Cyclosporine A inhibits Ca2+-dependent stimulation of the Na+/H+ antiport in human T cells.
The cyclic undecapeptide cyclosporine A (CsA) is a potent immunosuppressive agent that inhibits the initial activation of T lymphocytes. This agent appears to be most effective in blocking the action of mitogens such as concanavalin A and the calcium ionophore A23187, which cause an influx of Ca2+, but not those that may act by alternate mechanisms. These observations suggest that CsA may block a Ca2+-dependent step in T cell activation. We have shown that stimulation of the T3-T cell receptor complex-associated Ca2+ transporter activates the Na+/H+ antiport (Rosoff, P. M., and L. C. Cantley, 1985, J. Biol. Chem., 260: 14053-14059). The tumor-promoting phorbol esters, which are co-mitogenic for T cells, activate the exchanger by a separate pathway which is mediated by protein kinase C. Both the rise in intracellular Ca2+ and intracellular pH may be necessary for the successful triggering of cellular activation. In this report we show that CsA blocks the T3-T cell receptor-stimulated, Ca2+ influx-dependent activation of Na+/H+ exchange, but not the phorbol ester-mediated pathway in a transformed human T cell line. CsA inhibited mitogen-stimulation of interleukin-2 production in a separate cell line. CsA also inhibited vasopressin stimulation of the antiporter in normal rat kidney fibroblasts, but had no effect on serum or 12-O-tetradecanoyl phorbol 13-acetate stimulation. CsA did not affect serum or vasopressin or serum stimulation of normal rat kidney cell proliferation. CsA also had no effect on lipopolysaccharide or phorbol ester stimulation of Na+/H+ exchange activity or induction of differentiation in 70Z/3 pre-B lymphocytes in which these events are initiated by the protein kinase C pathway. These data suggest that mechanisms of activation of Na+/H+ exchange that involve an elevation in cytosolic Ca2+ are blocked by CsA but that C kinase-mediated regulation is unaffected. The importance of the Na+/H+ antiport in the regulation of growth and differentiation of T cells is discussed.


Prospective evaluation of transient elastography for the diagnosis of hepatic fibrosis in Asians: comparison with liver biopsy and aspartate transaminase platelet ratio index.
Transient elastography (TE) is a reliable non-invasive predictor of hepatic fibrosis, but data on TE in Asians are limited. To evaluate prospectively the accuracy of TE for diagnosis of hepatic fibrosis in Asians compared with APRI (aspartate transaminase to platelet ratio index). One hundred and twenty consecutive patients who underwent liver biopsy were enrolled. TE (Fibroscan) was performed by two independent operators. Fibrosis was graded by two independent pathologists using the METAVIR classification. Area under receiver operating curves (AUROC) were used to evaluate the accuracy of TE and APRI in diagnosing significant fibrosis (F >or= 2) and cirrhosis (F4). Predominant aetiologies were hepatitis B (48%), non-alcoholic steatohepatitis (14%) and hepatitis C (8%). TE was unsuccessful in five patients (4.2%) because of small inter-costal space (three patients), obesity and ascites. There was good correlation between TE and fibrosis (r = 0.606). AUROC for diagnosis of significant fibrosis was 0.856 (95% CI 0.779-0.932) for TE and 0.673 (95% CI 0.568-0.777) for APRI. AUROC for diagnosis of cirrhosis was 0.924 (95% CI 0.857-0.990) for TE and 0.626 (95% CI 0.437-0.815) for APRI. Optimal TE value was 9.0 kPa for diagnosis of significant fibrosis and 16.0 kPa for cirrhosis with specificity/sensitivity/PPV/NPV/accuracy of 82.6%/85.2%/80.9%/86.7%/84.1% and 88.9%/82.7%/32.0%/98.8%/83.2%, respectively. Transient elastography is a reliable predictor of hepatic fibrosis in Asians. Failure of TE in Asians is commonly because of small inter-costal space. TE is superior to APRI for non-invasive diagnosis of hepatic fibrosis and cirrhosis.


Localization of actin and myosin for the study of ameboid movement in Dictyostelium using improved immunofluorescence.
The distribution of actin and myosin in Dictyostelium amebae at different developmental stages was studied by improved immunofluorescence ("agar-overlay" technique). Both were localized at the cortical region of amebae in all early developmental stages. In amebae with polarized morphology, bright fluorescence with antiactin was seen in the anterior pseudopode. The cortex in the posterior end was also stained with antiactin. On the other hand, very specific crescent-shaped staining with antimyosin was seen at the posterior cortex. In cells in contact with each other, actin was concentrated at the contact region, whereas myosin was localized specifically in the cortex on the other side of the contact region. At the aggregation stage, when monopodial amebae migrate forming streams, actin staining was seen all around the cell periphery, with intense fluorescence in the anterior pseudopode. On the other hand, specific staining of myosin was seen only at the posterior cortex. The cleavage furrow of cells performing cytokinesis displayed distinct myosin staining, and this staining represented the filamentous structure aligned in parallel to the axis of constriction. These findings indicate that myosin staining reflects the portion of the cell cortex where contraction occurs and the motive force of ameboid movement is generated at the posterior cortex of a migrating cell.


Assessing range of cervical rotation after laminoplasty using axial CT.
Although many authors have reported on cervical range of motion after laminoplasty, they have focused on flexion and extension based on lateral radiographs, not on axial rotation. In this study, we assessed cervical rotation from C1 to T1 after laminoplasty using computed tomography. Eighteen consecutive patients with cervical myelopathy who had undergone laminoplasty were observed. Patient was placed in the supine position on the computed tomography scan table. After the scans in this neutral position were completed, the patient actively rotated his neck as far as possible taking care that the shoulders remained in the horizontal plane. We measured the C1 to T1, C1 to C2, and C2 to T1 rotation angles preoperatively, and at 2 weeks and 6 months after surgery. The average C1 to T1 rotation angles preoperatively were 46 degrees on the right and 45 degrees on the left. The percentage of C1 to C2 rotation during global cervical rotation (C1 to T1) was 62%. C1 to T1 rotation angle significantly decreased at two weeks after surgery but recovered to almost preoperative levels (11% decreases) by 6 months after surgery with no difference between right and left motion. The average C2 to T1 subaxial rotation angles did not significantly decreased after surgery. Rotation angle after laminoplasty decreased slightly at 2 weeks after surgery but recovered almost to preoperative levels by 6 months. Subaxial rotation (C2 to T1) angles did not significantly decreased after surgery.


Dairy Intake and Body Composition and Cardiometabolic Traits among Adults: Mendelian Randomization Analysis of 182041 Individuals from 18 Studies.
Associations between dairy intake and body composition and cardiometabolic traits have been inconsistently observed in epidemiological studies, and the causal relationship remains ill-defined. We performed Mendelian randomization analysis using an established genetic variant located upstream of the lactase gene (LCT-13910 C/T, rs4988235) associated with dairy intake as an instrumental variable (IV). The causal effects of dairy intake on body composition and cardiometabolic traits (lipids, glycemic traits, and inflammatory factors) were quantified by IV estimators among 182041 participants from 18 studies. Each 1 serving/day higher dairy intake was associated with higher lean mass [β (SE) = 0.117 kg (0.035); P = 0.001], higher hemoglobin A1c [0.009% (0.002); P < 0.001], lower LDL [-0.014 mmol/L (0.006); P = 0.013], total cholesterol (TC) [-0.012 mmol/L (0.005); P = 0.023], and non-HDL [-0.012 mmol/L (0.005); P = 0.028]. The LCT-13910 C/T CT + TT genotype was associated with 0.214 more dairy servings/day (SE = 0.047; P < 0.001), 0.284 cm higher waist circumference (SE = 0.118; P = 0.017), 0.112 kg higher lean mass (SE = 0.027; P = 3.8 × 10-5), 0.032 mmol/L lower LDL (SE = 0.009; P = 0.001), and 0.032 mmol/L lower TC (SE = 0.010; P = 0.001). Genetically higher dairy intake was associated with increased lean mass [0.523 kg per serving/day (0.170); P = 0.002] after correction for multiple testing (0.05/18). However, we find that genetically higher dairy intake was not associated with lipids and glycemic traits. The present study provides evidence to support a potential causal effect of higher dairy intake on increased lean mass among adults. Our findings suggest that the observational associations of dairy intake with lipids and glycemic traits may be the result of confounding.


Application of Rank Annihilation Factor Analysis for Antibacterial Drugs Determination by Means of pH Gradual Change-UV Spectral Data.
The main objective of this study was to develop a simple and efficient spectrophotometric technique combined with chemometrics for the simultaneous determination of sulfamethoxazole (SMX) and trimethoprim (TMP) in drug formulations. Specifically, we sought: (i) to evaluate the potential use of rank annihilation factor analysis (RAFA) to pH gradual change spectrophotometric data in order to provide sufficient accuracy and model robustness; and (ii) to determine SMX and TMP concentration in drug formulations without tedious pre-treatments such as derivatization or extraction techniques which are time-consuming and require hazardous solvents. In the proposed method, the spectra of the sample solutions at different pH values were recorded and the pH-spectra bilinear data matrix was generated. On these data, RAFA was then applied to estimate the concentrations of SMX and TMP in synthetic and real samples. Applying RAFA showed that the two drugs could be determined simultaneously with concentration ratios of SMX to TMP varying from 1:30 to 30:1 in the mixed samples (concentration range is 1-30 µg mL-1 for both components). The limits of detection were 0.25 and 0.38 µg mL-1 for SMX and TMP, respectively. The proposed method was successfully applied to the simultaneous determination of SMX and TMP in some synthetic, pharmaceutical formulation and biological fluid samples. In addition, the means of the estimated RSD (%) were 1.71 and 2.18 for SMX and TMP, respectively, in synthetic mixtures. The accuracy of the proposed method was confirmed by spiked recovery test on biological samples with satisfactory results (90.50-109.80%).


Prevention of post-herpetic neuralgia using transcutaneous electrical nerve stimulation.
Post-herpetic neuralgia (PHN) is the most common complication of herpes zoster (HZ) and is difficult to treat. The role of antiviral agents and nonpharmacologic procedures in preventing PHN is not entirely clear. Recent retrospective study showed that transcutaneous electrical nerve stimulation (TENS) may completely prevent PHN. The aim of our study was to identify predictors for PHN and evaluate the treatment with antiviral agents and TENS. We conducted a multicenter prospective, randomized intervention study in patients with a new onset of HZ. Immunocompromised patients were excluded. Patients were randomly assigned to four groups (TENS, Antiviral agents, TENS and Antiviral agents, and Control Group). At the inclusion, the following criteria were recorded: age, gender, duration of pain before the onset of the rash, the number of efflorescence, the intensity of pain, and the analgesic prescribed. During the follow-up, we recorded a spontaneous pain sensation, pain intensity, and presence of allodynia, hyperalgesia, or paraesthesia. With each additional year of age, the odds for the presence of PHN with unchanged values of other predictors increase (odds ratio (OR) = 1.03 [1.01; 1.05], p = 0.001). The same is true for the initial intensity of the pain (OR = 1.25 [1.09; 1.43], p = 0.002). The odds for acute and subacute herpetic neuralgia are greater than for PHN. The odds for subacute herpetic neuralgia are the lowest in the group treated with TENS (OR = 0.15 [0.05; 0.47], p = 0.001). PHN cannot be completely prevented. TENS as a single therapy was found the most successful among the tested treatments in reducing the incidence of subacute herpetic neuralgia.


The molecular genetic makeup of acute lymphoblastic leukemia.
Genomic profiling has transformed our understanding of the genetic basis of acute lymphoblastic leukemia (ALL). Recent years have seen a shift from microarray analysis and candidate gene sequencing to next-generation sequencing. Together, these approaches have shown that many ALL subtypes are characterized by constellations of structural rearrangements, submicroscopic DNA copy number alterations, and sequence mutations, several of which have clear implications for risk stratification and targeted therapeutic intervention. Mutations in genes regulating lymphoid development are a hallmark of ALL, and alterations of the lymphoid transcription factor gene IKZF1 (IKAROS) are associated with a high risk of treatment failure in B-ALL. Approximately 20% of B-ALL cases harbor genetic alterations that activate kinase signaling that may be amenable to treatment with tyrosine kinase inhibitors, including rearrangements of the cytokine receptor gene CRLF2; rearrangements of ABL1, JAK2, and PDGFRB; and mutations of JAK1 and JAK2. Whole-genome sequencing has also identified novel targets of mutation in aggressive T-lineage ALL, including hematopoietic regulators (ETV6 and RUNX1), tyrosine kinases, and epigenetic regulators. Challenges for the future are to comprehensively identify and experimentally validate all genetic alterations driving leukemogenesis and treatment failure in childhood and adult ALL and to implement genomic profiling into the clinical setting to guide risk stratification and targeted therapy.


The HeartQoL: part II. Validation of a new core health-related quality of life questionnaire for patients with ischemic heart disease.
Evaluation of health-related quality of life (HRQL) is important in improving the quality of patient care. The aim of this study was to determine the psychometric properties of the HeartQoL in patients with ischemic heart disease (IHD), specifically angina, myocardial infarction (MI), or ischemic heart failure. Data for the interim validation of the HeartQoL questionnaire were collected in (a) a cross-sectional survey and (b) a prospective substudy of patients undergoing either a percutaneous coronary intervention (PCI) or referred to cardiac rehabilitation (CR) and were then analyzed to determine the reliability, validity, and responsiveness of the HeartQoL questionnaire. We enrolled 6384 patients (angina, n = 2111, 33.1%; MI, n = 2351, 36.8%; heart failure, n = 1922, 30.1%) across 22 countries speaking 15 languages in the cross-sectional study and 730 patients with IHD in the prospective substudy. The HeartQoL questionnaire comprises 14-items with physical and emotional subscales and a global score (range 0-3 (poor to better HRQL). Cronbach's α was consistently ≥0.80; convergent validity correlations between similar HeartQoL and SF-36 subscales were significant (r ≥ 0.60, p < 0.001); discriminative validity was confirmed with predictor variables: health transition, anxiety, depression, and functional status. HeartQoL score changes following either PCI or CR were significant (p < 0.001) with effect sizes ranging from 0.37-0.64. The HeartQoL questionnaire is reliable, valid, and responsive to change allowing clinicians and researchers to (a) assess baseline HRQL, (b) make between-diagnosis comparisons of HRQL, and (c) evaluate change in HRQL in patients with angina, MI, or heart failure with a single IHD-specific HRQL instrument.


Ranking the invasions of cheaters in structured populations.
The identification of the most influential individuals in structured populations is an important research question, with many applications across the social and natural sciences. Here, we study this problem in evolutionary populations on static networks, where invading cheaters can lead to the collapse of cooperation. We propose six strategies to rank the invading cheaters and identify those which mostly facilitate the collapse of cooperation. We demonstrate that the type of successful rankings depend on the selection strength, the underlying game, and the network structure. We show that random ranking has generally little ability to successfully identify invading cheaters, especially for the stag-hunt game in scale-free networks and when the selection strength is strong. The ranking based on degree can successfully identify the most influential invaders when the selection strength is weak, while more structured rankings perform better at strong selection. Scale-free networks and strong selection are generally detrimental to the performance of the random ranking, but they are beneficial for the performance of structured rankings. Our research reveals how to identify the most influential invaders using statistical measures in structured communities, and it demonstrates how their success depends on population structure, selection strength, and on the underlying game dynamics.


GATA-4 regulates Bcl-2 expression in ovarian granulosa cell tumors.
Excessive cell proliferation and decreased apoptosis have been implicated in the pathogenesis of ovarian granulosa cell tumors (GCTs). We hypothesized that transcription factor GATA-4 controls expression of the antiapoptotic factor Bcl-2 and the cell cycle regulator cyclin D2 in normal and neoplastic granulosa cells. To test this hypothesis, a tissue microarray based on 80 GCTs was subjected to immunohistochemistry for GATA-4, Bcl-2, and cyclin D2, and the data were correlated to clinical and histopathological parameters. In addition, quantitative RT-PCR for GATA-4, Bcl-2, and cyclin D2 was performed on 21 human GCTs. A mouse GCT model was used to complement these studies. The role of GATA-4 in the regulation of Bcl2 and ccdn2 (coding for cyclin D2) was studied by transactivation assays, and by disrupting GATA-4 function with dominant negative approaches in mouse and human GCT cell lines. We found that GATA-4 expression correlated with Bcl-2 and cyclin D2 expression in human and murine GCTs. Moreover, GATA-4 enhanced Bcl-2 and cyclin D2 promoter activity in murine GCT cells. Whereas GATA-4 overexpression up-regulated and dominant negative GATA-4 suppressed Bcl-2 expression in human GCT cells, the effects on cyclin D2 were negligible. Our results reveal a previously unknown relationship between GATA-4 and Bcl-2 in mammalian granulosa cells and GCTs, and suggest that GATA-4 influences granulosa cell fate by transactivating Bcl-2.


Orthogonal self-assembled monolayers: alkanethiols on gold and alkane carboxylic acids on alumina.
This work demonstrates the practicality of forming two self-assembled monolayers (SAMs), independently but simultaneously, by adsorption of two different adsorbates from a common solution onto a substrate exposing two different materials at its surface. The experimental procedure and the degree of independence achieved in the resulting SAMs are illustrated by examination of monolayers obtained by adsorption of alkanethiols on gold and alkane carboxylic acids on alumina. This procedure provides a method for modifying the surface characteristics of microlithographically generated patterns and offers a versatile technique for controlling solid-vapor and solid-liquid interfacial properties in systems having patterns with dimensions of the order of 1 micrometer.


Functional and molecular adaptations in skeletal muscle of myoglobin-mutant mice.
Myoglobin is a cytoplasmic hemoprotein that is restricted to cardiomyocytes and oxidative skeletal myofibers and facilitates oxygen delivery during periods of high metabolic demand. Myoglobin content in skeletal muscle increases in response to hypoxic conditions. However, we previously reported that myoglobin-null mice are viable and fertile. In the present study, we define important functional, cellular, and molecular compensatory adaptations in the absence of myoglobin. Mice without myoglobin manifest adaptations in skeletal muscle that include a fiber type transition (type I to type II in the soleus muscle), increased expression of the hypoxia-inducible transcription factors hypoxia-inducible factor (HIF)-1alpha and HIF-2 (endothelial PAS domain protein), stress proteins such as heat shock protein 27, and the angiogenic growth factor vascular endothelial growth factor (soleus muscle), as well as increased nitric oxide metabolism (extensor digitorum longus). The resulting changes in angiogenesis, nitric oxide metabolism, and vasomotor regulation are likely to account for preserved exercise capacity of animals lacking myoglobin. These results demonstrate that mammalian organisms are capable of a broad spectrum of adaptive responses that can compensate for a potentially serious defect in cellular oxygen transport.


Computerized ultrasound image analysis for noninvasive evaluation of hepatic steatosis.
To assess the diagnostic value of a particular set of local intensity parameters extracted from ultrasound liver images in conjunction with support vector machine (SVM) classifiers for liver steatosis grading in respect to the "gold standard" provided by liver biopsy. We prospectively enrolled in the study 228 patients with chronic hepatopathies. All the patients underwent liver biopsy and abdominal ultrasound examination. For quantitative ultrasound assessment of liver steatosis, an image analysis software was developed, which extracts three local intensity parameters from regions of interest (ROI) in the ultrasound section and analyzes their depth variation: the coefficient of variation of luminance (CVL), the median luminance (ml ), and the hepato-splenic attenuation index (HSAI). For steatosis grading, SVM classifiers were trained on the input feature spaces provided by the above mentioned parameters. The statistical significance of the steatosis grading was assessed on a significant test set using SVM classifiers, in terms of sensibility, specificity and through the ROC curves. A cut-off value of 0.362 of the CVL of the liver performed the liver steatosis grading with an accuracy of 89.17% (p<0.0001). A cut-off value of 0.27 of the HSAI performed the prediction of the moderate-severe liver steatosis with an accuracy of 87%. The proposed computer analysis method of ultrasound images proved innovative and useful for the initial non-invasive assessment and grading of liver steatosis, with an additional advantage of reduced computational complexity and accessibility. The CVL provided a very good accuracy (89.17%) for an AUROC of 0.923 for the classification of liver steatosis in two severity categories (mild versus moderate-severe).


Insufficient fluconazole exposure in pediatric cancer patients and the need for therapeutic drug monitoring in critically ill children.
Fluconazole is recommended as first-line treatment in invasive candidiasis in children and infants. Although timely achievement of adequate exposure of fluconazole improves outcome, therapeutic drug monitoring is currently not recommended. We conducted a retrospective study of critically ill children treated with fluconazole from January 2007 to October 2013 and for whom fluconazole concentrations were available. We collected demographic, clinical, and treatment data through review of the medical records and determined the correlation of clinical variables with the fluconazole concentration. Additionally, we assessed the relation between the fluconazole concentration and the time to culture conversion in patients with proven invasive candidiasis. In total, 99 pediatric patients met the inclusion criteria. The fluconazole concentration was considered subtherapeutic in 40% of the patients. Multiple linear regression analysis showed a significant, independent, and positive association of the fluconazole trough concentration with the fluconazole dose (P <.001), weight (P = .009), and the serum urea concentration (P = .003), and a significant, independent, and negative association with age (P = .004) and cancer as an underlying condition (P = .003). A higher fluconazole concentration was associated with a shorter time to culture conversion (hazard ratio = 1.076 [95% confidence interval, 1.017-1.138]; P = .011). The fluconazole concentration is not sufficient in pediatric cancer patients with the currently recommended dose regimen, and a higher fluconazole dose is required to achieve adequate drug exposure. Therapeutic drug monitoring of fluconazole can be a valuable tool to detect possible underexposure in critically ill children.


Total Pancreatectomy With Islet Autotransplantation Resolves Pain in Young Children With Severe Chronic Pancreatitis.
Fear of diabetes and major surgery may prohibit referral of young children severely affected by pancreatitis for total pancreatectomy with islet autotransplant (TPIAT). We evaluated outcomes in our youngest TPIAT recipients, 3 to 8 years of age at surgery. Medical records were reviewed for 17 children (9 girls) ages 8 years or younger undergoing TPIAT from 2000 to 2014. Most (14/17) had genetic risk factors for pancreatitis. Since 2006, TPIAT recipients were followed prospectively with health questionnaires including assessments of pain and narcotic use, and scheduled hemoglobin A1c (HbA1c) and mixed-meal tolerance tests (6 mL/kg Boost HP) before surgery, and at regular intervals after. Patients are 1 to 11 years post-TPIAT (median 2.2 years). Data are reported as median (25th, 75th percentile). All had relief of pain, with all 17 patients off narcotics at most recent follow-up. Hospitalization rates decreased from 5.0 hospitalization episodes per person-year of follow-up before TPIAT, to 0.35 episodes per person-year of follow-up after TPIAT. Fourteen (82%) discontinued insulin, higher than the observed insulin independence rate of 41% in 399 patients older than 8 years of age undergoing TPIAT over the same interval (P = 0.004). Median post-TPIAT HbA1c was 5.9% (5.6%, 6.3%), and within patient post-TPIAT mean HbA1c was ≤6.5% for all but 2 patients. Young children with severe refractory chronic pancreatitis may be good candidates for TPIAT, with high rates of pain relief and insulin independence, and excellent glycemic control in the majority.


Thymoquinone: An IRAK1 inhibitor with in vivo and in vitro anti-inflammatory activities.
Thymoquinone (TQ) is a bioactive component of black seed (Nigella sativa) volatile oil and has been shown to have anti-oxidative, anti-inflammatory, and anti-cancer properties. In the present study, we explored the molecular mechanisms that underlie the anti-inflammatory effect of TQ and its target proteins using lipopolysaccharide (LPS)-stimulated murine macrophage-like RAW264.7 and human monocyte-like U937 cells, together with LPS/D-galactosamine (GalN)-induced acute hepatitis and HCl/EtOH-induced gastritis mouse models. TQ strongly inhibited the production of nitric oxide (NO) and repressed NO synthase (iNOS), tumor necrosis factor (TNF)-α, cyclooxygenase (COX)-2, interleukin (IL)-6, and IL-1β expression in LPS-activated RAW264.7 cells. Treatment of LPS/D-GalN-induced hepatitis and EtOH/HCl-induced gastritis mouse models with TQ significantly ameliorated disease symptoms. Using luciferase reporter gene assays, we also showed that the nuclear levels of transcription factors and phosphorylation patterns of signaling proteins, activator protein (AP)-1, and nuclear factor (NF)-κB pathways were all affected by TQ treatment. Finally, we used additional kinase and luciferase validation assays with interleukin-1 receptor-associated kinase 1 (IRAK1) to show that IRAK1 is directly suppressed by TQ treatment. Together, these findings strongly suggest that the anti-inflammatory actions of TQ are caused by suppression of IRAK-linked AP-1/NF-κB pathways.


Autocorrelation properties of fully coherent beam with and without orbital angular momentum.
The spatial correlation singularity of a partially coherent vortex beam was demonstrated recently [Phys. Rev. Lett. 92, 143905 (2004)], and it was shown that the cross-correlation singularity disappears when the spatial coherence is high. In this paper, we demonstrate that the spatial autocorrelation function of a fully coherent beam in the far-field is equivalent to the Fourier transform of its intensity in the source plane. Our theoretical and experimental results show that, depending on both the radial and azimuthal mode indices (p, λ) of the incident light beam, the distribution of the far-field autocorrelation function displays a series of concentric, alternate bright and dark rings. This phenomenon may be used to determine the topological charge (the azimuthal index) of light beam with a nonzero radial index.


RETRACTED: Znhit1 inhibits breast cancer by up-regulating PTEN to deactivate the PI3K/Akt/mTOR pathway.
This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). This article has been retracted at the request of the Editor-in-Chief. Given the comments regarding this article "This paper belongs to a set of over 400 papers (as per February 2020) that share very similar Western blots with tadpole-like shaped bands, the same background pattern, and striking similarities in title structures, paper layout, bar graph design, and - in a subset - flow cytometry panels", the journal requested the authors to provide the raw data. However, the authors were not able to fulfil this request and therefore the Editor-in-Chief decided to retract the article.


Parathyroid adenomas in the aortopulmonary window.
To describe localization studies in nine patients with ectopic parathyroid adenomas in the aortopulmonary window. Nine patients with ectopic parathyroid tissue (eight adenomas, one hyperplastic gland) in the aortopulmonary window were examined with ultrasound (US), computed tomography (CT), magnetic resonance (MR) imaging, and scintigraphy. Diagnostic arteriography (n = 4) and venous sampling (n = 3) were performed in the first four patients; arteriography for the purpose of staining was attempted in the last five patients. The results of CT and MR imaging studies were positive in eight of nine patients (89%) and five of eight patients (63%), respectively. The results of thallium/technetium scintigraphy were negative in three patients scanned (0%), but the results of a repeat study in one patient were positive (33%). Sestamibi scans were positive in six of six patients (100%). Single photon emission CT was performed in all six patients and enabled distinction between adenomas in the aortopulmonary window and those in the thymus. Ectopic parathyroid glands in the aortopulmonary window are usually detected at sestamibi scintigraphy, and SPECT is helpful in distinguishing these adenomas from more common adenomas in the anterior mediastinum. CT and MR imaging studies can also enable this distinction, but imaging must extend below the aortic arch.


Study of gaseous interactions in carbon nanotube field-effect transistors through selective Si(3)N(4) passivation.
Carbon nanotube field-effect transistors with Si(3)N(4) passivated source and drain contacts and exposed carbon nanotube channel show n-type characteristics in air. In contrast, by passivating only the source contact, a diode-like behavior with a maximum current rectification ratio of 4.6 × 10(3) is observed. The rectifying characteristic vanishes in a vacuum but recovers once the devices are exposed to air. From our experiments, key parameters, such as critical gas pressure, adsorption energy of oxygen molecules and the contact barrier height modulation, can be obtained for studying the gaseous interaction in the carbon nanotube devices.


Anaesthesia machine: checklist, hazards, scavenging.
From a simple pneumatic device of the early 20(th) century, the anaesthesia machine has evolved to incorporate various mechanical, electrical and electronic components to be more appropriately called anaesthesia workstation. Modern machines have overcome many drawbacks associated with the older machines. However, addition of several mechanical, electronic and electric components has contributed to recurrence of some of the older problems such as leak or obstruction attributable to newer gadgets and development of newer problems. No single checklist can satisfactorily test the integrity and safety of all existing anaesthesia machines due to their complex nature as well as variations in design among manufacturers. Human factors have contributed to greater complications than machine faults. Therefore, better understanding of the basics of anaesthesia machine and checking each component of the machine for proper functioning prior to use is essential to minimise these hazards. Clear documentation of regular and appropriate servicing of the anaesthesia machine, its components and their satisfactory functioning following servicing and repair is also equally important. Trace anaesthetic gases polluting the theatre atmosphere can have several adverse effects on the health of theatre personnel. Therefore, safe disposal of these gases away from the workplace with efficiently functioning scavenging system is necessary. Other ways of minimising atmospheric pollution such as gas delivery equipment with negligible leaks, low flow anaesthesia, minimal leak around the airway equipment (facemask, tracheal tube, laryngeal mask airway, etc.) more than 15 air changes/hour and total intravenous anaesthesia should also be considered.


What is the most reliable imaging modality for small colonic polyp characterization? Study of white-light, autofluorescence, and narrow-band imaging.
In vivo optical diagnosis of small colorectal polyps has potential clinical and cost advantages, but requires accuracy and high interobserver agreement for clinically acceptability. We aimed to assess interobserver variability and diagnostic performance of endoscopic imaging modalities in characterizing small colonic polyps. High quality still images of 80 polyps < 1 cm were recorded using white-light endoscopy (WLE), autofluorescence imaging (AFI) and narrow-band imaging with and without magnification (NBI and NBImag). All images were assessed for quality, prediction of polyp histology, and vascular pattern intensity (with NBI) by nine experienced colonoscopists (four experts in advanced imaging) from five UK centers. Interobserver agreement (kappa statistic), sensitivity, specificity, and accuracy were calculated compared with histopathological findings. Interobserver agreement for predicting polyp histology using NBImag was significantly better for experts (κ = 0.63, substantial) compared with nonexperts (κ = 0.30, fair; P < 0.001), and was moderate for all colonoscopists with WLE, AFI and NBI. Interobserver agreement for vascular pattern intensity using NBI was 0.69 (substantial) for experts and 0.57 (good) for nonexperts. NBImag had higher sensitivity than WLE (experts, 0.93 vs. 0.68, P < 0.001; nonexperts, 0.90 vs. 0.52, P < 0.001) and higher overall accuracy (experts, 0.76 vs. 0.64, P = 0.003; nonexperts 0.61 vs. 0.40, P < 0.001). AFI had worse accuracy than WLE for both expert colonoscopists (0.53 vs. 0.64, P = 0.02) and nonexperts (0.32 vs. 0.40, P = 0.04). Of the imaging modalities tested, NBImag appeared to have the best overall accuracy and interobserver agreement, although not adequate for in vivo diagnosis. NBI and AFI did not have better sensitivity, specificity, or accuracy compared with WLE.


Complications in 8509 laparoscopic Falope ring sterilizations performed under local anaesthesia.
During the 3-year period 1 January 1980-31 December 1982, 8509 laparoscopic Falope ring sterilizations were performed under local anaesthesia in rural areas of the Cape Province by the Sterilization Service of Tygerberg Hospital. Despite the fact that 476 of the patients had undergone previous lower abdominal surgery, major complications (anaphylactic shock after injection of lignocaine and inadvertent perforation of the bladder by the trocar) occurred in only 2 cases. It was not possible to complete the sterilization under local anaesthesia in 98 cases, resulting in a technical failure rate of 1.15%. A prospective study of the minor complications encountered among the 193 patients sterilized during November 1982 showed that torn tubes occurred in 3.1% and uterine perforation in 2.1%. This can be partially explained by the fact that evidence of previous pelvic infection was seen during laparoscopy in 9.3% of cases. The pregnancy rate after sterilization was 0.28% for the group as a whole.


Introducing a new prognostic instrument for long-term mortality prediction in COPD patients: the CADOT index.
The BODE (BMI, Obstruction - FEV1, Dyspnoea - mMRC, Exercise - 6-MWT) and the ADO (Age, Dyspnoea - mMRC, Obstruction - FEV1) indices are widely used prognosis assessment tools for long-term mortality prediction in COPD patients but subject to limitations for use in daily clinical practice. The aim of this research was to construct a prognostic instrument that prevents these limitations and which would serve as a complementary prognostic tool for clinical use in these patients. The data of 699 COPD subjects were extracted from the Czech Multicentre Research Database (CMRD) of COPD patients (the derivation cohort) and analysed to identify factors associated with the long-term risk of mortality. These were entered into the ROC analysis and reclassification analysis. Those with the strongest discriminative power were used to construct the new index (CADOT). The new index was validated on 187 patients of the CIROCO+ cohort (Netherlands; the validation cohort). The CADOT was constructed by adding two newly identified prognosis-determining factors, chronic heart failure (CHF) and TLCO, to the ADO index. In a head-to-head comparison, the CADOT index showed highest c-statistic values compared to the BODE and ADO indices (0.701 vs 0.677 vs 0.644, respectively). The prognostic power was more definitive when applied to the Dutch validation (CIROCO+) cohort (0.842 vs 0.799 vs 0.825, respectively). The CADOT index has comparable prognostic power to the BODE and ADO indices. The CADOT is complementary/an alternative to the BODE (if 6-MWT is not feasible) and ADO (with less dependence on the age factor) indices. ClinicalTrials.gov (NCT01923051).


Systematic review: factors associated with risk for and possible prevention of cognitive decline in later life.
Many biological, behavioral, social, and environmental factors may contribute to the delay or prevention of cognitive decline. To summarize evidence about putative risk and protective factors for cognitive decline in older adults and the effects of interventions for preserving cognition. English-language publications in MEDLINE, HuGEpedia, AlzGene, and the Cochrane Database of Systematic Reviews from 1984 through 27 October 2009. Observational studies with 300 or more participants and randomized, controlled trials (RCTs) with 50 or more adult participants who were 50 years or older, drawn from general populations, and followed for at least 1 year were included. Relevant, good-quality systematic reviews were also eligible. Information on study design, outcomes, and quality were extracted by one researcher and verified by another. An overall rating of the quality of evidence was assigned by using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) criteria. 127 observational studies, 22 RCTs, and 16 systematic reviews were reviewed in the areas of nutritional factors; medical factors and medications; social, economic, or behavioral factors; toxic environmental exposures; and genetics. Few of the factors had sufficient evidence to support an association with cognitive decline. On the basis of observational studies, evidence that supported the benefits of selected nutritional factors or cognitive, physical, or other leisure activities was limited. Current tobacco use, the apolipoprotein E epsilon4 genotype, and certain medical conditions were associated with increased risk. One RCT found a small, sustained benefit from cognitive training (high quality of evidence) and a small RCT reported that physical exercise helps to maintain cognitive function. The categorization and definition of exposures were heterogeneous. Few studies were designed a priori to assess associations between specific exposures and cognitive decline. The review included only English-language studies, prioritized categorical outcomes, and excluded small studies. Few potentially beneficial factors were identified from the evidence on risk or protective factors associated with cognitive decline, but the overall quality of the evidence was low. Agency for Healthcare Research and Quality and the National Institute on Aging, through the Office of Medical Applications of Research, National Institutes of Health.


Pregnancy wastage among HIV infected women in a high HIV prevalence district of India.
Bagalkot district in Karnataka state is one of the highest HIV prevalence districts in India. A large proportion of the girls also marry at early age in the district and negative pregnancy outcomes among the HIV positive women likely to have large pregnancy wastages. Therefore, this study examined the pregnancy wastages and the associated factors among HIV positive women in a high prevalent district in India. We used data from a cross-sectional survey conducted recently among randomly selected currently married HIV positive women, 15-29 years of age, in one of the high HIV prevalence districts in India. The study used the experience of reported pregnancy wastage as an outcome variable, and both bi-variate and multivariate logistic regression analyses were carried out to understand the factors associated with the pregnancy wastage among HIV infected women. Overall, 17% of the respondents reported pregnancy wastage, of which 81% were due to spontaneous abortions. Respondents who became pregnant since testing HIV positive reported significantly higher level of pregnancy wastage as compared to those were pregnant before they were tested for HIV. (AOR = 1.9; p = 0.00). While a positive association between duration of marriage and pregnancy wastage was noticed (AOR = 7.4; p = 0.01), there was a negative association between number of living children and pregnancy wastage (AOR = 0.24; p = 0.00). Living in a joint family was associated with increased reporting of pregnancy wastage as compared to those living in nuclear families (AOR = 1.7; p = 0.03). HIV prevention and care programs need to consider the reproductive health needs of HIV infected married women as a priority area since large proportion of these women reported negative pregnancy outcomes. There is also a need to explore ways to raise the age at marriage in order to stop women getting married before the legal age at marriage.


Potential trends in Attention Deficit Hyperactivity Disorder (ADHD) drug use on a college campus: wastewater analysis of amphetamine and ritalinic acid.
Attention Deficit Hyperactivity Disorder (ADHD) medication use is on the rise in the United States. The most widely used ADHD medications are the amphetamine-type compounds Adderall (mixed amphetamine salts) and Ritalin (methylphenidate). According to survey data ADHD medications are used as a study drug or "Smart Drug" by students without a prescription on college campuses. Survey data of non-prescribed drug use has limitations with accurate reporting and no empirical data of usage exists in the literature. This study looks for trends in the use of these drugs on a college campus among low-stress and high stress periods. The metabolites of these two drugs, amphetamine and ritalinic acid, are quantified in campus wastewater using solid phase extraction (SPE) and liquid chromatography-tandem mass spectrometry (LC-MS/MS). Trends show a possible increase in amphetamine levels during periods of high stress such as midterms, the last week of classes and finals week over levels from the baseline low stress weeks such as the first week of classes. Both semesters from the 2011-12 academic year were studied and the highest increase over baseline (760%) occurred during finals week of the second semester. Ritalinic acid levels gradually climbed first semester but had no obvious periodic trend second semester.


Epstein-Barr virus regulates activation and processing of the third component of complement.
Serum incubated with purified EBV was found to contain C3 cleavage fragments characteristic of C3c. Since the cofactors necessary for such cleavage of C3b by factor I are not normally present in serum, EBV was tested for factor I cofactor activity. Purified EBV from both human and marmoset EBV-producing cell lines was found to act as a cofactor for the factor I-mediated breakdown C3b to iC3b and iC3b to C3c and C3dg. EBV also acted as a cofactor for the factor I-mediated cleavage of C4b to iC4b and iC4b to C4c and C4d. EBV from both the human and marmoset cell lines accelerated the decay of the alternative pathway C3 convertase. The classical pathway C3 convertase was unaffected. Multiple lines of evidence eliminated the possibility that marmoset or human CR1 was responsible for the functional activities of EBV preparations. The spectrum of activities was different from CR1 in that EBV and EBV-expressing cell lines failed to rosette with C3b or particles bearing C3b, the primary functional assay for CR1, and EBV did not accelerate classical pathway C3 convertase decay, another property of CR1. In addition, CR1 could not be detected immunologically on marmoset or human EBV-expressing cells and mAbs to CR1 failed to alter EBV-produced decay acceleration and factor I cofactor activities, although the antibodies blocked the same CR1-dependent functional activities. The multiple complement regulatory activities exhibited by purified EBV derived from human and marmoset cells differ from those of any of the known C3 or C4 regulatory proteins. These various activities would be anticipated to provide survival value for the virus by subverting complement- and cell-dependent host defense mechanisms.


Adult intussusception in Asians: clinical presentations, diagnosis, and treatment.
Adult intussusception is a rare clinical entity. The presentations and optimal management of adult intussusception in Asians have seldom been reported. The purpose of this study was to determine the causes and management of adult intussusception in Taiwan. A retrospective review performed at four medical centers in Taiwan identified 46 patients, at least 18 years old, with a diagnosis of intestinal intussusception from January 1992 to December 2005. Data related to presentations, diagnosis, treatment, and pathology were analyzed. There were 28 men and 18 women with a mean age of 58 (range 19-83) years. Twenty-five patients were diagnosed with enteric intussusception and 21 patients with colonic intussusception. Disease in 35 (76.1%) patients was caused by a benign lead point. The most common symptom was abdominal pain, which was seen in all patients. Twenty-five patients presented with acute symptoms that they experienced over a period of less than 3 days. The preoperative diagnosis was 89.1% because of the wide use of abdominal computed tomography (CT). The most sensitive diagnostic modality was abdominal CT (88.6%). For all patients, 76% with enteric intussusception and 28.6% with colonic intussusception underwent operative reduction. At the time of writing, 71.7% patients were still alive. Only two patients died of postoperative complications. Most patients with adult intussusception in our series were men, and most intussusceptions were benign and of enteric origin. The most sensitive diagnostic modality is abdominal CT scan. Operative reduction is recommended for enteric intussusceptions but not for colonic intussusceptions. The prognosis of adult intussusception after surgery is good except for malignant intussusception.


Stable isotope turnover and half-life in animal tissues: a literature synthesis.
Stable isotopes of carbon, nitrogen, and sulfur are used as ecological tracers for a variety of applications, such as studies of animal migrations, energy sources, and food web pathways. Yet uncertainty relating to the time period integrated by isotopic measurement of animal tissues can confound the interpretation of isotopic data. There have been a large number of experimental isotopic diet shift studies aimed at quantifying animal tissue isotopic turnover rate λ (%·day(-1), often expressed as isotopic half-life, ln(2)/λ, days). Yet no studies have evaluated or summarized the many individual half-life estimates in an effort to both seek broad-scale patterns and characterize the degree of variability. Here, we collect previously published half-life estimates, examine how half-life is related to body size, and test for tissue- and taxa-varying allometric relationships. Half-life generally increases with animal body mass, and is longer in muscle and blood compared to plasma and internal organs. Half-life was longest in ecotherms, followed by mammals, and finally birds. For ectotherms, different taxa-tissue combinations had similar allometric slopes that generally matched predictions of metabolic theory. Half-life for ectotherms can be approximated as: ln (half-life) = 0.22*ln (body mass) + group-specific intercept; n = 261, p<0.0001, r2 = 0.63. For endothermic groups, relationships with body mass were weak and model slopes and intercepts were heterogeneous. While isotopic half-life can be approximated using simple allometric relationships for some taxa and tissue types, there is also a high degree of unexplained variation in our models. Our study highlights several strong and general patterns, though accurate prediction of isotopic half-life from readily available variables such as animal body mass remains elusive.


Dosage sensitivity shapes the evolution of copy-number varied regions.
Dosage sensitivity is an important evolutionary force which impacts on gene dispensability and duplicability. The newly available data on human copy-number variation (CNV) allow an analysis of the most recent and ongoing evolution. Provided that heterozygous gene deletions and duplications actually change gene dosage, we expect to observe negative selection against CNVs encompassing dosage sensitive genes. In this study, we make use of several sources of population genetic data to identify selection on structural variations of dosage sensitive genes. We show that CNVs can directly affect expression levels of contained genes. We find that genes encoding members of protein complexes exhibit limited expression variation and overlap significantly with a manually derived set of dosage sensitive genes. We show that complexes and other dosage sensitive genes are underrepresented in CNV regions, with a particular bias against frequent variations and duplications. These results suggest that dosage sensitivity is a significant force of negative selection on regions of copy-number variation.


Retroviral coexpression of two different types of drug resistance genes to protect normal cells from combination chemotherapy.
Drug resistance genes can protect normal hematopoietic cells from the toxicity of anticancer agents. Because chemotherapeutic agents are often used in combination in current clinical protocols, coexpression of two different drug resistance genes should be useful in protecting normal bone marrow cells from the hematotoxicities caused by combination chemotherapy. In this study, we have combined the human multidrug resistance gene (MDR1) and human O6-methylguanine DNA methyltransferase (MGMT) gene as drug resistance genes. For the coexpression of two drug resistance genes, we have constructed two bicistronic retrovirus vectors. One vector is Ha-MDR-IRES-MGMT, in which translation of the MDR1 cDNA is cap-dependent and MGMT translation is dependent on an internal ribosome entry site (IRES). The other is Ha-MGMT-IRES-MDR, which has cap-dependent MGMT translation and IRES-dependent MDR1 translation. MGMT-negative HeLa derivative (MR) cells transduced with these retroviruses showed resistance to vincristine (from MDR1) and 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosou rea (ACN; from MGMT). Cells transduced with Ha-MDR-IRES-MGMT showed higher resistance to vincristine and lower resistance to ACNU than those transduced with Ha-MGMT-IRES-MDR. In any case, the resistance levels of cells transduced with either vector were high enough to select transduced cells with vincristine or ACNU. The expression levels of P-glycoprotein or MGMT in the transduced cells determined by FACS and Western blot analysis correlated well with the extent of resistance to vincristine and ACNU, respectively. All of the MGMT-transduced cells expressed higher amounts of MGMT than the MGMT-expressing parental cell line HeLa S3. Murine bone marrow cells transduced with Ha-MDR-IRES-MGMT and selected with vincristine also showed simultaneous resistance to vincristine and ACNU. These results suggest that bicistronic retroviral vectors allow the functional coexpression of two different types of drug resistance genes. This strategy could be applicable to any combination of drug resistance genes.


The Circadian Clock, Shift Work, and Tissue-Specific Insulin Resistance.
Obesity and type 2 diabetes (T2D) have become a global health concern. The prevalence of obesity and T2D is significantly higher in shift workers compared to people working regular hours. An accepted hypothesis is that the increased risk for metabolic health problems arises from aberrantly timed eating behavior, that is, eating out of synchrony with the biological clock. The biological clock is part of the internal circadian timing system, which controls not only the sleep/wake and feeding/fasting cycle, but also many metabolic processes in the body, including the timing of our eating behavior, and processes involved in glucose homeostasis. Rodent studies have shown that eating out of phase with the endogenous clock results in desynchronization between rhythms of the central and peripheral clock systems and between rhythms of different tissue clocks (eg, liver and muscle clock). Glucose homeostasis is a complex process that involves multiple organs. In the healthiest situation, functional rhythms of these organs are synchronized. We hypothesize that desynchronization between different metabolically active organs contributes to alterations in glucose homeostasis. Here we summarize the most recent information on desynchronization between organs due to shift work and shifted food intake patterns and introduce the concept of phenotypic flexibility, a validated test to assess the contribution of each organ to insulin resistance (IR) in humans. We propose this test as a way to provide further insight into the possible desynchronization between tissue clocks. Because different types of IR benefit from different therapeutic approaches, we also describe different chronotherapeutic strategies to promote synchrony within and between metabolically active organs.


The unusual mineral vaterite in shells of the freshwater bivalve Corbicula fluminea from the UK.
Asian clams (Corbicula fluminea) with abnormally thickened shell valves were found in four rivers in the UK (Rivers Yare, Waveney, Thames and New Bedford River). The material making up these malformations was the rare calcium carbonate polymorph vaterite. Vaterite is seldom found in the natural environment because it is less stable than the other calcium carbonate polymorphs (aragonite and calcite). In the few reported cases of vaterite formation in molluscs, it is usually related to unusual biomineralisation events such as shell regeneration, pearls and initial stages of shell formation. We compared two populations from the Rivers Yare and Waveney in the Norfolk Broads, UK, one (River Waveney) displaying dominantly the normal Corbicula shell form with aragonitic shells. In the River Yare population, all individuals sampled had shell deformations to different extents. These deformations were apparent as bulges on the inside of the ventral shell margin. X-ray diffraction confirmed that the shell material in the bulges of recently collected clams was vaterite. Other parts of the deformed shells were aragonitic. The shell deformations alter the shell morphology, leading to higher and wider shells. The shell microstructure is fibrous in the vateritic parts and crossed-lamellar in the aragonitic parts of deformed or non-deformed shells. The cause for the malformations is probably a disrupted biomineralisation process in the bivalves. Fossil Corbicula specimens from the late Pleistocene had similar deformations, suggesting that this is not a response to anthropogenic causes, such as pollution.


Effects of left inferior prefrontal stimulation on episodic memory formation: a two-stage fMRI-rTMS study.
Successful recovery of words from episodic memory relies strongly on semantic processes at the time of encoding. Evidence from several functional magnetic resonance imaging (fMRI) studies has shown that changes in neural activity in the left inferior prefrontal cortex (LIPFC) during semantic encoding predict subsequent memory performance. This evidence has been taken to suggest that LIPFC plays a critical role in memory formation. Functional neuroimaging findings, however, do not establish a causal brain-behavior relationship. To determine whether there is a causal link between LIPFC involvement at encoding and subsequent success in memory performance, we conducted a two-part study in which we first used fMRI to localize encoding-related activation in LIPFC and then employed repetitive transcranial magnetic stimulation (rTMS) to manipulate neural processes in LIPFC during semantic encoding. To demonstrate the neuroanatomical specificity of any observed effect and to control for nonspecific rTMS side effects, we also stimulated neural processes in two control sites. Using frameless stereotaxy, we positioned the stimulation coil to target (1) the LIPF region that was activated during fMRI (mean xyz = -48 35 5); (2) the homologous right-hemisphere region; and (3) an additional left parietal control site. At each site, "stimulated" items (600 msec of 7-Hz rTMS with Cadwell Round Coil) were intermixed with items presented without concurrent stimulation. Subsequently, subjects performed a recognition memory task for the words encountered. We found support for the predicted causal brain-behavior relationship, which was specific to LIPFC. When comparing recognition scores for stimulated items, normalized for variations in performance on nonstimulated trials, we found that words encoded under LIPFC stimulation were subsequently recognized with higher accuracy than words encoded under stimulation in the two cortical control sites. By contrast, no performance difference emerged when the two control sites were compared with each other. Based on additional analyses of the rTMS effects observed directly at the time of encoding (i.e., on semantic-decision performance), we suggest that LIPFC stimulation may have produced its effect on recognition memory, at least in part, through the triggering of more extensive processing of the stimulated items and an ensuing gain in item distinctiveness. Physiological processes of facilitation probably also contributed to the observed memory benefit. Together, these findings suggest that LIPFC does play a causal role in episodic memory formation.


Induction of IDO by bacille Calmette-Guérin is responsible for development of murine depressive-like behavior.
Chronic inflammation activates the tryptophan-degrading enzyme IDO, which is well known to impair T cell proliferation. We have previously established that bacille Calmette-Guérin (BCG), an attenuated form of Mycobacterium bovis, is associated with persistent activation of IDO in the brain and chronic depressive-like behavior, but a causative role has not been established. In these experiments we used both pharmacologic and genetic approaches to test the hypothesis that IDO activation is responsible for the development of chronic depression that follows BCG infection. BCG induced TNF-alpha, IFN-gamma, and IDO mRNA steady-state transcripts in the brain as well as the enzyme 3-hydroxyanthranilic acid oxygenase (3-HAO) that lies downstream of IDO and generates the neuroactive metabolite, quinolinic acid. Behaviors characteristic of depression were apparent 1 wk after BCG infection. Pretreatment with the competitive IDO inhibitor 1-methyltryptophan fully blocked BCG-induced depressive-like behaviors. Importantly, IDO-deficient mice were completely resistant to BCG-induced depressive-like behavior but responded normally to BCG induction of proinflammatory cytokines. These results are the first to prove that the BCG-induced persistent activation of IDO is accompanied by the induction of 3-hydroxyanthranilic acid oxygenase and that IDO is required as an initial step for the subsequent development of chronic depressive-like behavior.


Taenia solium oncosphere adhesion to intestinal epithelial and Chinese hamster ovary cells in vitro.
The specific mechanisms underlying Taenia solium oncosphere adherence and penetration in the host have not been studied previously. We developed an in vitro adhesion model assay to evaluate the mechanisms of T. solium oncosphere adherence to the host cells. The following substrates were used: porcine intestinal mucosal scrapings (PIMS), porcine small intestinal mucosal explants (PSIME), Chinese hamster ovary cells (CHO cells), epithelial cells from ileocecal colorectal adenocarcinoma (HCT-8 cells), and epithelial cells from colorectal adenocarcinoma (Caco-2 cells). CHO cells were used to compare oncosphere adherence to fixed and viable cells, to determine the optimum time of oncosphere incubation, to determine the role of sera and monolayer cell maturation, and to determine the effect of temperature on oncosphere adherence. Light microscopy, scanning microscopy, and transmission microscopy were used to observe morphological characteristics of adhered oncospheres. This study showed in vitro adherence of activated T. solium oncospheres to PIMS, PSIME, monolayer CHO cells, Caco-2 cells, and HCT-8 cells. The reproducibility of T. solium oncosphere adherence was most easily measured with CHO cells. Adherence was enhanced by serum-binding medium with >5% fetal bovine serum, which resulted in a significantly greater number of oncospheres adhering than the number adhering when serum at a concentration less than 2.5% was used (P < 0.05). Oncosphere adherence decreased with incubation of cells at 4 degrees C compared with the adherence at 37 degrees C. Our studies also demonstrated that T. solium oncospheres attach to cells with elongated microvillus processes and that the oncospheres expel external secretory vesicles that have the same oncosphere processes.


The political economy of academic publishing: On the commodification of a public good.
This paper provides an institutional and empirical analysis of the highly concentrated market of academic publishing, characterized by over proportionally high profit margins for publishing companies. The availability of latest research findings is an important issue for researchers, universities and politicians alike. Open access (OA) publication provides a promising but also costly solution to overcome this problem. However, in this paper we argue that OA publication costs are an important, but by far not the only way for academic publishers to gain access to public funding. In contrast, our study provides a comprehensive overview of the channels through which public expenditure benefits big academic publishing companies. Furthermore, we offer the results of an explorative case study, where we estimate the annual financial flows of public expenditures in Austria for the field of social sciences. In all, these expenditures add up to about 66.55 to 103.2 million € a year, which amounts to a fourth of total public funding for this field. Against this background, we contribute to the debate whether and to what extent public subsidies are justified for economically successful companies.


HIV protease inhibitors inhibit FACE1/ZMPSTE24: a mechanism for acquired lipodystrophy in patients on highly active antiretroviral therapy?
HIV-PIs (HIV protease inhibitors) have proved to be of great benefit for the millions of people suffering from AIDS. However, one of the side effects of this component of combined highly active antiretroviral therapy is lipodystrophy, which affects a large number of the patients taking this class of drug. It has been shown that many of these protease inhibitors inhibit the ZMPSTE24 enzyme responsible for removing the farnesylated tail of prelamin A, which is a nuclear lamina component that has been implicated in some of the nuclear laminopathies. Build up of this protein somehow leads to acquired lipodystrophy, possibly through its interaction with a transcription factor called SREBP-1 (sterol-regulatory-element-binding protein-1). The downstream effect of this is altered fatty acid metabolism and sterol synthesis, which may cause lipodystrophy in patients. The build-up of this protein also appears to have morphological consequences on the nucleus and we reveal, by dual-axis electron tomography, a complex nucleoplasmic reticulum that forms after HIV-PI treatment as a result of acute farnesylated prelamin A accumulation. A greater understanding of the molecular mechanisms leading to lipodystrophy will hopefully facilitate the design of improved HIV-PIs that do not cause this debilitating side effect.


Skeletal muscle ceramide species in men with abdominal obesity.
Obesity is a risk factor for diabetes and its consequences, including accelerated ageing and mortality. The underlying factor could be accumulation of certain lipid moieties, such as ceramides (CER) and diacylgycerol (DAG) within muscle tissue, which are known to promote insulin resistance (IR), induce inflammation and oxidative injury, ultimately altering muscle function. First, to study the relationship between body composition and age (independent variables) with skeletal muscle accumulation of lipid species, oxidative injury and strength. Second, to analyze the relationship between muscle tissue metabolites and insulin resistance, inflammation and lymphocyte telomere length, the latter as an indicator of ageing. The sample included 56 healthy sedentary males, scheduled for inguinal hernia surgery, aged 27 to 80 y. Each individual was subject to anthropometric measurements, body composition assessment through radiologic densitometry (DEXA), measurement of handgrip and quadriceps strength, serum biochemical parameters (lipoproteins, creatinine, high sensitivity C reactive protein [hsCRP], fasting and post glucose insulin and glucose concentrations for calculation of IR through the Matsuda and HOMA-IR indexes), and extraction of peripheral leukocytes for measurement of telomere length. During the surgical procedure, a sample of muscle tissue was obtained (anterior abdominal oblique) in order to measure CER and DAG (and sub species according to chain length and saturation) by mass spectrometry, 4 hydroxy-2-nonenal adducts (4-HNE) using electron microscopy immunohistochemistry, and carboxymethyl-lisine (CML) by immunohistochemistry, the latter as indicators of oxidative stress (OS). Body mass index (BMI) of twenty six individuals was > 25 k/m2, while BMI of 7 was > 30 k/m2. Overweight/obese individuals, did not exhibit differences in skeletal muscle lipid metabolites, however total CER and specific long chain CER sub-species (20 and 22 carbon) increased significantly among individuals with a central fat distribution (n = 14) as well as in glucose intolerant subjects (n =23). A negative association was found between mononuclear leukocyte telomere length and 20 and 22 carbon CER (rho = - 0.4 and -0.5 0 p < 0.05). Muscle strength was not associated with any of the measured muscle metabolites or markers of OS. A multiple regression analysis accepted central abdominal fat and telomere length as significant predictors of CER (R2 = 0.28). An association was found between accumulation of specific ceramide species in muscle tissue and abdominal obesity, glucose intolerance and shortening of leukocyte telomeres, although not with muscle oxidative injury or dysfunction.


Hydrogen inhalation reduced epithelial apoptosis in ventilator-induced lung injury via a mechanism involving nuclear factor-kappa B activation.
We recently demonstrated the inhalation of hydrogen gas, a novel medical therapeutic gas, ameliorates ventilator-induced lung injury (VILI); however, the molecular mechanisms by which hydrogen ameliorates VILI remain unclear. Therefore, we investigated whether inhaled hydrogen gas modulates the nuclear factor-kappa B (NFκB) signaling pathway. VILI was generated in male C57BL6 mice by performing a tracheostomy and placing the mice on a mechanical ventilator (tidal volume of 30 ml/kg or 10 ml/kg without positive end-expiratory pressure). The ventilator delivered either 2% nitrogen or 2% hydrogen in balanced air. NFκB activation, as indicated by NFκB DNA binding, was detected by electrophoretic mobility shift assays and enzyme-linked immunosorbent assay. Hydrogen gas inhalation increased NFκB DNA binding after 1h of ventilation and decreased NFκB DNA binding after 2h of ventilation, as compared with controls. The early activation of NFκB during hydrogen treatment was correlated with elevated levels of the antiapoptotic protein Bcl-2 and decreased levels of Bax. Hydrogen inhalation increased oxygen tension, decreased lung edema, and decreased the expression of proinflammatory mediators. Chemical inhibition of early NFκB activation using SN50 reversed these protective effects. NFκB activation and an associated increase in the expression of Bcl-2 may contribute, in part, to the cytoprotective effects of hydrogen against apoptotic and inflammatory signaling pathway activation during VILI.


Competitive adsorption of heavy metals in soil underlying an infiltration facility installed in an urban area.
Accumulation of heavy metals at elevated concentration and potential of considerable amount of the accumulated heavy metals to reach the soil system was observed from earlier studies in soakaways sediments within an infiltration facility in Tokyo, Japan. In order to understand the competitive adsorption behaviour of heavy metals Zn, Ni and Cu in soil, competitive batch adsorption experiments were carried out using single metal and binary metal combinations on soil samples representative of underlying soil and surface soil at the site. Speciation analysis of the adsorbed metals was carried out through BCR sequential extraction method. Among the metals, Cu was not affected by competition while Zn and Ni were affected by competition of coexisting metals. The parameters of fitted 'Freundlich' and 'Langmuir' isotherms indicated more intense competition in underlying soil compared to surface soil for adsorption of Zn and Ni. The speciation of adsorbed metals revealed less selectivity of Zn and Ni to soil organic matter, while dominance of organic bound fraction was observed for Cu, especially in organic rich surface soil. Compared to underlying soil, the surface soil is expected to provide greater adsorption to heavy metals as well as provide greater stability to adsorbed metals, especially for Cu.


Dollars for lives: the effect of highway capital investments on traffic fatalities.
This study examines the effect of highway capital investments on highway fatalities. We used state-level data from the 48 contiguous states in the United States from 1968 through 2010 to estimate the effects on highway fatalities of capital expenditures and highway capital stock. We estimated these effects by controlling for a set of control variables together with state and year dummy variables and state-specific linear time trends. We found that capital expenditures and capital stock had significant and negative effects on highway fatalities. States faced with declines in gas tax revenues have already cut back drastically on spending on roads including on maintenance and capital outlay. If this trend continues, it may undermine traffic safety. While states and local governments are currently fiscally strained, it is important for them to continue investments in roadways to enhance traffic safety and, more significantly, to save lives.


Soft-tissue sarcomas of the diaphragm: a report from the Intergroup Rhabdomyosarcoma Study Group from 1972 to 1997.
To describe clinical details and outcome of children and adolescents with primary sarcomas of the diaphragm treated on Intergroup Rhabdomyosarcoma Studies (IRS) I through IV. We reviewed the records of 15 patients with sarcoma of the diaphragm who were entered on IRS Group protocols between 1972 and 1997. Patient ages at diagnosis ranged from 0.5 to 20 years (median, 13 yrs), and 10 were girls. Patients had chest pain, dyspnea, and/or coughing, decreased breath sounds, and occasionally hepatomegaly. Localized, gross residual disease after initial surgery was present in 10 patients, and five had metastases at diagnosis (pleura, 3; pericardium, 1; lungs and bones, 1). Tumor subtypes were alveolar rhabdomyosarcoma (RMS) in five cases, embryonal RMS in three, undifferentiated sarcoma in three, extraosseous Ewing sarcoma in three, and unclassified sarcoma in one. Treatment consisted of radiation therapy to the primary tumor and metastases when feasible, and combination chemotherapy with vincristine, actinomycin D, and cyclophosphamide with or without doxorubicin, ifosfamide, cisplatin, and etoposide. Ten patients achieved complete remission (67%), four obtained a partial remission, and one was improved. Five patients (33%) are continuously failure-free and alive at a median of 8.8 years from diagnosis (range, 1.1-15 yrs). However, the other 10 patients experienced relapse at 0.3 to 2 years from start of therapy (median, 1 yr). Sites of relapse were local in five, distant in three, and combined in two. Death after relapse occurred at 0.39 to 2.6 years (median, 1.6 yrs) from diagnosis. Sarcomas of the diaphragm are generally deemed unresectable at diagnosis and/or are metastatic. Most of them are not embryonal rhabdomyosarcomas. Treatment with more effective primary chemotherapy to shrink the tumor, followed-up by surgical resection and radiation therapy, should improve the prognosis for patients with sarcomas arising in the diaphragm, especially for the majority who have localized tumors.


Brain viral burden, neuroinflammation and neurodegeneration in HAART-treated HIV positive injecting drug users.
The long-term impact of chronic human immunodeficiency virus (HIV) infection on brain status in injecting drug users (IDU) treated with highly active antiretroviral therapy (HAART) is unknown. Viral persistence in the brain with ongoing neuroinflammation may predispose to Alzheimer-like neurodegeneration. In this study, we investigated the brains of ten HAART-treated individuals (six IDU and four non-DU), compared with ten HIV negative controls (six IDU and four non-DU). HIV DNA levels in brain tissue were correlated with plasma and lymphoid tissue viral loads, cognitive status, microglial activation and Tau protein and amyloid deposition. Brain HIV proviral DNA levels were low in most cases but higher in HIV encephalitis (n = 2) and correlated significantly with levels in lymphoid tissue (p = 0.0075), but not with those in plasma. HIV positive subjects expressed more Tau protein and amyloid than HIV negative controls (highest in a 58 year old), as did IDU, but brain viral loads showed no relation to Tau and amyloid. Microglial activation linked significantly to HIV positivity (p = 0.001) and opiate abuse accentuated these microglial changes (p = 0.05). This study confirms that HIV DNA persists in brains despite HAART and that opiate abuse adds to the risk of brain damage in HIV positive subjects. Novel findings in this study show that (1) plasma levels are not a good surrogate indicator of brain status, (2) viral burden in brain and lymphoid tissues is related, and (3) while Tau and amyloid deposition is increased in HIV positive IDU, this is not specifically related to increased HIV burden within the brain.


Catalytic dehydrocoupling of amines and boranes by an incipient tin(ii) hydride.
The facile heterodehydrocoupling of a range of primary or secondary amines and even ammonia with pinacolborane (HBPin) was accomplished using {ArMe6Sn(μ-OMe)}2 (1, ArMe6 = C6H3-2,6-(C6H2-2,4,6-Me3)2) as pre-catalysts for a catalytically active tin(ii) hydride. The more sterically hindered pre-catalyst 2, {AriPr4Sn(μ-OMe)}2 (AriPr4 = C6H3-2,6-(C6H3-2,6-iPr2)2) facilitated the dehydrocoupling only of primary amines with HBPin, and at an increased rate relative to the less crowded {ArMe6Sn(μ-OMe)}2. Also presented is {ArMe6Sn(μ-NEt2)}2 (3), which can be converted into the structurally characterizable {ArMe6Sn(μ-NEt2)(μ-H)SnArMe6} (4) via the addition of pinacol borane. This, alongside stoichiometric studies, give insight into the mechanism of the catalysis.


The phosphoinositides exist in multiple metabolic pools in rabbit platelets.
The labelling of the phosphoinositides and phosphatidic acid in washed rabbit platelets incubated with [32P]phosphate or [3H]glycerol was studied in the presence of isotope and after unincorporated isotope had been removed. With both isotopes the increase in the specific radioactivity of phosphatidylinositol 4,5-bisphosphate (PIP2) lagged behind that of phosphatidylinositol 4-phosphate (PIP) but the specific radioactivity remained higher after unincorporated isotope had been removed. This result was consistent with the presence of a second pool of PIP2, which interconverted slowly with the pool of PIP2 which was in direct equilibrium with PIP, proposed to explain the increase in specific radioactivity of PIP2 which accompanies the decrease in amount of PIP2 at 10 s in ADP-stimulated platelets. In platelets labelled with [3H]glycerol, the specific radioactivity of PIP2 became higher than that of PIP and the specific radioactivity of PIP became higher than that of phosphatidylinositol (PI). These results were interpreted to indicate that there were two pools of PIP; of these the pool with the higher specific radioactivity was the precursor of PIP2. Similarly, two pools of PI were proposed. The presence of pools of the phosphoinositides with different specific radioactivities necessitates the measurement of chemical amount of these compounds when studying the effect of stimulation of the platelets, since changes in labelling may not accurately reflect changes in the amount of the phosphoinositides.


Contrast-enhanced Ultrasound for Detection of Crohn's Disease Activity: Systematic Review and Meta-analysis.
Reports on imaging of active Crohn's disease (aCD) using contrast-enhanced ultrasound (CEUS) are encouraging. However, the statistical power of most published papers is limited due to the small size of the patient groups included. This study was performed to verify the diagnostic value of CEUS in detecting aCD. A systematic literature search was performed by two independent reviewers for articles on the test characteristics of CEUS for the identification of aCD. The quality of the analysed studies was evaluated using a quality assessment tool for diagnostic accuracy studies (QUADAS-2). Pooling was performed using a diagnostic random-effect model and bivariate analysis. Eight articles were included in the final analysis, with a total of 332 patients. There was no significant publication bias. Significant heterogeneity was found regarding CEUS methodology and sonographic definitions of aCD. In a bivariate analysis, pooled sensitivity was 0.94 (95% CI 0.87-0.97) and pooled specificity was 0.79 (95% CI 0.67-0.88). Spearman correlation statistics presented no significant diagnostic threshold effect (r = 0.12, p > 0.9). Subgroup analysis showed that relative intestine wall enhancement had the highest diagnostic value (area under the curve 94%), while the presence of enhancement and analysis of the slope were less useful (area under the curve 91 and 90%, respectively). CEUS presents good sensitivity and moderate specificity in the detection of the aCD. Large-scale randomized trials with quantitative evaluation of CEUS images are necessary to promote this technique in clinical practice.


[The impasses of unconditional poverty: the experience of Collective Ombudsman in the Leopoldina region, Rio de Janeiro (RJ, Brazil)].
The experience of Collective Ombudsman developed in the Leopoldina region, city of Rio de Janeiro, enlarges the traditional vision of health vigilance and consists in organizing a system of qualitative evaluation of the sanitary vigilance able to identify the health problems of the population and the methods utilized in the attempt to overcome these problems. Health professionals, religious and community leaders congregated in monthly forums to present and discuss living conditions perceived in the communities in which they carry on their activities. From the point of view of the social dimensions involved in the health-illness processes, this work aims to discuss the way that poverty compromises the popular classes' health, especially for the mental health and the "diffuse suffering". The methodology allowed us to organize, in a systematic way, the listening and favored the recognition of local knowledge, constructed from the life experiences of the people who deal with the suffering, the illness and their determinants on the life conditions of the poor population. The precarious living conditions for a significant part of the population were perceived as generating impasses in the resolution of their health problems. The results point towards the importance of understanding the health problems of the population, the resources utilized to face them and proposals for possible solutions in the field of health.


Bone mineral density in patients with human immunodeficiency virus infection.
The Object of this study was to determine whether HIV infection is associated with decreased bone mineral density (BMD). BMD was measured by dual-energy X-ray absorptiometry at total body, lumbar spine, and hip in 45 men with HIV infection and compared with sex, age, and weight-matched controls. Repeat scans were performed after a mean interval of 15 months in 21 patients to determine whether there were detectable losses of BMD. Compared with controls, the HIV patients had marginally lower BMD at the lumbar spine (P = 0.04) but there was no significant difference in total body or hip BMD. None of the patients had reduced BMD to levels associated with a diagnosis of osteoporosis. On longitudinal follow-up, a small decrease in total body BMD (-1.6%; P = 0.02) was observed but there was no significant change in spine and hip BMD. In spite of the many features of HIV infection that might be expected to cause a reduction in BMD such as cytokine activation, decreased physical activity, small bowel disease, hypogonadism, and direct infection of osteogenic cells by HIV, we found only minimal differences in BMD between HIV patients and controls. Furthermore, the HIV patients studied did not appear to show excessive loss in bone mineral over time.


Global SUMOylation on active chromatin is an acute heat stress response restricting transcription.
Cells have developed many ways to cope with external stress. One distinctive feature in acute proteotoxic stresses, such as heat shock (HS), is rapid post-translational modification of proteins by SUMOs (small ubiquitin-like modifier proteins; SUMOylation). While many of the SUMO targets are chromatin proteins, there is scarce information on chromatin binding of SUMOylated proteins in HS and the role of chromatin SUMOylation in the regulation of transcription. We mapped HS-induced genome-wide changes in chromatin occupancy of SUMO-2/3-modified proteins in K562 and VCaP cells using ChIP-seq. Chromatin SUMOylation was further correlated with HS-induced global changes in transcription using GRO-seq and RNA polymerase II (Pol2) ChIP-seq along with ENCODE data for K562 cells. HS induced a rapid and massive rearrangement of chromatin SUMOylation pattern: SUMOylation was gained at active promoters and enhancers associated with multiple transcription factors, including heat shock factor 1. Concomitant loss of SUMOylation occurred at inactive intergenic chromatin regions that were associated with CTCF-cohesin complex and SETDB1 methyltransferase complex. In addition, HS triggered a dynamic chromatin binding of SUMO ligase PIAS1, especially onto promoters. The HS-induced SUMOylation on chromatin was most notable at promoters of transcribed genes where it positively correlated with active transcription and Pol2 promoter-proximal pausing. Furthermore, silencing of SUMOylation machinery either by depletion of UBC9 or PIAS1 enhanced expression of HS-induced genes. HS-triggered SUMOylation targets promoters and enhancers of actively transcribed genes where it restricts the transcriptional activity of the HS-induced genes. PIAS1-mediated promoter SUMOylation is likely to regulate Pol2-associated factors in HS.


[Risks scenarios frameworks in the context of an oil refinery installation at Pernambuco State].
The magnitude of the environmental and social problems due to urbanization, industrialization and exhaustion of natural resources has shown an increase in the impact on health and environment. Paradoxically, the consumption patterns demand for the expansion in the industrial production based on the exploitation of the non-renewable resources, which technological risks, especially from the petrochemical industry, have put difficulties on the risk control and health surveillance. The petroleum refining is an activity potentially damageable to the environment and human health, particularly to workers. The main objective of this study was to characterize the scenarios of risk to environmental health due to an oil refinery installation in the Metropolitan Region of Recife (Pernambuco). Based on secondary data and literature review, a Social Reproduction Matrix was made contextualizing the problems in the biological, consciousness and conduct, economic, policy and ecological dimensions, enabling to presume the risks to support the health surveillance development and organization in the state, with intersectoriality, social participation, and able to intervene on risks and prevent diseases among the workers and people in the territory.


Micronutrient Synergy in the Fight against Hepatocellular Carcinoma.
The incidence of hepatocellular carcinoma (HCC), once thought to be a rare tumor in North America, has rapidly increased in recent years in the United States. Current treatment modalities to halt the progression of this disease are only marginally effective. The mainstay treatment is liver transplantation, which is often confronted with donor shortage. Invasion, metastasis and recurrence contribute to the high mortality rate of this disease. Matrix metalloproteinases (MMPs) that degrade the extracellular matrix (ECM) have been associated with the progression, invasion and metastasis of the disease. We have developed strategies to strengthen the ECM collagen and inhibit MMPs through micronutrients such as lysine, proline and ascorbic acid. Addition of epigallocatechin gallate or green tea extract to these micronutrients synergistically enhanced anti-carcinogenic activity in HepG2 cells. Addition of certain other micronutrients, such as N-acetylcysteine, selenium, copper and zinc (NM) synergistically enhanced the anticancer activity of the mixture in a model of hepatocellular carcinoma using HepG2 cells. In vitro studies using HepG2 demonstrated that NM was very effective in inhibiting cell proliferation (by MTT assay), MMPs secretion (by gelatinase zymography), cell invasion (through Matrigel) and induction of apoptosis (by live green caspase). In addition, NM was shown to down-regulate urokinase plasminogen activator (by fibrin zymography) and up-regulate tissue inhibitors of metalloproteinases (by reverse zymography) in another HCC cell line, SK-Hep-1. MMP-2 and MMP-9 activities were further modulated by phorbol 12-myristate 13-acetate (PMA) induction and inhibited by NM. In previous studies, NM inhibited Sk-Hep-1 xenografts in nude mice and also inhibited hepatic metastasis of B16FO melanoma cells. Our results suggest that NM is an excellent candidate for therapeutic use in the treatment HCC by inhibiting critical parameters in cancer development and progression, such as proliferation, invasion and metastasis, and by inducing apoptosis.


New Directions in Exercise Prescription: Is There a Role for Brain-Derived Parameters Obtained by Functional Near-Infrared Spectroscopy?
In the literature, it is well established that regular physical exercise is a powerful strategy to promote brain health and to improve cognitive performance. However, exact knowledge about which exercise prescription would be optimal in the setting of exercise-cognition science is lacking. While there is a strong theoretical rationale for using indicators of internal load (e.g., heart rate) in exercise prescription, the most suitable parameters have yet to be determined. In this perspective article, we discuss the role of brain-derived parameters (e.g., brain activity) as valuable indicators of internal load which can be beneficial for individualizing the exercise prescription in exercise-cognition research. Therefore, we focus on the application of functional near-infrared spectroscopy (fNIRS), since this neuroimaging modality provides specific advantages, making it well suited for monitoring cortical hemodynamics as a proxy of brain activity during physical exercise.


Ciliary and retinal changes in myotonic dystrophy.
We examined 15 patients with myotonic dystrophy by cycloscopy, ophthalmoscopy, and fluorescein angiography. In six cases, we found depigmentation in the relatively short ciliary processes, which may account for ocular hypotony in this disorder. Eight of the patients had retinal lesions, three with butterfly-shaped dystrophy, two with reticular dystrophy, and three with peripheral yellow flecks. These lesions were biomicroscopically at the level of the retinal pigment epithelium or in the deep retinal layer and did not substantially alter visual functions. Psychophysical and electrophysiologic test results were normal or only slightly affected. The butterfly-shaped and reticular dystrophies in myotonic dystrophy may be variant forms of patterned dystrophy of the retinal pigment epithelium. The peripheral yellow flecks in a stone-wall configuration noted in this disorder are particularly unique and, to our knowledge, have not been documented previously.


Percutaneous epidural lysis of adhesions in chronic lumbar radicular pain: a randomized, double-blind, placebo-controlled trial.
Chronic radicular pain can occur after disc pathology and failed back surgery. An evidence-based effective therapeutic option is not available nor does a gold standard exist. A randomized controlled trial to analyze the clinical efficacy of percutaneous epidural lysis of adhesions in chronic radicular pain. Prospective randomized placebo controlled interventional trial. Power calculation based on a feasibility trial. Medical university centers. Within 4 years a total of 381 patients with chronic radicular pain lasting longer than 4 months which failed to respond to conservative treatments were screened and 90 patients were enrolled. They were randomly assigned to receive either percutaneous neurolysis or placebo with concealed allocation in permuted blocks of 4 to 8, stratified by treatment center. The primary outcome measure was the differences in percent change of Oswestry Disability Index (ODI) scores 3 months after intervention. Secondary outcome measures were difference in percent change of ODI scores and Visual Analog Scale (VAS) 6 and 12 months after intervention and success rates defined as at least 50% reduction in ODI scores and VAS scores (mean change from baseline) at 3, 6, and 12 months after treatment. Explorative, 2-sided group comparisons for baseline characteristics between active treatment and controls were done using the t-test for 2 independent samples for quantitative data and Fisher's exact test for binary data. The ODI and VAS scores as well as the success rates for ODI vs VAS were significantly better 3, 6, and 12 months in the lysis group vs the control group. The ODI in the lysis group improved from 55.3 ± 11.6 to 26.4 ± 10.8 after 3 months. The placebo group improved from 55.4 ± 11.5 to 41.8 ± 14.6 (P < 0.01). VAS improved from 6.7 ± 1.1 to 2.9 ± 1.9 in the active group and from 6.7 ± 1.1 to 4.8 ± 2.2 (P < 0.01) after placebo. Twelve month follow-up shows further improvement, the differences remain significant. In multiple linear regression, forward and backward variable selection methods resulted in the same covariate model confirming the univariate result for group comparison in the primary analysis. No severe side effects occurred but minor transient neurological effects such as partial sensomotoric deficits did. One dura puncture and one catheter displacement were found. Specific effects of single treatment components cannot be specified because there was no imaging examination after treatment. Based on the findings of our study as well as other studies, we believe the minimally invasive percutaneous adhesiolysis procedure should be the first choice treatment option for patients with chronic lumbosacral radicular pain who present with clinical history and findings similar to those of the patients enrolled in our study.


Quantifying heterogeneities in arbovirus transmission: Description of the rationale and methodology for a prospective longitudinal study of dengue and Zika virus transmission in Iquitos, Peru (2014-2019).
Current knowledge of dengue virus (DENV) transmission provides only a partial understanding of a complex and dynamic system yielding a public health track record that has more failures than successes. An important part of the problem is that the foundation for contemporary interventions includes a series of longstanding, but untested, assumptions based on a relatively small portion of the human population; i.e., people who are convenient to study because they manifest clinically apparent disease. Approaching dengue from the perspective of people with overt illness has produced an extensive body of useful literature. It has not, however, fully embraced heterogeneities in virus transmission dynamics that are increasingly recognized as key information still missing in the struggle to control the most important insect-transmitted viral infection of humans. Only in the last 20 years have there been significant efforts to carry out comprehensive longitudinal dengue studies. This manuscript provides the rationale and comprehensive, integrated description of the methodology for a five-year longitudinal cohort study based in the tropical city of Iquitos, in the heart of the Peruvian Amazon. Primary data collection for this study was completed in 2019. Although some manuscripts have been published to date, our principal objective here is to support subsequent publications by describing in detail the structure, methodology, and significance of a specific research program. Our project was designed to study people across the entire continuum of disease, with the ultimate goal of quantifying heterogeneities in human variables that affect DENV transmission dynamics and prevention. Because our study design is applicable to other Aedes transmitted viruses, we used it to gain insights into Zika virus (ZIKV) transmission when during the project period ZIKV was introduced and circulated in Iquitos. Our prospective contact cluster investigation design was initiated by detecttion of a person with a symptomatic DENV infection and then followed that person's immediate contacts. This allowed us to monitor individuals at high risk of DENV infection, including people with clinically inapparent and mild infections that are otherwise difficult to detect. We aimed to fill knowledge gaps by defining the contribution to DENV transmission dynamics of (1) the understudied majority of DENV-infected people with inapparent and mild infections and (2) epidemiological, entomological, and socio-behavioral sources of heterogeneity. By accounting for factors underlying variation in each person's contribution to transmission we sought to better determine the type and extent of effort needed to better prevent virus transmission and disease.


The Stress and Vascular Catastrophes in Newborn Rats: Mechanisms Preceding and Accompanying the Brain Hemorrhages.
In this study, we analyzed the time-depended scenario of stress response cascade preceding and accompanying brain hemorrhages in newborn rats using an interdisciplinary approach based on: a morphological analysis of brain tissues, coherent-domain optical technologies for visualization of the cerebral blood flow, monitoring of the cerebral oxygenation and the deformability of red blood cells (RBCs). Using a model of stress-induced brain hemorrhages (sound stress, 120 dB, 370 Hz), we studied changes in neonatal brain 2, 4, 6, 8 h after stress (the pre-hemorrhage, latent period) and 24 h after stress (the post-hemorrhage period). We found that latent period of brain hemorrhages is accompanied by gradual pathological changes in systemic, metabolic, and cellular levels of stress. The incidence of brain hemorrhages is characterized by a progression of these changes and the irreversible cell death in the brain areas involved in higher mental functions. These processes are realized via a time-depended reduction of cerebral venous blood flow and oxygenation that was accompanied by an increase in RBCs deformability. The significant depletion of the molecular layer of the prefrontal cortex and the pyramidal neurons, which are crucial for associative learning and attention, is developed as a consequence of homeostasis imbalance. Thus, stress-induced processes preceding and accompanying brain hemorrhages in neonatal period contribute to serious injuries of the brain blood circulation, cerebral metabolic activity and structural elements of cognitive function. These results are an informative platform for further studies of mechanisms underlying stress-induced brain hemorrhages during the first days of life that will improve the future generation's health.