyphenols, including dietary polyphenols such as resveratrol, are important components in the plant antioxidant and defence systems. They are also known to exert beneficial effects on human health through diet. As they are produced, these polyphenols may be subjected to deleterious enzymic oxidation by the plant polyphenol oxidases. They are generally synthesized as glycosides like 5,4'-dihydroxystilbene-3-O-beta-D-glucopyranoside, the 3-glucoside of resveratrol. The effects of the glycosylation and methylation of the parent resveratrol on its enzymic oxidation were studied. Methyl and glucosyl derivatives were synthesized using simple one-step methodologies. The kinetics of their enzymic oxidation by tyrosinases were defined. Substitution at the p-hydroxy group, by either glucose or methyl, abolished enzymic oxidation by both mushroom and grape tyrosinases. Substitution at the m-hydroxy group with methyl had a small effect, but substitution with glucose resulted in a much lower affinity of the enzymes for the glycoside. We suggest that glycosylation of polyphenols in nature helps to protect these vital molecules from enzymic oxidation, extending their half-life in the cell and maintaining their beneficial antioxidant capacity and biological properties.


An ab initio molecular orbital study of intramolecular hydrogen bonding in ortho-substituted arylamides: implications for the parameterization of molecular mechanics force fields.
The aromatic oligoamide (arylamide) foldamer class, characterized by the repetitive aromatic-amide pattern, is one of the most intensively studied foldamer families. In this article, the potential energy profiles with regard to torsional motions around the two types of aromatic-amide bonds (C(a)-C(p) and C(a)-N) are obtained at the B3LYP/6-311G(d,p) level of theory. The effect of ortho substituents with different hydrogen bonding abilities (OCH(3) vs. SCH(3) ) on the torsional potential profiles is analyzed in detail. There are several findings that have implications in foldamer design. The ortho-SCH(3) substituent on the benzene ring produces a much more flexible arylamide backbone with respect to the OCH(3) substituent, as it restricts the C(a)-C(p) torsion to a lesser extent. Interestingly, the rigidifying effect of the ortho-SCH(3) substituent on the C(a)-N torsion is very similar to that of the OCH(3) substituent on the same linkage type. In addition, the SCH(3) substituent prefers a perpendicular orientation with respect to the benzene ring to the in-plane one. It is also found that reparameterization of the corresponding torsional parameters, sometimes specific to the ortho substituent type, in the general amber force field is necessary for an accurate description of the backbone torsions in arylamides. Six sets of partial charge/torsional parameters for each linkage (C(a)-C(p) or C(a)-N)/substituent (OCH(3) or SCH(3) ) combination are obtained based on the ab initio torsional profiles. Initial assessments of these parameters show good agreement with the ab initio results.


Interleukin-1beta and signaling of interleukin-1 in vascular wall and circulating cells modulates the extent of neointima formation in mice.
Interleukin (IL)-1 is an important mediator of inflammation and cardiovascular disease. Here, we examined the role of IL-1 in arterial neointima formation. Carotid artery neointima was induced by ligation, and arteries were harvested 4 weeks after injury. The neointima/media of mice deficient in the IL-1 signaling receptor (IL-1R1(-/-)) was significantly reduced compared to IL-1R1(+/+) controls (P < 0.01). IL-1R1(+/+) mice receiving subcutaneous IL-1ra also had significantly reduced neointima/media compared with placebo (P < 0.05). IL-1beta(-/-) mice had reduced neointima/media compared to wild-type (P < 0.05), whereas IL-1alpha(-/-) mice were no different from controls. Mice deficient in the P2X(7) receptor (involved in IL-1 release) or caspase-1 (involved in IL-1 activation) did not differ in their response to carotid ligation compared to controls. To examine the site of IL-1 signaling, we generated chimeric mice. IL-1R1(+/+) mice receiving IL-1R1(-/-) marrow and IL-1R1(-/-) mice receiving IL-1R1(+/+) marrow both had significantly reduced neointima/media compared with IL-1R1(+/+) to IL-1R1(+/+) (P < 0.05) but had significantly greater neointima/media than IL-1R1(-/-) to IL-1R1(-/-) controls (P < 0.05). These data confirm the importance of IL-1beta signaling in mediating arterial neointima formation and suggest the involvement of IL-1 signaling in both circulating and arterial wall cells. Furthermore, receptor antagonism may be a better therapeutic target than interruption of IL-1beta processing or release.


Diffraction effects in the propagation of radiation in polarizable layers.
The very low transmission of light through holes smaller than the wavelength has been found to be enhanced for subwavelength apertures in metallic surfaces with periodic corrugations. This effect has been attributed to the interaction of light with surface plasmons. Similar effects obtained subsequently for non-metallic surfaces have been attributed to evanescent waves on the surface produced by the diffracted Bloch waves from different points in the array. We present an exact solution of Maxwell's equations in the discrete dipole approximation (DDA) for a periodic array of polarizable point dipoles in a layer. Metallic as well as non metallic layers are described. When the wavelength is smaller than the lattice period there is a Bragg's scattered wave, while for subwavelength conditions an evanescent wave on the surface appears. The transmission/reflection coefficients are found to oscillate as a function of frequency, with resonances occurring in a broad range of frequencies depending on the polarizability, at which the evanescent field is enhanced. A detailed study is presented for nanostructured arrays. We find that this model agrees with features observed in experiments through hole arrays supporting the role played by diffraction during light transmission through such arrays without invoking surface plasmons and providing a base to analyze more complex geometries.


Mesalamine (5-ASA) for the prevention of recurrent diverticulitis.
Diverticular disease is a common condition that increases in prevalence with age. Recent theories on the pathogenesis of diverticular inflammation have implicated chronic inflammation similar to that seen in ulcerative colitis. Mesalamine, or 5-aminosalicylic acid (5-ASA), is a mainstay of therapy for individuals with ulcerative colitis. Accordingly, 5-ASA has been studied for prevention of recurrent diverticulitis. To evaluate the efficacy of mesalamine (5-ASA) for prevention of recurrent diverticulitis. We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 8), in the Cochrane Library; Ovid MEDLINE (from 1950 to 9 September 2017); Ovid Embase (from 1974 to 9 September 2017); and two clinical trials registries for ongoing trials - Clinicaltrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform database (9 September 2017).We also searched proceedings from major gastrointestinal conferences - Digestive Disease Week (DDW), United European Gastroenterology Week (UEGW), and the American College of Gastroenterology (ACG) Annual Scientific Meeting - from 2010 to September 2017. In addition, we scanned reference lists from eligible publications, and we contacted corresponding authors to ask about additional trials. We included randomised controlled clinical trials comparing the efficacy of 5-ASA versus placebo or another active drug for prevention of recurrent diverticulitis. We used standard methodological procedures as defined by Cochrane. Three review authors assessed eligibility for inclusion. Two review authors selected studies, extracted data, and assessed methodological quality independently. We calculated risk ratios (RRs) for prevention of diverticulitis recurrence using an intention-to-treat principle and random-effects models. We assessed heterogeneity using criteria for Chi2 (P < 0.10) and I2 tests (> 50%). To explore sources of heterogeneity, we conducted a priori subgroup analyses. To assess the robustness of our results, we carried out sensitivity analyses using different summary statistics (RR vs odds ratio (OR)) and meta-analytical models (fixed-effect vs random-effects). We included in this review seven studies with a total of 1805 participants. We judged all seven studies to have unclear or high risk of bias. Investigators found no evidence of an effect when comparing 5-ASA versus control for prevention of recurrent diverticulitis (31.3% vs 29.8%; RR 0.69, 95% confidence interval (CI) 0.43 to 1.09); very low quality of evidence).Five of the seven studies provided data on adverse events of 5-ASA therapy. The most commonly reported side effects were gastrointestinal symptoms (epigastric pain, nausea, and diarrhoea). No significant difference was seen between 5-ASA and control (67.8% vs 64.6%; RR 0.98, 95% CI 0.91 to 1.06; P = 0.63; moderate quality of evidence), nor was significant heterogeneity observed (I2 = 0%; P = 0.50). The effects of 5-ASA on recurrence of diverticulitis are uncertain owing to the small number of heterogenous trials included in this review. Rates of recurrent diverticulitis were similar among participants using 5-ASA and control participants. Effective medical strategies for prevention of recurrent diverticulitis are needed, and further randomised, double-blinded, placebo-controlled trials of rigorous design are warranted to specify the effects of 5-ASA (mesalamine) in the management of diverticulitis.


Inhibition of AMP-Activated Protein Kinase at the Allosteric Drug-Binding Site Promotes Islet Insulin Release.
The AMP-activated protein kinase (AMPK) is a metabolic stress-sensing αβγ heterotrimer responsible for energy homeostasis. Pharmacological inhibition of AMPK is regarded as a therapeutic strategy in some disease settings including obesity and cancer; however, the broadly used direct AMPK inhibitor compound C suffers from poor selectivity. We have discovered a dihydroxyquinoline drug (MT47-100) with novel AMPK regulatory properties, being simultaneously a direct activator and inhibitor of AMPK complexes containing the β1 or β2 isoform, respectively. Allosteric inhibition by MT47-100 was dependent on the β2 carbohydrate-binding module (CBM) and determined by three non-conserved CBM residues (Ile81, Phe91, Ile92), but was independent of β2-Ser108 phosphorylation. Whereas MT47-100 regulation of total cellular AMPK activity was determined by β1/β2 expression ratio, MT47-100 augmented glucose-stimulated insulin secretion from isolated mouse pancreatic islets via a β2-dependent mechanism. Our findings highlight the therapeutic potential of isoform-specific AMPK allosteric inhibitors.


Evidence for recent diarrhoeal morbidity as a risk factor for persistent diarrhoea: a case-control study.
The association between persistent diarrhoea and 'recent morbidity' defined as that occurring within the two-month period immediately preceding the onset of persistent diarrhoea was investigated in a population-based case-control study in rural North India. In two separate matched case-control analyses children with persistent diarrhoea (cases) were compared to population controls (five controls matched to each case) and acute diarrhoeal controls (three controls matched to each case). After correcting for possible confounding variables, comparing children with persistent diarrhoea and matched population controls, presence of a recent diarrhoeal illness was significantly associated with persistent diarrhoea with an odds ratio (OR) 2.6 (95%) confidence interval (CI): 1.1-7.1; p less than 0.05); during infancy this OR was 5.2 (95% CI: 1.0-31.9; p less than 0.01). Comparing children with persistent diarrhoea to matched acute diarrhoeal controls, presence of recent diarrhoeal illness was associated with an OR of 5.1 (95% CI: 1.3-20.3) in favour of the episode becoming persistent; in infants this OR was 10.4 (95% CI: 1.1-132.4; p less than 0.001).


Dealkylation of 24-ethylsterols by Tetrahymena pyriformis.
When Tetrahymena pyriformis was incubated with sitosterol ([24R]-24-ethylcholest-5-en-3 beta-ol]) or its trans-delta22-derivative (stigmasterol), the C-24-dealkylated product, cholesta-5,7,trans-22-trien-3 beta-ol, was obtained in both cases. 24(S)-24-Ethylcholesta-5,7,trans-22-trien-3 beta-ol also was found to be a metabolite. When sitosterol was the substrate, 24(R)-24-ethylcholesta-5,7-dien-3 beta-ol was obtained as a third product. Identifications were made by mass spectroscopy, quantitative chromatography, labeling with 14C, and by other means. The dealkylated product (cholestratrienol) represented 30 percent of the sterols isolable after incubation. The administration of sterols to this organism did not induce sterol biosynthesis, since 2-14C-mevalonate failed to yield radioactive sterol in the presence of added stigmasterol.


The optics and performance of dual-focus fluorescence correlation spectroscopy.
Fluorescence correlation spectroscopy (FCS) is an important spectroscopic technique which can be used for measuring the diffusion and thus size of fluorescing molecules at pico- to nanomolar concentrations. Recently, we introduced an extension of conventional FCS, which is called dual-focus FCS (2fFCS) and allows absolute diffusion measurements with high precision and repeatability. It was shown experimentally that the method is robust against most optical and sample artefacts which are troubling conventional FCS measurements, and is furthermore able to yield absolute values of diffusion coefficients without referencing against known standards. However, a thorough theoretical treatment of the performance of 2fFCS is still missing. The present paper aims at filling this gap. Here, we have systematically studied the performance of 2fFCS with respect to the most important optical and photophysical factors such as cover slide thick-ness, refractive index of the sample, laser beam geometry, and optical satu-ration. We show that 2fFCS has indeed a superior performance when com-pared with conventional FCS, being mostly insensitive to most potential ab-errations when working under optimized conditions.


Toward Accurate, Policy-Relevant Fossil Fuel CO2 Emission Landscapes.
The bottom-up (BU) approach has been used to develop spatiotemporally resolved, sectorally disaggregated fossil fuel CO2 (FFCO2) emission data products. These efforts are critical constraints to atmospheric assessment of anthropogenic fluxes in addition to offering the climate change policymaking community usable information to guide mitigation. In the United States, there are two high-resolution FFCO2 emission data products, Vulcan and the Anthropogenic Carbon Emissions System (ACES). As a step toward developing improved, accurate, and detailed FFCO2 emission landscapes, we perform a comparison of the two data products. We find that while agreeing on total FFCO2 emissions at the aggregate scale (relative difference = 1.7%), larger differences occur at smaller spatial scales and in individual sectors. Differences in the smaller-emitting sectors are likely errors in ACES input data or emission factors. ACES advances the approach for estimating emissions in the gas and oil sector, while Vulcan shows better geocoordinate correction in the electricity production sector. Differences in the subcounty residential and commercial building sectors are driven by different spatial proxies and suggest a task for future investigation. The gridcell absolute median relative difference, a measure of the average gridcell-scale relative difference, indicates a 53.5% difference. The recommendation for improved BU granular FFCO2 emission estimation includes review, assessment, and archive of point source geolocations, CO emission input data, CO and CO2 emission factors, and uncertainty approaches including those due to spatial errors. Finally, intensives where local utility data are publicly available could test the spatial proxies used in estimating residential and commercial building emissions. These steps toward best practices will lead to more accurate, granular emissions, enabling optimal emission mitigation policy choices.


Design tool for TOF and SL based 3D cameras.
Active illumination 3D imaging systems based on Time-of-flight (TOF) and Structured Light (SL) projection are in rapid development, and are constantly finding new areas of application. In this paper, we present a theoretical design tool that allows prediction of 3D imaging precision. Theoretical expressions are developed for both TOF and SL imaging systems. The expressions contain only physically measurable parameters and no fitting parameters. We perform 3D measurements with both TOF and SL imaging systems, showing excellent agreement between theoretical and measured distance precision. The theoretical framework can be a powerful 3D imaging design tool, as it allows for prediction of 3D measurement precision already in the design phase.


Clinical outcomes in infants with cystic fibrosis transmembrane conductance regulator (CFTR) related metabolic syndrome.
An unavoidable outcome of cystic fibrosis newborn screening (CF NBS) programs is the detection of infants with an indeterminate diagnosis. The United States CF Foundation recently proposed the term cystic fibrosis transmembrane conductance regulator related metabolic syndrome (CRMS) to describe infants with elevated immunoreactive trypsinogen (IRT) on NBS who do not meet diagnostic criteria for CF. The objective of this study was to describe the clinical outcomes of infants with CRMS identified through an IRT/DNA algorithm. We reviewed the records of all infants with CRMS diagnosed at our CF Center from 2002 to 2010. We identified 12 infants, and compared them to 27 infants diagnosed with CF by NBS. Compared to CF patients, CRMS patients were more likely to be pancreatic sufficient as assessed by fecal elastase measurement (100% vs. 8%, P < 0.01). Their weight for age percentile was normal from birth. A positive oropharyngeal (OP) culture for Pseudomonas aeruginosa (Pa) was found in 25% of CRMS patients. One patient with the F508del/R117H/7T genotype was reassigned the diagnosis of CF after he had a positive OP culture for Pa, and his follow up sweat Cl at 1 year of life was 73 mmol/L. CF patients were more likely to receive oral antibiotics and be hospitalized for pulmonary symptoms. Our results indicate that CRMS patients can develop signs of CF disease, but have a milder clinical course than CF infants. Close initial monitoring of these patients is warranted. Pediatr. Pulmonol. 2011; 46:1079-1084. © 2011 Wiley Periodicals, Inc.


A novel leg-shaking Drosophila mutant defective in a voltage-gated K(+)current and hypersensitive to reactive oxygen species.
1,1'-Dimethyl-4,4'-bipyridinium dichloride (methyl viologen; paraquat), an herbicide that causes depletion of NADPH and generates excessive reactive oxygen species (ROS) in vivo, has been used to screen for ROS-sensitive Drosophila mutants. One mutant so isolated, named quiver(1) (qvr(1)), has a leg-shaking phenotype. Mutants of the Shaker (Sh), Hyperkinetic (Hk), and ether a go-go (eag) genes, which encode different K(+) channel subunits that regulate the A-type K(+) current (I(A)) in different ways, exhibit leg shaking under ether anesthesia and have heightened metabolic rates and shortened life spans. We found that Sh, Hk, and eag mutant flies were all hypersensitive to paraquat. Double-mutant combinations among the three channel mutations and qvr(1) had drastically enhanced sensitivity to paraquat. Synaptic transmission at the larval neuromuscular junction was increased in the qvr(1) mutant to the level of Sh mutants. Similar to eag Sh double mutants, double mutants of eag and qvr(1) showed striking enhancement in synaptic transmission and a wings-down phenotype, the hallmarks of extreme hyperexcitability. Voltage-clamp experiments demonstrated that the qvr(1) mutation specifically disrupted the Sh-dependent I(A) current without altering the other currents [I(K), Ca(2+)-activated fast (I(CF)) and slow (I(CS)) currents, and I(Ca)] in larval muscles. Several deficiency strains of the qvr locus failed to complement qvr(1) and confirmed that ether-induced leg shaking, reduced I(A) current, and paraquat hypersensitivity map to the same locus. Our results suggest that the qvr gene may encode a novel K(+) channel-related polypeptide and indicate a strong link between a voltage-activated K(+) current and vulnerability to ROS.