Immunogold evidence suggests that coupling of K+ siphoning and water transport in rat retinal Müller cells is mediated by a coenrichment of Kir4.1 and AQP4 in specific membrane domains.
Postembedding immunogold labeling was used to examine the subcellular distribution of the inwardly rectifying K+ channel Kir4.1 in rat retinal Müller cells and to compare this with the distribution of the water channel aquaporin-4 (AQP4). The quantitative analysis suggested that both molecules are enriched in those plasma membrane domains that face the vitreous body and blood vessels. In addition, Kir4. 1, but not AQP4, was concentrated in the basal approximately 300-400 nm of the Müller cell microvilli. These data indicate that AQP4 may mediate the water flux known to be associated with K+ siphoning in the retina. By its highly differentiated distribution of AQP4, the Müller cell may be able to direct the water flux to select extracellular compartments while protecting others (the subretinal space) from inappropriate volume changes. The identification of specialized membrane domains with high Kir4.1 expression provides a morphological correlate for the heterogeneous K+ conductance along the Müller cell surface.


The development and progression of diabetic retinopathy in type I diabetic patients: a cohort study.
To describe the course and risk factors for development and progression of retinopathy, we studied a cohort of 333 Israeli Jewish patients with Type 1 (insulin-dependent) diabetes mellitus. The median age at diagnosis was 9.5 (range 0.04-26.2) years and the median duration of follow-up was 14 (range 1.6-30) years. Evaluation of both retinae was performed yearly since referral and HbA1 values were tested every 3 months since 1978. During a follow-up of 4070 patient-years, 162 patients developed non-proliferative retinopathy. The median retinopathy-free interval was 14.9 years and after 30 years all patients were affected. Pre-pubertal duration of diabetes was relevant. Independent and significant risk factors for early onset of non-proliferative retinopathy were: poor cumulative glycaemic control (median retinopathy-free interval in the 1st vs 4th quartiles of mean HbA1 values over all years: 18.0 vs 12.5 years, p = 0.0001); onset of diabetes during or after puberty (median retinopathy-free interval in patients with onset of diabetes before, during or after pubescence: 16.3, 13.2 and 14.0 years, respectively, p = 0.0001); and non-Ashkenazi Jewish origin (median retinopathy-free interval 15.8 years in Ashkenazi vs 14.0 in non-Ashkenazi patients, p = 0.0004). Of 162 patients with non-proliferative retinopathy, progression to proliferative retinopathy occurred in 37, during 707 patient-years. The first event of proliferative retinopathy was diagnosed within the 1st year after non-proliferative retinopathy evolved, and at 6.3 years since onset of non-proliferative retinopathy 75% of the patients were still free of proliferative changes. Risk factors significantly and independently associated with an early progression to the proliferative stage were: poor glycaemic control in the last 3 years prior to the development of proliferative retinopathy and non-Ashkenazi Jewish origin. All patients in the 4th quartile of HbA1 values were affected by proliferative retinopathy within 11.6 years after onset of non-proliferative retinopathy.


[Variants in the disorders of the system regulating the aggregate status of the blood in patients with chronic gastritis and duodenitis].
Parameters were studied characterising the system of blood aggregate state control (BASC) in 693 patients with chronic gastritis and duodenitis. Suggested in the paper are six variants of the hemocoagulation and fibrinolysis inadequacy, such as latent hypercoagulation (a decline in spontaneous fibrinolysis), manifest hypercoagulation (enhanced tolerability of plasma to heparin), isolated paracoagulation (positive fibrinogen B or ethanol test), latent hypocoagulation (clot retraction is reduced or levels of fibrinogen are raised), structural hypocoagulation (spontaneous fibrinolysis is on the increase), manifest hypocoagulation (lowered tolerance of plasma to heparin). An algorithm of the BASC system is submitted allowing the diagnosis to be rendered automatic and differentiated therapy treatments to be prescribed.


Molecular Evolution and Spatial Transmission of Severe Fever with Thrombocytopenia Syndrome Virus Based on Complete Genome Sequences.
Severe fever with thrombocytopenia syndrome virus (SFTSV) was a novel tick-borne bunyavirus that caused hemorrhagic fever with a high fatality rate in East Asia. In this study we analyzed the complete genome sequences of 122 SFTSV strains to determine the phylogeny, evolution and reassortment of the virus. We revealed that the evolutionary rate of three genome segments were different, with highest in the S segment and lowest in the L segment. The SFTSV strains were phylogenetically classified into 5 lineages (A, B, C, D and E) with each genome segment. SFTSV strains from China were classified in all 5 lineages, strains from South Korea were classified into 3 lineages (A, D, and E), and all strains from Japan were classified in only linage E. Using the average evolutionary rate of the three genome segments, we found that the extant SFTSV originated 20-87 years ago in the Dabie Mountain area in central China. The viruses were then transmitted to other areas of China, Japan and South Korea. We also found that six SFTSV strains were reassortants. Selection pressure analysis suggested that SFTSV was under purifying selection according to the four genes (RNA-dependent RNA polymerase, glycoprotein, nucleocapsid protein, non-structural protein), and two sites (37, 1033) of glycoproteins were identified as being under strong positive selection. We concluded that SFTSV originated in central China and spread to other places recently and the virus was under purifying selection with high frequency of reassortment.


Molecular investigation of a fungemia outbreak due to Candida parapsilosis in an intensive care unit.
We investigated a nosocomial cluster of four Candida parapsilosis fungemia episodes that occurred in a neurological intensive care unit over a two-week period. The four infected patients had received parenteral nutrition through central lines, and all four had catheter-related candidemia. All of the isolates were susceptible to all of the antifungals tested, including amphotericin B, fluconazole, voriconazole, and caspofungin. They had strictly related fingerprints, based on randomly amplified polymorphic DNA analysis. Additional DNA sequencing data revealed that they were same strain. Although no isolate of Candida parapsilosis was recovered from other clinical, surveillance, or environmental samples, nosocomial spread of this yeast ceased, following the reinforcement of infection-control measures. Candida parapsilosis may require an intravascular foreign body to cause fungemia, but this outbreak shows that it can be transmitted nosocomially and can cause epidemics.


Interaction of mycophenolate mofetil and HLA matching on renal allograft survival.
The importance of HLA matching for renal transplantation outcomes has been appreciated for several decades. It has been hypothesized that as pharmacologic immunosuppression becomes stronger and more specific, the impact of HLA matching may be vanishing. Mycophenolate Mofetil (MMF) has been demonstrated to both decrease acute rejection and improve three-year graft survival. It is possible that with new immunosuppressive regimens containing MMF the relative effect of HLA matching may be altered. To determine the relative impact of HLA matching in patients on MMF we undertook an analysis of the United States Renal Transplant Data Registry (USRDS). All primary, solitary renal transplants registered at the USRDS between January 1995 and June 1997, on initial immunosuppression that included either MMF or AZA were followed until June 1998. Primary study end points were graft and patient survival. Kaplan-Meier analysis was performed to compare AZA vs. MMF treated patients by HLA mismatch. Cox proportional hazard models were used to investigate the interaction between HLA mismatch and AZA versus MMF therapy on the study endpoints. All multivariate analyses were corrected for 13 potential confounding pretransplant variables including intention to treat immunosuppression. A total of 19,675 patients were analyzed (8,459 on MMF and 11,216 on AZA). Overall three year graft survival was higher in the MMF group when compared to the AZA group (87% vs. 84% respectively P<0.001). For both AZA and MMF three-year graft survival improved with fewer HLA donor-recipient mismatches. Comparing zero antigen mismatches to six antigen mismatches, the relative improvement was comparable for both patients on AZA (92.4% vs. 80.6%) and MMF (95.2% vs. 82.9%). By Cox proportional hazard model the relative risk for graft loss decreased significantly in both the AZA and MMF treated patients with increased HLA matching. The use of MMF does not obviate the benefits of HLA matching, while HLA matching does not minimize the benefits of MMF on long term graft survival. Our study would suggest that HLA matching and MMF therapy are additive factors in decreasing the risk for renal allograft loss.


Symposium review: Strategies to improve the efficiency and profitability of heifer raising.
Regional Research Project NC-2042 has a main objective to study calf and heifer nutrition. Within this objective, feeding the postweaned heifer is considered a major priority to improve the profitability and sustainability of US dairy farms. Through optimizing nutrient utilization by precision feeding, using alternative feeds, high-fiber diets, and feed additives, this research group has worked to enhance dairy heifer nutrition. Research has focused on precision feeding heifers and incorporating high- and low-fiber diets into this system of feeding. This is accomplished by meeting the nutrient needs of the heifer for a desired rate of growth while enhancing total-tract nutrient digestibility, reducing waste and improving profitability. High-fiber forages have been studied as a means of controlling ad libitum dry matter intakes and thus weight gain in heifers. These results provide producers with a means of feeding heifers while reducing costs. Similarly, utilizing alternative feedstuffs in heifer diets has also been a major research area for this group including comprehensive research on distillers co-products, and new protein sources such as camelina and carinata meals. Results indicated that these products can be satisfactorily incorporated into heifer diets. Studying feed additives has also been a function of the research group. Research with Ascophyllum nodosum and cinnamaldehyde indicated that calves find these additives unpalatable and that supplementing cinnamaldehyde to postweaned heifers showed no benefit. However, sodium butyrate and yeast supplementation proved to be beneficial in the growth and feed efficiency of heifers. Research from this group has an effect on heifer feeding, resulting in new information that can aid in the sustainability of dairy farms. This review will focus on the area of postweaned heifer nutrition.


Functionally independent components of the late positive event-related potential during visual spatial attention.
Human event-related potentials (ERPs) were recorded from 10 subjects presented with visual target and nontarget stimuli at five screen locations and responding to targets presented at one of the locations. The late positive response complexes of 25-75 ERP average waveforms from the two task conditions were simultaneously analyzed with Independent Component Analysis, a new computational method for blindly separating linearly mixed signals. Three spatially fixed, temporally independent, behaviorally relevant, and physiologically plausible components were identified without reference to peaks in single-channel waveforms. A novel frontoparietal component (P3f) began at approximately 140 msec and peaked, in faster responders, at the onset of the motor command. The scalp distribution of P3f appeared consistent with brain regions activated during spatial orienting in functional imaging experiments. A longer-latency large component (P3b), positive over parietal cortex, was followed by a postmotor potential (Pmp) component that peaked 200 msec after the button press and reversed polarity near the central sulcus. A fourth component associated with a left frontocentral nontarget positivity (Pnt) was evoked primarily by target-like distractors presented in the attended location. When no distractors were presented, responses of five faster-responding subjects contained largest P3f and smallest Pmp components; when distractors were included, a Pmp component appeared only in responses of the five slower-responding subjects. Direct relationships between component amplitudes, latencies, and behavioral responses, plus similarities between component scalp distributions and regional activations reported in functional brain imaging experiments suggest that P3f, Pmp, and Pnt measure the time course and strength of functionally distinct brain processes.


Tumor-Treating Fields: A Fourth Modality in Cancer Treatment.
Despite major advances in therapy, cancer continues to be a leading cause of mortality. In addition, toxicities of traditional therapies pose a significant challenge to tolerability and adherence. TTFields, a noninvasive anticancer treatment modality, utilizes alternating electric fields at specific frequencies and intensities to selectively disrupt mitosis in cancerous cells. TTFields target proteins crucial to the cell cycle, leading to mitotic arrest and apoptosis. TTFields also facilitate an antitumor immune response. Clinical trials of TTFields have proven safe and efficacious in patients with glioblastoma multiforme (GBM), and are FDA approved for use in newly diagnosed and recurrent GBM. Trials in other localized solid tumors are ongoing. Clin Cancer Res; 24(2); 266-75. ©2017 AACR.


[Comparative characteristics of native proteinases of the cyanobacteria Plectonema boryanum and Anabaena variabilis and those induced by cyanophages].
Physico-chemical and catalytic properties of proteinases of native and induced cells of cyanobacteria Plectonema boryanum have been comparatively studied. It has been established that at early stages of reproduction of cyanophage LPP-3 in cyanobacteria P. boryanum is formed de novo proteinase complex consisting at least of five enzymes. Proteinases induced by the virus are distinguished from those of native cells by a series of physico-chemical characteristics and possess higher catalytic activity. Analogous virus-induced changes in proteinase complex also occur in the system cyanobacterium Anabaena variabilis--cyanophage A-1. Possible functions of certain enzymes of proteinase complex in the virus pathology of cyanobacteria cells are discussed in the paper.


Formation of a regulatory factor X/X2 box-binding protein/nuclear factor-Y multiprotein complex on the conserved regulatory regions of HLA class II genes.
Coordinate regulation of MHC class II genes occurs in a tissue-specific and cytokine-inducible manner. While the upstream regulatory sequences are conserved among all MHC class II genes, multiple base pair changes are found, even within the essential X box region. Analysis of all class II X boxes reveals differential binding between two transcription factors known to interact with the X box region, regulatory factor X and X2 box-binding protein (RFX and X2BP) of the HLA-DRA gene. These data presented a paradox with regard to the coordinate regulation of the class II genes if the factors though to regulate the HLA-DRA gene do not bind to the homologous sequence of all class II genes. Previous results suggested that cooperative interactions between the DNA binding proteins may be the key to understanding this paradox. Here RFX/X2BP/DNA complexes were formed on all class II isotypes regardless of the ability of the X box region to bind either factor individually. To further determine the role of the interactions between the X and Y factors, multiprotein/DNA complexes containing RFX, X2BP, NF-Y, and X-Y box DNA of the DRA and DRB genes were formed. This quaternary complex was extremely stable to competitor DNA, with a half-life > 4 h. These results suggest that the conserved X and Y boxes of class II genes function similarly and define a single multiprotein regulatory complex for class II expression in B cells.


The interrelation of LH-RH, ovarian steroids and the adenohypophysis.
In this presentation experimental evidence is reviewed and new information is presented concerning the question of cyclic fluctuations in pituitary responsiveness to endogenous and exogenous hypothalamic-releasing hormones as well as the direct role of steroids in modulating pituitary sensitivity. Experiments are described which show that four-day and five-day cyclic rats respond differently to LH-RH, presumably because of differences in secretion patterns of ovarian steroids. The direct role of these steroids in this process was investigated both from the morphological (light and electron microscopy) and physiological (radioimmunoassay measurement of LH) viewpoint in hypophysectomized rats bearing pituitary homografts. It was found that steroids may directly alter both the morphology and the secretory function of pituitary gonadotrophs. Estradiol was found to depress the amount of LH that was secreted while progesterone was seen to influence primarily the time of LH release following LH-RH injection. Thus, it appears that direct feedback effects of ovarian steroids at the level of the pituitary are important regulators of the sensitivity of pituitary gonadotrophs to the LH- releaseing action of hypothalamic LH-RH.


Multiscale simulations reveal TDP-43 molecular-level interactions driving condensation.
The RNA-binding protein TDP-43 is associated with mRNA processing and transport from the nucleus to the cytoplasm. TDP-43 localizes in the nucleus as well as accumulating in cytoplasmic condensates such as stress granules. Aggregation and formation of amyloid-like fibrils of cytoplasmic TDP-43 are hallmarks of numerous neurodegenerative diseases, most strikingly present in >90% of amyotrophic lateral sclerosis (ALS) patients. If excessive accumulation of cytoplasmic TDP-43 causes, or is caused by, neurodegeneration is presently not known. In this work, we use molecular dynamics simulations at multiple resolutions to explore TDP-43 self- and cross-interaction dynamics. A full-length molecular model of TDP-43, all 414 amino acids, was constructed from select structures of the protein functional domains (N-terminal domain, and two RNA recognition motifs, RRM1 and RRM2) and modeling of disordered connecting loops and the low complexity glycine-rich C-terminus domain. All-atom CHARMM36m simulations of single TDP-43 proteins served as guides to construct a coarse-grained Martini 3 model of TDP-43. The Martini model and a coarser implicit solvent C⍺ model, optimized for disordered proteins, were subsequently used to probe TDP-43 interactions; self-interactions from single-chain full-length TDP-43 simulations, cross-interactions from simulations with two proteins and simulations with assemblies of dozens to hundreds of proteins. Our findings illustrate the utility of different modeling scales for accessing TDP-43 molecular-level interactions and suggest that TDP-43 has numerous interaction preferences or patterns, exhibiting an overall strong, but dynamic, association and driving the formation of biomolecular condensates.


Sequential expression, activity and nuclear localization of prolyl oligopeptidase protein in the developing rat brain.
Prolyl oligopeptidase (POP) is a serine protease that hydrolyzes peptides shorter than 30-mer. Some evidence has recently been obtained that POP can generate protein-protein interactions and therefore participate in various physiological and pathological events. Several studies have reported that POP may be involved in neurogenesis since its activity increases during development and can be found in the nucleus of proliferating tissues. In cell cultures, POP has been shown to be localized in the nucleus, but only early in the development, since during maturation it is moved to the cytosol. We have now studied for the first time the expression of POP protein, its enzymatic activity and nuclear localization in vivo in the developing rat brain. We observed that enzymatic activity of POP is highest on embryonic day 18 while the protein amounts reach their peak at birth. Furthermore, POP is located in the nucleus only early in the development but is transferred to the cytosol already before parturition. Our in vivo results confirm the previous cell culture results supporting the role of POP in neurogenesis. A discordance of antenatal protein amounts and enzymatic activities is suggesting a tight regulation of POP activity and possibly even a nonhydrolytic role at that stage.


Ensuring Nutritional Security in India through Wheat Biofortification: A Review.
Undernourishment of nutrients, also known as hidden hunger, affects over 2 billion populace globally. Even though stunting among children below five years of age has decreased in India in the last ten years, India is home to roughly thirty percent of the world's population of stunted pre-schoolers. A significant improvement has been witnessed in the targeted development and deployment of biofortified crops; approximately 20 million farm households from developing counties benefit from cultivating and consuming biofortified crops. There is ample scope for including biofortified varieties in the seed chain, ensuring nutritional security. Wheat is a dietary staple in India, typically consumed as wholemeal flour in the form of flatbreads such as chapatti and roti. Wheat contributes to nearly one fifth of global energy requirements and can also provide better amounts of iron (Fe) and zinc (Zn). As a result, biofortified wheat can serve as a medium for delivery of essential micronutrients such as Fe and Zn to end users. This review discusses wheat biofortification components such as Fe and Zn dynamics, its uptake and movement in plants, the genetics of their buildup, and the inclusion of biofortified wheat varieties in the seed multiplication chain concerning India.


Influence of Care on the Prevention of Bacteremia in Hemodialysis: Systematic Review.
Central venous catheter-related infection is the most common complication in patients on hemodialysis. Nursing care is essential for its maintenance, minimizing risk factors, and avoiding complications, such as bacteremia. A systematic review was conducted to identify the influence of nursing care on the prevention of bacteremia due to hemodialysis catheter. The primary endpoint was the bacteremia rate measured as number of events per 1000 catheter days. The rate of bacteremia in the studies ranged from 0.2 to 5.47 events per 1000 catheter days after the application of nursing care. Several studies have shown a significant reduction in central venous catheter bacteremia with the application of management protocols, appropriate vigilance, and monitoring, as well as the inclusion of the Plan Do Check Act cycle and education.


[Role of cAMP in regulating hippocampal neuronal reactivity in vitro].
The author studied the effect of the elevated cAMP content on the efficacy of the synaptic systems of the hippocamp. The population spike (PS) response to Shaffer collateral electric stimulation was recorded in the CA1 field. The PS amplitude served as criterion of cell reactivity. Use was made of dibutyryl-cAMP (db-cAMP), an analog of cAMP, well penetrating the membrane, and of 8-/Cl-acetylaminoethylthio/-cAMP, an inhibitor of phosphodiesterase (PDE) of irreversible action, leading to cAMP accumulation by the cell. Introduction of db-cAMP into the bath medium evoked an abrupt increase in the PS amplitude, followed by gradual diminution of the response until complete depression PDE inhibitor evoked a gradual and irreversible increase of the PS amplitude. The data suggest that the secondary messenger cAMP plays an important role in synaptic processes occurring in the hippocamp.


Regulation of BTB Dynamics in Spermatogenesis-Insights From the Adjudin Model.
During spermatogenesis, cell organelles, and germ cells, most notably haploid spermatids, are transported across the seminiferous epithelium so that fully developed spermatids line-up at the edge of the tubule lumen to undergo spermiation at stage VIII of the cycle. Studies have suggested that the microtubule (MT)-based cytoskeleton is necessary to support these cellular events. However, the regulatory molecule(s) and underlying mechanism(s) remain poorly understood. Herein, we sought to better understand this event by using an adjudin-based animal model. Adult rats were treated with adjudin at low-dose (10 mg/kg b.w.) which by itself had no notable effects on spermatogenesis. Rats were also treated with low-dose adjudin combined with overexpression of 2 endogenously produced blood-testis barrier (BTB) modifiers, namely rpS6 (ribosomal protein S6, the downstream signaling protein of mammalian target of rapamycin complex 1 [mTORC1]) and F5-peptide (a biological active peptide released from laminin-γ3 chain at the Sertoli-spermatid interface) versus the 2 BTB modifiers alone. Overexpression of these 2 BTB modifiers in the testis was shown to enhance delivery of adjudin to the testis, effectively inducing disruptive changes in MT cytoskeletons, causing truncation of MT conferred tracks that led to their collapse across the epithelium. The net result was massive germ cell exfoliation in the tubules, disrupting germ cell transport and cell adhesion across the seminiferous epithelium that led to aspermatogenesis. These changes were the result of disruptive spatial expression of several MT-based regulatory proteins. In summary, MT cytoskeleton supported by the network of MT regulatory proteins is crucial to maintain spermatogenesis.


Detecting Personalized Determinants During Drug Treatment from Omics Big Data.
Targeted therapy is the foundation of personalized medicine in cancer, which is often understood as the right patient using the right drug. Thinking from the viewpoint of determinants during personalized drug treatment, the genetics, epigenetics and metagenomics would provide individual-specific biological elements to characterize the personalized responses for therapy. Such personalized determinants should be not only understood as specific to one person, while they should have certain replicate observations in a group of individuals but not all, which actually provide more credible and reproducible personalized biological features. The requirement of detecting personalized determinants is well supported by novel high-throughput sequencing technologies and newly temporal-spatial experimental protocols, which quickly produce the omics big data. In this mini-review, we would like to give a brief introduction firstly on the advanced drug or drug-like therapy with genetics, epigenetics and metagenomics, respectively, from the viewpoint of personalized determinants; then summarize the computational methods helpful to analyze the corresponding omics data under the consideration of personalized biological context; and particularly focus on metagenomics to discuss current data, method, and opportunity for personalized medicine. Totally, detecting personalized determinants during drug treatment from omics big data will bring the precision medicine or personalized medicine from concept to application. More and more inspiring biotechnologies, data resources, and analytic approaches will benefit All of US in the near future.


Tibial turn-up for long distal femoral bone loss.
Since 1990, seven patients have been treated by the authors with the tibial turn-up procedure. They have ranged in age from 8 to 37 years; four were skeletally mature adults and three were children. All seven patients were faced with a clinical situation that required surgical removal of a long portion of their affected distal femur. Three of the adult patients initially were treated for osteosarcoma with long distal femoral resections and allograft arthrodesis of the knee. The allografts ultimately failed, two because of aseptic failure and one because of infection. One patient required distal femoral removal for chronic osteomyelitis and pathologic fracture. Of the three children who were treated, two had turn-ups after long resection of the distal femur for bone malignancy, and one had a secondary turn-up after failure of a long distal femoral endoprosthesis. The technique uses the normal ipsilateral tibia as a vascularized pedicle graft to restore femoral length. The ultimate result, even after very high above knee resection, is a long above knee amputation stump. The followup of the patients in the current study ranged from 2 to 8 years. All patients achieved healing and were able to wear above knee prostheses. The tibial turn-up is an effective procedure that results in a long functional above knee amputation stump even after very high above knee resections.


Autophagy is decreased in triple-negative breast carcinoma involving likely the MUC1-EGFR-NEU1 signalling pathway.
Triple-negative breast carcinoma (TN) is a heterogeneous cancer type expressing EGFR in 75% of cases. MUC1 is a large type I sialylated glycoprotein comprising two subunits (α and β chains, also called respectively MUC1-VNTR and MUC1-CT), which was found to regulate EGFR activity through endocytic internalisation. Endocytosis and autophagy use the lysosome pathway involving NEU1. Recently, a molecular EGFR-MUC1-NEU1 complex was suggested to play a role in EGFR pathway. In the aim to understand the relationship between EGFR-MUC1-NEU1 complex and autophagy in breast carcinoma, we compared triple negative (TN) showing a high-EGFR expression with luminal (LUM) presenting low-EGFR level. We studied the expression of MUC1-VNTR, MUC1-CT and NEU1 in comparison with those of two molecular actors of autophagy, PI3K (p110β) and Beclin1. A total of 87 breast cancers were split in two groups following the immunohistochemical classification of breast carcinoma: 48 TN and 39 LUM. Our results showed that TN presented a high expression of EGFR and a low expression of MUC1-VNTR, MUC1-CT, NEU1, Beclin-1 and PI3Kp110β. Moreover, in TN, a positive statistical correlation was observed between Beclin-1 or PI3Kp110β and MUC1-VNTR or NEU1, but not with EGFR. In conclusion, our data suggest that autophagy is reduced in TN leading likely to the deregulation of EGFR-MUC1-NEU1 complex and its associated cellular pathways.


Paclitaxel/carboplatin/etoposide versus gemcitabine/irinotecan in the first-line treatment of patients with carcinoma of unknown primary site: a randomized, phase III Sarah Cannon Oncology Research Consortium Trial.
To compare the results of empiric first-line therapy with paclitaxel/carboplatin/etoposide (PCE) versus gemcitabine/irinotecan, both followed by single-agent gefitinib, in patients with carcinoma of unknown primary site. Patients with previously untreated carcinoma of unknown primary site were randomized to receive either PCE or gemcitabine/irinotecan. Responding and stable patients continued treatment for 4 to 6 cycles. Patients with no evidence of tumor progression at that time received single-agent gefitinib until tumor progression. The trial was designed to detect an improvement in the 2-year survival rate from 20% to 30%. Between September 2003 and July 2008, 198 patients entered this multicenter, community-based trial. Because of slow accrual, the trial was stopped short of its target accrual of 320 patients. Clinical characteristics were comparable for patients receiving PCE (N = 93) and gemcitabine/irinotecan (N = 105). PCE and gemcitabine/irinotecan produced similar 2-year survival (15% vs. 18%), median survival (7.4 months vs. 8.5 months), median progression-free survival (3.3 months vs. 5.3 months), and response rate (18% vs. 18%). Grade 3/4 neutropenia, thrombocytopenia, anemia, febrile neutropenia, and red blood cells transfusions were more common with PCE; diarrhea was more common with gemcitabine/irinotecan. The median duration of gefitinib maintenance was 3 months, suggesting no role as a maintenance therapy in this setting. The PCE and gemcitabine/irinotecan regimens have comparable efficacy in the first-line treatment of patients with carcinoma of unknown primary site. Gemcitabine/irinotecan is the preferable regimen, due to its favorable toxicity profile. However, the moderate efficacy of both regimens underscores the need for novel treatment approaches in this patient population.


Economic Approaches to Estimating Benefits of Regulations Affecting Addictive Goods.
The question of how to evaluate lost consumer surplus in benefit-cost analyses has been contentious. There are clear health benefits of regulations that curb consumption of goods with health risks, such as tobacco products and foods high in fats, calories, sugar, and sodium. Yet, if regulations cause consumers to give up goods they like, the health benefits they experience may be offset by some utility loss, which benefit-cost analyses of regulations need to take into account. This paper lays out the complications of measuring benefits of regulations aiming to curb consumption of addictive and habitual goods, rooted in the fact that consumers' observed demand for such goods may not be in line with their true preferences. Focusing on the important case of tobacco products, the paper describes four possible approaches for estimating benefits when consumers' preferences may not be aligned with their behavior, and identifies one as having the best feasibility for use in applied benefit-cost analyses in the near term.


Retrospective analysis of mantle cell lymphoma: experience of the "Gruppo Italiano per lo Studio dei Linfomi" (GISL).
Mantle cell lymphoma is a recently recognized histologic entity with specific biological and clinical features. Clinically, the reported unfavorable outcome of these patients has focused attention on this category of non-Hodgkin's lymphoma (NHL). The slide specimens of 69 NHL patients, originally classified as Working Formulation (WF) group B and E, were reviewed. The clinical features at presentation, response to therapy, response duration and survival were analyzed in cases reclassified as MCL. The correlation between clinical and histologic characteristics and the final outcome was evaluated. Out of 69 cases, 34 specimens were reclassified as MCL; in 6 patients, previously classified as WF group B, the nodular pattern was confirmed; in 2 instances the blastoid form was recognized. After a median follow-up of 35.7 months, the entire series displayed a median overall survival of 41.2 months; a significantly longer survival was associated with the nodular histologic pattern, IPI score < 2, response achievement, and a higher Hb level. The vast majority of patients received anthracycline-containing combination chemotherapy. Complete remission rate was 38.8% and overall response rate was 67.6%; response achievement was significantly influenced only by Hb level. Median response duration was 23.3 months. The present study confirms the unfavorable clinical course of MCL and the possible need for an alternative therapeutic strategy for this NHL category. Therefore, the correct identification of MCL at diagnosis appears of relevance.


Substance use disorder patients who are mandated to treatment: characteristics, treatment process, and 1- and 5-year outcomes.
A substantial number of patients with substance use disorders (SUDs) are mandated to treatment by the justice system. However, little is known about their characteristics and how they fare during treatment and in the longer term compared with nonmandated, justice-system-involved patients and patients not involved in the justice system. This prospective study (n=2,095) examined differences in pretreatment characteristics, treatment perceptions and satisfaction, during-treatment changes, and 1- and 5-year outcomes among these three types of patients and tested whether differences in pretreatment characteristics or during-treatment changes could help explain posttreatment outcome similarities or differences. Mandated patients had a less severe clinical profile at treatment intake, yet this did not account for their observed similar/better outcomes, which appeared because of the similar therapeutic gains made during treatment. Treatment perceptions and satisfaction were also comparable across groups. These findings appear to support the idea that judicial mandates can provide an opportunity for offenders with SUDs to access and benefit from needed treatment.


Neural signature of inattentional deafness.
Inattentional deafness is the failure to hear otherwise audible sounds (usually alarms) that may occur under high workload conditions. One potential cause for its occurrence could be an attentional bottleneck that occurs when task demands are high, resulting in lack of resources for processing of additional tasks. In this fMRI experiment, we explore the brain regions active during the occurrence of inattentional deafness using a difficult perceptual-motor task in which the participants fly through a simulated Red Bull air race course and at the same time push a button on the joystick to the presence of audio alarms. Participants were instructed to focus on the difficult piloting task and to press the button on the joystick quickly when they noticed an audio alarm. The fMRI results revealed that audio misses relative to hits had significantly greater activity in the right inferior frontal gyrus IFG and the superior medial frontal cortex. Consistent with an attentional bottleneck, activity in these regions was also present for poor flying performance (contrast of gates missed versus gates passed for the flying task). A psychophysiological interaction analysis from the IFG identified reduced effective connectivity to auditory processing regions in the right superior temporal gyrus for missed audio alarms relative to audio alarms that were heard. This study identifies a neural signature of inattentional deafness in an ecologically valid situation by directly measuring differences in brain activity and effective connectivity between audio alarms that were not heard compared to those that were heard. Hum Brain Mapp 38:5440-5455, 2017. © 2017 Wiley Periodicals, Inc.


Upper intensity limit for prolonged aerobic exercise in chronic heart failure.
The highest power sustainable in VO2 and blood lactate steady-state conditions is named "critical power" (CP) and marks the upper limit for prolonged aerobic exercise performance. CP is thus of particular interest for continuous aerobic training prescription, but no data are available as to CP in chronic heart failure (CHF) patients, that is, a population in which aerobic training is a widely accepted nonpharmacologic treatment. The aim of this study was to evaluate CP in a group of CHF and in two groups of age-matched untrained (UT-N) and trained (TR-N) normal subjects. Fifteen untrained CHF, five UT-N, and five TR-N underwent one incremental and five very high/severe-intensity constant-power cardiopulmonary exercise tests (CPT). Power versus time to exhaustion data from CPT were fitted by a hyperbola, whose power asymptote is CP. Subsequently, all participants exercised at CP with blood lactate sampling every 2 min. CP was 80 ± 21, 129 ± 17, and 199 ± 35 W in CHF, UT-N, and TR-N, respectively (all comparisons P < 0.005). These values corresponded to 66% ± 6%, 66% ± 6%, and 74% ± 3% of peak power in CHF, UT-N, and TR-N, respectively (TR-N vs both CHF and UT-N, P < 0.05) and to 81% ± 26%, 91% ± 11%, and 83% ± 9% of HR reserve in CHF, UT-N, and TR-N, respectively (NS). All participants exercised for 30 min in VO2, blood lactate, ventilation, and HR steady-state conditions at CP but not at the lowest-power CPT (>CP ~ 10%). The upper intensity limit for prolonged aerobic exercise, that is, CP, is equal to 65% of peak power in CHF patients. This finding provides a physiologically meaningful reference for continuous aerobic training prescription in this population.


Vascularized vitreous membranes in congenital retinoschisis.
Congenital retinoschisis is a bilateral x-linked disease characterized by a stellate maculopathy and retinoschisis. The pathogenesis is unknown. This article describes a patient with congenital retinoschisis and documents the unique development of vascularized vitreous membranes. A posterior vitreous separation with subsequent vascularization of the posterior hyaloid face occurs early in the course of the disease process and is coincident with the development of maculopathy and schisis cavities. This process may represent an important element in the pathogenesis of the maculopathy and schisis cavities in congenital retinoschisis. With atrophy of the neovascular tissue, a membrane remains and consists of a thickened area of the posterior hyaloid face.


Routine use of PCR-reverse cross-blot hybridization assay for rapid identification of Mycobacterium species growing in liquid media.
A PCR-reverse cross-blot hybridization assay procedure that is able to rapidly identify 13 species of clinically relevant mycobacteria was evaluated for routine use in the identification of acid-fast isolates growing in BACTEC 460 TB (12B and 13A) and BACTEC 9000 MB (Myco/F) liquid media. Eight of the probes used were already described by Kox et al. (L. F. F. Kox et al., J. Clin. Microbiol. 33:3225-3233, 1995). In addition, we used six other probes specific for M. chelonae, M. malmoense or M. szulgai, M. genavense, M. gordonae, M. terrae, and M. marinum/M. ulcerans that we designed ourselves. This procedure allowed us to identify 459 mycobacterial species directly from broth cultures of 5,466 clinical samples collected over 1 year and processed with the radiometric or nonradiometric BACTEC system. Our results were in agreement with those obtained by conventional identification methods and also with those obtained by mycolic acid analysis by high-performance liquid chromatography. This assay seems to be a reliable procedure for the routine identification of mycobacteria, providing an accurate identification of mycobacterial isolates more rapidly than conventional tests, with remarkable implications for an efficacious specific antimycobacterial therapy.


Accelerated dynamic Fourier velocity encoding by exploiting velocity-spatio-temporal correlations.
To describe how the information content in a Fourier velocity encoding (FVE) scan can be transformed into a very sparse representation and to develop a method that exploits the compactness of the data to significantly accelerate the acquisition. For validation, fully sampled FVE datasets were acquired in phantom and in vivo experiments. Fivefold and eightfold acceleration was simulated by using only one fifth or one eighth of the data for reconstruction in the proposed method based on the k-t BLAST framework. Reconstructed images were compared quantitatively to those from the fully sampled data. Velocity spectra in the accelerated datasets were comparable to the spectra from fully sampled datasets. The detected peak velocities remained accurate even at eightfold acceleration, and the overall shape of the spectra was well preserved. Slight temporal smoothing was seen in the accelerated datasets. A novel technique for accelerating time-resolved FVE scan is presented. It is possible to accelerate FVE to acquisition speeds comparable to a standard time-resolved phase-contrast scan.


Late diagnosis of human immunodeficiency virus infections in high-risk groups in Karachi, Pakistan.
Human immunodeficiency virus (HIV) infection prevalence in Pakistan has been increasing in high-risk groups, including people who inject drugs (PWID) and transgender hijra sex workers (TG-HSWs) nationwide. Effective control of HIV requires early diagnosis of the infection. We investigated recency of HIV infections in newly-diagnosed cases in PWID and TG-HSWs. This was an observational study with convenience sampling. Overall, 210 HIV-positive subjects comprising an equal number of PWID and TG-HSWs were included. Antibody avidity was tested using the Maxim HIV-1 Limiting Antigen Avidity (LAg) EIA (Maxim Biomedical, Inc. Rockville, Maryland, USA). The mean age of study subjects was 29.5 years: PWID, 28.5 years and TG-HSWs, 30.4 years. Study subjects were married, 27%, or unmarried. Eighteen percent of individuals had recently-acquired HIV infections: 19% of PWID and 17% of TG-HSWs. Eighty-two percent of individuals had long-term HIV infections: 81% of PWID and 83% of TG-HSWs. This is the first study identification of recent HIV-1 infections in Pakistan. We show that most newly-diagnosed HIV patients in the high-risk groups studied had long-term infections. There is an urgent need for intervention in these groups to facilitate early diagnosis and treatment of HIV infection to reduce transmission in Pakistan.


Estimating the true prevalence of Fasciola hepatica in cattle slaughtered in Switzerland in the absence of an absolute diagnostic test.
A survey of 1,331 cattle presented for slaughter at two abattoirs in Switzerland was used to estimate the true prevalence of Fasciola hepatica infection and the diagnostic parameters of visual meat inspection, coproscopy after sedimentation technique, a commercial ELISA test for specific antibody detection in serum and the post mortem microscopic detection of eggs in bile. Faeces, blood and the gall bladder were taken from most cattle presented for slaughter. In addition, livers that were rejected by the meat inspectors were also dissected to examine for the presence of liver fluke. Bayesian techniques (Markov Chain-Monte Carlo) were used to estimate the diagnostic parameters of each of these procedures and the true prevalence of bovine fasciolosis. The true prevalence of F. hepatica infection was estimated at 18.0% (95% credible intervals 15.9-20.3%). The diagnostic sensitivity of coproscopy, bile examination, antibody ELISA and meat inspection were estimated at 69.0% (57.3-79.7%), 93.4% (88.0-97.5%), 91.7% (87.2-95.2%) and 63.2% (55.6-70.6%), respectively. The diagnostic specificity of the ELISA test was estimated at 93.7% (91.7-95.2%). These results demonstrate that the prevalence of bovine fasciolosis is higher than previously thought due to the low sensitivity of meat inspection. They also demonstrate that traditional coproscopy can be very efficient if there is repeated sampling, resulting in sensitivity of approximately 92%.


Metformin overcomes high glucose-induced insulin resistance of podocytes by pleiotropic effects on SIRT1 and AMPK.
Podocyte insulin sensitivity is critical for glomerular function, and the loss of appropriate insulin signaling leads to alterations and disorders featuring diabetic nephropathy. Energy-sensing pathways, such as AMP-dependent protein kinase (AMPK) and protein deacetylase SIRT1, have been shown to play an important role in insulin resistance. The absence of a stimulating effect of insulin on glucose uptake into podocytes after exposure to hyperglycemic conditions has been demonstrated to be related to a decreased level and activity of SIRT1 protein, leading to reduced AMPK phosphorylation. The present work was undertaken to investigate metformin's ability to restore the insulin responsiveness of podocytes by regulating SIRT1 and AMPK activities. Primary rat podocytes cultured with standard or high glucose concentrations for 5days were transfected with siRNAs targeting SIRT1, AMPKα1, or AMPKα2. SIRT1 activity was measured by a fluorometric method. Insulin-stimulated changes in glucose uptake were used to detect insulin resistance. Podocyte permeability was measured by a transmembrane albumin flux assay to examine podocytes functioning. Our results demonstrated that metformin activated SIRT1 and AMPK, prevented hyperglycemia-induced reduction of SIRT1 protein levels, ameliorated glucose uptake into podocytes, and decreased glomerular filtration barrier permeability. Furthermore, metformin activated AMPK in a SIRT1-independent manner, as the increase in AMPK phosphorylation after metformin treatment was not affected by SIRT1 downregulation. Therefore, the potentiating effect of metformin on insulin-resistant podocytes seemed to be dependent on AMPK, as well as SIRT1 activity, establishing multilateral effects of metformin action.


Determination of 1,3-dichloropropanol in soy and related sauces by using gas chromatography/mass spectrometry.
A gas chromatography/mass spectrometry method for 3-MCPD in foods and food ingredients was modified for the determination of 1,3-DCP in soy and related sauces. The method was validated by using a blank soy sauce. The detection limit, quantitation limit and recoveries were determined, and identities were confirmed by mass spectrometry on the basis of analyses of test portions spiked with 1,3-DCP at 10, 25, 50 and 100 ng g(-1). The spiked test portions were quantitated by using an internal standard calibration curve. For the spiked test portions, the mean internal standard-corrected recovery for 1,3-DCP was 100% with a relative standard deviation of 1.32%. The limits of detection and quantitation were determined as 0.055 and 0.185 ng g(-1), respectively. The method also was compared with a headspace GC/MS method recently developed by the UK's Central Science Laboratory. Results from the method comparison showed that the recoveries for the spiked test portions, as well as the amounts of 1,3-DCP found in the retail products, were comparable.


[Low-flow priapism associated with systemic lupus erythematosus and nephrotic syndrome].
To present a case of priapism associated with systemic lupus erythematosus and nephrotic syndrome. A 29-year-old male patient with a history of multiple pathologies consulted at the emergency services with painful priapism of 12 hours' duration. The intracavernosal aspirated blood had a venous appearance. Among the risk factors analyzed, systemic lupus erythematosus and nephrotic syndrome are recognized to cause hypercoagulability, a condition that can lead to low flow priapism. There was no response to lavage-aspiration or intracorporeal administration of an alpha-adrenergic agonist. The high surgical risk of the patient advised against surgery. The priapism gradually diminished until complete remission on the sixth day. The patient has remained without spontaneous erection. Systemic lupus erythematosus and nephrotic syndrome can cause low flow priapism. The best treatment is by prevention with adequate antithrombotic prophylaxis.


The cost-effectiveness of lipid lowering in patients with diabetes: results from the 4S trial.
The purpose of this study is to investigate the cost-effectiveness of simvastatin in diabetic patients, using prospectively collected outcomes data from the Scandinavian Simvastatin Survival Study. Diabetic patients were identified using two different classifications schemes: Clinical history (diabetic, non-diabetic) and the new American Diabetes Association definition (diabetic, impaired fasting glucose, normal fasting glucose). The analysis is based on prospectively collected data from the trial on hospitalization for cardiovascular problems, study drug utilization and mortality. The incremental cost per life year saved with simvastatin is estimated using costs from Sweden (primary) and other European countries. Hospitalizations for cardiovascular problems were considerably reduced with simvastatin therapy, with the greatest differences in the diabetic subgroups. Reductions in hospitalizations in the diabetic group resulted in substantial hospital cost savings that offset 67 to 76 % of the drug cost (depending on the classification used). For the diabetic patients, the estimates of the cost per life-year gained ranged from 1600 Euros (based on clinical history) to 3200 Euros (based on American Diabetes Association) using Swedish costs. In the other evaluated European countries treatment with simvastatin showed a favourable cost-effectiveness ratio independent of differences in local health care unit costs. For all subgroups in the diabetic classification schemes, treatment with simvastatin resulted in estimates of cost per life-year gained that were well within the range generally considered to be cost effective. Based on the Scandinavian Simvastatin Survival Study, simvastatin therapy provides good value for money in both diabetic and non-diabetic patients with cardiovascular disease. [Diabetologia (1999) 42: 1293-1301]


Relationship between TRAIL and Left Ventricular Ejection Fraction in Patients with ST-Elevation Myocardial Infarction Treated with Primary Percutaneous Coronary Intervention.
Apoptosis plays an important role in the myocardial injury after acute myocardial infarction and in the subsequent development of heart failure. To clarify serum kinetics of apoptotic markers TRAIL and sFas and their relation to left ventricular ejection fraction (LVEF) in patients with ST-elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (pPCI). In 101 patients with STEMI treated with pPCI, levels of TRAIL and sFas were measured in series of serum samples obtained during hospitalization and one month after STEMI. LVEF was assessed at admission and at one month. Major adverse cardiovascular events (MACE, i.e., death, re-MI, and hospitalization for heart failure and stroke) were analysed during a two-year followup. Serum level of TRAIL significantly decreased one day after pPCI (50.5pg/mL) compared to admission (56.7pg/mL), subsequently increased on day 2 after pPCI (58.8pg/mL), and reached its highest level at one month (70.3pg/mL). TRAIL levels on days 1 and 2 showed a significant inverse correlation with troponin and a significant positive correlation with LVEF at baseline. Moreover, TRAIL correlated significantly with LVEF one month after STEMI (day 1: r=0.402, p<0.001; day 2: r=0.542, p<0.001). On the contrary, sFas level was significantly lowest at admission (5073pg/mL), increased one day after pPCI (6370pg/mL), and decreased on day 2 (5548pg/mL). Significantly highest sFas level was marked at one month (7024pg/mL). sFas failed to correlate with LVEF at baseline or at one month. Both TRAIL and sFas showed no ability to predict improvement of LVEF one month after STEMI or a 2-year MACE (represented by 3.29%). In STEMI treated with pPCI, TRAIL reaches its lowest serum concentration after reperfusion. Low TRAIL level is associated with worse LVEF in the acute phase of STEMI as well as one month after STEMI. Higher TRAIL level appears to be beneficial and thus TRAIL seems to represent a protective mediator of post-AMI injury.


[Hemoglobin solutions: volume replacement or oxygen therapy?].
The development of haemoglobin solutions has progressed significantly in the last 15 years because of a perceived short fall in allogeneic blood within the next decades and increased concern about transmitted infectious diseases. Animal studies have shown that modern highly purified and chemically modified haemoglobin preparations are free of toxic side effects, provide adequate volume replacement and have vasoconstrictive effects that enhance systemic vascular resistance and mean arterial pressures after haemorrhage and in models of nearly complete blood replacement. Microcirculatory effects of haemoglobin-based oxygen carriers are dependent on the respective organ and species in which they are applied and on their degree of purification and chemical modification. Because of different physico-chemical properties in comparison with red cells, haemoglobin solutions provide sufficient tissue oxygenation in areas with critically restricted perfusion even when applied in small doses. First studies in volunteers and patients showed efficacy and tolerability of different newly developed haemoglobin solutions during acute normovolaemic haemodilution and in perioperative blood replacement. However, only little information exists to date in terms of metabolism of haemoglobin preparations and their potential immunogenicity and immunosuppressive side effects. Technical problems with the clinical use of haemoglobin solutions arise because of interference of plasma haemoglobin with routine laboratory tests and oximetry. Future indications for haemoglobin solutions as an oxygen therapeutic allow for application of small doses of such preparations and may help to avoid major technical problems. More clinical studies have to be undertaken to confirm the effectivity and safety of the different haemoglobin solutions and to find out the optimal indications beyond acute preclinical and perioperative blood replacement.


Clinical experiment to assess effectiveness of virtual reality teen smoking cessation program.
Smoking has increasingly become a burden on America's health and economic status. The fact that four out of every five adult smokers begins tobacco use before the age of eighteen indicates a need for teenage smoking cessation programs. The Virtual Reality Medical Center created an internet-based program that addresses the issue by utilizing cue exposure therapy in home and school environments to teach teens which cues trigger nicotine cravings and how to combat those cravings. The effectiveness of the program was measured through questionnaires administered before and after its use. Results indicated that the participants were engaged in the virtual environment, and that, in every aspect of the program, at least 8% more participants were knowledgeable about the subject than prior to the use of the program. Success of such a program could reduce teen smoking rates, ultimately leading to reduced smoking mortalities, complications, and costs overall.


Nutritional screening and early treatment of malnutrition in cancer patients.
BACKGROUND: Malnutrition is a frequent complication in patients with cancer and can negatively affect the outcome of treatments. On the other hand, side effects of anticancer therapies can also lead to inadequate nutrient intake and subsequent malnutrition. The nutritional screening aims to identify patients at risk of malnutrition for prompt treatment and/or careful follow-up. METHODS AND RESULTS: This manuscript highlights the need of an interdisciplinary approach (oncologist, nutritionist, dietitian, psychologist, etc.) to empower patients who are experiencing loss of physiological and biological function, fatigue, malnutrition, psychological distress, etc., as a result of cancer disease or its treatment, and maintain an acceptable quality of life. CONCLUSIONS: It is necessary to make all healthcare professionals aware of the opportunity to identify cancer patients at risk of malnutrition early in order to plan the best possible intervention and follow-up during cancer treatment and progression.


Force fluctuations at the transition from quasi-static to inertial granular flow.
We analyse the rheology of gravity-driven, dry granular flows in experiments where individual forces within the flow bulk are measured. We release photoelastic discs at the top of an incline to create a quasi-static erodible bed over which flows a steady 2D avalanche. The flowing layers we produce are dense (φ ≈ 0.8), thin (h ≈ 10d), and in the slow to intermediate flow regime (I = 0.1 to 1). Using particle tracking and photoelastic force measurements we report coarse-grained profiles for packing fraction, velocity, shear rate, inertial number, and stress tensor components. In addition, we define a quantitative measure for the rate of generation of new force chain networks and we observe that fluctuations extend below the boundary between dense flow and quasi-static layers. Finally, we evaluate several existing definitions for granular fluidity, and make comparisons among them and the behaviour of our experimentally-measured stress tensor components. Our measurements of the non-dimensional stress ratio μ show that our experiments lie within the local rheological regime, yet we observe rearrangements of the force network extending into the quasi-static layer where shear rates vanish. This elucidates why non-local rheological models rely on the notion of stress diffusion, and we thus propose non-local effects may in fact be dependent on the local force network fluctuation rate.


Molecular dynamics simulation links conformation of a pore-flanking region to hyperekplexia-related dysfunction of the inhibitory glycine receptor.
Inhibitory glycine receptors mediate rapid synaptic inhibition in mammalian spinal cord and brainstem. The previously identified hyperekplexia mutation GLRA1(P250T), located within the intracellular TM1-2 loop of the GlyR alpha1 subunit, results in altered receptor activation and desensitization. Here, elementary steps of ion channel function of alpha1(250) mutants were resolved and shown to correlate with hydropathy and molar volume of residue alpha1(250). Single-channel recordings and rapid activation kinetic studies using laser pulse photolysis showed reduced conductance but similar open probability of alpha1(P250T) mutant channels. Molecular dynamics simulation of a helix-turn-helix motif representing the intracellular TM1-2 domain revealed alterations in backbone conformation, indicating an increased flexibility in these mutants that paralleled changes in elementary steps of channel function. Thus, the architecture of the TM1-2 loop is a critical determinant of ion channel conductance and receptor desensitization.


KRAS mutation screening by chip-based DNA hybridization--a further step towards personalized oncology.
The use of predictive biomarkers can help to improve therapeutic options for the individual cancer patient. For the treatment of colon cancer patients with anti-EGFR-based drugs, the KRAS mutation status has to be determined to pre-select responders that will benefit from this medication. Amongst others, array-based tests have been established for profiling of the KRAS mutation status. Within this article we describe an on-chip hybridization technique to screen therapeutic relevant KRAS codon 12 mutations. The DNA chip-based platform enables the reliable discrimination of selected mutations by allele-specific hybridization. Here, silver deposits represent robust endpoint signals that allow for a simple naked eye rating. With the here presented assay concept a precise identification of heterozygous and homozygous KRAS mutations, even against a background of up to 95% wild-type DNA, was realizable. The applicability of the test was successfully proven for various cancer cell lines as well as clinical tumour samples. Thus, the chip-based DNA hybridization technique seems to be a promising tool for KRAS mutation analysis to further improve personalized cancer treatment.


Fetal hemoglobin-containing cells have the same mean corpuscular hemoglobin as cells without fetal hemoglobin: a reciprocal relationship between gamma- and beta-globin gene expression in normal subjects and in those with high fetal hemoglobin production.
We have developed methodology that allows comparison of the mean corpuscular hemoglobin (MCH) of fetal hemoglobin (HbF)-containing red cells (F cells) with the MCH of non-F cells from the same individual. To do this, suspensions of peripheral blood erythrocytes and their internal contents are fixed with an imidodiester, dimethyl-3,3'-dithiobispropionimidate dihydrochloride (DTBP). Thereafter fixed cells are made permeable to antisera by treatment with Triton X-100 and isopropanol, reacted with a mouse monoclonal antibody (MoAb) against HbF, and then with fluorescein-conjugated antimouse IgG. No appreciable hemoglobin is lost during such manipulation. Red cells from a diversity of subjects were thus treated and examined microscopically, first by transmitted light and then by epifluorescence. A direct correlation between Coulter-derived MCH and mean absorbance of 415 nm transmitted light was found for 100 unfixed (r = 0.96) and for 100 antibody-treated fixed-permeabilized red cells (r = 0.99) among individuals selected so as to provide a range of Coulter MCH values between 20 and 35. Comparisons of microscopically derived MCH of F cells and non-F cells were statistically nondistinguishable (P greater than 0.05) in all subjects. Such comparisons included normal individuals (less than 1% F cells), SS patients (7% to 48% F cells), subjects with congenital anemia (22% to 65% F cells), individuals with heterocellular hereditary persistence of HbF (HPFH) (12% to 21% F cells), and heterozygotes for beta + thalassemia (11% to 31% F cells). We conclude that gamma- and beta-globin production within F cells is regulated in a reciprocal fashion both among normal individuals and among individuals with elevated HbF production.


Alamandine injection in the periaqueductal gray and rostral ventromedial medulla attenuates allodynia induced by sciatic nerve ligation in rats.
Alamandine, a peptide known to interact with Mas-related G protein-coupled receptor subtype D (MrgD), has been implicated in moderating inflammatory signals. MrgD receptors are abundantly found in pain transmission pathways, but the role of alamandine/MrgD in pain modulation has not been thoroughly explored. This study aimed to investigate the effects of alamandine (10, 40, and 100 pmol) in a rat model of allodynia induced by sciatic nerve ligation, with a specific focus on examining the involvement of MrgD receptors, NMDAR1, and serotonin transporter (SERT) in the ventrolateral periaqueductal gray (vlPAG) and rostral ventromedial medulla (RVM). Microinjection of alamandine into the vlPAG at a dose of 100 pmol and into the RVM at doses of 40 and 100 pmol resulted in a significant increase in paw withdrawal threshold (PWT). Additionally, co-administration of D-Pro7-Ang-(1-7) at 50 pmol, an MrgD receptor antagonist, effectively blocked the analgesic effects of alamandine. Immunofluorescence analysis confirmed the presence of MrgD receptors in both the vlPAG and RVM regions. Importantly, an upregulation of MrgD receptor expression was observed following allodynia induction, suggesting a potential compensatory mechanism in response to pain. Our findings support the co-localization of MrgD receptors with NMDAR1 in vlPAG neurons, suggesting their ability to initiate analgesic pathways similar to those activated by NMDA receptors in the vlPAG. Furthermore, our results underscore a significant co-localization of MrgD receptors with the SERT in the RVM, underscoring their potential impact on serotonergic neurons involved in promoting analgesic effects.


[From macro to micro thyroid carcinoma: records of a clinical hospital from 1991 to 2010].
The prevalence of thyroid cancer has increased, particularly in nodules smaller than 10 mm, probably due to the growing use of routine thyroid ultrasound. There is controversy about the biological behavior of micro carcinomas and the relevance of their early detection. To characterize the clinical presentation of thyroid cancer over 20 years in an University medical center and to evaluate the differences between macro and micro carcinomas. We reviewed 1547 surgical biopsy records of thyroid cancer in our institution obtained between 1991 and 2010. We observed a sustained increase in the rate of thyroidectomies for thyroid cancer (per 1000 surgical procedures) in the study period. Papillary, follicular, mixed, medullary and anaplastic carcinomas were observed in 95, 3, 2, 0.5 and 0.1% of biopsies, respectively. The incidence of tumors of less than 10 mm (micro carcinoma) also increased. Those findings were associated with a significant decrease in tumor aggressiveness, determined by a low frequency of surgical margin involvement of thyroid capsule, perithyroid tissue invasion, vascular permeation and lymph node metastases. The increased prevalence of thyroid cancer, especially of micro carcinomas, may reflect the greater use of diagnostic ultrasound or represent a real change in the biological behavior of this disease and our data suggest that further studies are needed to know the impact of early treatment in the outcome of those patients because of the real less histologic agressiveness of micro carcinomas.


Genetic analysis of the gamma-aminobutyrate utilization pathway in Escherichia coli K-12.
The control mutation that results in a concomitant severalfold increase in the activities of gamma-aminobutyrate-alpha-ketoglutarate transaminase (GSST, EC 188.8.131.52) and succinic semialdehyde dehydrogenase (SSDH, EC 22.214.171.124), leading to the acquisition of the ability to utilize gamma-aminobutyrate (GABA) as the sole source of nitrogen by Escherichia coli K-12 mutants, was mapped by mating and transduction with P1kc. The locus affected, gabC, is approximately 48% co-transduced with the thyA gene, located at min 55 of the E. coli K-12 chromosome. The structural gene of the first enzyme in the GABA pathway, GSST, was mapped by interrupted mating, using one of the GSST-less mutants, DB742, isolated in this work. The mutated locus, gabT, is situated at about min 73 of the E. coli chromosome, close to the gltC gene. Genetic evidence concerning the sensitivity of the enzymes of the GABA pathway to catabolite repression under different physiological conditions suggests that the two structural genes of the GABA regulon do not constitute one operon.


Advanced Treatment and Imaging in Colonoscopy: The Pocket-Creation Method for Complete Resection and Linked Color Imaging for Better Detection of Early Neoplastic Lesions by Colonoscopy.
Early detection and resection of neoplastic lesions are key objectives to diminish colorectal cancer mortality. Resection of superficial colorectal neoplasms, cold snare polypectomy, endoscopic mucosal resection, and endoscopic submucosal dissection have all been developed and used worldwide. The pocket-creation method facilitates the resection of tumors in difficult and routine locations. Early detection is the most important first step to maximize the benefits of recent advancements in endoscopic techniques. However, the detection of small, flat-shaped, or faded color lesions remains difficult. Linked color imaging, a novel multi-light technology, facilitates the recognition of minor differences in tissue by enhancing the color contrast between early colorectal neoplasms and surrounding normal mucosa in a bright field of view. The most striking feature of linked color imaging is its ability to display the color of early neoplastic lesions as distinct from inflammatory changes, both of which have similar "redness" when viewed using white light imaging. To increase the detection rate of neoplasms, linked color imaging should be used from the outset for endoscopic observation. Early detection of superficial colorectal tumors can result in decreased mortality from colorectal cancer and maintain a good quality of life for patients.


Potential risk factors for cutaneous squamous cell carcinoma include oral contraceptives: results of a nested case-control study.
Recently, a population-based case-control study observed a 60% increased odds ratio (OR) for cutaneous squamous cell carcinoma (SCC) among women who had ever used oral contraceptives (OCs) compared with non users (95% confidence interval (CI) = 1.0-2.5). To further characterize the putative association between OC use and SCC risk, we conducted a nested case-control study using a large retrospective cohort of 111,521 Kaiser Permanente Northern California members. Multivariable conditional logistic regression was used to estimate ORs and CIs adjusting for known and hypothesized SCC risk factors. Pre-diagnostic OC use was associated with a statistically significant increased OR for SCC in univariate analysis (OR = 2.4, CI = 1.2-4.8), with borderline statistical significance in multivariable analysis (CI = 2.0, CI = 0.91-4.5). Given the high incidence of SCC in the general population and the prevalent use of OCs among women in the United States, there is a need for more large, carefully designed epidemiologic studies to determine whether the observed association between OC use and SCC can be replicated and to better understand the etiologic basis of an association if one exists.


Naringin inhibits ovarian tumor growth by promoting apoptosis: An in vivo study.
The aim of the present study was to investigate the antitumor activities of naringin in ovarian cancer, and to assess the underlying mechanisms. Ovarian tumor cells were implanted into nude mice to produce ovarian tumors in vivo. The mice were divided into six groups: Control, low dose naringin [0.5 mg/kg, intraperitoneal (i.p.)], middle dose naringin (1 mg/kg, i.p.), high dose naringin (2 mg/kg, i.p.), positive control (cisplatin, 2 mg/kg, i.p.) and a combination of cisplatin and naringin (both 2 mg/kg). Following administration of naringin and/or cisplatin, the tumor size and weight were measured. Apoptosis of tumor cells was detected using a terminal deoxynucleotidyl transferase dUTP nick end labeling assay. Apoptosis-associated gene expression was detected using reverse transcription-polymerase chain reaction and immunohistochemistry. In the range of 0.5-2 mg/kg, naringin dose-dependently inhibited tumor growth, as demonstrated by a decrease in tumor size and weight. Naringin promoted apoptosis of the ovarian tumor cells. Additionally, naringin reduced the expression of B-cell lymphoma (Bcl)-2, Bcl-extra large (Bcl-xL), cyclin D1, c-Myc and survivin, while it increased the expression of caspase-3 and caspase-7. The data demonstrated that naringin inhibited ovarian tumor growth in vivo. Its mechanisms may be associated with caspase-7-, caspase-3-, Bcl-2- and Bcl-xL-mediated apoptosis. Nevertheless, the clinical application of naringin in the treatment of ovarian cancer requires further study.


Immunoprophylaxis of viral hepatitis: a practical guide.
There are presently available immune globulin preparations of proven efficacy and safety in the prophylaxis of type A and B viral hepatitis. Active vaccines for prevention of type B hepatitis are now available and are safe and effective. None of these preparations has been associated with the development of HTLV-III/LAV/HIV infection. Preexposure prophylaxis for type B hepatitis is indicated for health care workers who have frequent contact with blood, and most endoscopists would be among this group of high-risk individuals. Prenatal screening of pregnant women for HBsAg provides an opportunity to intervene in the vicious cycle of perpetuating a population of hepatitis B carriers via perinatal transmission. Unfortunately until serological tags for the non-A non-B hepatitis viruses are identified, there will be no effective vaccination for this form of hepatitis. Patients who already have acute or chronic viral hepatitis must await the advent of safe and effective antiviral agents for treatment of these viral infections.


Photoacoustic tomography: in vivo imaging from organelles to organs.
Photoacoustic tomography (PAT) can create multiscale multicontrast images of living biological structures ranging from organelles to organs. This emerging technology overcomes the high degree of scattering of optical photons in biological tissue by making use of the photoacoustic effect. Light absorption by molecules creates a thermally induced pressure jump that launches ultrasonic waves, which are received by acoustic detectors to form images. Different implementations of PAT allow the spatial resolution to be scaled with the desired imaging depth in tissue while a high depth-to-resolution ratio is maintained. As a rule of thumb, the achievable spatial resolution is on the order of 1/200 of the desired imaging depth, which can reach up to 7 centimeters. PAT provides anatomical, functional, metabolic, molecular, and genetic contrasts of vasculature, hemodynamics, oxygen metabolism, biomarkers, and gene expression. We review the state of the art of PAT for both biological and clinical studies and discuss future prospects.


[Assessment and clinical aspects of community professional care of elderly with alcohol misuse].
For elderly living in the community, alcohol misuse is not uncommon. Experience of professionals of social care services to face alcoholism misuse has rarely been assessed. The work of these professionals is to allow aged people to stay at home in spite of impaired physical and/or mental age-related abilities. We studied the experienced difficulties and feelings of professional caregivers for ten aged subjects with alcohol misuse compared to ten aged subjects without, to identify their needs in terms of training for the home care service associations. The participants took part in an interview and completed a research questionnaire concerning their reactions to alcohol misuse in elderly subjects. No significant difference was found between the responses from the two groups. All participants felt powerless in front of the denial of the alcohol misuse by the patients and experienced difficulties with the behavior of some family members. They reported that they would be comforted by the opportunity to share their experiences with colleagues and people in charge. They hoped to meet specialized teams in the field of addictions to develop skills for supporting elderly people with regard of alcohol misuse. Presently, the services in charge of the aged people should review the interventions and training of their employees, especially of those caring for subjects with alcohol misuse, to improve the quality of their actions in an evolving environment.


Epidemiology of Open Tibia fractures presenting to a tertiary referral centre in Southern Malawi: a retrospective study.
Road traffic accidents in Malawi have increased in recent years resulting in a high incidence of trauma seen in the hospitals as well as a high prevalence of musculoskeletal impairment in the community. Open fractures are a common consequence of road traffic accidents and the tibia is the most common long bone open fracture. Epidemiology of open tibia fractures at the largest tertiary level hospital in Malawi and incidence of infections of open fractures managed at the institution. This was a retrospective study of consecutive open tibia fracture patients seen and admitted to Queen Elizabeth Central Hospital's (QECH) orthopedic department from 1st January 2019 to 31st December 2019. Patients with life-threatening head, chest, or abdominal injuries were excluded as management takes priority over any limb-threatening injury. There were 72 open tibia fractures screened, and 60 of these met our entry criteria; 6 patients did not, while 6 patient files were missing. The median age of patients was 36 years, IQR (27-44.75) with Males making up 82%(n=49) of open fractures. Most of the open tibia fractures were caused by road traffic accidents 63%(n=38), followed by assaults 18%(n=11), falls 17%(n=10), and industrial accidents 2%(n=1). 26.7% (n=16) of open tibia fractures developed an infection. We found that patients' average length of stay was 16. 9(IQR 9.5-31.25) days. Most of the injuries (68.3%, n=41) were moderate to high energy injuries being Gustilo et al. grade II and III open tibia fractures. This study identified that open tibia fractures were common in our hospital and that were often high energy injuries requiring an extended hospital stay to manage. The infection rate noted was higher than that reported on average in lower- and middle-income countries. There is a need to do more robust prospective studies in the area to gather more information.


Selective modification of glutathione metabolism.
Glutathione, a tripeptide thiol found in virtually all cells, functions in metabolism, transport, and cellular protection. It participates in the reduction of disulfides and other molecules, and conjugates with compounds of exogenous and endogenous origin. It protects cells against the destructive effects of reactive oxygen intermediates and free radicals. Modifications of glutathione metabolism may be achieved by administration of selective enzyme inhibitors, and also by giving compounds that increase glutathione synthesis. Such effects are useful in chemotherapy and radiation therapy and in protecting cells against the toxic effects of drugs, other foreign compounds, and oxygen.


Interventions to enhance newborn care in north-West Ethiopia: the experiences of health care professionals.
The provision of optimal and quality services during labour, delivery and in the early neonatal period is highly required to accelerate the reduction of neonatal deaths and improve the quality of life of newborns. The availability of competent health professionals and the essential medicines and supplies in the health facilities are compulsory. Cost-effective interventions exist to prevent more than 80% of all newborn deaths. However, an unacceptably high number of newborns are dying in the study area, and much is not known about the main contributing factors in primary healthcare settings. This study aimed to explore and describe the quality of care provided to newborns in the primary healthcare units. Qualitative exploratory and descriptive design was employed. Focus group discussions were held with 26 participants (11 health workers and 15 health extension workers) in three woredas in the West Gojjam zone, Ethiopia. Health workers and health extension workers were purposely selected. Thematic analysis was undertaken. The primary healthcare facilities play a major role in the provision of essential services for newborns in the critical periods, including during labor and birth, immediately after birth and in the early postnatal care period. Resuscitation of birth asphyxia, prevention of hypothermia, initiation of breastfeeding, application of tetracycline, vitamin k injection, weighing babies and chlorhexidine application were identified as immediate essential intervention for the newborns. However, these interventions are hampered by factors such as lack of adequately trained staff & hands-on skills; weak referral linkage; stock-out of essential medicines and supplies and poor quality for early postnatal care home visits. In order to enhance the quality of newborns healthcare provision, the health-systems constraints at health centres and heath posts level should be fixed to provide the required services for newborns. This requires allocation of adequate resources to tackle health facilities readiness related bottlenecks, such as the frequent stock out or lack of essential supplies, equipment, and medicines, lack of proper space for the service provision, not systematic replenishing of the revised job-aids and maintenance of medical equipment, poor infection prevention including water and sanitation in the maternity wards and newborn corners.


Elevated plasma level of Pentraxin 3 is associated with emphysema and mortality in smokers.
Pentraxin 3 (PTX3) influences innate immunity and inflammation, host defence, the complement cascade and angiogenesis. PTX3 expression in lung and blood of subjects with tobacco exposure, and its potential relationship with disease pattern and clinical outcome are poorly understood. Using independent platforms and cohorts, we identified associations of PTX3 gene expression in lung tissue and plasma from current and former tobacco smokers (with and without chronic obstructive pulmonary disease, COPD) to disease phenotypes including quantitative CT determined emphysema, lung function, symptoms and survival. Two putative regulatory variants of the PTX3 gene were examined for association with COPD manifestations. The relationship between plasma PTX3 and hyaluronic acid levels was further examined. PTX3 gene expression in lung tissue was directly correlated with emphysema severity (p<0.0001). Circulating levels of PTX3 were inversely correlated with FEV1 (p=0.006), and positively associated with emphysema severity (p=0.004) and mortality (p=0.008). Two PTX3 gene regulatory variants were associated with a lower risk for emphysema and expiratory airflow obstruction, and plasma levels of PTX3 and hyaluronic acid were related. These data show strong and overlapping associations of lung and blood PTX3 levels, and PTX3 regulatory gene variants, with the severity of airflow obstruction, emphysema and mortality among smokers. These findings have potential implications regarding the pathogenesis of smoking-related lung diseases and warrant further exploration for the use of PTX3 as a predictive biomarker.


Profile of paediatric emergency cases in Yemen: the need for evidence-based guidelines.
This study describes the status and characteristics of children presenting to emergency services in hospitals and health centres in Yemen in order to inform the development of guidelines for paediatric emergency services. Information was collected from 7 hospitals and 2 health centres in 5 governorates about 3454 cases, mostly aged < 2 years old. The majority of paediatric emergency cases were due to respiratory system problems (28.6%) and gastrointestinal problems (25.5%); 36.4% of children presented with a duration of complaint exceeding 4 days. One-third of cases (33.2%) were treated with 3rd generation cephalosporins alone or in combination with other antibiotics. The mortality rate was 1.9%. The most important causes of death were cardiac and respiratory failure.


Magnetic resonance imaging features of presumed intracerebral hemorrhages in dogs show a significant association between apparent diffusion coefficient peripheral layer and estimated bleeding age and commonly exhibit a T2 blackout effect.
In humans, intracranial hematomas commonly exhibit a T2 blackout effect (BOE) with diffusion-weighted imaging (DWI) and apparent diffusion coefficient (ADC) maps. Published descriptions of comparable findings in dogs with intracerebral hemorrhages are lacking. Aims of this retrospective observational study were to describe the appearance of presumed intracerebral hemorrhages (PICHs) in DWI regardless of the underlying etiology and presence of T2 blackout effect (T2 BOE) in dogs and to test potential associations with DWI and ADC findings versus the estimated age of the hemorrhage. Magnetic resonance imaging studies of dogs with presumed PICHs based on the combined evaluation of T2*W gradient echo and/or susceptibility-weighted imaging, T1W and T2W images were enrolled. The age of the hemorrhage was estimated according to published criteria based on T1W and T2W sequences. The association between the age of the hemorrhage and the appearance of each finding (stratified or mixed), their signal intensities in DWI/ADC and the presence of the T2 BOE, was evaluated. A total of 35 PICHs were included: 13 of them were stratified and 22 had a mixed aspect. Only the ADC appearance of the peripheral layer in stratified PICHs was significantly associated with estimated age of the hemorrhage (p = .033), being hypointense in all hyperacute cases and hypo-/isointense in acute cases. The T2 BOE was present in 29/35 PICHs. The DWI sequences showed limited utility to date PICHs in this study population. As in humans, the T2 BOE was commonly seen in DWI and ADC maps of dogs with PICHs.


Long-term in vivo study of biodegradable Zn-Cu stent: A 2-year implantation evaluation in porcine coronary artery.
In the present study, a novel biodegradable Zn-0.8Cu coronary artery stent was fabricated and implanted into porcine coronary arteries for up to 24 months. Micro-CT analysis showed that the implanted stent was able to maintain structural integrity after 6 months, while its disintegration occurred after 9 months of implantation. After 24 months of implantation, approximately 28 ± 13 vol% of the stent remained. Optical coherence tomography and histological analysis showed that the endothelialization process could be completed within the first month after implantation, and no inflammation responses or thrombosis formation was observed within 24 months. Cross-section analysis indicated that the subsequent degradation products had been removed in the abluminal direction, guaranteeing that the strut could be replaced by normal tissue without the risk of contaminating the circulatory system, causing neither thrombosis nor inflammation response. The present work demonstrates that the Zn-0.8Cu stent has provided sufficient structural supporting and exhibited an appropriate degradation rate during 24 months of implantation without degradation product accumulation, thrombosis, or inflammation response. The results indicate that the Zn-0.8Cu coronary artery stent is promising for further clinical applications. STATEMENT OF SIGNIFICANCE: Although Zn and its alloys have been considered to be potential candidates of biodegradable metals for vascular stent use, by far, no Zn-based stent with appropriate medical device performance has been reported because of the low mechanical properties of zinc. The present work presents promising results of a Zn-Cu biodegradable vascular stent in porcine coronary arteries. The Zn-Cu stent fabricated in this work demonstrated adequate medical device performance both in vitro and in vivo and degraded at a proper rate without safety problems induced. Furthermore, large animal models have more cardiovascular similarities as humans. Results of this study may provide further information of the Zn-based stents for translational medicine research.


Does antagonism at 5-HT2A receptors potentiate D₂ blockade-induced disruption of conditioned avoidance response?
Existing evidence in the literature shows that antagonism at 5-HT2A receptors potentiates D₂ antagonism-induced disruption of conditioned avoidance response (CAR), a behavioral index of antipsychotic activity, suggesting that combining 5-HT2A antagonism with D₂ antagonism may confer an enhanced antipsychotic effect. The present study reexamined this issue and further investigated other behavioral effects of drug-drug interaction, mainly the conditioned drug effect (via drug-drug conditioning) and 5-HT2A antagonism's modulation on antipsychotic-induced sensitization (an enhanced avoidance disruption). Well-trained adult male Sprague-Dawley rats were first repeatedly tested for 7 days under haloperidol (HAL; 0.05 mg/kg, subcutaneous [sc], a typical antipsychotic drug with potent D2 antagonism), MDL100907 (0.5 and 1.0 mg/kg, sc, a selective 5-HT2A antagonist), combined MDL100907 and HAL, or vehicle control, followed by one challenge test under MDL100907 (0.5 mg/kg) to assess the conditioned drug effect and one challenge test under HAL (0.025 mg/kg) to assess HAL sensitization. Results showed that MDL100907 by itself had no effect on CAR. Importantly, MDL100907 treatment did little to alter the acute and sensitized effects of HAL-induced (0.05 mg/kg, sc) suppression of CAR under various treatment conditions. Repeated pairing of MDL100907 (1.0 mg/kg) with HAL rendered MDL100907 itself to exhibit an "acquired" CAR disruptive effect through a drug-drug conditioning process. These results do not support the notion that 5-HT2A receptor blockade enhances the antipsychotic-like effects of typical antipsychotic drugs, although they do highlight the importance of drug-drug conditioning process in altering drug efficacy in polypharmacy. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Synthesis and Investigation of Electro-Optical Properties of H-Shape Dibenzofulvene Derivatives.
We have synthetized two classes of dibenzofulvene-arylamino derivatives with an H-shape design, for a total of six different molecules. The molecular structures consist of two D-A-D units connected by a thiophene or bitiophene bridge, using diarylamino substituents as donor groups anchored to the 2,7- (Group A) and 3,6- (Group B) positions of the dibenzofulvene backbone. The donor units and the thiophene or bithiophene bridges were used as chemico-structural tools to modulate electro-optical and morphological-electrical properties. A combination of experiments, such as absorption measurements (UV-Vis spectroscopy), cyclic voltammetry, ellipsometry, Raman, atomic force microscopy, TD-DFT calculation and hole-mobility measurements, were carried out on the synthesized small organic molecules to investigate the differences between the two classes and therefore understand the relevance of the molecular design of the various properties. We found that the anchoring position on dibenzofulvene plays a crucial key for fine-tuning the optical, structural, and morphological properties of molecules. In particular, molecules with substituents in 2,7 positions (Group A) showed a lower structural disorder, a larger molecular planarity, and a lower roughness.


Beneficial Effects of Ethyl-Cyanoacrylate Coating Against Candida Albicans Biofilm Formation.
The aim of this study was to verify whether modifications made in a hard chairside reline resin by an ethyl-cyanoacrylate adhesive, ECA (Super Bonder®, Loctite, Itapevi, SP, Brazil) would be able to inhibit or reduce Candida albicans biofilm formation on its surface, comparing to a commercial surface sealant (BisCover®, Bisco, Schaumburg, USA). Reline resin specimens were fabricated and randomly divided into 6 groups (n=8): CG (control group), no surface treatment; ECA1, ECA coating on the surface before sterilization; ECA2, ECA coating after sterilization; ECA3, ECA incorporated in the resin bulk; DPE1, BisCover® coating before sterilization; DPE2, BisCover® coating after sterilization. Specimens were inoculated with C. albicans SC5314 (1x107 cells/mL) and incubated for 24 h. Then, the biofilm were stained with LIVE/DEAD® BaclightTM L7007 Kit and analyzed by Confocal Laser Scanning Microscopy. The images were evaluated by bioImageL® v.2.0 software and total biovolume (µm3), viable cells (%), and covered area (%) were calculated. Data were statistically analyzed by Kruskal-Wallis and Dunn tests (p<0.05). Results showed that ECA-coated groups presented better results, reducing C. albicans biofilm formation. Acquired images revealed that these groups (ECA1 and ECA2) presented a reduced number of cells, mostly in yeast form (less pathogenic), while the other groups presented higher number of cells, mostly in hyphae form (more pathogenic). Based on these findings, a beneficial effect of Super Bonder® coating reline resins surface could be demonstrated, suggesting a promising way to prevent fungal biofilm formation on dentures.


The effect of meclofenamate on renal blood flow in the unanesthetized dog: relation to renal prostaglandins and sodium balance.
We compared the effects of sodium meclofenamate (5 mg/kg i.v.), an inhibitor of prostaglandin synthesis, on renal function in six unanesthetized dogs maintained for 5 to 7 days before the experiment on 100 mEq/day of NaCl and after sodium depletion by furosemide administration and salt deprivation. Plasma renin activity (PRA) during sodium depletion (12.35 +/- 3.93 ng ml-1 hr-1) was higher than during sodium repletion (1.46 +/- 0.47 ng ml-1 hr-1; P less than .05). The administration of meclofenamate did not alter mean arterial pressure, renal blood flow, urine volume, excretion of sodium and potassium or PRA in the sodium replete dog. However, during sodium depletion meclofenamate reduced renal blood flow from 168 +/- 35 to 105 +/- 23 ml/min (P less than .01) and urine flow from 0.32 +/- 0.09 to 0.16 +/- 0.05 ml/min (P less than .05) but did not affect mean arterial pressure, electrolyte excretion or PRA. The meclofenamate-induced reduction in renal blood flow during sodium depletion was well correlated with control PRA. After administration of meclofenamate, the urinary excretion of immunoreactive prostaglandin E2 fell by 66% (P less than .05) in the sodium replete dog and by 72% (P less than .05) in the sodium depleted dog. This study demonstrates that the effects of meclofenamate on renal hemodynamics vary with the state of sodium balance and in relation to PRA.


Treatment with iron increases weight gain and psychomotor development.
Previous work at this hospital and elsewhere has shown that anaemia in toddlers is common and is associated with psychomotor delay. It seemed unclear, however, whether this association was cause and effect or merely due to the same underprivileged environment. A double blind randomised intervention study was, therefore, performed. After an initial assessment 97 children with anaemia (haemoglobin 8-11 g/dl) aged 17-19 months received either iron and vitamin C or vitamin C only (control group) for two months and were then reassessed. The children who received the iron had an increased rate of weight gain and more of them achieved the expected rate of development. While iron deficiency anaemia is unlikely to be the only factor in the slower development of children living in underprivileged circumstances, it can at least be easily identified and treated. Routine child health surveillance in such areas should include a haemoglobin determination.