Biopharmaceutical Understanding of Excipient Variability on Drug Apparent Solubility Based on Drug Physicochemical Properties. Case Study: Superdisintegrants.
The presence of different excipient types/brands in solid oral dosage forms may affect product performance and drug bioavailability. Understanding the biopharmaceutical implications of superdisintegrant variability (changes in material properties), variation (changes in excipient amount) and interchangeability (use of different excipient types with the same intended functionality) in oral drug performance would be beneficial for the development of robust final dosage forms. The current study investigated the impact of superdisintegrants (sodium starch glycolate, croscarmellose sodium, crospovidone) on the apparent solubility of drugs with different physicochemical properties (drug ionisation, drug lipophilicity, drug aqueous solubility). Compendial and biorelevant media were used to assess the impact of gastrointestinal conditions on the effects of excipient on drug apparent solubility. For the majority of compounds, changes in drug apparent solubility were not observed in superdisintegrant presence, apart from the cases of highly ionised compounds (significant decrease in drug solubility) and/or compounds that aggregate/precipitate in solution (significant increase in drug solubility). Excipient variability did not greatly affect the impact of excipients on drug apparent solubility. The use of multivariate data analysis identified the biopharmaceutical factors affecting excipient performance. The construction of roadmaps revealed that superdisintegrants may be of low risk for the impact of excipients on oral drug performance based on drug solubility alone; superdisintegrants activity could still be a risk for oral bioavailability due to their effects on tablet disintegration.


Comparison of accelerometry stride time calculation methods.
Inertial sensors such as accelerometers and gyroscopes can provide a multitude of information on running gait. Running parameters such as stride time and ground contact time can all be identified within tibial accelerometry data. Within this, stride time is a popular parameter of interest, possibly due to its role in running economy. However, there are multiple methods utilised to derive stride time from tibial accelerometry data, some of which may offer complications when implemented on larger data files. Therefore, the purpose of this study was to compare previously utilised methods of stride time derivation to an original proposed method, utilising medio-lateral tibial acceleration data filtered at 2Hz, allowing for greater efficiency in stride time output. Tibial accelerometry data from six participants training for a half marathon were utilised. One right leg run was randomly selected for each participant, in which five consecutive running stride times were calculated. Four calculation methods were employed to derive stride time. A repeated measures analysis of variance (ANOVA) identified no significant difference in stride time between stride time calculation methods (p=1.00), whilst intra-class coefficient values (all >0.95) and coefficient of variance values (all <1.5%) indicate good reliability. Results indicate that the proposed method possibly offers a simplified technique for stride time output during running gait analysis. This method may be less influenced by "double peak" error and minor fluctuations within the data, allowing for accurate and efficient automated data output in both real time and post processing.


[Glucotransporters: clinical, molecular and genetic aspects].
Oxidation of glucose is the major source of obtaining cell energy, this process requires glucose transport into the cell. However, cell membranes are not permeable to polar molecules such as glucose; therefore its internalization is accomplished by transporter proteins coupled to the cell membrane. In eukaryotic cells, there are two types of carriers coupled to the membrane: 1) cotransporter Na+-glucose (SGLT) where Na+ ion provides motive power for the glucose´s internalization, and 2) the glucotransporters (GLUT) act by facilitated diffusion. This review will focus on the 14 GLUT so far described. Despite the structural homology of GLUT, different genetic alterations of each GLUT cause specific clinical entities. Therefore, the aim of this review is to gather the molecular and biochemical available information of each GLUT as well as the particular syndromes and pathologies related with GLUT´s alterations and their clinical approaches.


Radiation Oncologists' Approach to Internal Mammary Lymph Node Radiotherapy in Breast Cancer: The Turkish Society for Radiation Oncology Breast Cancer Study Group (TROD 06-005 Survey Study).
This study aimed to examine the practice patterns of radiation oncologists in Turkey regarding radiotherapy to the regional lymph nodes, including internal mammary lymph nodes (IMNs), and identify the factors influencing their clinical decisions in breast cancer patients. A nationwide, 19-point questionnaire was sent to the physician members of the Turkish Society for Radiation Oncology (TROD). In total, 165 radiation oncologists completed the survey, corresponding to a 27% response rate. Regional radiotherapy was used in 64.2% of the patients with 1-3 axillary lymphatic involvement and unfavorable prognostic factors. In contrast, 61.2% of the respondents indicated that IMN should be included in the target volume for regional radiotherapy when the patient had one positive node after axillary lymph node dissection (ALND) in the inner quadrant and central region tumors. However, 71.5% of the respondents chose to include the IMN in the non-inner quadrant and non-central region tumors for patients with four or more positive nodes after ALND. The decision to offer internal mammary lymph node radiotherapy (IMNRT) varied widely and significantly among respondents, years in practice, and the rates of dedicating their clinical time to patients with breast cancer. The results of this survey revealed significant national variation in attitudes regarding the treatment of IMN. Thus, this study may also help document the impact of future studies on clinical practice.


Application of Octacalcium Phosphate with an Innovative Household-scale Defluoridator Prototype and Behavioral Determinants of its Adoption in Rural Communities of the East African Rift Valley.
Natural fluoride contamination of drinking water is a serious issue that affects several countries of the world. Its negative health impact is well documented in the East African Rift Valley, where water consumption with fluoride ( F - ) concentration greater than 1.5 mg/L can cause fluorosis to people. Within the framework of the European Union (EU) Horizon 2020 FLOWERED project, we first designed an effective defluoridation device based on innovative application of octacalcium phosphate (OCP) and then explored its acceptance within rural communities. The prototype (FLOWERED Defluoridator Device [FDD]) essentially is composed of a 20-L tank and a recirculating pump that guarantees the interaction between water and OCP. The device is powered by a car battery for a fixed pumping working time using a fixed amount of OCP for every defluoridation cycle. The results of tests performed in the rural areas of Tanzania show that a standardized use of the prototype can lower the dissolved F - from an initial concentration of 21 mg/L to below the World Health Organization (WHO) drinkable limit of 1.5 mg/L in 2 h without secondary negative effects on water quality. The approximate cost of this device is around US$220, whereas that of OCP is about $0.03/L of treated water. As with any device, acceptance requires a behavioral change on behalf of rural communities that needed to be investigated. To this end, we piloted a survey to explore how psychological and socioeconomic factors influence the consumption of fluoride-free water. Results show that the adoption of FDD and OCP is more appealing to members of the rural communities who are willing to pay more and have a high consumption of water. Moreover, we suggest that given the low level of knowledge about fluorosis diseases, the government should introduce educational programs to make rural communities aware of the negative health consequences. Integr Environ Assess Manag 2020;16:856-870. © 2020 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC).


Glutamine acts as a neuroprotectant against DNA damage, beta-amyloid and H2O2-induced stress.
Glutamine is the most abundant free amino acid in the human blood stream and is 'conditionally essential' to cells. Its intracellular levels are regulated both by the uptake of extracellular glutamine via specific transport systems and by its intracellular synthesis by glutamine synthetase (GS). Adding to the regulatory complexity, when extracellular glutamine is reduced GS protein levels rise. Unfortunately, this excess GS can be maladaptive. GS overexpression is neurotoxic especially if the cells are in a low-glutamine medium. Similarly, in low glutamine, the levels of multiple stress response proteins are reduced rendering cells hypersensitive to H(2)O(2), zinc salts and DNA damage. These altered responses may have particular relevance to neurodegenerative diseases of aging. GS activity and glutamine levels are lower in the Alzheimer's disease (AD) brain, and a fraction of AD hippocampal neurons have dramatically increased GS levels compared with control subjects. We validated the importance of these observations by showing that raising glutamine levels in the medium protects cultured neuronal cells against the amyloid peptide, Aβ. Further, a 10-day course of dietary glutamine supplementation reduced inflammation-induced neuronal cell cycle activation, tau phosphorylation and ATM-activation in two different mouse models of familial AD while raising the levels of two synaptic proteins, VAMP2 and synaptophysin. Together, our observations suggest that healthy neuronal cells require both intracellular and extracellular glutamine, and that the neuroprotective effects of glutamine supplementation may prove beneficial in the treatment of AD.


Associations of PON1 and genetic ancestry with obesity in early childhood.
Obesity in children has become an epidemic in the U.S. and is particularly prominent in minority populations such as Mexican-Americans. In addition to physical activity and diet, genetics also plays a role in obesity etiology. A few studies in adults and adolescents suggest a link between obesity and paraoxonase 1 (PON1), a multifunctional enzyme that can metabolize organophosphate pesticides and also has antioxidant properties. We determined PON1192 genotype and arylesterase levels (ARYase, measure of PON1 enzyme quantity), to characterize the relationship between PON1 and obesity in young Mexican-American children (n = 373) living in an agricultural community in California. Since PON1 polymorphisms and obesity both vary between ethnic groups, we estimated proportional genetic ancestry using 106 ancestral informative markers (AIMs). Among children, PON1192 allele frequencies were 0.5 for both alleles, and the prevalence of obesity was high (15% and 33% at ages two and five, respectively). The average proportion of European, African, and Native American ancestry was 0.40, 0.09, and 0.51, yet there was wide inter-individual variation. We found a significantly higher odds of obesity (9.3 and 2.5- fold) in PON1192QQ children compared to PON1192RR children at ages two and five, respectively. Similar relationships were seen with BMI Z-scores at age two and waist circumference at age five. After adjusting for genetic ancestry in models of PON1 and BMI Z-score, effect estimates for PON1192 genotype changed 15% and 9% among two and five year old children, respectively, providing evidence of genetic confounding by population stratification. However even after adjustment for genetic ancestry, the trend of increased BMI Z-scores with increased number of PON1192 Q alleles remained. Our findings suggest that PON1 may play a role in obesity independent of genetic ancestry and that studies of PON1 and health outcomes, especially in admixed populations, should account for differences due to population stratification.


[Thinness and overweight in children from Amsterdam: a trend analysis and forecast].
To determine the trends in prevalence of moderate and severe thinness, overweight and obesity in children living in Amsterdam between 2009 and 2013 and estimate prevalences for 2020. Historical cohort study. 158,730 measurements of height and weight of 112,405 children from Amsterdam were analysed. Moderate thinness, severe thinness, overweight and obesity were determined using international BMI cut-off values. Trends were analysed using Generalized Estimating Equations (GEE) for two age groups: pre-schoolers (2 and 3 years) and school-aged children (5, 10 and 14 years). The 'self-projecting method,' which allowed us to extend former trends into the future, was used to estimate prevalences for 2020. The prevalence of moderate thinness increased significantly in both age groups. The prevalence of severe thinness did not change. The prevalences of overweight and obesity declined significantly in both age groups. These trends were most evident in children of Dutch origin. Other ethnic groups also showed declining prevalences but not in both age groups or both categories of overweight. The prognosis for 2020 shows a further decline in the prevalence of overweight and obesity and an increase in the prevalence of thinness. A decline in the prevalences of overweight and obesity was observed in Amsterdam children, including children of Turkish and Moroccan origin. The prevalence rates are still high, so investing in prevention remains necessary. The prevalence of moderate thinness also seems to be increasing. Continued monitoring of children in all BMI classes is therefore important.


[Effects of tillage and nitrogen application rate on soil nitrogen transformation and yield in a winter wheat/summer maize multiple cropping system].
In the winter-wheat and summer-maize multiple cropping system in lime concretion black soil of Huanghuaihai Plain, the effects of three tilling methods (conventional tillage, rotary tillage, subsoiling tillage) in wheat season coupling with three nitrogen treatments (120 kg·hm-2, 225 kg·hm-2, 330 kg·hm-2) before maize sowing on the activities of microorganisms and enzymes re-lated nitrogen transformation, and inorganic nitrogen content in the rhizosphere soil during the main growth stages of maize, as well as the yield were investigated. The results showed that the rotary tillage had the highest ammonification intensity, and the more nitrogen was put in, the higher were the activities of microorganisms and enzymes related to soil nitrogen transformation. The activities of nitrification, denitrification and urease of subsoiling tillage was significantly higher than those of conventional and rotary tillage. Furthermore, in subsoiling tillage treatment, increasing nitrogen fertili-zer could promote soil nitrogen transformation while excessive nitrogen input inhibited soil nitrogen transformation, though the latter had higher yield and soil inorganic nitrogen content. The treatment of subsoiling tillage coupling with 225 kg·hm-2 nitrogen, was best for soil nitrogen transformation while the treatment of subsoiling tillage coupling with 330 kg·hm-2 nitrogen, had the highest corn yield.


Increased early mortality and morbidity after total hip arthroplasty in patients with socioeconomic disadvantage: a report from the Swedish Hip Arthroplasty Register.
Background and purpose - Socioeconomic status is associated with the outcome of major surgery. We investigated the association of socioeconomic status with the risk of early mortality and readmissions after primary total hip arthroplasty (THA). Patients and methods - We obtained information on income, education, immigration, and cohabiting status as well as comorbidities of 166,076 patients who underwent primary THA due to primary osteoarthritis (OA) from the Swedish Hip Arthroplasty Register, the Swedish National Inpatient Register and Statistics Sweden. Multivariable Cox regression models were fitted to estimate the adjusted risk of mortality or readmissions within 90 days after index surgery. Results - Compared with patients on a low income, the adjusted risk of 30-day mortality was considerably lower in patients on a high income (hazard ratio [HR] 0.5, 95% confidence interval [CI] 0.3-0.7) and in those on a medium income (HR 0.7, CI 0.6-0.9). Similar risk reductions were found for the endpoint 90-day mortality. Patients with a high income had a lower adjusted risk of readmission for cardiovascular reasons than those with a low income (HR 0.7, CI 0.6-0.9), as had those with a higher level of education (adjusted HR 0.7, CI 0.6-0.9). Patients with higher socioeconomic status had a lower degree of comorbidities than socioeconomically disadvantaged patients. However, adjusting for socioeconomic confounders in multivariable models only marginally influenced the predictive ability of the models, as expressed by their area under the curve. Interpretation - Income and level of education are strongly associated with early mortality and readmissions after primary THA, and both parameters are closely connected to health status. Since adjustment for socioeconomic confounders only marginally improved the predictive ability of multivariable regression models our findings indicate that comorbidities may under certain circumstances serve as an acceptable proxy measure of socioeconomic background.


Role of iron and copper during benzene toxicity.
Role of transition metal ions in expression of benzene toxicity has been suggested. Intraperitoneal administration of benzene to female albino rats daily for 10 days resulted in accumulation of iron in liver nuclei, without any change in copper content. Incubation of hydroquinone (HQ), one of the principal metabolites of benzene with rat liver nuclei resulted in formation of thiobarbituric acid reactive products (TBAR). However, presence of bathocuproine, a copper chelator and EDTA, an iron chelator caused significant inhibition of TBAR release. Thus, the present study revealed that iron accumulation and involvement of copper in nuclear damage induced by HQ.


Changes in gastrointestinal hormone responses, insulin sensitivity, and beta-cell function within 2 weeks after gastric bypass in non-diabetic subjects.
Roux-en-Y gastric bypass (RYGB) surgery causes profound changes in secretion of gastrointestinal hormones and glucose metabolism. We present a detailed analysis of the early hormone changes after RYGB in response to three different oral test meals designed to provide this information without causing side effects (such as dumping). We examined eight obese non-diabetic patients before and within 2 weeks after RYGB. On separate days, oral glucose tolerance tests (25 or 50 g glucose dissolved in 200 mL of water) and a liquid mixed meal test (200 mL 300 kcal) were performed. We measured fasting and postprandial glucose, insulin, C-peptide, glucagon, total and intact glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-2 (GLP-2), peptide YY(3-36) (PYY), cholecystokinin (CCK), total and active ghrelin, gastrin, somatostatin, pancreatic polypeptide (PP), amylin, leptin, free fatty acids (FFA), and registered postprandial dumping. Insulin sensitivity was measured by homeostasis model assessment of insulin resistance. Fasting glucose, insulin, ghrelin, and PYY were significantly decreased and FFA was elevated postoperatively. Insulin sensitivity increased after surgery. The postprandial response increased for C-peptide, GLP-1, GLP-2, PYY, CCK, and glucagon (in response to the mixed meal) and decreased for total and active ghrelin, leptin, and gastrin, but were unchanged for GIP, amylin, PP, and somatostatin after surgery. Dumping symptoms did not differ before and after the operation or between the tests. Within 2 weeks after RYGB, we found an increase in insulin secretion and insulin sensitivity. Responses of appetite-regulating intestinal hormones changed dramatically, all in the direction of reducing hunger.


Preactive lesions in multiple sclerosis.
Knowledge of the early pathological changes observed in multiple sclerosis (MS) has advanced by implementation of many improved pathological, biochemical and imaging techniques. This review highlights the accumulating evidence for early pathological changes we term 'preactive lesions', characterized by clusters of activated microglia in otherwise normal-appearing white matter. Compelling evidence is accumulating for pathological changes in normal-appearing white matter of MS patients, which occur before the actual development of the active demyelinating lesion. Focal disorder has been documented in normal-appearing white matter of MS months to years before the appearance of gadolinium-enhancing lesions. In these foci, clusters of activated microglia are found in the absence of demyelination and clear leukocyte infiltration, distinguishing them from the traditional demyelinating active and chronic active lesions. Although the events that give rise to preactive lesions are still to be identified, oligodendrocyte abnormalities appear to be crucially involved. Importantly, preactive lesions do not always develop into demyelinating lesions but often appear to resolve without subsequent disorder. Preactive lesions in MS represent early stages in the formation of destructive MS lesions. As many of them spontaneously resolve, they are expected to hold important clues to stop the inflammatory process in MS.


HIV care using differentiated service delivery during the COVID-19 pandemic: a nationwide cohort study in the US Department of Veterans Affairs.
The Department of Veterans Affairs (VA) is the largest provider of HIV care in the United States. Changes in healthcare delivery became necessary with the COVID-19 pandemic. We compared HIV healthcare delivery during the first year of the COVID-19 pandemic to a prior similar calendar period. We included 27,674 people with HIV (PWH) enrolled in the Veterans Aging Cohort Study prior to 1 March 2019, with ≥1 healthcare encounter from 1 March 2019 to 29 February 2020 (2019) and/or 1 March 2020 to 28 February 2021 (2020). We counted monthly general medicine/infectious disease (GM/ID) clinic visits and HIV-1 RNA viral load (VL) tests. We determined the percentage with ≥1 clinic visit (in-person vs. telephone/video [virtual]) and ≥1 VL test (detectable vs. suppressed) for 2019 and 2020. Using pharmacy records, we summarized antiretroviral (ARV) medication refill length (<90 vs. ≥90 days) and monthly ARV coverage. Most patients had ≥1 GM/ID visit in 2019 (96%) and 2020 (95%). For 2019, 27% of visits were virtual compared to 64% in 2020. In 2019, 82% had VL measured compared to 74% in 2020. Of those with VL measured, 92% and 91% had suppressed VL in 2019 and 2020. ARV refills for ≥90 days increased from 39% in 2019 to 51% in 2020. ARV coverage was similar for all months of 2019 and 2020 ranging from 76% to 80% except for March 2019 (72%). Women were less likely than men to be on ARVs or to have a VL test in both years. During the COVID-19 pandemic, the VA increased the use of virtual visits and longer ARV refills, while maintaining a high percentage of patients with suppressed VL among those with VL measured. Despite decreased in-person services during the pandemic, access to ARVs was not disrupted. More follow-up time is needed to determine whether overall health was impacted by the use of differentiated service delivery and to evaluate whether a long-term shift to increased virtual healthcare could be beneficial, particularly for PWH in rural areas or with transportation barriers. Programmes to increase ARV use and VL testing for women are needed.


Plasmodium falciparum: analysis of the antibody specificity to the surface of the trophozoite-infected erythrocyte.
Current opinion supports the view that immunity to the surface of the trophozoite-infected erythrocyte (IE) is to Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP-1). Here we provide further evidence using the mutant cell line 1776/C10 which no longer expresses PfEMP-1 at the IE surface, due to a subtelomeric deletion in chromosome 9. We have measured antibody reactivity to this mutant in comparison to it's intact isogenic parent line 1776, which does express PfEMP-1, using the sensitive technique of flow cytometry. IgG-specific antibodies (subclass IgG1) in the plasma of hyperimmune adults, reacted to 1776 but never to the 1776/C10 mutant. Antibody subclasses were also measured in individual plasma samples to the surface of trophozoite-IE. Predominantly IgG1 antibodies were detected, with a few individual plasma having additional IgG3 antibodies. Previous studies have used the agglutination assay to measure sero-conversion to PfEMP-1. Here we show that both agglutination and flow cytometric methods are comparable, suggesting that agglutination of trophozoite-IE is mediated by IgG antibodies. Comparison of the isogenic cell lines 1776 and 1776/C10 differing in expression of PfEMP-1 provides further evidence that IgG antibodies, in particular of the cytophilic subclasses, mediate recognition of PfEMP-1.


A numerical taxonomic study of anaerobic gram-negative bacilli classified as Bacteroides ureolyticus isolated from patients with non-gonococcal urethritis.
A numerical taxonomic study of 64 strains of anaerobic Gram-negative bacilli isolated from men with non-gonococcal urethritis, two unclassified laboratory strains of 'corroding bacilli', and 12 other strains of anaerobic Gram-negative bacilli, including nine received as anaerobic curved rods and three as 'Bacteroides corrodens' (B. ureolyticus), isolated from women with bacterial vaginosis, was undertaken. Seventeen reference anaerobic strains belonging to the genera Bacteroides, Fusobacterium, Mobiluncus, Mitsuokella and Wolinella were included. Morphological, biochemical and physiological characteristics were examined in 103 tests. The resemblance between the 95 strains was calculated using the SSM, SJ and DP coefficients for cluster analyses based on the UPGMA method. All three approaches gave similar groupings, and the estimated average probability of test error was 2.46%. The strains fell into 10 phenons. The unclassified strains from men and three from women with lower genital-tract infections, and the laboratory strains of 'corroding bacilli' clustered in one phenon with the reference strains of B. ureolyticus, indicating that they correspond to B. ureolyticus. The other unclassified strains of anaerobic curved rods clustered as a distinct phenon. They correspond to species of the newly described genus Mobiluncus. The taxonomic data and the compilation of diagnostic tables serve as a useful guide for the laboratory identification of clinical isolates regarded as B. ureolyticus.


Microwave-assisted synthesis and antioxidant properties of hydrazinyl thiazolyl coumarin derivatives.
Coumarin derivatives exhibit a wide range of biological properties including promising antioxidant activity. Furthermore, microwave-assisted organic synthesis has delivered rapid routes to N- and O-containing heterocycles, including coumarins and thiazoles. Combining these features, the use of microwave-assisted processes will provide rapid access to a targeted coumarin library bearing a hydrazino pharmacophore for evaluation of antioxidant properties Microwave irradiation promoted 3 of the 4 steps in a rapid, convergent synthesis of a small library of hydrazinyl thiazolyl coumarin derivatives, all of which exhibited significant antioxidant activity comparable to that of the natural antioxidant quercetin, as established by DPPH and ABTS radical assays Microwave dielectric heating provides a rapid and expedient route to a series of hydrazinyl thiazolyl coumarins to investigate their radical scavenging properties. Given their favourable properties, in comparison with known antioxidants, these coumarin derivatives are promising leads for further development and optimization.


A systematic review of studies evaluating diffusion and dissemination of selected cancer control interventions.
With this review, the authors sought to determine what strategies have been evaluated (including the outcomes assessed) to disseminate cancer control interventions that promote the uptake of behavior change. Five topic areas along the cancer care continuum (smoking cessation, healthy diet, mammography, cervical cancer screening, and control of cancer pain) were selected to be representative. A systematic review was conducted of primary studies evaluating dissemination of a cancer control intervention. Thirty-one studies were identified that evaluated dissemination strategies in the 5 topic areas. No strong evidence currently exists to recommend any one dissemination strategy as effective in promoting the uptake of cancer control interventions. The authors conclude that there is a strong need for more research into dissemination of cancer control interventions. Future research should consider methodological issues such as the most appropriate study design and outcomes to be evaluated.


Comprehensive Stress Effect of Thin Coatings and Silicon-Carbon Lattice Mismatch on Nano-Scaled Transistors with Protruding Poly Gate.
Enhancing the mobility in metal-oxide-semiconductor field-effect transistors (MOSFETs) with narrow channel widths is highly sensitive to the stress effects of Si channel when related advanced strain engineering is introduced and is compatible with semiconductor processes. In practice, layouts have significant effect on the device performance, especially for the protruding gate width on shallow trench isolation structures. The geometric parameter is investigated by systematically analysing an n-channel MOSFET composed of silicon-carbon (SiC) stressors embedded in the source and drain (S/D) regions and a tensile contact etch stop layer (CESL) using three-dimensional finite element simulation. Tensile CESL (1.1 GPa) and a SiC S/D stressor with a carbon mole fraction of 1.65% are loaded on the structure. The difference in the interactive percentages between the mechanical bending effect of the CESL from the top of the poly gate and the downward force of the CESL adjacent to the spacer sidewall of the gate occurs when the protruding gate width is increased. Results indicate that mobility was highly enhanced by approximately 72.5% at a width of approximately 0.2 μm. The mechanical bending effect becomes dominant when the gate width is more than 0.2 μm. Consequently, the mobility gain decays and consequently converges toward a constant.


CD127 Expression in Naive and Memory T Cells in HIV Patients Who Have Undergone Long-Term HAART.
To evaluate cluster of differentiation (CD)127 expression in T cells of patients with HIV-1 and the relationship of CD127 expression with disease progression. We divided 139 patients infected with human immunodeficiency virus type 1 (HIV-1) who had undergone highly active antiretroviral therapy (HAART) into 3 groups: patients with poor recovery (CD4+T < 350/μ;L, patients with general recovery (CD4+T = 350 - ∼600/μL) and patients with good recovery (CD4+T > 600/μL). Counts and percentages of naïve (CD45RA+) and memory (CD45RO+) T cells and CD127 expression were determined using flow cytometry. CD4+CD45RO+, CD4+CD45RA+, CD4+ CD45RO+ CD127+, and CD4+CD45RA+CD127+T-cell counts in patients with good recovery were higher than in patients with poor recovery and those with general recovery patients (P <.05). Percentages of CD45RO+ were increased, and percentages of CD45RA+ and CD127 in T cells were decreased in patients with poor and general recovery (P <.05). CD127 values were positively correlated with CD4+T-cell counts and percentages of CD45RA+ subsets (P <.05). CD127 expression in T cells is decreased in patients with HIV-1 and is related to recovery of CD4+T-cell counts and to naïve subsets.


Mfsd2a-based pharmacological strategies for drug delivery across the blood-brain barrier.
The blood-brain barrier (BBB) keeps the central nervous system (CNS) safe from various brain diseases, while the BBB makes it difficult for effective drugs to enter the CNS. Mfsd2a is specifically expressed on the cell membrane of brain-microvascular endothelial cell (BMEC) and is implicated in the delivery of some substances across the BBB. Mfsd2a is the first inhibitor of the transcytosis and the first transporter for lysophosphatidylcholine-docosahexaenoic acid (LPC-DHA) in BMECs. The crucial dual function of Mfsd2a puts forward two kinds of Mfsd2a-based strategies for carrying drugs from blood to the CNS. First, the reversible inhibition of Mfsd2a may temporarily induce a general disinhibition of the transcytosis in BMECs to transport macromolecular drugs across the BBB (Strategy One). Second, Mfsd2a could be used for the transport of some small-molecule drugs chemically coupled to LPC across the BBB (Strategy Two), which is quite similar to the carrier-mediated transport (CMT) via the glucose transporter (GluT1) and the L-type amino acid transporter 1 (LAT1). We here analyze and discuss the clinical significance of the two Mfsd2a-based strategies, including therapeutic potential, available pharmaceuticals, side effects, administration procedures, and disease types. In summary, the regulatory role of Mfsd2a deepens our knowledge of the function of the BBB, potentially contributing to the effective drug delivery in the treatments for neurodegenerative diseases, brain tumors, and life-threatening infections in the CNS.


Computational approaches to dissociative chemisorption on metals: towards chemical accuracy.
We review the state-of-the-art in the theory of dissociative chemisorption (DC) of small gas phase molecules on metal surfaces, which is important to modeling heterogeneous catalysis for practical reasons, and for achieving an understanding of the wealth of experimental information that exists for this topic, for fundamental reasons. We first give a quick overview of the experimental state of the field. Turning to the theory, we address the challenge that barrier heights (Eb, which are not observables) for DC on metals cannot yet be calculated with chemical accuracy, although embedded correlated wave function theory and diffusion Monte-Carlo are moving in this direction. For benchmarking, at present chemically accurate Eb can only be derived from dynamics calculations based on a semi-empirically derived density functional (DF), by computing a sticking curve and demonstrating that it is shifted from the curve measured in a supersonic beam experiment by no more than 1 kcal mol-1. The approach capable of delivering this accuracy is called the specific reaction parameter (SRP) approach to density functional theory (DFT). SRP-DFT relies on DFT and on dynamics calculations, which are most efficiently performed if a potential energy surface (PES) is available. We therefore present a brief review of the DFs that now exist, also considering their performance on databases for Eb for gas phase reactions and DC on metals, and for adsorption to metals. We also consider expressions for SRP-DFs and briefly discuss other electronic structure methods that have addressed the interaction of molecules with metal surfaces. An overview is presented of dynamical models, which make a distinction as to whether or not, and which dissipative channels are modeled, the dissipative channels being surface phonons and electronically non-adiabatic channels such as electron-hole pair excitation. We also discuss the dynamical methods that have been used, such as the quasi-classical trajectory method and quantum dynamical methods like the time-dependent wave packet method and the reaction path Hamiltonian method. Limits on the accuracy of these methods are discussed for DC of diatomic and polyatomic molecules on metal surfaces, paying particular attention to reduced dimensionality approximations that still have to be invoked in wave packet calculations on polyatomic molecules like CH4. We also address the accuracy of fitting methods, such as recent machine learning methods (like neural network methods) and the corrugation reducing procedure. In discussing the calculation of observables we emphasize the importance of modeling the properties of the supersonic beams in simulating the sticking probability curves measured in the associated experiments. We show that chemically accurate barrier heights have now been extracted for DC in 11 molecule-metal surface systems, some of which form the most accurate core of the only existing database of Eb for DC reactions on metal surfaces (SBH10). The SRP-DFs (or candidate SRP-DFs) that have been derived show transferability in many cases, i.e., they have been shown also to yield chemically accurate Eb for chemically related systems. This can in principle be exploited in simulating rates of catalyzed reactions on nano-particles containing facets and edges, as SRP-DFs may be transferable among systems in which a molecule dissociates on low index and stepped surfaces of the same metal. In many instances SRP-DFs have allowed important conclusions regarding the mechanisms underlying observed experimental trends. An important recent observation is that SRP-DFT based on semi-local exchange DFs has so far only been successful for systems for which the difference of the metal work function and the molecule's electron affinity exceeds 7 eV. A main challenge to SRP-DFT is to extend its applicability to the other systems, which involve a range of important DC reactions of e.g. O2, H2O, NH3, CO2, and CH3OH. Recent calculations employing a PES based on a screened hybrid exchange functional suggest that the road to success may be based on using exchange functionals of this category.


Endoscopic versus direct vision for saphenous vein graft harvesting in coronary artery bypass surgery.
Recent reports have suggested harvesting of the greater saphenous vein for coronary artery bypass (CABG) using endoscopic techniques (endoscopic) results in early graft closure, higher rates of myocardial infarction (MI) and death. We explored the impact of this technique performed by experienced operators on postoperative morbidities, MI and death in our CABG patients. All non-emergent patients presenting for first time CABG surgery from 2006 to June 2009 were included. Data pertaining to surgery, readmissions, cardiac catheterization and interventions during long term follow-up were extracted from our local STS and ACC registries. Linear and logistic regressions with clinical covariates were conducted to determine if vein harvest technique group predicted the major outcomes. Propensity score matching (PSM) was completed to simulate randomization and improve covariate balance across the endoscopic and direct vision groups. One thousand nine hundred and eighty-eight (N.=1988) patients were evaluated in this study (N.=1734 endoscopic group and N.=254 direct vision group). The perioperative major adverse outcomes (mortality within 30 days, stroke, reoperation for bleeding, prolonged ventilation and readmission within 30 days) were 17.8% in the endoscopic group and 25.2% in the direct vision group. The rate of leg infections was 0.3% for the endoscopic group and 1.6% for the direct vision group. After adjustment for covariates, the direct vision group had significantly greater risk for prolonged ventilation (P=0.03), MACE (P=0.02) and mortality within 30 days (P=0.01), but only marginally greater risk for leg infections (P=0.052). In the isolated CABG patients, operative death was 1% for the endoscopic group and 1.7% in the direct vision group (P=0.62). After PSM the endoscopic group was similar on all outcomes except for having fewer MACE (P=0.04). In a mean follow-up of 22.1±10.5 months, there were no significant differences in the overall rate and time to event for repeat revascularization, death and myocardial infarction. With maximum follow up of 39.6 months, 84 deaths were documented (N.=67 endoscopic and N.=17 direct vision). The outcomes captured by the number of postoperative morbidities, incidence of myocardial infarction and/or the rate of death for the endoscopic technique were comparable to patients in whom the open techniques was used. There was a trend towards a decrease in leg infections with the use of the endoscopic device. Based on this study we consider the device safe and effective with experienced operators.


Differential effects of rapamycin on mammalian target of rapamycin signaling functions in mammalian cells.
Rapamycin and its analogues have shown promising anticancer activities in preclinical and clinical studies. However, the mechanism whereby rapamycin inhibits signaling through the mammalian target of rapamycin (mTOR) remains poorly understood. Here, we show that the FKBP12/rapamycin complex is an essentially irreversible inhibitor of mTOR kinase activity in vitro. However, we observe no suppression of mTOR catalytic activity after immunoprecipitation from rapamycin-treated cells. These results suggest either that rapamycin acts as a reversible kinase inhibitor in intact cells or that the cellular effects of rapamycin are not mediated through global suppression in mTOR kinase activity. To better understand the cellular pharmacology of rapamycin, we compared the individual and combined effects of rapamycin and kinase-inactive mTOR expression on a panel of mTOR-dependent cellular responses. These studies identified glycolytic activity, amino acid transporter trafficking, and Akt kinase activity as novel, mTOR-modulated functions in mammalian cells. Whereas kinase-inactive mTOR did not enhance the decreases in cell size and glycolysis induced by rapamycin, expression of this mTOR mutant significantly enhanced the inhibitory effects of rapamycin on cell proliferation, 4EBP1 phosphorylation, and Akt activity. Unexpectedly, amino acid transporter trafficking was perturbed by kinase-inactive mTOR but not by rapamycin, indicating that this process is rapamycin insensitive. These results indicate that rapamycin exerts variable inhibitory actions on mTOR signaling functions and suggest that direct inhibitors of the mTOR kinase domain will display substantially broader anticancer activities than rapamycin.


[Basal and luliberin-stimulated gonadotropin secretion in ovariectomized female rats with streptozotocin-induced diabetes].
In vitro insulin effect on basal and LH-RH-stimulated gonadotropin secretion in oophorectomized female rats with streptozotocin diabetes administered estradiol as replacing hormone therapy was studied. The results were compared to those obtained after a similar incubation of adenohypophyses of oophorectomized rats and of oophorectomized rats administered estradiol. Estradiol was found to change the type of LH-RH-stimulated gonadotropin secretion in oophorectomized animals. Basal, but not LH-RH-stimulated gonadotropin secretion, was increased in rats with experimental diabetes as against other groups. Insulin inhibited basal and increased LH-RH-stimulated gonadotropin secretion in oophorectomized rats with streptozotocin diabetes administered estradiol. A conclusion is made about impaired sensitivity of hypophyseal gonadotrophs to LH-RH in streptozotocin diabetes and about a possible contribution of insulin to regulation of body reproductive system at the level of hypophysis.


Targeting intercellular adhesion molecule-1 prolongs survival in mice bearing bevacizumab-resistant glioblastoma.
Intercellular cell adhesion molecule 1 (ICAM-1; also known as CD54) is overexpressed in bevacizumab-resistant glioblastoma. In the present study, we tested our hypothesis that highly expressed ICAM-1 mediates glioblastoma's resistance to antiangiogenic therapy. We validated ICAM-1 overexpression in tumors resistant to antiangiogenic therapy using real-time polymerase chain reaction, immunohistochemistry, and Western blotting. We also detected ICAM1 expression in most glioma stem cells (GSCs). We investigated the mechanism of ICAM-1 overexpression after bevacizumab treatment and found that ICAM-1 protein expression was markedly increased in a time-dependent manner in GSC11 and GSC17 cells under hypoxic conditions in vitro. We also found that hypoxia induced ICAM-1 overexpression through the up-regulation of phosphorylated signal transducer and activator of transcription (p-STAT3). Hypoxia-induced p-STAT3 increased the mRNA transcription of ICAM-1, which we could inhibit with the STAT3 inhibitor AZD1480. Next, we used GFP-tagged ICAM-1 shRNA lentivirus to knock down ICAM-1 in GSC11 and GSC17 glioma cell lines. Then, we injected shICAM-1 GSC11 and scramble glioma stem cells into the brains of nude mice. Mice bearing tumors from shICAM-1 GSC11 cells survived significantly longer than mice injected with control cells did. The tumor sizes was significantly decreased in mice bearing tumors from shICAM-1 cells than that in mice bearing tumors from GFP-tagged GSC11 control cells. Knocking down ICAM-1 suppressed tumor invasion in vitro and in vivo and inhibited macrophage infiltration to the tumor site in bevacizumab-treated mice. Our findings suggest that ICAM-1 is a potentially important mediator of tumor migration and invasion in bevacizumab-resistant glioblastoma. Targeting ICAM-1 may provide a new strategy for enhancing the efficacy of antiangiogenic therapy against glioblastoma and preventing the invasive phenotype of the disease.


Immunosenescence in the wild? A longitudinal study in a long-lived seabird.
Longitudinal studies of various vertebrate populations have demonstrated senescent declines in reproductive performance and survival probability to be almost ubiquitous. Longitudinal studies of potential underlying proximate mechanisms, however, are still scarce. Due to its critical function in the maintenance of health and viability, the immune system is among the potential (mediators of) proximate mechanisms that could underlie senescence. Here, we studied three innate immune parameters-haemagglutination titre, haemolysis titre and haptoglobin concentration-in a population of common terns (Sterna hirundo) known to undergo actuarial senescence. We repeatedly sampled birds of known sex and age across 11 years and used random regression models to (a) quantify how immune parameters vary among individuals and (b) describe within-individual age-specific changes in, and potential trade-offs between, immune parameters. Our models revealed no differences between males and females in haemagglutination titre and haptoglobin concentration, and very low among-individual variation in these parameters in general. Within individuals, haemagglutination titre increased with age, while haptoglobin concentration did not change. We found no indication for selective (dis)appearance in relation to haemagglutination titre or haptoglobin concentration, nor for the existence of a trade-off between them. Haemolysis was absent in the majority (76%) of samples. Common terns do not exhibit clear senescence in haemagglutination titre and haptoglobin concentration and show very little among-individual variation in these parameters in general. This may be explained by canalisation of the immune parameters or by the colonial breeding behaviour of our study species, but more longitudinal studies are needed to facilitate investigation of links between species' characteristics and immunosenescence in wild animals.


Lessons from Epidemiology: The Burden of Liver Disease.
Liver cirrhosis is responsible for more than 1 million deaths annually and the majority of these deaths are preventable. There is marked geographical variation in rates of mortality due to cirrhosis, and this variation in liver disease burden exemplifies the links between population risks for liver disease and mortality. The differing geographical distribution of the major risks factors for the development of liver disease including alcohol consumption, hepatitis C virus (HCV) infection, hepatitis B virus infection, and obesity and the metabolic syndrome has the potential to highlight opportunities for intervention, while the evolution of these risk factors provides insights into understanding the future burden of liver disease. This review focuses on the use of population data to identify high-risk areas and populations that would benefit from preventative interventions to reduce the mortality from liver disease. Specific strategies that are effective at the policy and public health levels are discussed to illustrate the impact these can have if widely implemented. The impact of therapies that have the potential to change the natural history of liver disease, including direct acting antivirals for HCV infection is also described. Finally, the challenges of describing the epidemiology of non-alcoholic fatty liver disease are highlighted to illustrate the need to understand the natural history of disease to inform and influence the development of novel therapies.


Ethyl pyruvate protects colonic anastomosis from ischemia-reperfusion injury.
Ethyl pyruvate is a simple derivative in Ca(+2)- and K(+)-containing balanced salt solution of pyruvate to avoid the problems associated with the instability of pyruvate in solution. It has been shown to ameliorate the effects of ischemia-reperfusion (I/R) injury in many organs. It has also been shown that I/R injury delays the healing of colonic anastomosis. In this study, the effect of ethyl pyruvate on the healing of colon anastomosis and anastomotic strength after I/R injury was investigated. Anastomosis of the colon was performed in 32 adult male Wistar albino rats divided into 4 groups of 8 individuals: (1) sham-operated control group (group 1); (2) 30 minutes of intestinal I/R by superior mesenteric artery occlusion (group 2); (3) I/R+ ethyl pyruvate (group 3), ethyl pyruvate was administered as a 50-mg/kg/d single dose; and (4) I/R+ ethyl pyruvate (group 4), ethyl pyruvate administration was repeatedly (every 6 hours) at the same dose (50 mg/kg). On the fifth postoperative day, animals were killed. Perianastomotic tissue hydroxyproline contents and anastomotic bursting pressures were measured in all groups. When the anastomotic bursting pressures and tissue hydroxyproline contents were compared, it was found that they were decreased in group 2 when compared with groups 1, 3, and 4 (P < .05). Both anastomotic bursting pressure (P = .005) and hydroxyproline content (P < .001) levels were found to be significantly increased with ethyl pyruvate administration when compared with group 2. When ethyl pyruvate administration doses were compared, a significant difference was not observed (P > .05). Ethyl pyruvate significantly prevents the delaying effect of I/R injury on anastomotic strength and healing independent from doses of administration.


SPRR2C, DEFB4A, WIF1, CRY2, and KRT19 are correlated with the development of atopic eczema.
Atopic eczema (AE) is a chronic relapsing inflammatory skin disease. This study aims to identify key genes related to the development of AE. The GSE6012 dataset was obtained from the Gene Expression Omnibus (GEO) database. The limma package was used to analyze differentially expressed genes (DEGs). Then, the weighted gene co-expression network analysis (WGCNA) package was utilized to generate weighted correlation networks of up-and downregulated genes. Additionally, the WGCNA package was used for enrichment analyses to explore the underlying functions of DEGs in modules (weighted correlation sub-networks) significantly associated with AE. A total of 515 DEGs were identified between lesional and non-lesional skin samples. For the upregulated genes, the blue module was found to have a significant positive correlation with AE. Importantly, small proline-rich protein 2C (SPRR2C) and defensin, beta 4A (DEFB4A) exhibited higher |log fold change (FC) values and were the key nodes of the network. Moreover, KEGG pathway analysis revealed that the upregulated genes in the blue module were primarily involved in cytokine-cytokine receptor interaction. Additionally, for the downregulated genes, the brown module was found to have a significant positive correlation with AE. Further, WNT inhibitory factor 1 (WIF1), cryptochrome 2 (CRY2), and keratin 19 (KRT19) had higher |log FC| values and were key nodes of the network. SPRR2C, DEFB4A, WIF1, CRY2, KRT19 and cytokine-cytokine receptor interaction might be correlated with the development of AE.


Barrier Access Control Using Sensors Platform and Vehicle License Plate Characters Recognition.
The paper proposes a sensors platform to control a barrier that is installed for vehicles entrance. This platform is automatized by image-based license plate recognition of the vehicle. However, in situations where standardized license plates are not used, such image-based recognition becomes non-trivial and challenging due to the variations in license plate background, fonts and deformations. The proposed method first detects the approaching vehicle via ultrasonic sensors and, at the same time, captures its image via a camera installed along with the barrier. From this image, the license plate is automatically extracted and further processed to segment the license plate characters. Finally, these characters are recognized with the help of a standard optical character recognition (OCR) pipeline. The evaluation of the proposed system shows an accuracy of 98% for license plates extraction, 96% for character segmentation and 93% for character recognition.


Monkeypox (mpox) in immunosuppressed patients.
The World Health Organization (WHO) proclaimed a public health emergency in July 2022 due to the emergence of Mpox (formerly monkeypox) while the globe was still dealing with the COVID-19 epidemic. The characteristics of mpox in immunocompetent individuals are well-characterized, despite difficulties in diagnostics, immunization, and access to treatment that persist in low-income countries. Patients with weakened immune systems are more likely to spread an illness and die from it than healthy people because they cannot mount a protective immune response against it, such as a neutralizing IgG and poxvirus-specific Th1 response. A health warning on severe mpox in people who are immunocompromised due to Human Immunodeficiency virus (HIV) and other illnesses was released by the U.S. Centers for Disease Control and Prevention (CDC) on September 29, 2022. The advice does not specifically include primary immunodeficiency, but it does define other immunocompromising disorders as "having autoimmune disease with immunodeficiency as a clinical component". Both those with healthy immune systems and those with weakened immune systems, such as those who are immunosuppressed, older people, children, etc., have encountered serious health issues, but the latter group is more likely to do so. According to the advisory, "of the people with severe mpox manifestations for whom CDC has been consulted, the majority have had HIV with CD4 counts 200 cells/ml, indicating substantial immunosuppression". However, new cases are still expected to be discovered, especially in low-income countries with limited access to diagnosis, treatment, and prevention, and where a large percentage of the mpox-infected population also has advanced HIV infection. Thus, further research is always needed to determine the best way to treat mpox in immunocompromised people. In this context, we discussed /reviewed the mpox clinical presentation, available treatment options and current preventive guidelines in immunocompromised patients.


Establishing the diagnosis of lymphoma: from initial biopsy to clinical staging.
Successful therapy for most of the non-Hodgkin's lymphomas requires an accurate pathologic diagnosis. Routine morphologic examination of excisional biopsies from nodal or extranodal sites provides the cornerstone for establishing a definitive diagnosis. The list of ancillary studies, however, used to complement these routine approaches is increasing both in number and complexity. Proper use of these diagnostic tools can be of great help in arriving at the correct diagnosis in difficult cases. Fine-needle aspiration and needle-core biopsies have a role in lymphoma staging and in the assessment of recurrent disease, but are limited as primary diagnostic tests. This review will focus on the standard approaches used to establish a diagnosis of malignant lymphoma, and the clinical utility of immunophenotypic, molecular genetic, and cytogenetic studies in providing useful data for diagnosis. The standard practice of synthesizing all of the data from multiparameter analysis to arrive at a diagnosis in difficult cases will be emphasized.


Steering in locoregional deep hyperthermia: evaluation of common practice with 3D-planning.
In Rotterdam, fifteen years of clinical experience with deep hyperthermia has sublimated in empirical treatment guidelines. In this paper, a hyperthermia treatment planning system (HTPS) is employed to investigate the effect of these guidelines on global power distribution, their effectiveness and the rationale behind each guideline. Four guidelines were investigated. The first two prescribe steering actions for balancing intraluminal temperatures and alleviating complaints of deep-seated pain or pressure. The third guideline handles superficial complaints of pain or heat sensation. The last guideline states that frequency should be increased from 77 MHz upwards in case of multiple, opposite, painful regions uncontrollable by the previous steering actions. For all steering actions it is assumed that input power is increased until complaints occur. Sigma Hyperplan was used to calculate specific absorption rate (SAR) distributions for five patient models with locally advanced cervical cancer. Absorbed power ratios of different regions of interest were evaluated to illustrate steering efficacy and complaint reduction. Phase steering is effective in shifting the central power distribution to the periphery, and is an appropriate method to balance temperatures or to handle deep-seated complaints. Reduction of amplitude is the proper action to alleviate superficial complaints of heat or pressure. Compression of the SAR distribution, mainly in the lateral direction, is predicted with increasing frequency. Hence, for complaints in the lower back or on the sides, a frequency increase should be considered. We conclude that the results of the HTPS are in close agreement with the empirical steering guidelines.


Radio Frequency-Activated Nanoliposomes for Controlled Combination Drug Delivery.
This work was conducted in order to design, characterize, and evaluate stable liposomes containing the hydrophobic drug raloxifene HCl (RAL) and hydrophilic doxycycline HCl (DOX), two potentially synergistic agents for treating osteoporosis and other bone lesions, in conjunction with a radio frequency-induced, hydrophobic magnetic nanoparticle-dependent triggering mechanism for drug release. Both drugs were successfully incorporated into liposomes by lipid film hydration, although combination drug loading compromised liposome stability. Liposome stability was improved by reducing the drug load and by including Pluronics® (PL) in the formulations. DOX did not appear to interact with the phospholipid membranes comprising the liposomes, and its release was maximized in the presence of radio frequency (RF) heating. In contrast, differential scanning calorimetry (DSC) and phosphorus-31 nuclear magnetic resonance ((31)P-NMR) analysis revealed that RAL developed strong interactions with the phospholipid membranes, most notably with lipid phosphate head groups, resulting in significant changes in membrane thermodynamics. Likewise, RAL release from liposomes was minimal, even in the presence of RF heating. These studies may offer useful insights into the design and optimization of multidrug containing liposomes. The effects of RAL on liposome characteristics and drug release performance underscore the importance of appropriate physical-chemical analysis in order to identify and characterize drug-lipid interactions that may profoundly affect liposome properties and performance early in the formulation development process.


Objective assessment of automatic language comprehension mechanisms in the brain: Novel E/MEG paradigm.
Assessing the brain activity related to language comprehension is required in a range of situations. Particularly in cases when subjects' cooperation with instructions cannot be guaranteed (e.g., in neurological patients), a protocol is needed that could be independent from attention and behavioral tasks. In this study, we aimed at designing a novel approach for neuromagnetic recordings of brain activity which could allow for probing the neural foundations underpinning three key levels of speech comprehension: lexical, semantic, and (morpho)syntactic, without requiring active attention on speech input or any active task, while keeping the recording session duration as short as possible. To this end, we designed two different auditory paradigms using the same set of single word-based lexical, semantic, and syntactic contrasts: a modified version of the multifeature oddball paradigm and an equiprobable design. Combined magnetoencephalography/electroencephalography data were recorded form young, healthy participants, presented with these stimuli while watching a silent movie. Data from the equiprobable design yielded significant activations in temporal and inferior frontal areas associated with the lexical, semantic, and morphosyntactic contrasts. In turn, neural dissociations observed in the multifeature paradigm emerged mainly in temporal cortices, and were confined to the lexical and semantic conditions with a striking lack of any statistically significant effects for syntactic violations. Our findings indicate that, by employing the equiprobable design, a comprehensive range of key linguistic processes could be assessed in a passive, attention-free manner within a relatively short time (here, ~27 min), thus making this paradigm a time-efficient and patient-friendly tool.


[The clinico-immunological subtypes of systemic lupus erythematosus].
Based on clinico-immunologic studies subtypes of systemic lupus erythematosus (SLE) were distinguished. The ANF-R++H-DNA-CH50 variant determines acute onset of SLE with renal injury in the form of diffuse glomerulonephritis. The ANF-Sp-RNP-RF mirrors the development of Raynaud's syndrome, Sjögren's syndrome, polymyositis, pneumosclerosis and myocarditis. The ANF-Sp-Ro-RF variant is associated with skin derangement in the form of discoid foci, anular, papulosquamous eruption, vitiligo, hyperpigmentation, and cerebrovasculitis. The Ro-anti-Po, La-anti-La system is related to the idea of SLE, seronegative in accordance with ANF, when rat liver sections are used as a substrate in immunofluorescence.


Polychromatic Light Exposure as a Therapeutic in the Treatment and Management of Parkinson's Disease: A Controlled Exploratory Trial.
Parkinson's disease (PD) is a disorder characterized by loss of dopamine (DA) in the nigro-striatal dopamine (NSD) system with the primary symptoms of bradykinaesia, rigidity, tremor, and altered gate. Secondary symptoms including depression, insomnia, involuntary movement, and psychiatric side effects are also commonly observed. While the treatment focus for the past 50 years has been aimed at replacing deficient DA, to relieve the primary symptoms, more recent studies have suggested that the circadian system plays a critical role in the etiology and treatment of this disorder. Several case studies and open label trials have implemented bright light therapy (BT) in an attempt to repair sleep, depression and even the primary motor symptoms of this disorder, however controlled studies are yet to be fully implemented. In this controlled trial, patients that had been maintained on BT daily for 4 months to 5 years previously were assigned to one of three groups: continued polychromatic light, continued with red light or discontinued polychromatic light for a 2 week period. The Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDSUPDRS), The Parkinson's Disease Questionnaire (PDQ-39), The Beck Depression Inventory II, The Beck Anxiety Inventory, The Epworth Sleep Scale (ESS) and a global rating scale were used to assess patients prior to and at 1 and 2 weeks after commencing the trial. Patients continuing polychromatic BT showed significant improvement on the MDSUPDRS Rating Scale (12 points; p = 0.028), the PDQ-39 (10 points; p = 0.011), ESS (4 points; p = 0.013), and numerous motor and secondary symptoms on a global rating scale. Performance on standardized motor tests also incrementally improved in this group while those exposed to red light and those that discontinued BT treatment deteriorated. These results demonstrate that strategically applied polychromatic light was beneficial in reducing many primary motor and secondary symptoms of PD. Further work investigating the role of light in mitigating PD symptoms and involvement of the circadian system will provide further advances in the treatment of PD. Clinical Trial Registration: http://www.anzctr.org.au, identifier ACTRN12617001309370.


Individual and Sequential Chromatin Immunoprecipitation Protocols.
DNA regulatory elements nucleate the interaction of several transcription factors in conjunction with ubiquitous and/or tissue-specific cofactors in order to regulate gene expression making it relevant to determine the profiles of cohabitation of several proteins on the chromatin fiber. Chromatin immunoprecipitation (ChIP) has been broadly used to determine the profile of several histone posttranslational modifications as well as transcription factor occupancy in vivo. However, individual ChIP does not resolve whether the epitope under study is present at the same time on a given genomic location. Here we describe the ChIP-re-ChIP assay that represents a direct strategy to determine the in vivo co-localization of proteins or histone posttranslational modifications in a chromatinized template on the basis of double and independent rounds of immunoprecipitation with high-quality ChIP-grade antibodies.


Exploring trade-offs between fisheries and conservation of the vaquita porpoise (Phocoena sinus) using an Atlantis ecosystem model.
Minimizing fishery bycatch threats might involve trade-offs between maintaining viable populations and economic benefits. Understanding these trade-offs can help managers reconcile conflicting goals. An example is a set of bycatch reduction measures for the Critically Endangered vaquita porpoise (Phocoena sinus), in the Northern Gulf of California, Mexico. The vaquita is an endemic species threatened with extinction by artisanal net bycatch within its limited range; in this area fisheries are the chief source of economic productivity. We analyze trade-offs between conservation of the vaquita and fisheries, using an end-to-end Atlantis ecosystem model for the Northern Gulf of California. Atlantis is a spatially-explicit model intended as a strategic tool to test alternative management strategies. We simulated increasingly restrictive fisheries regulations contained in the vaquita conservation plan: implementing progressively larger spatial management areas that exclude gillnets, shrimp driftnets and introduce a fishing gear that has no vaquita bycatch. We found that only the most extensive spatial management scenarios recovered the vaquita population above the threshold necessary to downlist the species from Critically Endangered. The scenario that excludes existing net gear from the 2008 area of vaquita distribution led to moderate decrease in net present value (US$ 42 million) relative to the best-performing scenario and a two-fold increase in the abundance of adult vaquita over the course of 30 years. Extended spatial management resulted in the highest recovery of the vaquita population. The economic cost of proposed management actions was unequally divided between fishing fleets; the loss of value from finfish gillnet fisheries was never recovered. Our analysis shows that managers will have to confront difficult trade-offs between management scenarios for vaquita conservation.


Comparison of plaque- and enzyme-linked immunospot-based assays to measure the neutralizing activities of monoclonal antibodies specific to domain III of dengue virus envelope protein.
The plaque reduction neutralization test (PRNT) is used widely to measure the neutralization activity of anti-dengue virus (DENV) antibodies, but it is time-consuming and labor-intensive and has low sample throughput. For fast and convenient measurement of neutralizing antibodies, especially in evaluating the efficiency of the DENV vaccines on a large scale, a new method is needed to replace PRNT. In recent decades, several microneutralization assays have been developed to overcome the limitations of PRNT. In the present study, we evaluated one of these, the enzyme-linked immunospot microneutralization test (ELISPOT-MNT), in comparison with PRNT. ELISPOT-MNT is performed in 96-well format, and the plaques are developed after 2 to 4 days using an ELISA to transform them into spots, which are detected automatically with an ELISPOT instrument. The assay is faster than PRNT, has a high throughput, and is more objective. We used 10 monoclonal antibodies (MAbs) against domain III of the DENV envelope protein (EDIII) to evaluate the two assays; all of these MAbs cross-react with all four serotypes of DENV as measured by immunofluorescence assay. The two neutralization assays were performed simultaneously to measure the 50% inhibitory concentration (IC(50)) of these MAbs. Using PRNT as the reference and treating IC(50) values higher than 50 μg/ml of MAbs as negative, ELISPOT-MNT showed a sensitivity of 95.6% and specificity of 88.24% when 10 MAbs were tested against four DENV serotype strains. A good correlation (R(2) = 0.672; P = 0.000) was observed between the two assays, making ELISPOT-MNT a potentially valuable method for measure of neutralizing antibodies against DENV.


Nurr1 is not essential for the development of prepulse inhibition deficits induced by prenatal immune activation.
Inflammation-induced disruption of fetal neurodevelopmental processes has been linked to the precipitation of long-lasting behavioral abnormalities and associated neuropathology. Recent longitudinal investigations in prenatal immune activation models have revealed developmental correspondences between the ontogeny of specific dopaminergic neuropathology and the postnatal onset of distinct forms of dopamine-dependent functional abnormalities implicated in schizophrenia. Two examples of such developmental correspondences are increased expression of the orphan nuclear receptor Nurr1 (NR4A2) in ventral midbrain areas and disruption of prepulse inhibition of the acoustic startle reflex, with both the neuroanatomical and behavioral effects emerging only in adult but not pre-pubertal subjects exposed to prenatal maternal inflammation. In the present study, we tested the hypothesis that Nurr1 may be a critical molecular mediator of prepulse inhibition deficits induced by prenatal immune activation. To this end, we compared the effects of prenatal immune challenge on adult PPI in wild-type (wt) mice and mice with a heterozygous constitutive deletion of Nurr1 (Nurr1+/-) using a well established mouse model of maternal immune activation by exposure to the viral mimetic poly(I:C) (=polyriboinosinic-polyribocytidilic acid). We found that prenatal poly(I:C) treatment on gestation day 9 was similarly effective in disrupting prepulse inhibition in adult wt and Nurr1+/- mice. Prenatal poly(I:C) treatment also generally increased midbrain Nurr1-positive cells and counteracted the genetically driven Nurr1 deficit in the substantia nigra. Our data thus suggest that at least under the present experimental conditions, Nurr1 is not essential for the development of prepulse inhibition deficits induced by prenatal immune activation.


A new serovar in the Grippotyphosa serogroup comprising leptospiral isolates from different regions.
Pulsed-field gel electrophoresis (PFGE) studies performed with leptospiral isolates led us to suspect the existence of a new serovar in the Grippotyphosa serogroup. The results obtained with reference serological techniques used in leptospiral identification, including cross-agglutination absorption and monoclonal antibody techniques, confirmed the existence of a new serovar exemplified by strain Dadas I. Four other isolates from different regions of the world were submitted for identification by PFGE and produced NotI restriction patterns similar to that of strain Dadas I. Our data demonstrate the power of PFGE for identifying leptospiral isolates. The name dadas is proposed for the new serovar.


Epithelioid malignant peripheral nerve sheath tumor: clinicopathologic analysis of 63 cases.
Epithelioid malignant peripheral nerve sheath tumor (EMPNST) is rare and differs from conventional malignant peripheral nerve sheath tumor by showing diffuse S-100 protein positivity, infrequent association with NF1, and occasional origin in a schwannoma. Loss of INI1 expression is seen in a subset of tumors. The purpose of this study was to further define clinicopathologic features and outcome data in a large series of EMPNST. Sixty-three cases were identified in consultation files. The patient group consisted of 33 men and 30 women; the median age was 44 years (range, 6 to 80 y). One patient was reported to have NF1. One patient had 3 seemingly separate primary EMPNSTs during his 12-year clinical course. The median tumor size was 3.0 cm (range, 0.4 to 20 cm), and tumors were located most frequently on the lower extremity (30/63; 48%) and trunk (16/63; 25%). Most tumors were superficial (5 dermal, 38 subcutaneous); 15 were subfascial, and 5 were visceral. Microscopically, tumors comprised a relatively uniform but clearly atypical population of epithelioid cells. The majority of tumors demonstrated a multilobular growth pattern, with lobules and nests surrounded by myxoid and/or fibrous stroma. Tumor cells were round, polygonal, or ovoid and had round vesicular nuclei and abundant amphophilic to palely eosinophilic cytoplasm. Focal spindled morphology was seen in one third of cases. Most tumors (55/63; 87%) showed marked cytologic atypia with irregular vesicular nuclei and prominent nucleoli. Mitotic rate ranged from 1 to 46/10 HPF (median, 5/10 HPF); atypical mitotic figures were seen in 7 cases. Necrosis was present in 17 tumors. Twelve tumors were associated with a nerve. Nine tumors arose in a schwannoma (6 conventional type, 3 epithelioid) and 1 in a neurofibroma (in the NF1 patient). All tumors expressed S-100 protein, and the majority showed strong and diffuse staining (87%; 55/63). There was no expression of the melanocytic markers Mart-1/Melan-A (0/58), HMB-45 (0/57), and MiTF (0/9). Other immunohistochemical results included variable staining for GFAP (24/40; 60%) and EMA (4/29; 14%), whereas keratin was consistently negative (0/33). INI1 expression was lost in 67% of tumors examined (35/52). Most tumors were treated by surgical resection; 13 also received chemotherapy and/or radiation. Follow-up data were available for 31 cases and ranged in duration from 3 months to 20 years (median, 36 mo). Twenty-two patients have no evidence of disease at the time of follow-up. Nine patients developed local recurrence, 3 of whom were reported to be disease-free at the time of latest follow-up (44 mo, 19 y, and 20 y). Five patients developed distant metastases, and 4 patients died of disease (including 2 with unresectable recurrent tumors). Recurrence, metastasis, and disease-related death were observed independent of anatomic site or depth. In summary, EMPNST is a morphologically distinct variant that most commonly affects adults on the lower extremity or trunk, although a wide age range and site distribution are seen. Most tumors arise in superficial soft tissue, are diffusely S-100 positive, and two thirds show INI1 loss. On the basis of available follow-up information there is a comparatively low risk for recurrence and metastasis, irrespective of tumor depth.


Phospho-ibuprofen (MDC-917) suppresses breast cancer growth: an effect controlled by the thioredoxin system.
We have recently synthesized phospho-ibuprofen (P-I; MDC-917), a safer derivative of ibuprofen, which has shown anti-cancer activity. We investigated its efficacy and mechanism of action in the treatment of breast cancer in preclinical models. We evaluated the anti-breast-cancer efficacy of P-I alone or incorporated into liposomes (Lipo-P-I) in human estrogen receptor-positive (MCF-7) and triple-negative, i.e., estrogen receptor-negative, progesterone receptor-negative and HER2-negative (MDA-MB231) breast cancer cell lines - as they represent the most frequent (estrogen receptor-positive) and the most difficult-to-treat (triple-negative) subtypes of breast cancer - and their xenografts in nude mice. We assessed the effect of P-I on the levels of reactive oxygen nitrogen species in response to P-I using molecular probes, on the thioredoxin system (expression and redox status of thioredoxin-1 (Trx-1) and thioredoxin reductase activity), on cyclooxygenase 2, NF-κB and mitogen-activated protein kinase cell signaling; and on the growth of xenografts with stably knocked-down Trx-1. Compared with controls, P-I 400 mg/kg/day inhibited the growth of MDA-MB231 xenografts by 266%, while the growth of MCF-7 xenografts was inhibited 51% byP-I 300 mg/kg/day and 181% by Lipo-P-I 300 mg/kg/day. In both cell lines, P-I induced oxidative stress and suppressed the thioredoxin system (oxidized Trx-1 and decreased its expression; inhibited thioredoxin reductase activity). These changes triggered downstream redox signaling: the activity of NF-κB was suppressed and the Trx-1-ASK1 complex was dissociated, activating the p38 and JNK mitogen-activated protein kinase cascades. Trx-1 knockdown abrogated the anti-cancer effect of P-I in vitro and in vivo. P-I is safe and effective against breast cancer. Liposomal formulation enhances its efficacy; the effect is heavily dependent on the induction of oxidative stress and the suppression of the thioredoxin system. P-I merits further evaluation as an agent for the treatment of breast cancer.


New pleuromutilin derivatives with enhanced antimicrobial activity. I. Synthesis.
A series of new derivatives of the antibiotic pleuromutilin, produced by some Basidiomycetes, was synthesized by chemical modification of natural pleuromutilin. Most of them contain basic functional groups in the side chain at C14 of the mutilin skeleton. The monotosylate of pleuromutilin was used as a versatile intermediate for displacement by N-, O- and S-nucleophiles.


Cadmium minimization in wheat: A critical review.
Cadmium (Cd) accumulation in wheat (Triticum aestivum L.) and its subsequent transfer to food chain is a major environmental issue worldwide. Understanding wheat response to Cd stress and its management for aiming to reduce Cd uptake and accumulation in wheat may help to improve wheat growth and grain quality. This paper reviewed the toxic effects, tolerance mechanisms, and management of Cd stress in wheat. It was concluded that Cd decreased germination, growth, mineral nutrients, photosynthesis and grain yield of wheat and plant response to Cd toxicity varies with cultivars, growth conditions and duration of stress applied. Cadmium caused oxidative stress and genotoxicity in wheat plants. Stimulation of antioxidant defense system, osmoregulation, ion homeostasis and over production of signalling molecules are important adaptive strategies of wheat under Cd stress. Exogenous application of plant growth regulators, inorganic amendments, proper fertilization, silicon, and organic, manures and biochar, amendments are commonly used for the reduction of Cd uptake in wheat. Selection of low Cd-accumulating wheat cultivars, crop rotation, soil type, and exogenous application of microbes are among the other agronomic practices successfully employed in reducing Cd uptake by wheat. These management practices could enhance wheat tolerance to Cd stress and reduce the transfer of Cd to the food chain. However, their long-term sustainability in reducing Cd uptake by wheat needs further assessment.


Performance evaluation of the open-source Yet Another Spindle Algorithm sleep staging algorithm against gold standard manual evaluation of polysomnographic records in adolescence.
To evaluate an automatic sleep scoring algorithm against manual polysomnography sleep scoring. Yet Another Spindle Algorithm automatic sleep staging algorithm. Manual sleep scoring. 327 nights (151 healthy adolescents), from the NCANDA study. Participants underwent one-to-three overnight polysomnography recordings, one consisting of an event-related-potential paradigm. Epoch by Epoch and discrepancy analyses (Bland Altman plots) were conducted on the overall sample. Epoch by Epoch and discrepancy analysis were repeated separately on standard polysomnography nights and event-related potential nights. Regression models were estimated on age, sex, scorer, and site of recording, separately on standard polysomnography nights and event-related potential nights. The Yet Another Spindle Algorithm sleep scoring algorithm's average sensitivity of 93.04% for Wake, 87.67% for N2, 84.46% for N3, 86.02% for rapid-eye-movement, and 40.39% for N1. Specificity was 96.75% for Wake, 97.31% for N1, 88.87% for N2, 97.99% for N3, and 97.70% for rapid-eye-movement. The Matthews Correlation Coefficient was highest in rapid-eye-movement sleep (0.85) while lowest in N1 (0.39). Cohen's Kappa mirrored Matthews Correlation Coefficient results. In Bland-Altman plots, the bias between Yet Another Spindle Algorithm and human scoring showed proportionality to the manual scoring measurement size. Yet Another Spindle Algorithm performance was reduced in event-related-potential/polysomnography nights for N3 and rapid-eye-movement. According to the Matthews Correlation Coefficient, the Yet Another Spindle Algorithm performance was affected by younger age, male sex, recording sites, and scorers. Results support the use of Yet Another Spindle Algorithm to score adolescents' polysomnography sleep records, possibly with classification outcomes supervised by an expert scorer.


Early androgen effects on spatial and mechanical abilities: evidence from congenital adrenal hyperplasia.
There is considerable controversy about the origins of sex differences in cognitive abilities, particularly the male superiority in spatial abilities. We studied effects of early androgens on spatial and mechanical abilities in adolescents and young adults with congenital adrenal hyperplasia (CAH). On tests of three-dimensional mental rotations, geography, and mechanical knowledge, females with CAH scored higher than their unaffected sisters, and males with CAH scored lower than their unaffected brothers. Exploratory regression analyses suggest that androgens affect spatial ability in females directly and through male-typed activity interests. Findings indicate that early androgens influence spatial and mechanical abilities, and that androgen effects on abilities may occur in part through effects on sex-typed activity interests.


Analysis of the miRNA Profiles of Melanoma Exosomes Derived Under Normoxic and Hypoxic Culture Conditions.
MicroRNAs (miRNAs) transported in melanoma-derived exosomes function as intercellular messengers supporting tumor survival and progression. Hypoxia increases melanoma phenotypic plasticity, drug resistance, and metastasis. We determined the miRNA profiles in exosomes derived from melanoma cells grown under hypoxic and normoxic conditions by microarray analyses and reverse transcription-polymerase chain reaction (RT-PCR) in order to analyze the potential influence of vesicle-transported miRNAs on cancer-related pathways and transcriptional programs. Despite phenotypical differences of the four cell lines used, their exosomes shared the majority of miRNAs. The levels of three miRNAs were higher in normoxic exosomes, whereas 15 miRNAs were significantly more abundant under hypoxic conditions. Pathway analysis pointed at several cellular processes contributing to proliferation, drug resistance, and modification of the tumor microenvironment, including immunosuppression. The miRNA-expression profiles of exosomes from patient-derived melanoma cells are modified by oxygen concentration and reflect the phenotypic changes of melanoma cells under different growth conditions.


Multiple familial cutaneous glomangioma: a pedigree of 4 generations and critical analysis of histologic and genetic differences of glomus tumors.
Glomangiomas are benign tumors arising from neuromyoarterial cells surrounding cutaneous arteriovenous anastomoses that serve as temperature regulators. They exist as solitary or multiple types, occurring sporadically or in a familial pattern, the latter of which is rare. We describe a 4-generation pedigree of familial cutaneous glomangioma, in addition to the 3 other well-documented pedigrees reported in the literature to date, and we clarify ways in which to distinguish the different types of glomus tumors. Nodular skin lesions of 4 affected family members were analyzed by histologic, immunohistologic, and electron microscopic methods. To elucidate the gene defect in this family, we searched for a linkage to a candidate locus on chromosome 11q23 previously identified in paragangliomas, one form of glomus tumor, in 16 family members of 4 generations by using polymorphic markers. The diagnosis of disseminated cutaneous glomangiomas was confirmed histologically in 4 family members of 3 different generations. Glomangiomas were transmitted in an autosomal dominant pattern via the paternal line. Genetic linkage analysis of the affected family members excluded linkage to chromosome 11q23. An autosomal dominant pattern of inheritance has been described for glomus tumors of the paraganglioma type originating from the APUD cell system, the underlying genetic defect of which has been mapped to chromosome 11q23. In contrast, we show that the genetic defect in disseminated cutaneous glomus tumors of the glomangioma type deriving from smooth muscle cells or pericytes is not linked to chromosome 11. Thus we suggest that the common term glomus tumor, used for both paragangliomas and glomangiomas in the current literature, is misleading and should be avoided because these tumors have different histologic derivation and genetic origin.


Identifying cancer driver genes in tumor genome sequencing studies.
Major tumor sequencing projects have been conducted in the past few years to identify genes that contain 'driver' somatic mutations in tumor samples. These genes have been defined as those for which the non-silent mutation rate is significantly greater than a background mutation rate estimated from silent mutations. Several methods have been used for estimating the background mutation rate. We propose a new method for identifying cancer driver genes, which we believe provides improved accuracy. The new method accounts for the functional impact of mutations on proteins, variation in background mutation rate among tumors and the redundancy of the genetic code. We reanalyzed sequence data for 623 candidate genes in 188 non-small cell lung tumors using the new method. We found several important genes like PTEN, which were not deemed significant by the previous method. At the same time, we determined that some genes previously reported as drivers were not significant by the new analysis because mutations in these genes occurred mainly in tumors with large background mutation rates. The software is available at: http://linus.nci.nih.gov/Data/YounA/software.zip.


The stimulation of glycogenolysis in isolated hepatocytes by opioid peptides.
The opioid peptides [Leu]enkephalin and dynorphin-(1-13) were shown to enhance glycogen breakdown when added directly to hepatocytes. This was the result of a concerted effect on the enzymes of glycogen metabolism, with a stimulation of glycogen phosphorylase activity and a simultaneous decrease in glycogen synthase I activity. The latter only became significant when the enzyme was activated by incubating the cells in presence of 20 mM- or 40 mM-glucose. The effect of the opioid peptides was independent of an increase in cyclic AMP or any change in the activity ratio of the cyclic AMP-dependent protein kinase and was abolished by depleting the cells of Ca2+. Both [Leu]enkephalin and dynorphin-(1-13) produced a significant decrease in cyclic AMP formation, suggesting that in liver, as in neuronal tissue, they may act by inhibiting adenylate cyclase activity.


First reported chikungunya fever outbreak in the republic of Congo, 2011.
Chikungunya is an Aedes -borne disease characterised by febrile arthralgia and responsible for massive outbreaks. We present a prospective clinical cohort study and a retrospective serological study relating to a CHIK outbreak, in the Republic of Congo in 2011. We analysed 317 suspected cases, of which 308 (97.2%) lived in the city of Brazzaville (66.6% in the South area). Amongst them, 37 (11.7%) were CHIKV+ve patients (i.e., biologically confirmed by a real-time RT-PCR assay), of whom 36 (97.3%) had fever, 22 (66.7%) myalgia and 32 (86.5%) arthralgia. All tested negative for dengue. The distribution of incident cases within Brazzaville districts was compared with CHIKV seroprevalence before the outbreak (34.4% in 517 blood donors), providing evidence for previous circulation of CHIKV. We applied a CHIK clinical score to 126 patients recruited within the two first day of illness (including 28 CHIKV+ves (22.2%)) with sensitivity (78.6%) and specificity (72.4%) values comparing with those of the referent study in Reunion Island. The negative predictive value was high (92%), but the positive predictive value (45%) indicate poor potential contribution to medical practice to identify CHIKV+ve patients in low prevalence outbreaks. However, the score allowed a slightly more accurate follow-up of the evolution of the outbreak than the criterion "fever+arthralgia". The complete sequencing of a Congolase isolate (Brazza_MRS1) demonstrated belonging to the East/Central/South African lineage and was further used for producing a robust genome-scale CHIKV phylogenetic analysis. We describe the first Chikungunya outbreak declared in the Republic of Congo. The seroprevalence study conducted amongst blood donors before outbreak provided evidence for previous CHIKV circulation. We suggest that a more systematic survey of the entomological situation and of arbovirus circulation is necessary in Central Africa for better understanding the environmental, microbiological and sociological determinants of emergence.


Association between chronic blood pressure changes and development of Alzheimer's disease.
Epidemiological studies suggest an association between chronic blood pressure (BP) changes and Alzheimer's disease (AD). In particular, there is growing evidence that hypertensive people that do not have their BP adequately treated and controlled in midlife are more likely to develop AD in late-life. It has been hypothesized that cerebrovascular disease is a common pathway which connects hypertension and AD in individuals with apolipoprotein E genotype through brain hypoperfusion and hypoxia. This could accelerate amyloid-β aggregation that disrupts cell-to-cell connectivity and leads to eventual brain neuron loss. Also, high BP contributes to worsen AD by raising oxidative stress and inflammatory response. Aging-related structural and functional disturbances appear to exacerbate the deleterious effect of chronic hypertension on cerebral blood flow autoregulation. There is evidence suggesting that some antihypertensive drug classes reduce the risk and progression of AD more than others. Further prospective randomized studies comparing different classes of antihypertensive drugs are needed to provide more evidence regarding their effects on AD risk. Hypotension could be a consequence of the incident dementia and conversely deteriorate the outcome of AD by worsening brain hypoperfusion. Frequent home BP monitoring should be carried out in AD patients to detect harmful orthostatic hypotension.


[Characteristics of the action of euphylline and the activity of forms of cAMP phosphodiesterase in lymphocytes of patients with bronchial asthma].
Two forms of cAMP phosphodiesterase were isolated from lymphocytes by using centrifugation in sucrose density gradient. The activities of both forms do not differ in healthy persons and in patients with bronchial asthma during asphyxia-free period. During the attack the activity of the high molecular form of the enzyme increases. Euphylline exerts the inhibitory effect on the activity and consequently on the general activity of the enzyme.


Large, heterometallic coordination cages based on ditopic metallo-ligands with 3-pyridyl donor groups.
Ditopic N-donor ligands with terminal 4-pyridyl groups are omnipresent in coordination-based self-assembly. The utilization of ligands with 3-pyridyl donor groups is significantly less common, because the intrinsic conformational flexibility of these ligands tends to favor the formation of small aggregates. Here, we show that large Pd6L1212+ cages can be obtained by reaction of Pd(ii) salts with metallo-ligands L bearing terminal 3-pyridyl groups. The easy-to-access metallo-ligands contain an Fe(ii) clathrochelate core. These sterically demanding clathrochelate complexes prevent the formation of smaller aggregates, which is observed for less bulky analogous building blocks. The cages were shown to bind BF4- and BPh4- anions in aqueous solvent mixtures, whilst the lateral size of the clathrochelate significantly affects their guest encapsulation behavior.


Comparison of journals of suicidology: a bibliometric study from 2006–2010.
Three English-language journals deal explicitly with suicide phenomena. To the best of our knowledge, no previous study has analyzed the subject content of these three journals. To review the abstracts of the three suicide-related journals in order to clarify the subjects of the papers. We examined all abstracts of every paper published in Crisis: The Journal of Crisis Intervention and Suicide Prevention, Archives of Suicide Research, and Suicide and Life-Threatening Behavior for the 5 years between 2006 and 2010, and categorized each paper by subject. We found that the journals were similar with respect to subject allocation. Most papers dealt with epidemiological issues (32.7-40.1% of abstracts); prevention (5.8%-15.3%) and research (8.3%-10.6%) were next best represented subjects. Clinical papers comprised from 2.8% to 8.2% of the studies published. English-language suicide journals publish a preponderance of epidemiological studies. Clinical studies are relatively underrepresented.


Platelet activation and inhibition of malarial cytoadherence by the anti-CD36 IgM monoclonal antibody NL07.
The surface glycoprotein CD36 (GPIV) is known to mediate the adhesion of Plasmodium falciparum malaria-infected red blood cells and to be a receptor for extracellular matrix proteins such as collagen and thrombospondin. The murine monoclonal IgM antibody NL07, which is specific for CD36, has now been shown to also be a potent inhibitor of the adhesion of P falciparum malaria-infected red blood cells to C32 melanoma cells. Treatment of platelets with NL07 monoclonal antibody resulted in rapid degranulation, release of ATP and serotonin, increase in [Ca2+]i, and tyrosine phosphorylation of a substrate protein of 130 kD. In about one-half of the experiments, activation with NL07 resulted in the formation of small aggregates of 10 to 30 platelets, whereas in the other half of the experiments, large aggregates were seen similar to those induced by adenosine diphosphate (ADP) and these large aggregates could be converted to the small aggregates by ATP alpha S or by AP-2 or other antibodies against GPIIb and/or IIIa. Microaggregates of 2 to 5 platelets were seen with Glanzmann's platelets that constitutively lack GPIIb/IIIa. Aggregate formation was not seen with heat-treated serum, in the presence of anti C1q antibodies, or when using C5-, C8-, or C9-deficient human sera. Although activation of platelets with purified complement components results in a slow morphologic change without aggregation, involvement of CD36 results in rapid complement-mediated activation leading to formation of small aggregates that is largely independent of GPIIb/IIIa and that, under certain circumstances, proceeds to the formation of large ADP-dependent aggregates.


Magnesium Accumulation in Two Contrasting Varieties of Lycopersicum esculentum L. Fruits: Interaction with Calcium at Tissue Level and Implications on Quality.
As the productivity and quality of tomato fruits are responsive to Mg applications, without surpassing the threshold of toxicity, the assessment of potential levels of Mg accumulation in tissues, as well as the interactions with Ca and physicochemical properties, prompt this study. An agronomic workflow for Mg enrichment, consisting of six foliar applications of MgSO4 with four concentrations (0%, 0.25%, 1% and 4%), equivalent to 0, 43.9, 175.5 and 702 g ha-1, was applied on two tomato (Lycopersicum esculentum L.) genotypes (Heinz1534 and Heinz9205). During fruit development, leaf gas exchange was screened, with only minor physiological deviations being found. At harvest, Mg contents among tissues and the interactions with Ca were analyzed, and it was found that in both varieties a higher Mg/Ca ratio prevailed in the most external part of the fruit sprayed with 4% MgSO4. However, Mg distribution prevailed relatively near the epidermis in H1534, while in H9205 the higher contents of this nutrient occurred in the core of the fruit, which indicated a decrease of the relative proportion of Ca. The morphologic (height and diameter), physical (dry weight and density) and colorimetric parameters, and the total soluble solids of fruits, did not reveal significant changes in both tomato varieties. It was further concluded that foliar application until 4% MgSO4 does not have physiological impacts in the fruit's quality of both varieties, but in spite of the different patterns of Mg accumulation in tissues, if the mean value in the whole fruit is considered, this nutrient prevails in H1534. This study thus suggests that variety H1534 can be used to attain tomato fruits with added value, providing an option of further processing to achieve food products with functional properties, ultimately proving a beneficial option to producers, the food processing industry and consumers. Moreover, the study reinforces the importance of variety choice when designing enrichment workflows.