Antibiotic resistance of Helicobacter pylori in Nanjing, China: a cross-section study from 2018 to 2023.
The increasing prevalence of antibiotic resistance in cases of Helicobacter pylori (H. pylori) infection has emerged as a significant global issue. This study offers a comprehensive examination of the alterations in drug resistance exhibited by H. pylori in the Nanjing region of China during the preceding five years. Another important objective is to investigate the influence of levofloxacin medication history on genotypic and phenotypic resistance. This research screened 4277 individuals diagnosed with H. pylori infection between April 2018 and May 2023. The phenotype and genotypic resistance were evaluated using the Kirby-Bauer disk diffusion and PCR method. The most recent primary resistance rates for metronidazole, clarithromycin, levofloxacin, amoxicillin, furazolidone, and tetracycline were recorded at 77.23% (2385/3088), 37.24% (1150/3088), 27.72% (856/3088), 0.52% (16/3088), 0.19% (6/3088), and 0.06% (2/3088), respectively. For the recent five years, we observed a notable upsurge in the rate of metronidazole resistance and a slight elevation of clarithromycin and levofloxacin resistance. The documented resistance rates to single-drug, dual-drug, triple-drug, and quadruple-drug regimens were 35.39%, 28.32%, 25.72%, and 0.21%, respectively. The prevalence of multidrug-resistant strains escalated, rising from 37.96% in 2018 to 66.22% in 2023. The rate of phenotypic and genotypic resistance rate (57.10% and 65.57%) observed in strains obtained from patients without a levofloxacin treatment history was significantly lower than the rate in strains obtained from those with a history of levofloxacin treatment (88.73% and 94.74%). The prevailing gyrA mutations were primarily N87K (52.35%, 345/659), accompanied by D91N (13.96%, 92/659), and closely followed by D87G (10.77%, 71/659). For gyrA mutations, the 91-amino acid mutants exhibit a higher likelihood of discrepancies between phenotypic and genotypic resistance than the 87-amino acid mutants. The extent of antibiotic resistance within H. pylori remains substantial within the Nanjing region. If levofloxacin proves ineffective in eradicating H. pylori during the initial treatment, its use in subsequent treatments is discouraged. The employment of levofloxacin resistance genotype testing can partially substitute conventional antibiotic sensitivity testing. Notably, predicting phenotypic resistance of levofloxacin through PCR requires more attention to the mutation type of gyrA to improve prediction accuracy.


Association between lipid levels and the risk of Parkinson's disease in individuals with diabetes mellitus: A nationwide population-based cohort study.
Many studies have examined the positive association between diabetes mellitus (DM) and the risk of Parkinson's disease (PD). Dyslipidemia has been reported to be prevalent in patients with diabetes; thus, lipid levels and the drugs for dyslipidemia could influence the development of PD in patients with DM. This study aimed to examine the association between lipid levels and the risk of PD in individuals with DM and evaluate whether the association changes with the use of statins. This nationwide population-based retrospective cohort study included individuals with DM according to the International Classification of Diseases between 2009 and 2012. Among the 2,361,633 patients with DM followed up for up to 9 years, 17,046 were newly diagnosed with PD. Patients with DM were categorized into quartile groups of total cholesterol, low-density lipoprotein cholesterol, and triglyceride levels. There was an inverse association between lipid levels and PD development in the unadjusted model; however, this relationship became less significant after adjusting the use of statins in triglyceride and total cholesterol. In the analysis stratified by statin use, total cholesterol level was associated with decreased PD risk in non-statin users with DM; however, there was no significant association between total cholesterol level and PD risk in statin users. We found an inverse relationship between lipid levels and PD risk in patients with DM, which was influenced by statin use. Future studies about optimal target lipid levels relevant to PD risk considering statin dose in DM patients are needed.


Factors Affecting Thyroid Elastography in Healthy Children and Patients with Hashimoto's Thyroiditis
Hashimoto's thyroiditis (HT) is the most common form of thyroiditis in childhood. In addition to thyroid ultrasonography, shear-wave elastography (SWE) can evaluate thyroid parenchyma tissue stiffness, and more detailed findings can be obtained with this method. We aimed to evaluate the relationship between SWE values and clinical, biochemical and hormonal parameters of patients with HT and in healthy individuals. We compared 46 newly diagnosed HT cases with 46 healthy controls. We examined the effect of all metabolic parameters and thyroid-related markers on SWE values. The mean SWE values in those patients with euthyroid HT were 12.5±5.1 kilopascal (kPa), whereas it was 8.2±2.82 kPa in healthy controls (p<0.001). Although the clinical [age, gender and body mass index (BMI)] and laboratory parameters (such as thyroid function tests, homeostasis model assessment of insulin resistance, insulin-like growth factor-1 values, which we think may affect SWE scores) of those children with HT and the healthy controls were statistically similar (p>0.05), except for their thyroid autoantibodies and thyroglobulin, SWE values and thyroid volume were significantly higher in those individuals with HT (p<0.001). Multiple linear regression analysis was performed to evaluate the direction and degree of the effect of the variables on thyroid elasticity scores. It was observed that age (p=0.002), BMI standard deviation score (SDS) (p=0.04) and anti-thyroid peroxidase (p=0.008) levels were effective on the thyroid elasticity score in the regression model. We detected a SWE cut-off value of 9.68 kPa with 68% sensitivity and 72% specificity, a 70% positive predictive value, and a 69% negative predictive value in thyroid elastography when differentiating between cases with HT and healthy controls. Our results show that no metabolic factor other than BMI SDS has any effect on SWE scores, especially in healthy children. There was a positive correlation between BMI SDS and SWE in healthy children (r=0.353; p=0.02), but not in those patients with HT (r=0.196; p=0.19). Likewise, age is another factor affecting SWE only in healthy children. We do not recommend routine evaluation of any laboratory parameters other than thyroid functions before thyroid elastography.


Heat Shock Protein 47 Maintains Cancer Cell Growth by Inhibiting the Unfolded Protein Response Transducer IRE1α.
HSP47 is a collagen-specific protein chaperone expressed in fibroblasts, myofibroblasts, and stromal cells. HSP47 is also expressed in and involved in growth of cancer cells in which collagen levels are extremely low. However, its role in cancer remains largely unclear. Here, we showed that HSP47 maintains cancer cell growth via the unfolded protein response (UPR), the activation of which is well known to be induced by endoplasmic reticulum (ER) stress. We observed that HSP47 forms a complex with both the UPR transducer inositol-requiring enzyme 1α (IRE1α) and ER chaperone BiP in cancer cells. Moreover, HSP47 silencing triggered dissociation of BiP from IRE1α and IRE1α activation, followed by an increase in the intracellular level of reactive oxygen species (ROS). Increase in ROS induced accumulation of 4-hydroxy-2-nonenal-protein adducts and activated two UPR transducers, PKR-like ER kinase (PERK) and activating transcription factor 6α (ATF6α), resulting in impaired cancer cell growth. Our work indicates that HSP47 expressed in cancer cells relieves the ER stress arising from protein synthesis overload within these cells and tumor environments, such as stress induced by hypoxia, low glucose, and pH. We also propose that HSP47 has a biological role that is distinct from its normal function as a collagen-specific chaperone. IMPLICATIONS: HSP47 maintains cancer cell growth by inhibiting IRE1α.


Self-Supervised Electroencephalogram Representation Learning for Automatic Sleep Staging: Model Development and Evaluation Study.
Deep learning models have shown great success in automating tasks in sleep medicine by learning from carefully annotated electroencephalogram (EEG) data. However, effectively using a large amount of raw EEG data remains a challenge. In this study, we aim to learn robust vector representations from massive unlabeled EEG signals, such that the learned vectorized features (1) are expressive enough to replace the raw signals in the sleep staging task, and (2) provide better predictive performance than supervised models in scenarios involving fewer labels and noisy samples. We propose a self-supervised model, Contrast with the World Representation (ContraWR), for EEG signal representation learning. Unlike previous models that use a set of negative samples, our model uses global statistics (ie, the average representation) from the data set to distinguish signals associated with different sleep stages. The ContraWR model is evaluated on 3 real-world EEG data sets that include both settings: at-home and in-laboratory EEG recording. ContraWR outperforms 4 recently reported self-supervised learning methods on the sleep staging task across 3 large EEG data sets. ContraWR also supersedes supervised learning when fewer training labels are available (eg, 4% accuracy improvement when less than 2% of data are labeled on the Sleep EDF data set). Moreover, the model provides informative, representative feature structures in 2D projection. We show that ContraWR is robust to noise and can provide high-quality EEG representations for downstream prediction tasks. The proposed model can be generalized to other unsupervised physiological signal learning tasks. Future directions include exploring task-specific data augmentations and combining self-supervised methods with supervised methods, building upon the initial success of self-supervised learning reported in this study.


Accommodation as a function of age and the linearity of the response dynamics.
The changes with age in the accommodation responses to dynamic stimuli can reveal useful information on the factors underlying presbyopia development. Analysis of the monocular accommodation responses of 19 normal observers (ages 18-49 years) to stimuli whose vergence varied sinusoidally with time at different temporal frequencies (peak-to-peak stimulus 1.33-2.38 D, at 0.05-1.00 Hz) showed that at all ages both the gain and phase of the response were essentially linear functions of the temporal frequency. Extrapolation of least-squares, regression line fits to the gain data for each subject gave the gain at zero frequency, G0, and the cut-off frequency, fc, at which the gain fell to zero. G0 reduced with age but fc remained essentially constant at about 1.7 Hz, up to at least the age of about 40. The magnitude of the response to step stimuli covering the same stimulus range was well correlated with the value of G0. The linear changes in phase lag with temporal frequency corresponded to simple time delays td. The time lag varied from close to zero for the youngest subjects to about 0.5 s for the subjects in their late forties. There was substantial variation between the responses of subjects of similar age: those subjects with high values of G0 also tended to have low values of td, both effects probably being due to the superior ability of some individuals to predict the sinusoidal changes in the accommodation stimulus. Comparison of theoretical step responses, derived by applying linear theory to the parameters obtained from the results for the sinusoidal stimuli, with the actual responses to unpredictable steps for the same subjects supports the view that prediction effects and other possible factors make linear theory inapplicable to this type of data. The results are discussed in the context of current ideas on the development of presbyopia: it is suggested that the constancy of fc with age is the result of the ciliary body maintaining its efficiency, whereas the fall in G0 and increase in td result from increases in lens rigidity.


Spatial and habitat distribution of Anopheles gambiae and Anopheles arabiensis (Diptera: Culicidae) in Banambani village, Mali.
We studied the larval distribution and composition of Anopheles arabiensis Patton, An. gambiae s.s. Giles, and its forms, among local habitats; and their association with the adults between these habitats in Banambani village, Mali during the mid-rainy seasons of 1997-1999. For species and form identification we used polymerase chain reaction (PCR) and PCR-restriction fragment-length polymorphism (RFLP). Differences among species in the distribution of larvae were observed in 1998, but not in 1997 or 1999, although they were on the borderline of statistical significance. Differences among the M and S molecular forms were statistically significant in 1999 when rainfall was high, but not in the two prior, drier sampling periods. Combining all information into the Fisher multiple comparisons test, there were statistically significant differences between species and molecular forms during the 3-yr study period. Hybrid larvae between the M and S forms were observed (0.57%), the first such observation to our knowledge. In spite of differences among larval distribution, no differences of adult species composition were observed among habitats. Factors that influence the distributions of An. gambiae larval populations are discussed.


Revisiting the Warburg effect in cancer cells with proteomics. The emergence of new approaches to diagnosis, prognosis and therapy.
Most cancer cells exhibit elevated levels of glycolysis and this metabolic pathway seems to be related to a greater glucose uptake. This phenomenon, known as the Warburg effect, is considered one of the most fundamental metabolic alterations during malignant transformation. Originally, Warburg hypothesised that the aerobic glycolysis of cancer cells could be just an aspect of a more complex metabolic adaptation. However, this intriguing discovery was partially misinterpreted and disregarded over time. In recent years, the peculiarities of cancer cell metabolism have been re-evaluated in light of new metabolic data that seem to confirm and to widen the original concept of the Warburg effect. In fact, biochemical, molecular, and, above all, proteomic studies on the multifaceted roles of glycolytic enzymes in cancer cells in general, and in cancer stem cells in particular, seem to suggest more complex functional adaptations. These adaptations result in significantly altered protein expression patterns, and they have fundamental implications for diagnosis, prognosis and therapy. Revisiting the Warburg effect in cancer cells with a proteomic approach could deepen our knowledge of cancer cell metabolism and of cancer cell biology in general. Moreover, by identifying useful diagnostic, prognostic and therapeutic targets, it could significantly impact clinical practice.


Scopafungin, a crystalline antibiotic produced by Streptomyces hygroscopicus var. enhygrus var. nova.
Scopafungin (U-29,479) is a crystalline, nonpolyenic antimicrobial agent obtained from the culture broth of Streptomyces hygroscopicus var. enhygrus var. nova UC-2397. Scopafungin inhibits, in vitro, a variety of pathogenic fungi, yeasts, and gram-positive bacteria.


Translog, a web browser for studying the expression divergence of homologous genes.
Increasing amount of data from comparative genomics, and newly developed technologies producing accurate gene expression data facilitate the study of the expression divergence of homologous genes. Previous studies have individually highlighted factors that contribute to the expression divergence of duplicate genes, e.g. promoter changes, exon structure heterogeneity, asymmetric histone modifications and genomic neighborhood conservation. However, there is a lack of a tool to integrate multiple factors and visualize their variety among homologous genes in a straightforward way. We introduce Translog (a web-based tool for Transcriptome comparison of homologous genes) that assists in the comparison of homologous genes by displaying the loci in three different views: promoter view for studying the sharing/turnover of transcription initiations, exon structure for displaying the exon-intron structure changes, and genomic neighborhood to show the macro-synteny conservation in a larger scale. CAGE data for transcription initiation are mapped for each transcript and can be used to study transcription turnover and expression changes. Alignment anchors between homologous loci can be used to define the precise homologous transcripts. We demonstrate how these views can be used to visualize the changes of homologous genes during evolution, particularly after the 2R and 3R whole genome duplication. We have developed a web-based tool for assisting in the transcriptome comparison of homologous genes, facilitating the study of expression divergence.


Dynein axonemal heavy chain 10 deficiency causes primary ciliary dyskinesia in humans and mice.
Primary ciliary dyskinesia (PCD) is a congenital, motile ciliopathy with pleiotropic symptoms. Although nearly 50 causative genes have been identified, they only account for approximately 70% of definitive PCD cases. Dynein axonemal heavy chain 10 (DNAH10) encodes a subunit of the inner arm dynein heavy chain in motile cilia and sperm flagella. Based on the common axoneme structure of motile cilia and sperm flagella, DNAH10 variants are likely to cause PCD. Using exome sequencing, we identified a novel DNAH10 homozygous variant (c.589C > T, p.R197W) in a patient with PCD from a consanguineous family. The patient manifested sinusitis, bronchiectasis, situs inversus, and asthenoteratozoospermia. Immunostaining analysis showed the absence of DNAH10 and DNALI1 in the respiratory cilia, and transmission electron microscopy revealed strikingly disordered axoneme 9+2 architecture and inner dynein arm defects in the respiratory cilia and sperm flagella. Subsequently, animal models of Dnah10-knockin mice harboring missense variants and Dnah10-knockout mice recapitulated the phenotypes of PCD, including chronic respiratory infection, male infertility, and hydrocephalus. To the best of our knowledge, this study is the first to report DNAH10 deficiency related to PCD in human and mouse models, which suggests that DNAH10 recessive mutation is causative of PCD.


Isoenzymes of glutathione transferase in rat kidney cytosol.
Glutathione transferases from rat kidney cytosol were purified about 40-fold by chromatography on S-hexylglutathione linked to epoxy-activated Sepharose 6B. Further purification by fast protein liquid chromatography with chromatofocusing in the pH interval 10.6-7.6 resolved five major peaks of activity with 1-chloro-2,4-dinitrobenzene as the second substrate. Four of the peaks were identified with rat liver transferases 1-1, 1-2, 2-2 and 4-4 respectively. The criteria used for identification included physical properties, reactions with specific antibodies, substrate specificities and sensitivities to several inhibitors. The fourth major peak is a 'new' form of transferase, which has not been found in rat liver. This isoenzyme, glutathione transferase 7-7, has a lower apparent subunit Mr than any of the transferases isolated from rat liver cytosol, and does not react with antibodies raised against the liver enzymes. Glutathione transferases 3-3 and 3-4, which are abundant in liver, were only present in very small amounts. In a separate chromatofocusing separation in a lower pH interval, an additional peak was eluted at pH 6.3. This isoenzyme is characterized by its high activity with ethacrynic acid.


Variation in provider vaccine purchase prices and payer reimbursement.
The purpose of this work was to collect data regarding vaccine prices and reimbursements in private practices. Amid reports of physicians losing money on vaccines, there are limited supporting data to show how much private practices are paying for vaccines and how much they are being reimbursed by third-party payers. We conducted a cross-sectional survey of a convenience sample of private practices in 5 states (California, Georgia, Michigan, New York, and Texas) that purchase vaccines for administration to privately insured children/adolescents. Main outcome measures included prices paid to purchase vaccines recommended for children and adolescents and reimbursement from the 3 most common, non-Medicaid payers for vaccine purchase and administration. Detailed price and reimbursement data were provided by 76 practices. There was a considerable difference between the maximum and minimum prices paid by practices, ranging from $4 to more than $30 for specific vaccines. There was also significant variation in insurance reimbursement for vaccine purchase, with maximum and minimum reimbursements for a single vaccine differing from $8 to more than $80. Mean net yield per dose (reimbursement for vaccine purchase minus price paid per dose) varied across vaccines from a low of approximately $3 to more than $24. Reimbursement for the first dose of vaccine administered ranged from $0 to more than $26, with a mean of $16.62. There is a wide range of prices paid by practices for the same vaccine product and in the reimbursement for vaccines and administration fees by payers. This variation highlights the need for individual practices to understand their own costs and reimbursements and to seek opportunities to reduce costs and increase reimbursements.


Comparison of population-averaged and cluster-specific models for the analysis of cluster randomized trials with missing binary outcomes: a simulation study.
The objective of this simulation study is to compare the accuracy and efficiency of population-averaged (i.e. generalized estimating equations (GEE)) and cluster-specific (i.e. random-effects logistic regression (RELR)) models for analyzing data from cluster randomized trials (CRTs) with missing binary responses. In this simulation study, clustered responses were generated from a beta-binomial distribution. The number of clusters per trial arm, the number of subjects per cluster, intra-cluster correlation coefficient, and the percentage of missing data were allowed to vary. Under the assumption of covariate dependent missingness, missing outcomes were handled by complete case analysis, standard multiple imputation (MI) and within-cluster MI strategies. Data were analyzed using GEE and RELR. Performance of the methods was assessed using standardized bias, empirical standard error, root mean squared error (RMSE), and coverage probability. GEE performs well on all four measures--provided the downward bias of the standard error (when the number of clusters per arm is small) is adjusted appropriately--under the following scenarios: complete case analysis for CRTs with a small amount of missing data; standard MI for CRTs with variance inflation factor (VIF) <3; within-cluster MI for CRTs with VIF≥3 and cluster size>50. RELR performs well only when a small amount of data was missing, and complete case analysis was applied. GEE performs well as long as appropriate missing data strategies are adopted based on the design of CRTs and the percentage of missing data. In contrast, RELR does not perform well when either standard or within-cluster MI strategy is applied prior to the analysis.


lontophoresis: Clinical Research in Musculoskeletal lnf lammatory Conditions.
Fifty patients with various musculoskeletal inflammatory conditions were treated with iontophoresis (direct current 5 milliamperes, 20 minutes). The treatment drugs were 1 cubic centimeter, 4 milligrams per milliliter of dexamethasone sodium phosphate (Decadron) combined with 2 cubic centimeters of 4% Xylocaine. Thirty-eight of the 50 patients had an excellent relief of pain and symptoms, seven reported moderate relief, and five patients had little or no change. There were no significant side effects. It was concluded that iontophoresis is an effective mode of delivering ionized antiinflammatory drugs to inflamed tissues. It is effective, painless, and safe, and provides a viable treatment. J Orthop Sports Phys Ther 1982;4(2):109-112.


Vitamin D Control of Hematopoietic Cell Differentiation and Leukemia.
It is now well known that in the mammalian body vitamin D is converted by successive hydroxylations to 1,25-dihydroxyvitamin D (1,25D), a steroid-like hormone with pleiotropic properties. These include important contributions to the control of cell proliferation, survival and differentiation, as well as the regulation of immune responses in disease. Here, we present recent advances in current understanding of the role of 1,25D in myelopoiesis and lymphopoiesis, and the potential of 1,25D and analogs (vitamin D derivatives; VDDs) for the control of hematopoietic malignancies. The reasons for the unimpressive results of most clinical studies of the therapeutic effects of VDDs in leukemia and related diseases may include the lack of a precise rationale for the conduct of these studies. Further, clinical trials to date have generally used extremely heterogeneous patient populations and, in many cases, small numbers of patients, generally without controls. Although low calcemic VDDs have been used and combined with agents that can increase the leukemia cell killing or differentiation effects in acute leukemias, the sequencing of agents used for combination therapy should to be more clearly delineated. Most importantly, it is recommended that in future clinical trials the rationale for the basis of the enhancing action of drug combinations should be clearly articulated and the effects on anticancer immunity should also be evaluated.


Effects of Early Intervention on Visual Function in Preterm Infants: A Randomized Controlled Trial.
Objectives: To determine the effectiveness of an early intervention program in enhancing visual function in very preterm infants. Methods: We conducted a RCT. We included preterm infants born between 25+0 and 29+6 weeks of gestational age (GA), without severe morbidities, and their families. Infants were randomized to either receive Standard Care (SC) or Early Intervention (EI). SC, according to NICU protocols, included Kangaroo Mother Care and minimal handling. EI included, in addition to routine care, parental training according to the PremieStart program, and multisensory stimulation (infant massage and visual interaction) performed by parents. Visual function was assessed at term equivalent age (TEA) using a prevalidated battery evaluating ocular spontaneous motility, ability to fix and follow a target, reaction to color, stripes discrimination and visual attention at distance. Results: Seventy preterm (EI n = 34, SC n = 36) infants were enrolled. Thirteen were excluded according to protocol. Fifty-seven infants (EI = 27, SC = 30) were assessed at TEA. The two groups were comparable for parental and infant characteristics. In total, 59% of infants in the EI group achieved the highest score in all the nine assessed items compared to 17% in the SC group (p = 0.001): all infants in both groups showed complete maturation in four items, but EI infants showed more mature findings in the other five items (ocular motility both spontaneous and with target, tracking arc, stripes discrimination and attention at distance). Conclusions: Our results suggest that EI has a positive effect on visual function maturation in preterm infants at TEA. Trial Registration: clinicalTrial.gov (NCT02983513).


Bioavailability of tramadol hydrochloride after administration via different routes in rats.
Tramadol is a synthetic non-opiate analgesic drug and effective for many kinds of chronic and acute pain. This study compared the bioavailability of tramadol after different administration routes in rats (oral, buccal and nasal). A simple HPLC analytical approach was used to determine the concentration of tramadol in plasma. The pharmacokinetic behavior and bioavailability of tramadol after administration via different routes in rats were investigated. Nasal and buccal administration of tramadol resulted in a fast increase followed by a rapid decrease in the plasma tramadol concentration. The Cmax values following buccal and nasal administration were 6 times and 20 times higher than that of oral administration, respectively, (6827.85 ± 7970.87 ng/ml, 22191.84 ± 5364.86 ng/ml, vs 1127.03 ± 778.34 ng/ml). The relative bioavailabilities of the nasal- and buccal-administered drug when compared with the oral route were 504.8% and 183.4%, respectively, which is much higher than that of oral administration. Nasal and buccal administration increased the bioavailability of tramadol, which may allow for a reduction in the dose of tramadol and a subsequent decrease in both side effects and toxicity. Therefore, this approach provides an effective choice for the delivery of tramadol, an analgesic drug.


Total Synthesis of Resiniferatoxin Enabled by Radical-Mediated Three-Component Coupling and 7-endo Cyclization.
Resiniferatoxin (1) belongs to a daphnane diterpenoid family and has strong agonistic effects on TRPV1, a transducer of noxious temperature and chemical stimuli. The densely oxygenated trans-fused 5/7/6-tricarbocycle (ABC-ring) of 1 presents a daunting challenge for chemical synthesis. Here we report the development of a novel radical-based strategy for assembling 1 from three components: A-ring 9, allyl stannane 18b, and C-ring 17b. The 6-membered 17b, prepared from d-ribose derivative 19, was designed to possess the caged orthoester structure with α-alkoxy selenide as a radical precursor. Upon treatment of 17b with 18b, 9, and V-40, the potently reactive α-alkoxy bridgehead radical was generated from 17b and then sequentially coupled with 9 and 18b to yield 16b. This first radical reaction formed the hindered C9,10-linkage between the A and C-rings and extended the C4-chain on the A-ring in a stereoselective fashion. After derivatization of 16b into 15, the remaining 7-membered B-ring was cyclized in the presence of n-Bu3SnH and V-40 by utilizing the xanthate on the C-ring as the radical precursor and the allylic dithiocarbonate as the terminator. The second radical reaction thus enabled not only the 7-endo cyclization but also construction of the C8-stereocenter and the C6-exo olefin. Tricycle 14 was elaborated into the targeted 1 by a series of highly optimized chemoselective reactions. The present total synthesis of 1 demonstrates the advantages of radical reactions for linking hindered bonds within carbocycles without damaging preexisting functionalities, thereby offering a new strategic design for multistep target-oriented synthesis.


Identifying amyotrophic lateral sclerosis through interactions with an internet search engine.
Amyotrophic lateral sclerosis (ALS), a motor neuron disease, remains a clinical diagnosis with an average time from onset of symptoms to diagnosis of about 1 year. Herein we examine the possibility that interactions with an internet search engine can identify people with ALS. We identified 285 anonymous Bing users whose queries indicated that they had been diagnosed with ALS and matched them to: (1) 3276 control users; and (2) 1814 users whose searches indicated they had ALS disease mimics. We tested whether the ALS group could be distinguished from controls and disease mimics based on search engine query data. Finally, we conducted a prospective validation from participants who provided access to their Bing search data. The model distinguished between the ALS group and controls with an area under the curve (AUC) of 0.81. Model scores for the ALS group differed from the disease mimics group (rank sum test, p < .05 with Bonferroni correction). Mild cognitive impairment could not be distinguished from ALS (p > .05). In the prospective analysis, the model reached an AUC of 0.74. Our results suggest that interactions with search engines should be further studied to understand the potential to act as a tool to assist in screening for ALS and to reduce diagnostic delay.


Sex work among female workers in the traditional mining sector in Mali - results from the ANRS-12339 Sanu Gundo cross-sectional study in 2015.
Female sex workers (FSW) in mining sites are considered to be at very high risk of HIV infection. We aimed to characterize FSW at the Kôkôyô artisanal gold mining site in Mali, and identify factors associated with sex work using data from ANRS-12339 Sanu Gundo, a cross-sectional survey conducted in 2015 at the mine by ARCAD-SIDA, a Malian non-governmental organisation. People attending HIV-prevention activities were invited to participate in the quantitative and qualitative parts of the survey. A probit logistic regression was used for data analysis. Of 101 women who participated in the survey, 26.7% reported sex work as their main activity. Multivariate analysis showed that the probability of sex work as a main activity decreased by 1% per 1-year age increase (p = 0.020). Sex work was significantly more likely to be reported by single, divorced and widowed women (25.4% probability; p = 0.007). FSW were significantly more likely to be non-Malian (36.3% probability; p = 0.003), more likely to have a secondary activity (77% probability; p = 0.002), to work fewer than 56h/week (40.2% probability; p = 0.001) and to be in good health (12.1% probability; p = 0.016). In addition, being aware of the existence of sexually transmitted infection, using psychoactive substances, and having unprotected receptive anal sex during the previous six months were significantly associated with sex work (50.2%; p = 0.006; 45.6%, p = 0.003; and 7.4%, p = 0.016 probability, respectively). Qualitative findings confirm that poverty and boyfriends' refusal to use condoms remain key barriers to systematic condom use among FSW.


CpcM posttranslationally methylates asparagine-71/72 of phycobiliprotein beta subunits in Synechococcus sp. strain PCC 7002 and Synechocystis sp. strain PCC 6803.
Cyanobacteria produce phycobilisomes, which are macromolecular light-harvesting complexes mostly assembled from phycobiliproteins. Phycobiliprotein beta subunits contain a highly conserved gamma-N-methylasparagine residue, which results from the posttranslational modification of Asn71/72. Through comparative genomic analyses, we identified a gene, denoted cpcM, that (i) encodes a protein with sequence similarity to other S-adenosylmethionine-dependent methyltransferases, (ii) is found in all sequenced cyanobacterial genomes, and (iii) often occurs near genes encoding phycobiliproteins in cyanobacterial genomes. The cpcM genes of Synechococcus sp. strain PCC 7002 and Synechocystis sp. strain PCC 6803 were insertionally inactivated. Mass spectrometric analyses of phycobiliproteins isolated from the mutants confirmed that the CpcB, ApcB, and ApcF were 14 Da lighter than their wild-type counterparts. Trypsin digestion and mass analyses of phycobiliproteins isolated from the mutants showed that tryptic peptides from phycocyanin that included Asn72 were also 14 Da lighter than the equivalent peptides from wild-type strains. Thus, CpcM is the methyltransferase that modifies the amide nitrogen of Asn71/72 of CpcB, ApcB, and ApcF. When cells were grown at low light intensity, the cpcM mutants were phenotypically similar to the wild-type strains. However, the mutants were sensitive to high-light stress, and the cpcM mutant of Synechocystis sp. strain PCC 6803 was unable to grow at moderately high light intensities. Fluorescence emission measurements showed that the ability to perform state transitions was impaired in the cpcM mutants and suggested that energy transfer from phycobiliproteins to the photosystems was also less efficient. The possible functions of asparagine N methylation of phycobiliproteins are discussed.


Altered kidney function on the Acute Medical Unit.
Reduced kidney function, whether acute or chronic, is a highly significant biomarker of in most clinical settings. This is particularly true on the acute medical take where altered renal function is associated with a worse prognosis, and may also impact on immediate management strategies such as drug choice, dosing and suspension, and the use of contrast agents for imaging. In this edition of the Acute Medical Journal, Yang et al present the results of their study describing the renal function and associated characteristics in 2,070 consecutive patients presenting on the unselected medical take at their hospital over a 40 day period. In this study, the authors provide a wealth of information on the general characteristics of acute medical patients admitted with altered kidney function, be it CKD or AKI. Importantly, both chronic kidney disease (CKD) and acute kidney injury (AKI) are very highly prevalent. Indeed, in this study more than 5% of all medical admissions actually demonstrated evidence of both.


A new cloning system for Bacillus subtilis comprising elements of phage, plasmid and transposon vectors.
A new cloning system for Bacillus subtilis was devised which makes use of a combination of Tn917-containing phage SP beta derivatives and Tn917-containing Escherichia coli-B. subtilis shuttle plasmids. This system allows the initial cloning of genes in single copy, via 'prophage transformation', with a selection for complementation of mutational defects in B. subtilis hosts and permits subsequent transfer of the cloned material by homologous recombination to low-copy and high-copy vectors that replicate in both B. subtilis and E. coli. Because cloned sequences are adjacent to pB322-derived DNA in the recombinant phages, inserts can also be 'rescued' directly from the phage DNA after digestion with appropriate restriction enzymes, circularization of the fragments by ligation and transformation of an E. coli recipient. Two genomic libraries of B. subtilis chromosomal Sau3A-generated partial-digest fragments in the size ranges of 5-8 kb and 8-10 kb were constructed and screened for the complementation of mutations aroI906, cysA14, dal-1, glyB133, metC3, purA16, purB33, thrA5, trpC2 and recE4. In all cases, specialized transducing phages carrying inserts that complemented the selected markers were recovered. Inserts complementing the dal-1 and trpC2 mutations could be transferred from recombinant phages to Tn917-containing plasmids by homologous recombination without in vitro subcloning. Another insert complementing the purB33 mutation was rescued directly into E. coli from a recombinant phage DNA.


The Correlation between EGFR Mutation Status and DNA Content of Lung Adenocarcinoma Cells in Pleural Effusion.
Objectives: Lung adenocarcinomas with or without epidermal growth factor receptor (EGFR) mutations have shown different drug effects against EGFR inhibitors. But it is not very clear if EGFR mutation status affects the biological behavior of lung adenocarcinoma, because tumor gene regulation is very complicated and can be affected by many factors. We aimed to explore if EGFR mutation status is related with tumor malignant degree by investigating the relevance of EGFR mutation status with DNA content and aneuploid peaks of lung adenocarcinoma cells in pleural fluids without using EGFR-TKIs. Materials and Methods: 591 cases of lung adenocarcinoma patients in Hebei Tumor Hospital who had undergone EGFR gene detection and DNA quantitative analysis were collected from January 2012 to August 2018.They were divided into two groups: EGFR mutant group and non-mutant group. EGFR mutations were detected by Amplification Refractory Mutation System (ARMS) and ABI 7500 Fluorescence quantitative PCR with pleural effusions. DNA content and aneuploid peaks were detected by LD DNA image cytometry (DNA-ICM). Rank-sum test of SPSS 16 was used for statistical analysis. Results: The maximum DI, the mean DI of the first 20 cells greater than 5C, the percentage of cells greater than 5C and the number of cells greater than 9C of the first 20 cells in the mutant group were all higher than those in the non-mutant group, having statistical significance (p<0.001); the peaks of aneuploid cells in the mutant group occurred more often than those in the non-mutant group, having statistical significance (p<0.001). Conclusions: Our study has shown that advanced lung adenocarcinomas with EGFR-mutations had higher DI values, more aneuploid cells and more frequent aneuploid peaks compared with those without EGFR-mutations, suggesting that advanced lung adenocarcinomas with EGFR mutations are more aggressive than those without EGFR mutations.


Predicting Empathy From Resting State Brain Connectivity: A Multivariate Approach.
Recent task fMRI studies suggest that individual differences in trait empathy and empathic concern are mediated by patterns of connectivity between self-other resonance and top-down control networks that are stable across task demands. An untested implication of this hypothesis is that these stable patterns of connectivity should be visible even in the absence of empathy tasks. Using machine learning, we demonstrate that patterns of resting state fMRI connectivity (i.e. the degree of synchronous BOLD activity across multiple cortical areas in the absence of explicit task demands) of resonance and control networks predict trait empathic concern (n = 58). Empathic concern was also predicted by connectivity patterns within the somatomotor network. These findings further support the role of resonance-control network interactions and of somatomotor function in our vicariously driven concern for others. Furthermore, a practical implication of these results is that it is possible to assess empathic predispositions in individuals without needing to perform conventional empathy assessments.


Potential health gains for patients with metastatic renal cell carcinoma in daily clinical practice: A real-world cost-effectiveness analysis of sequential first- and second-line treatments.
Randomised controlled trials have shown that targeted therapies like sunitinib are effective in metastatic renal cell carcinoma (mRCC). Little is known about the current use of these therapies, and their associated costs and effects in daily clinical practice. We estimated the real-world cost-effectiveness of different treatment strategies comprising one or more sequentially administered drugs. Analyses were performed using patient-level data from a Dutch population-based registry including patients diagnosed with primary mRCC from January 2008 to December 2010 (i.e., treated between 2008 and 2013). The full disease course of these patients was estimated using a patient-level simulation model based on regression analyses of the registry data. A healthcare sector perspective was adopted; total costs included healthcare costs related to mRCC. Cost-effectiveness was expressed in cost per life-year and cost per quality-adjusted life-year (QALY) gained. Probabilistic sensitivity analysis was conducted to estimate the overall uncertainty surrounding cost-effectiveness. In current daily practice, 54% (336/621) of all patients was treated with targeted therapies. Most patients (84%; 282/336) received sunitinib as first-line therapy. Of the patients receiving first-line therapy, 30% (101/336) also received second-line therapy; the majority was treated with everolimus (40%, 40/101) or sorafenib (28%, 28/101). Current treatment practice (including patients not receiving targeted therapy) led to 0.807 QALYs; mean costs were €58,912. This resulted in an additional €105,011 per QALY gained compared to not using targeted therapy at all. Forty-six percent of all patients received no targeted therapy; of these patients, 24% (69/285) was eligible for sunitinib. If these patients were treated with first-line sunitinib, mean QALYs would improve by 0.062-0.076 (where the range reflects the choice of second-line therapy). This improvement is completely driven by the health gain seen amongst patients eligible to receive sunitinib but did not receive it, who gain 0.558-0.684 QALYs from sunitinib. Since additional costs would be €7,072-9,913, incremental costs per QALY gained are €93,107-111,972 compared to current practice. Health can be gained if more treatment-eligible patients receive targeted therapies. Moreover, it will be just as cost-effective to treat these patients with sunitinib as current treatment practice.


Benign intestinal pneumatosis associated with congenital Morgagni-Larrey diaphragmatic hernia.
Intestinal pneumatosis (IN) is an uncommon radiological finding defined as the accumulation of air in the gastrointestinal tract wall. Its clinical signs are nonspecific and include symptoms such as diarrhea or abdominal pain. It includes benign entities (with subtle symptoms and the accumulation of air in the form of cysts that appear as clustered nodular lesions on the endoscopy, collapsible and soft); or severe cases (symptoms indicative of general health compromise and linear accumulation of air or free fluid suggestive of hollow viscus perforation); which require different management. We present the case of a patient diagnosed with benign intestinal pneumatosis (BIN), associated with anatomical changes due to a diaphragmatic hernia. CASE REPORT We report the case of an 86-year-old woman with a Morgani-Larrey congenital diaphragmatic hernia (HML) (2) admitted due to exacerbation of chronic baseline diarrhea. A colonoscopy with biopsies was performed, but the study was incomplete due to colonic torsion at the hepatic angle deriving from HML, with uncomplicated colonic mucosa and absence of cystic nodulations. Figure 1a. Biopsies ruled out organicity. The abdominal computed tomography (CT) scan performed revealed the accumulation of pneumoperitoneum bubbles in the distal ileum and suprahepatic wall without identification of continuity changes, or signs of visceral perforation. Figure 1b-c. The patient was diagnosed with BIN associated with an anatomical change (HML). Medical treatment was initiated with metronidazole at a dose of 1500 mg/day for 1 week, along with the patient's usual probiotics, and commercial compounds containing xyloglucan (pea protein) to restore the intestinal barrier function. (3). The patient was discharged with complete resolution of the diarrhea. No surgical intervention for her HML was required. DISCUSSION The clinical and radiological data in the presence of IN help us differentiate between severe cases and BIN, the latter being managed conservatively without the need for medical or surgical treatment. The intestinal barrier restoration measures implemented in our patient may have contributed to this resolution, although there is not enough scientific evidence to support this. The endoscopic image of nodular cysts is not always present in these cases, and the diagnosis of choice for this condition is radiological and based on exclusion. (4).


Regulation of IgE receptor expression on human peripheral blood lymphocytes by lymphocytosis promoting factor (LPF), lectins and dexamethasone.
Using a monoclonal anti-human Fc epsilon R antibody (H107), we found that lymphocytosis promoting factor (LPF), phytohaemagglutinin (PHA-P) and Concanavalin A (Con A) could induce Fc epsilon R, detected by immunofluorescence study, on normal human peripheral blood lymphocytes without IgE. The number of Fc epsilon R bearing lymphocytes was increased by stimulation with 3, 10 and 10 micrograms/ml of LPF, PHA-P and Con A, respectively, from 6.0 +/- 3.0/1000 cells to 26.0 +/- 7.9, 54.0 +/- 6.7 and 24.8 +/- 7.1/1000 cells, respectively. Although the induction of Fc epsilon R occurred neither in the separated T-enriched fraction (TEF) nor the T-depleted fraction (TDF), it recovered when the two fractions were mixed. The cell free supernatants from TEF stimulated with LPF or PHA-P could increase Fc epsilon R(+) cells in TDF, whereas those from TDF failed to increase them in TEF. The results suggest that the induction of Fc epsilon R occurs mainly on B lymphocytes by the soluble factor(s) formed by T cells stimulated with LPF or PHA-P. The induction of Fc epsilon R by stimulants was completely inhibited by 10(-6) M dexamethasone. It was demonstrated that the effects of dexamethasone on lymphocytes were dual: one was on B cells to inhibit responsive increases of Fc epsilon R, and the other was on T cells to suppress the formation of the soluble factor(s) which induced Fc epsilon R on B cells.


Genetic population structure of turbot (Scophthalmus maximus L.) supports the presence of multiple hybrid zones for marine fishes in the transition zone between the Baltic Sea and the North Sea.
Genetic population structure of turbot (Scophthalmus maximus L.) in the Northeast Atlantic was investigated using eight highly variable microsatellite loci. In total 706 individuals from eight locations with temporal replicates were assayed, covering an area from the French Bay of Biscay to the Aaland archipelago in the Baltic Sea. In contrast to previous genetic studies of turbot, we found significant genetic differentiation among samples with a maximum pairwise FST of 0.032. Limited or no genetic differentiation was found among samples within the Atlantic/North Sea area and within the Baltic Sea, suggesting high gene flow among populations in these areas. In contrast, there was a sharp cline in genetic differentiation going from the low saline Baltic Sea to the high saline North Sea. The data were explained best by two divergent populations connected by a hybrid zone; however, a mechanical mixing model could not be ruled out. A significant part of the genetic variance could be ascribed to variation among years within locality. Nevertheless, the population structure was relatively stable over time, suggesting that the observed pattern of genetic differentiation is biologically significant. This study suggests that hybrid zones are a common phenomenon for marine fishes in the transition area between the North Sea and the Baltic Sea and highlights the importance of using interspecific comparisons for inferring population structure in high gene flow species such as most marine fishes.


Crystal Structures of Csm2 and Csm3 in the Type III-A CRISPR-Cas Effector Complex.
Clustered regularly interspaced short palindromic repeat (CRISPR) loci and CRISPR-associated (Cas) genes encode CRISPR RNAs (crRNA) and Cas proteins, respectively, which play important roles in the adaptive immunity system (CRISPR-Cas system) in prokaryotes. The crRNA and Cas proteins form ribonucleoprotein effector complexes to capture and degrade invading genetic materials with base complementarity to the crRNA guide sequences. The Csm complex, a type III-A effector complex, comprises five Cas proteins (Csm1-Csm5) and a crRNA, which co-transcriptionally degrades invading DNA and RNA. Here we report the crystal structures of the Staphylococcus epidermidis Csm2 (SeCsm2) and Thermoplasma volcanium Csm3 (TvCsm3) at 2.4- and 2.7-Å resolutions, respectively. SeCsm2 adopts a monomeric globular fold by itself, in striking contrast to the previously reported Thermotoga maritima Csm2, which adopted an extended conformation and formed a dimeric structure. We propose that the globular monomeric form is the bona fide structure of Csm2. TvCsm3 forms a filamentous structure in the crystals. The molecular arrangement of TvCsm3 is similar to that of the stacked Cmr4 proteins in the Cmr complex, suggesting the functionally relevant architecture of the present Csm3 structure. We constructed model structures of the Csm complex, which revealed that Csm3 binds the crRNA and periodically deforms the crRNA-target duplex by a similar mechanism to that of Cmr4 in the Cmr complex. The model and mutational analysis suggest that the conserved lysine residue of Csm2 is important for target RNA binding, and Csm2 stabilizes the active structure of the Csm complex to facilitate the reaction.


Ultrastructure of the surface structures and secretory glands of the rosette attachment organ of Gyrocotyle urna (Cestoda:Gyrocotylidea).
The surface structures and gland cells of the posterior rosette organ of Gyrocotyle urna Grube et Wagener, 1852, a member of the group presumed to be the most basal of the tapeworms (Cestoda: Gyrocotylidea), was studied by scanning electron and transmission electron microscopy. Surface structures on the outer (oriented away from the intestinal wall) and inner (in contact with the intestinal wall) rosette surfaces differ from each other and represent a transitional form between microvilli and microtriches typical of tapeworms (Eucestoda). The inner surface of the rosette possesses numerous glands. On the basis of the size and electron-density of their secretory granules, three types of unicellular gland cells can be distinguished. The least common type (Type I) is characterized by the production of small, round, electron-dense granules of about 0.3 microm in diameter, whereas another type of secretion (Type II) is formed from homogenous, moderately electron-dense, spheroidal granules of about 0.7 microm in diameter. The most common type of glands (Type III) is recognized by a secretion comprising large, elongate, electron-dense granules of about 1 microm long and 0.5 microm broad. The secretory granules of the three types of the glands are liberated by an eccrine mechanism and the gland ducts open via small pores on the inner rosette surface. The complex of secretory glands of the posterior rosette of G. urna is similar to those in the anterior attachment glands of monogeneans (as opposed to the types of glands present in other helminth groups). However, the tegumental surface structures of Gyrocotyle are supporting evidence for the relationship between the Gyrocotylidea and Eucestoda.


The essential role of drinking water and sanitation in primary health care.
The purpose of the paper is to draw attention to the fact that drinking water supply and the provision of sanitation facilities form an indispensable element in disease prevention and primary health care programmes. The world situation regarding the availability of drinking water and sanitation facilities is dramatic, in that more than 1500 million people lact proper facilities; the implications in terms of health and cost are stupendous. It is therefore a fortunate development that the International Drinking Water and Sanitation Decade (1981-1990) is on its way to an appealing initiative. The paper discusses water and sanitation related diseases, and the established experience that water and sanitation programmes can only have a health impact if they are jointly developed, and if they are integrated with health education. Operational implications of such programmes as an element of primary health care are reviewed.


Virus-inactivating effect of D-isoascorbic acid.
The effect of D-isoascorbic acid, an epimer of L-ascorbic acid, on viruses was investigated using a wide variety of bacterial viruses (phages) as model systems. D-isoascorbic acid exerted an inactivating effect on all phages examined. The reaction mechanism of virus inactivation by D-isoascorbic acid was investigated using phage J1 as a model system. Bubbling oxygen through the reaction mixture and the addition of H2O2 or transition metal ions into the reaction mixture enhanced the phage inactivation by D-isoascorbic acid. In contrast, nitrogen bubbling and the addition of reducing agents, chelating agents or radical scavengers prevented phage inactivation. Experiments using specific radical scavengers, superoxide dismutase or catalase showed that OH. could be mainly responsible for phage inactivation by D-isoascorbic acid. These findings are similar to those obtained with L-ascorbic acid, and indicate that phage-inactivating activity is independent of the stereoisomerism with inversion of the hydroxyl group at carbon 5 of ascorbic acids.


Development and validation of a risk scoring tool to predict respiratory syncytial virus hospitalization in premature infants born at 33 through 35 completed weeks of gestation.
The purpose of the study was to develop and validate a clinical instrument predicting the risk of respiratory syncytial virus (RSV)-associated hospitalization (RSV-H) in premature infants born at 33 through 35 completed weeks of gestation (33-35GA). An RSV risk scoring tool (RSV-RS) was developed by entering risk factors for RSV-H, determined in a Canadian prospective study, into a multiple logistic regression model. The scoring tool was then validated externally with data from a Spanish case-control study (FLIP). The Canadian cohort comprised 1758 RSV-positive infants born 33-35GA, of whom 66 (3.7%) had confirmed RSV-H. The FLIP data set comprised 186 (33.4%) RSV-H cases and 371 (66.7%) controls. The primary outcome measure was RSV-H. The RSV-RS score was the sum of the weighted probabilities for each included risk factor multiplied by 100 and ranged from 0 to 100. Receiver operator characteristic curve analyses determined cutoff points to predict subjects at low, moderate, or high RSV-H risk. The RSV-RS included 7 risk factors and cutoff scores of 0-48, 49-64, and 65- 100 for low-, moderate-, and high-risk subjects, respectively. For the Canadian cohort, RSV-RS sensitivity in predicting RSV-H cases was 68.2%, with 71.9% specificity. With the FLIP data set, the RSV-RS had lower accuracy (61.3% sensitivity; 65.8% specificity) but showed significant positive association with increased risk for RSV-H. The RSV-RS accurately identified 33-35GA infants at increased risk for RSV-H in a Canadian cohort. External validation with Spanish case-control study data further confirmed that the scoring tool is appropriate for the estimation of RSV-H risk.


Twenty year trends (1975-1995) in the incidence, in-hospital and long-term death rates associated with heart failure complicating acute myocardial infarction: a community-wide perspective.
To describe from a population-based perspective, recent and temporal (1975-1995) trends in the incidence, in-hospital and postdischarge case-fatality rates of heart failure (HF) complicating acute myocardial infarction (AMI). Extremely limited data are available describing the incidence and case-fatality rates associated with HF complicating AMI from a community-wide perspective. The medical records of 6,798 residents of the Worcester, Massachusetts metropolitan area with validated MI and without previous HF hospitalized in 10 annual periods between 1975 and 1995 were reviewed. The proportion of AMI patients developing HF during hospitalization declined between 1975-1978 (38%) and 1993-1995 (33%) (p < 0.001). After controlling for potentially confounding factors, the risk of developing HF declined progressively, albeit modestly, over time. In-hospital case-fatality rates of patients with AMI complicated by HF declined by approximately 46% between 1975-1978 (33%) and 1993-1995 (18%) (p < 0.001). Improving trends in hospital survival were observed after adjusting for potentially confounding prognostic factors. The one-year post-discharge mortality rate for hospital survivors of HF did not change over the 20-year period under study, even after controlling for additional prognostic characteristics. The results of this community-wide study suggest encouraging declines in the incidence and hospital death rates associated with HF complicating AMI. Continued efforts need to be directed towards the prevention of HF given the magnitude of this clinical syndrome. Efforts of secondary prevention are needed to identify and improve the treatment of patients with symptomatic left ventricular dysfunction following AMI given the lack of improvement in the long-term prognosis of these patients.


Effectors of mammalian telomere dysfunction: a comparative transcriptome analysis using mouse models.
Critical telomere shortening in the absence of telomerase in late generation Terc-/- mice (G3 Terc-/-) or loss of telomere capping due to abrogation of the DNA repair/telomere binding protein Ku86 (Ku86-/- mice) results in telomere dysfunction and organismal premature aging. Here, we report on genome-wide transcription in mouse G3 Terc-/-, Ku86-/- and G3 Terc-/-/Ku86-/- germ cells using high-density oligonucleotide microarrays. Although a few transcripts are modulated specifically in Ku86- or Terc-deficient cells, the observed transcriptional response is mainly inductive and qualitatively similar for all three genotypes, with highest transcriptional induction observed in double mutant G3 Terc-/-/Ku86-/- cells compared with either single mutant. Analysis of 92 known genes induced in G3 Terc-/-/Ku86-/- germ cells compared with wild-type cells shows predominance of genes involved in cell adhesion, cell-to-cell and cell-to-matrix communication, as well as increased metabolic turnover and augmented antioxidant responses. In addition, the data presented in this study support the view that telomere dysfunction induces a robust compensatory response to rescue impaired germ cell function through the induction of survival signals related to the PI3-kinase pathway, as well as by the coordinated upregulation of transcripts that are essential for mammalian spermatogenesis.


The xylose absorption test in normal Sudanese subjects.
The xylose absorption test was carried out in 50 healthy Sudanese men. The 5 g d-xylose oral loading dose was used. Nine subjects (18%) had a d-xylose absorption below the normal range. Thirty of the subjects were of low socioeconomic status and 20 of the subjects were of middle socioeconomic status; there was no difference in the xylose absorption between the two groups.


In vitro growth of murine T cells. V. The isolation and growth of lymphoid cells infiltrating syngeneic solid tumors.
A method has been developed for isolating and growing lymphoid cells infiltrating murine solid tumors. When tumor cell suspensions are placed in T cell growth factor (TCGF) lymphoid cells and not tumor cells proliferate. By 7 to 9 days lymphoid cells free of tumor can be harvested and grown continuously in TCGF. The growth of these cells is dependent on the presence of TCGF but not on the presence of concanavalin-A. Tumor cell suspensions that have been freed of T lymphoid cells by treatment with anti-Thy-1.2 serum and complement or by fractionation on Ficoll gradients exhibit no cell out-growth in TCGF. The lymphoid cells growing in TCGF exhibit significant cytotoxicity for syngeneic tumor cells and normal fibroblasts grown in culture but do no lyse normal lymphoid cells.


Overexpression of a human potassium channel suppresses cardiac hyperexcitability in rabbit ventricular myocytes.
The high incidence of sudden death in heart failure may reflect abnormalities of repolarization and heightened susceptibility to arrhythmogenic early afterdepolarizations (EADs). We hypothesized that overexpression of the human K+ channel HERG (human ether-a-go-go-related gene) could enhance repolarization and suppress EADs. Adult rabbit ventricular myocytes were maintained in primary culture, which suffices to prolong action potentials and predisposes to EADs. To achieve efficient gene transfer, we created AdHERG, a recombinant adenovirus containing the HERG gene driven by a Rous sarcoma virus (RSV) promoter. The virally expressed HERG current exhibited pharmacologic and kinetic properties like those of native IKr. Transient outward currents in AdHERG-infected myocytes were similar in magnitude to those in control cells, while stimulated action potentials (0.2 Hz, 37 degrees C) were abbreviated compared with controls. The occurrence of EADs during a train of action potentials was reduced by more than fourfold, and the relative refractory period was increased in AdHERG-infected myocytes compared with control cells. Gene transfer of delayed rectifier potassium channels represents a novel and effective strategy to suppress arrhythmias caused by unstable repolarization.


Impaired postural control of the lumbar spine is associated with delayed muscle response times in patients with chronic idiopathic low back pain.
Balance performance in unstable sitting and trunk muscle response to quick force release were measured in 16 patients with chronic low back pain and 14 matched healthy control subjects. To determine whether patients with low back pain will exhibit poorer postural control, which will be associated with longer average muscle response times. Larger postural sway during standing and delayed trunk muscle response times for patients with low back pain have been reported in several independent studies. Unstable sitting test was accomplished by attaching different sized hemispheres to the bottom of a seat. Subjects performed trials with eyes open and closed while the displacements of the center of pressure were measured with a force plate underneath the seat. Response to a quick force release was recorded from 12 major trunk muscles with surface electromyography. Subjects performed isometric trunk exertions in a semi-seated position when the resisted force was suddenly released with an electromagnet. Average muscle response times and balance performance were correlated using a linear regression analysis. Patients with low back pain demonstrated poorer balance performance than healthy control volunteers, especially at the most difficult levels. Patients also had delayed muscle response times to quick force release. Average muscle onset times together with age and weight correlated significantly with balance performance with closed eyes (R(2) = 0.46), but not with eyes opened (R(2) = 0.18). Patients with chronic low back pain demonstrated poorer postural control of the lumbar spine and longer trunk muscle response times than healthy control volunteers. Correlation between these two phenomena suggests a common underlying pathology in the lumbar spine.


Longitudinal lipidomic profiles during pregnancy and associations with neonatal anthropometry: findings from a multiracial cohort.
Maternal lipidomic profiling offers promise for characterizing lipid metabolites during pregnancy, but longitudinal data are limited. This study aimed to examine associations of longitudinal lipidomic profiles during pregnancy with multiple neonatal anthropometry using data from a multiracial cohort. We measured untargeted plasma lipidome profiles among 321 pregnant women from the NICHD Fetal Growth Study-Singletons using plasma samples collected longitudinally during four study visits at gestational weeks (GW) 10-14, 15-26, 23-31, and 33-39, respectively. We evaluated individual lipidomic metabolites at each study visit in association with neonatal anthropometry. We also evaluated the associations longitudinally by constructing lipid networks using weighted correlation network analysis and common networks using consensus network analysis across four visits using linear mixed-effects models with the adjustment of false discover rate. Multiple triglycerides (TG) were positively associated with birth weight (BW), BW Z-score, length and head circumference, while some cholesteryl ester (CE), phosphatidylcholine (PC), sphingomyelines (SM), phosphatidylethanolamines (PE), and lysophosphatidylcholines (LPC 20:3) families were inversely associated with BW, length, abdominal and head circumference at different GWs. Longitudinal trajectories of TG, PC, and glucosylcermides (GlcCer) were associated with BW, and CE (18:2) with BW z-score, length, and sum of skinfolds (SS), while some PC and PE were significantly associated with abdominal and head circumference. Modules of TG at GW 10-14 and 15-26 mainly were associated with BW. At GW 33-39, two networks of LPC (20:3) and of PC, TG, and CE, showed inverse associations with abdominal circumference. Distinct trajectories within two consensus modules with changes in TG, CE, PC, and LPC showed significant differences in BW and length. The results demonstrated that longitudinal changes of TGs during early- and mid-pregnancy and changes of PC, LPC, and CE during late-pregnancy were significantly associated with neonatal anthropometry. National Institute of Child Health and Human Development intramural funding.


Interactions between mood and the structure of semantic memory: event-related potentials evidence.
Recent evidence suggests that affect acts as modulator of cognitive processes and in particular that induced mood has an effect on the way semantic memory is used on-line. We used event-related potentials (ERPs) to examine affective modulation of semantic information processing under three different moods: neutral, positive and negative. Fifteen subjects read 324 pairs of sentences, after mood induction procedure with 30 pictures of neutral, 30 pictures of positive and 30 pictures of neutral valence: 108 sentences were read in each mood induction condition. Sentences ended with three word types: expected words, within-category violations, and between-category violations. N400 amplitude was measured to the three word types under each mood induction condition. Under neutral mood, a congruency (more negative N400 amplitude for unexpected relative to expected endings) and a category effect (more negative N400 amplitude for between- than to within-category violations) were observed. Also, results showed differences in N400 amplitude for both within- and between-category violations as a function of mood: while positive mood tended to facilitate the integration of unexpected but related items, negative mood made their integration as difficult as unexpected and unrelated items. These findings suggest the differential impact of mood on access to long-term semantic memory during sentence comprehension.


Reduced ambiguity and improved interpretability of bacterial genome-wide associations using gene-cluster-centric k-mers.
The wide adoption of bacterial genome sequencing and encoding both core and accessory genome variation using k-mers has allowed bacterial genome-wide association studies (GWAS) to identify genetic variants associated with relevant phenotypes such as those linked to infection. Significant limitations still remain because of k-mers being duplicated across gene clusters and as far as the interpretation of association results is concerned, which affects the wider adoption of GWAS methods on microbial data sets. We have developed a simple computational method (panfeed) that explicitly links each k-mer to their gene cluster at base-resolution level, which allows us to avoid biases introduced by a global de Bruijn graph as well as more easily map and annotate associated variants. We tested panfeed on two independent data sets, correctly identifying previously characterized causal variants, which demonstrates the precision of the method, as well as its scalable performance. panfeed is a command line tool written in the python programming language and is available at https://github.com/microbial-pangenomes-lab/panfeed.


Spectrum of Viral Pathogens in Blood of Malaria-Free Ill Travelers Returning to Canada.
Malaria is the most common specific cause of fever in returning travelers, but many other vectorborne infections and viral infections are emerging and increasingly encountered by travelers. We documented common and emerging viral pathogens in malaria-negative specimens from ill travelers returning to Canada. Anonymized, malaria-negative specimens were examined for various viral pathogens by real-time PCR. Samples were positive for herpes simplex viruses 1 or 2 (n = 21, 1.6%), cytomegalovirus (n = 4, 0.3%), Epstein-Barr virus (n = 194, 14.9%), dengue virus types 1-4 (n = 27, 2.1%), chikungunya virus (n = 5, 0.4%), and hepatitis A virus (n = 12, 0.9%). Travel-acquired viral pathogens were documented in >20% of malaria-negative specimens, of which 2.5% were infected with dengue and chikungunya viruses. Our findings support the anecdotal impression that these vectorborne pathogens are emerging among persons who travel from Canada to other countries.


Diffusion Basis Spectrum Imaging Detects Axonal Loss After Transient Dexamethasone Treatment in Optic Neuritis Mice.
Optic neuritis is a frequent first symptom of multiple sclerosis (MS) for which corticosteroids are a widely employed treatment option. The Optic Neuritis Treatment Trial (ONTT) reported that corticosteroid treatment does not improve long-term visual acuity, although the evolution of underlying pathologies is unclear. In this study, we employed non-invasive diffusion basis spectrum imaging (DBSI)-derived fiber volume to quantify 11% axonal loss 2 months after corticosteroid treatment (vs. baseline) in experimental autoimmune encephalomyelitis mouse optic nerves affected by optic neuritis. Longitudinal DBSI was performed at baseline (before immunization), after a 2-week corticosteroid treatment period, and 1 and 2 months after treatment, followed by histological validation of neuropathology. Pathological metrics employed to assess the optic nerve revealed axonal protection and anti-inflammatory effects of dexamethasone treatment that were transient. Two months after treatment, axonal injury and loss were indistinguishable between PBS- and dexamethasone-treated optic nerves, similar to results of the human ONTT. Our findings in mice further support that corticosteroid treatment alone is not sufficient to prevent eventual axonal loss in ON, and strongly support the potential of DBSI as an in vivo imaging outcome measure to assess optic nerve pathology.


[The origin of the eukaryotic cell. III. Principles of the morphofunctional organization of the eukaryotic cell].
The eukaryotic plasmalemma, eukaryotic cytoplasm with its usual cytomembranes, and eukaryotic nucleus are obligatory components of the eukaryotic cell. All other structural elements (organelles) are only derivates of the aforesaid cell components and they may be absent sometimes. There are protozoans having simultaneously no flagelles, mitochondria and chloroplasts (all the representatives of phylum Microspora, amoeba Pelomyxa palustris, and others). The following five general principles play the main role in the morphofunctional organization of the cell. The principle of hierarchy of block organization of living systems. Complex morphofunctional blocks (organelles) specific for the eukaryotic cell are formed. The compartmentalization principle. The main cell organelles (nuclei, flagellae, mitochondria, chloroplasts, etc.) undergo a relative morphological isolation from each other and other cell organelles by means of the total or partial surrounding by membranes; this may ensure the originality of their evolution and function. The principle of poly- and oligomerization of morphofunctional blocks. It permits the cell to enlarge its sizes and to raise the level of integration. The principle of heterochrony, including three subprinciples: conservatism of useful signs; a strong acceleration of evolutionary development of the separate blocks; simplification of the structure, reduction or total disappearance of some blocks. It explains a preservation of prokaryotic signs in the eukaryotic cell or in its organelles. The principle of independent origin of similar morphofunctional blocks in the process of evolution of living systems. The parallelism of the signs in unrelated groups of cells (or protists) arises due to this principle.


[Recurrent stomach complaints in children].
Next to headache recurrent gastro-intestinal complaints constitute the most common reason for medical consultation among daycare and school children. The use of more sophisticated examination methods has shown that in up to 50 per cent of cases the cause of the gastric complaints is a treatable disease or a functional anomaly of the gastro-intestinal tract. The commonest conditions are lactose intolerance, gluten sensitivity, gastro-oesophageal reflux, and gastritis. In some cases stomach pain is triggered by psychosomatic mechanisms. Depending upon the child's age, aetiological indications can sometimes be derived from history taking. In many cases the investigations can be made in the out-patient clinic. The cornerstones of treatment are various kinds of dietary elimination regimens, prokinetic agents, and antibiotics. Recently, the investigation of neuroendocrinological and neurophysiological processes related to psychosomatic causes of gastric complaints has once again become common.


Development of a Measure of Calculative Mindset (CM): Establishing a Nomological Net and Predictive Utility of the CM Measure.
A calculative mindset (CM) describes the tendency to analyze and convert qualitative social values into numeric or monetary metrics and is a predisposition that shapes behaviors and actions of the employee. CM has been manipulated in experimental studies, but it has not been investigated in field research due to the absence of a scale to measure CM. In study 1, we followed Hinkin's scale development protocol to conceptualize, develop, and validate a measure of CM to facilirate research in organizational contexts. In Study 2, we examined the relationship between CM and measures of performance, counterproductive work behavior (CWB), organizational citizenship behaviors (OCB), and in role-performance (IRP). Results from hierarchical regression analyses indicate that CM is related to these performance outcomes and explains incremental variance over established measures of the Five-Factor Model of personality. Implications for personality research, selection of human resources, and facilitation of an ethical workplace are discussed.


Antimicrobial and Antibiotic-Resistance Reversal Activity of Some Medicinal Plants from Cameroon against Selected Resistant and Non-Resistant Uropathogenic Bacteria.
Antibiotics' resistance is the leading cause of complications in the treatment of urinary tract infections. This study aimed to screen the antimicrobial potential of 8 plants from Cameroon against multi-resistant uropathogenic (MRU) bacteria and to investigate their antibioresistance reversal properties. Bioactive compounds were extracted from leaves of Leucanthemum vulgare, Cymbopogon citratus, Moringa oleifera and Vernonia amygdalina; barks of Cinchona officinalis and Enantia chlorantha barks and seeds of Garcinia lucida and leaves and seeds of Azadirachta indica using water and ethanol as solvents. The extracts were tested against Escherichia coli ATCC 25922, Staphylococcus aureus ATCC 6538 and Candida albicans 10231 using the well diffusion and the broth microdilution methods. The antibiotic-resistance reversal activity was assessed against selected MRU bacteria. The phytochemical composition and the elemental composition of the most active extracts were assessed respectively using HPLC-MS/MS and X-ray fluorescence (XRF) spectrometry. Among the most active plants, in decreasing order of antimicrobial activity we found ethanolic (EE) and aqueous extracts (AE) of E. chloranta bark (ECB), EE of L. vulgare leaves and G. lucida seeds. The best synergies between common antibiotics and extracts were found with EE-ECB which well-modulated kanamycin nitrofurantoin and ampicillin. All the compounds identified in EE-ECB were alkaloids and the major constituents were palmatine (51.63%), columbamine+7,8-dihydro-8-hydroxypalmatine (19.21%), jatrorrhizine (11.02%) and pseudocolumbamine (6.33%). Among the minerals found in EE-ECB (S, Si, Cl, K, Ca, Mn, Fe, Zn and Br), Br, Fe and Cl were the most abundant with mean fluorescence intensities of 4.6529, 3.4854 and 2.5942 cps/uA respectively. The ethanol extract of the bark of E. chlorantha has remarkable, broad-spectrum antimicrobial and contains several palmatine derivatives.


Novel potential targets for prevention of arterial restenosis: insights from the pre-clinical research.
Restenosis is the pathophysiological process occurring in 10-15% of patients submitted to revascularization procedures of coronary, carotid and peripheral arteries. It can be considered as an excessive healing reaction of the vascular wall subjected to arterial/venous bypass graft interposition, endarterectomy or angioplasty. The advent of bare metal stents, drug-eluting stents and of the more recent drug-eluting balloons, have significantly reduced, but not eliminated, the incidence of restenosis, which remains a clinically relevant problem. Biomedical research in pre-clinical animal models of (re)stenosis, despite its limitations, has contributed enormously to the identification of processes involved in restenosis progression, going well beyond the initial dogma of a primarily proliferative disease. Although the main molecular and cellular mechanisms underlying restenosis have been well described, new signalling molecules and cell types controlling the progress of restenosis are continuously being discovered. In particular, microRNAs and vascular progenitor cells have recently been shown to play a key role in this pathophysiological process. In addition, the advanced highly sensitive high-throughput analyses of molecular alterations at the transcriptome, proteome and metabolome levels occurring in injured vessels in animal models of disease and in human specimens serve as a basis to identify novel potential therapeutic targets for restenosis. Molecular analyses are also contributing to the identification of reliable circulating biomarkers predictive of post-interventional restenosis in patients, which could be potentially helpful in the establishment of an early diagnosis and therapy. The present review summarizes the most recent and promising therapeutic strategies identified in experimental models of (re)stenosis and potentially translatable to patients subjected to revascularization procedures.


Increased expression of interleukin-22 in patients with giant cell arteritis.
GCA is characterized by arterial remodelling driven by inflammation. IL-22 is an attractive cytokine which acts at the crosstalk between immune and stromal cells. We hypothesized that IL-22 might be induced in GCA and might be involved in disease pathogenesis. Patients subjected to temporal artery biopsies (TABs) naïve from therapy were enrolled: 27 biopsy-proven GCA, 8 biopsy-negative GCA, 21 biopsy-negative non-GCA patients. Expression of IL-22 was determined in TABs by immunohystochemistry, in plasma by ELISA, in peripheral blood mononuclear cells by real-time PCR and flow cytometry. Effects of IL-22 on viability and gene expression of primary cultures obtained from TABs were also evaluated. Inflamed TABs from GCA patients showed a higher expression of IL-22 and IL-22 specific receptor subunit (IL-22R1) than non-inflamed TABs. IL-22 was expressed in infiltrating immune cells and spindle shaped cells, IL-22R1 was expressed in endothelial cells. Patients with biopsy-proven GCA showed increased levels of IL-22 in plasma than patients with biopsy-negative GCA, without GCA and healthy subjects. Peripheral blood mononuclear cells from GCA patients expressed higher IL-22 transcript than healthy subjects. After stimulation in vitro with phorbol 12-myristate 13-acetate and ionomycin, the frequencies of Th22 and IL-22+ CD4+ lymphocytes were similar between patients with and without GCA. Treatment with IL-22 of primary cultures obtained from TABs increased cell viability under stress conditions and expression of B-cell activating factor. IL-22 is increased in patients with GCA and affects viability and gene expression of arterial cells, supporting a potential role in disease pathogenesis.


Cytosolic antibody delivery by lipid-sensitive endosomolytic peptide.
One of the major obstacles in intracellular targeting using antibodies is their limited release from endosomes into the cytosol. Here we report an approach to deliver proteins, which include antibodies, into cells by using endosomolytic peptides derived from the cationic and membrane-lytic spider venom peptide M-lycotoxin. The delivery peptides were developed by introducing one or two glutamic acid residues into the hydrophobic face. One peptide with the substitution of leucine by glutamic acid (L17E) was shown to enable a marked cytosolic liberation of antibodies (immunoglobulins G (IgGs)) from endosomes. The predominant membrane-perturbation mechanism of this peptide is the preferential disruption of negatively charged membranes (endosomal membranes) over neutral membranes (plasma membranes), and the endosomolytic peptide promotes the uptake by inducing macropinocytosis. The fidelity of this approach was confirmed through the intracellular delivery of a ribosome-inactivation protein (saporin), Cre recombinase and IgG delivery, which resulted in a specific labelling of the cytosolic proteins and subsequent suppression of the glucocorticoid receptor-mediated transcription. We also demonstrate the L17E-mediated cytosolic delivery of exosome-encapsulated proteins.


Lesion patterns and etiology of ischemia in superior cerebellar artery territory infarcts.
Infarcts in the territory of superior cerebellar artery (SCA) are uncommon. The clinical, and etiological mechanisms of different infarct patterns of SCA are not well known. Diffusion-weighted imaging (DWI) is superior to conventional magnetic resonance imaging for detecting acute small and multiple ischemic lesions. We studied 60 patients with lesions involving SCA territory proved by DWI, which have been selected from 3,800 patients with first ischemic stroke consecutively admitted to our stroke unit over a period of 5 years. There are 7 distinctive SCA lesion patterns: (1) a lesion was found in the medial (m) branch territory of SCA (mSCA) in 14 patients; (2) a lesion in the lateral (l) branch territory of SCA (lSCA) was seen in 9 patients; (3) a coexisting lesion involving mSCA and lSCA was found in 9 patients; (4) a lesion in cortical borderzones between SCA and m/l branches of the posterior inferior cerebellar artery (PICA) was observed in 6 patients; (5) a lesion in deep borderzones between lSCA and mSCA, and lPICA and mPICA was present in 8 patients; (6) a lesion involving the medial rostral cerebellum between the right and left SCA was found in 4 patients; (7) multiple lesions involving SCA and other vertebrobasilar artery territories were present in 10 patients. The main cause was possible artery-to-artery embolism from atherosclerotic vertebrobasilar arteries to distal branches of SCA in 20 patients (33%). Fourteen patients had a source of cardioembolism (23%), and 6 patients (8%) had concomitant atherosclerotic vertebrobasilar artery disease and a source of cardioembolism. An acute ischemic lesion in the SCA territory is mainly multiple. The lSCA territory was the most involved area. Small territorial infarcts were frequently associated with large territorial SCA infarcts. Borderzone SCA infarcts occurred in one third of the patients with transient benign symptoms. Mass effects are unusual despite the large amount of SCA involvement. Our results supported the fact that embolism is the predominant stroke mechanism in the SCA territory infarction.


Rapid detection of multidrug-resistant Mycobacterium tuberculosis using the malachite green decolourisation assay.
Early detection of drug resistance in Mycobacterium tuberculosis isolates allows for earlier and more effective treatment of patients. The aim of this study was to investigate the performance of the malachite green decolourisation assay (MGDA) in detecting isoniazid (INH) and rifampicin (RIF) resistance in M. tuberculosis clinical isolates. Fifty M. tuberculosis isolates, including 19 multidrug-resistant, eight INH-resistant and 23 INH and RIF-susceptible samples, were tested. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and agreement of the assay for INH were 92.5%, 91.3%, 92.5%, 91.3% and 92%, respectively. Similarly, the sensitivity, specificity, PPV, NPV and agreement of the assay for RIF were 94.7%, 100%, 100%, 96.8% and 98%, respectively. There was a major discrepancy in the tests of two isolates, as they were sensitive to INH by the MGDA test, but resistant by the reference method. There was a minor discrepancy in the tests of two additional isolates, as they were sensitive to INH by the reference method, but resistant by the MGDA test. The drug susceptibility test results were obtained within eight-nine days. In conclusion, the MGDA test is a reliable and accurate method for the rapid detection of INH and RIF resistance compared with the reference method and the MGDA test additionally requires less time to obtain results.


The association between depression and health-related quality of life in people with type 2 diabetes: a systematic literature review.
The relationships between co-morbid depression in people with diabetes and adverse outcomes including poor HbA(1c) control, adherence to medication and mortality have been examined and confirmed. However, as the awareness of the decrement to health-related quality of life (HRQOL) in people with diabetes and its clinical consequences grows, investigators have become increasingly interested in measuring HRQOL in clinical trials. Given that the psychological factors such as depression may contribute to diminished HRQOL, the present review sought to summarize the association between these variables in people with type 2 diabetes. Articles for a systematic review were obtained via a search performed using MEDLINE, EMBASE and PsycINFO (1980-2007).Fourteen articles fulfilled the inclusion criteria. Studies indicated that self-reported depressive symptoms markedly impaired HRQOL on several domains. However, depression was not related to all sub-domains of HRQOL in all studies, suggesting that the effects of depression on certain aspects of HRQOL may vary between clinical and demographic subgroups. Although a number of shortcomings identified in the current literature should be taken into account for future research, the importance of this review lies in the possibility it raises that the improvements in HRQOL and clinical practice may potentially be achieved by placing greater attention on the identification and management of depression.


Integrins modulate relapse to cocaine-seeking.
Relapse to cocaine-seeking involves impairments in plasticity at glutamatergic synapses in the nucleus accumbens. Integrins are cell adhesion molecules that bind to the extracellular matrix and regulate aspects of synaptic plasticity, including glutamate receptor trafficking. To determine a role for integrins in cocaine-seeking, rats were trained to self-administer cocaine, the operant response extinguished, and cocaine-seeking induced by a conditioned cue or noncontingent cocaine injection. This cocaine self-administration protocol reduced the content of the β3 integrin subunit in postsynaptic density of the accumbens core at 24 h after the last self-administration session. However, after 3 weeks of forced abstinence plus extinction training, the level of β3 was elevated and was further regulated over 120 min during cocaine-induced drug-seeking. A small peptide ligand [arginine-glycine-aspartate (RGD)] that mimics extracellular matrix protein binding to integrins was microinjected into the accumbens core during self-administration or extinction training, or just before cocaine-reinstated drug seeking. The daily RGD injections during self-administration or just before a reinstatement session inhibited cocaine-induced drug-seeking, while RGD microinjection during extinction training was without consequence on reinstated cocaine-seeking. Daily RGD during self-administration also prevented the enduring changes in β3 levels. Finally, reduced surface expression of the GluR2 subunit of the AMPA receptor is associated with cocaine-seeking, and daily RGD microinjections during self-administration training normalized the surface expression of GluR2. Together, these data indicate that the regulation integrins may contribute to cocaine-reinstated drug-seeking, in part by promoting reduced GluR2 surface expression.


Functional traits driving species role in the structure of terrestrial vertebrate scavenger networks.
Species assemblages often have a non-random nested organization, which in vertebrate scavenger (carrion-consuming) assemblages is thought to be driven by facilitation in competitive environments. However, not all scavenger species play the same role in maintaining assemblage structure, as some species are obligate scavengers (i.e., vultures) and others are facultative, scavenging opportunistically. We used a database with 177 vertebrate scavenger species from 53 assemblages in 22 countries across five continents to identify which functional traits of scavenger species are key to maintaining the scavenging network structure. We used network analyses to relate ten traits hypothesized to affect assemblage structure with the "role" of each species in the scavenging assemblage in which it appeared. We characterized the role of a species in terms of both the proportion of monitored carcasses on which that species scavenged, or scavenging breadth (i.e., the species "normalized degree"), and the role of that species in the nested structure of the assemblage (i.e., the species "paired nested degree"), therefore identifying possible facilitative interactions among species. We found that species with high olfactory acuity, social foragers, and obligate scavengers had the widest scavenging breadth. We also found that social foragers had a large paired nested degree in scavenger assemblages, probably because their presence is easier to detect by other species to signal carcass occurrence. Our study highlights differences in the functional roles of scavenger species and can be used to identify key species for targeted conservation to maintain the ecological function of scavenger assemblages.


Narrow bottlenecks affect Pea seedborne mosaic virus populations during vertical seed transmission but not during leaf colonization.
The effective size of populations (Ne) determines whether selection or genetic drift is the predominant force shaping their genetic structure and evolution. Populations having high Ne adapt faster, as selection acts more intensely, than populations having low Ne, where random effects of genetic drift dominate. Estimating Ne for various steps of plant virus life cycle has been the focus of several studies in the last decade, but no estimates are available for the vertical transmission of plant viruses, although virus seed transmission is economically significant in at least 18% of plant viruses in at least one plant species. Here we study the co-dynamics of two variants of Pea seedborne mosaic virus (PSbMV) colonizing leaves of pea plants (Pisum sativum L.) during the whole flowering period, and their subsequent transmission to plant progeny through seeds. Whereas classical estimators of Ne could be used for leaf infection at the systemic level, as virus variants were equally competitive, dedicated stochastic models were needed to estimate Ne during vertical transmission. Very little genetic drift was observed during the infection of apical leaves, with Ne values ranging from 59 to 216. In contrast, a very drastic genetic drift was observed during vertical transmission, with an average number of infectious virus particles contributing to the infection of a seedling from an infected mother plant close to one. A simple model of vertical transmission, assuming a cumulative action of virus infectious particles and a virus density threshold required for vertical transmission to occur fitted the experimental data very satisfactorily. This study reveals that vertically-transmitted viruses endure bottlenecks as narrow as those imposed by horizontal transmission. These bottlenecks are likely to slow down virus adaptation and could decrease virus fitness and virulence.


How reliable are pain scores? A pilot study of 20 healthy volunteers.
Pain scales such as the 100-MM Visual Analog Scale and the 10-point Numeric Rating Scale are used to describe pain intensity. The Visual Analog Scale and the Numeric Rating Scale provide accurate descriptors for a patient's perceived level of pain. But how accurate or reliable is a patient's perception of pain? To test the relationship between the intensity of the pain stimulus and pain perception, we devised an experiment using a convenience sample of 20 healthy adult volunteers. A cutaneous nerve stimulator delivered a series of shocks of increasing intensity to the individual via a pediatric EKG electrode. The participants indicated their threshold for "intolerable pain." With use of this same level of stimulus in subsequent shocks, the participants, blinded to the amount of stimulus, were then asked to rate each shock as either "the same," "a little less," or "a little more" than the baseline stimulus. They then recorded their VAS score for each stimulus. "Intolerable pain" varied widely between 8 mm to 73 mm; likewise, the level of stimulus that produced this pain ranged from 4 to 9. Once a person's threshold of "intolerable pain" had been reached, 49% of the subsequent shocks were perceived as different, even though the stimulus was exactly the same. This experiment showed that (1) given the same intensity of pain stimulus, different persons have different perceptions of pain; and (2) the same intensity of pain stimulus, given to the same person repeatedly, does not result in the same self-report of pain intensity.