An unusual phosphatidylinositol turnover pathway in noradrenaline-perfused rat hearts.
1. The phosphatidylinositol turnover pathway has been studied in noradrenaline-perfused rat hearts using anion-exchange high performance liquid chromatography. 2. The active calcium-releasing compound inositol-(1,4,5)trisphosphate was detected together with its degradation products inositol-(1,4)bisphosphate and inositol monophosphate. All these products increased in response to noradrenaline stimulation. 3. At noradrenaline perfusion times from 5 s to 20 min there was no appearance of inositol-(1,3,4,5)tetrakisphosphate or its degradation products: inositol-(1,3,4)trisphosphate or inositol-(1,3) and (3,4)bisphosphates. 4. These data suggest the absence of the inositol-(1,4,5)trisphosphate phosphorylation/dephosphorylation pathway in heart.


Bismuth (III) PVC membrane ion selective electrodes based on two compounds: acylhydrazone and thiosemicarbazone with 1,3,4-thiadiazole.
Two Bi(3+) selective electrodes based on L1 and L2 incorporated into a polyvinylchloride (PVC) membrane have been developed. The ionophores L1 and L2 are 2-(5-amino-1,3,4-thiadiazol-2-ylthio)-N'-benzylidene acetohydrazone and 1-(2-(5-amino-1,3,4-thiadiazol-2-ylthio) acetyl)-4-benzoylthiosemicarbazone, respectively. These electrodes are composed of dioctylphtalate (DOP) as a plasticizer and sodium tetraphenylborate (NaTPB) as the lipophilic additive. The best performance was obtained with the membrane compositions of L1 (0.30): PVC (33.22): DOP (66.36): NaTPB (0.12) (%, w/w) and L2 (1.00): PVC (33.00): DOP (65.91): NaTPB (0.09) (%, w/w). Two membrane electrodes show Nernstian response slopes towards Bi(3+) (20.2 and 19.7 mV/decade, respectively) over the concentration range of 10(-7)-10(-3) and 10(-7)-10(-2) M, respectively. The effects of the pH and the possible interfering cations were investigated. Both electrodes have a response time of about 10 s, and they can work in a certain concentration aqueous ethanol solution. The prepared electrodes were used as an indicator electrode in potentiometric titration of Bi(3+) ions with EDTA. The membrane sensors were also applied to the determination of Bi(3+) content in compound bismuth aluminate tablets.


Use of a cross reacting anti-idiotype to identify normal counterparts of neoplastic cells.
We have established that 9G4, a cross reacting monoclonal anti-idiotype identifies an epitope close the binding site of anti-I cold agglutinins. 9G4 positive lymphocytes comprise around 5% of B cells and are widely represented in all lymphoid tissue. They may be detected in 15 week fetal spleen at the time of the earliest appearance of B cells and thus form part of the basic B cell repertoire. Such antibodies are derived largely from CD5 positive B cells. 9G4 is thus a useful tool to investigate the normal counterpart of the CLL cell.


The importance of personal documentation for patients living with long-term illness symptoms after pituitary surgery: A Constructivist Grounded Theory study.
Despite surgical treatment, pituitary adenomas often cause long-term illness symptoms, that profoundly impact patients' quality of life physically, psychologically and socially. Healthcare professionals often fail to recognize and discuss the ensuing problems. Personal documentation, such as symptom monitoring, reflective writing or even posts on social media, may help this patient group to manage their daily life and support communication of their care needs. Documentation strategies and the role of documentation for people with long-term symptoms after pituitary adenoma surgery are currently unknown. To examine the effects and strategies of documenting symptoms, activities and physical and emotional well-being among people living with long-term pituitary adenoma. In this Constructivist Grounded Theory study, 12 individuals living with long-term illness symptoms after pituitary adenoma surgery described their documentation strategies in in-depth interviews using teleconferencing and photo-elicitation between August and October 2020. Strategies for documentation included analogue and digital media. One core category (Exercising autonomy) and three categories describing processes (Gaining insight, Striving for control and Sharing) emerged from the analysis. These three interrelated processes become an expression of autonomy to manage life and make sense of chronic illness. Personal documentation is a flexible tool that is used more extensively in times of ill health and less in times of relative well-being. Sharing documentation with healthcare professionals facilitated care planning and sharing with friends and family fostered emotional well-being. Personal documentation is a valuable resource for managing life after pituitary adenoma surgery. The current findings may be relevant to other chronic illnesses. Further research exploring potential tools for personal documentation is needed. We deliberately chose a Constructivist Grounded Theory approach for this interview study. Using Constructivist Grounded Theory, we gave people living with long-term symptoms a voice, allowing them to freely speak about managing their illness in connection with personal documentation. The theoretical sampling approach enabled us to invite participants that could provide a broad overview of the landscape of personal documentation.


Description of a new genus and thirteen new species of Ctenidae (Araneae, Ctenidae) from the Chocó region of Ecuador.
The genus Chococtenus n. gen. is established for a group of Ctenidae with a unique ventral and spine-like retrolateral tibial apophysis, primarily found in the Chocó-Tumbes-Magdalena corridor. Thirteen new species are described: Chococtenus otonga n. sp., C. neblina n. sp., C. cuchilla n. sp., C. fantasma n. sp., C. waitti n. sp., C. cappuccino n. sp., C. lasdamas n. sp., C. suffuscus n. sp., C. otongachi n. sp., C. kashakara n. sp., C. piemontana n. sp., C. luchoi n. sp. and C. duendecito n. sp. Ctenus acanthoctenoides Schmidt and Enoploctenus miserabilis (Strand) are transferred to Chococtenus.


Fully automated segmentation and radiomics feature extraction of hypopharyngeal cancer on MRI using deep learning.
To use convolutional neural network for fully automated segmentation and radiomics features extraction of hypopharyngeal cancer (HPC) tumor in MRI. MR images were collected from 222 HPC patients, among them 178 patients were used for training, and another 44 patients were recruited for testing. U-Net and DeepLab V3 + architectures were used for training the models. The model performance was evaluated using the dice similarity coefficient (DSC), Jaccard index, and average surface distance. The reliability of radiomics parameters of the tumor extracted by the models was assessed using intraclass correlation coefficient (ICC). The predicted tumor volumes by DeepLab V3 + model and U-Net model were highly correlated with those delineated manually (p < 0.001). The DSC of DeepLab V3 + model was significantly higher than that of U-Net model (0.77 vs 0.75, p < 0.05), particularly in those small tumor volumes of < 10 cm3 (0.74 vs 0.70, p < 0.001). For radiomics extraction of the first-order features, both models exhibited high agreement (ICC: 0.71-0.91) with manual delineation. The radiomics extracted by DeepLab V3 + model had significantly higher ICCs than those extracted by U-Net model for 7 of 19 first-order features and for 8 of 17 shape-based features (p < 0.05). Both DeepLab V3 + and U-Net models produced reasonable results in automated segmentation and radiomic features extraction of HPC on MR images, whereas DeepLab V3 + had a better performance than U-Net. The deep learning model, DeepLab V3 + , exhibited promising performance in automated tumor segmentation and radiomics extraction for hypopharyngeal cancer on MRI. This approach holds great potential for enhancing the radiotherapy workflow and facilitating prediction of treatment outcomes. • DeepLab V3 + and U-Net models produced reasonable results in automated segmentation and radiomic features extraction of HPC on MR images. • DeepLab V3 + model was more accurate than U-Net in automated segmentation, especially on small tumors. • DeepLab V3 + exhibited higher agreement for about half of the first-order and shape-based radiomics features than U-Net.


Pr-lynx1, a modulator of nicotinic acetylcholine receptors in the insect.
Insect nicotinic acetylcholine receptors (nAChRs) are targets for insecticides. Despite the importance of the nAChR as a major target for insecticide action, modulators of nAChRs in insects remain unidentified. Here we describe the cloning and identification of a nAChR modulator gene in an insect. This gene was isolated by searching the firefly Pyrocoelia rufa cDNA library, and the gene itself encodes a protein 120 amino acids in length, named Pr-lynx1. Pr-lynx1 shares all the features, including a cysteine-rich consensus motif and common gene structure, of the Ly-6/neurotoxin superfamily. The recombinant Pr-lynx1, which is expressed as a 12-kDa polypeptide in baculovirus-infected insect Sf9 cells, is normally present at the cell surface as a GPI-anchored protein. Northern and Western blot analyses revealed that Pr-lynx1 is expressed in various tissues, such as the ganglion, brain, mandibular muscle, proventriculus, leg muscle, and epidermis. This expression pattern is similar to the distribution of nAChRs as assayed by alpha3 nAChR immunoreactivity. Co-expression of Pr-lynx1 in Xenopus oocytes expressing alpha3beta4 nAChRs results in an increase in acetylcholine-evoked macroscopic currents, indicating a functional role of Pr-lynx1 as a protein modulator for nAChRs. This study on Pr-lynx1 is the first report of a modulator of nAChRs in an insect species.


Detection of diffuse skeletal lesions by monitoring the kinetics of labeled phosphonate.
A method of detecting of diffuse skeletal involvement in patients with metastatic tumors or with metabolic diseases is presented. The study consisted of 31 patients without bone disease and of 26 selected patients with diffuse skeletal involvement. The kinetics of 99mTc-dicarboxypropane diphosphonate (DPD) were calculated by monitoring the plasma and urine concentrations up to 5 hours after administration. Using these data, the renal clearance as well as the increase in urinary excretion of 99mTc-DPD were determined. The results indicate that measurement of the quantity of 99mTc-DPD excreted in the urine after 3 hours allows a reliable separation of the patients with diffuse skeletal lesions from normals. Other calculations such as renal clearance as well as the drop in plasma concentration were less sensitive. The test may be performed simultaneously with bone scintigraphy without additional radiation burden to the patient.


Feasibility of customised unipolar conversion using bipolar temporary pacing wires in patients after surgical repair of congenital heart disease.
Temporary pacing wires play a crucial role in the diagnosis and therapy of post-operative arrhythmia after surgery for congenital heart disease. At present, bipolar pacing wires are used in most institutions. In case of functional failure of these wires, a unipolar mode of stimulation and sensing should be theoretically possible as a rescue procedure. We tested the feasibility of the customised unipolar mode in 18 post-operative patients with congenital heart disease (age 9.2 ± 13.9 months, weight 6.3 ± 3.8 kg, and cardiopulmonary bypass time 70 ± 29 minutes). As there are two possible unipolar configurations, there are twice the number of testing parameters; of those, we compared sensing (mV) and pacing thresholds (V at 0.5 ms). Atrial sensing was significantly better in the unipolar modes (p < 0.001, p < 0.003). The ventricular unipolar sensing did not differ significantly in the "better" of the two possible configurations from the bipolar values (p = 0.363). For the unipolar pacing thresholds, only the "better" unipolar configuration did not differ significantly from the bipolar measurements (atrial: p = 0.058, ventricular: p = 0.138). There was no exit block or undersensing. The results demonstrate that unipolar stimulation and sensing using bipolar epicardial temporary pacing wires is feasible. In the case of failure of bipolar temporary pacing wires, this modality represents an easy rescue measure that in such cases should always be considered.


Influence of right coronary artery stenosis on exercise test responses and survival in patients with left main or left main equivalent disease.
Forty-two patients with angiographically documented left main coronary artery (LM) disease (luminal occlusion > or = 50%) and 30 patients with left main equivalent (LMEQ) disease (> or = 70% luminal occlusion of both the proximal left anterior descending artery and proximal left circumflex artery) were studied to determine the role of right coronary artery (RCA) involvement on exercise test responses and survival. Significant (> or = 70%) RCA stenosis was present in 30 (72%) of the 42 LM patients and 16 (53%) of the 30 LMEQ patients. No significant differences were observed between LM and LMEQ patients in any clinical or exercise variables or survival. Thus both groups were combined for analysis of the influence of RCA involvement (i.e., LM/LMEQ with RCA versus LM/LMEQ without RCA disease). Greater ischemic responses were observed in the LM/LMEQ group with significant stenosis of the RCA. The presence of RCA stenosis was associated with significantly greater horizontal or downsloping ST-segment depression during exercise (2.4 +/- 1.2 mm vs 1.3 +/- 1.4 mm; p < 0.001), and prolonged recovery time until normalization of the ST segment (3.2 +/- 1.4 min vs 2.0 +/- 1.9 min; p < 0.01). The LM/LMEQ without RCA disease group behaved like the subgroup with two-vessel disease, and responses of the LM/LMEQ group with RCA disease were similar to the group with three-vessel disease. The annual survival in LM/LMEQ with RCA disease was worse than that in LM/LMEQ without RCA disease (average annual mortality rates = 7.5% vs 1.0%, respectively; p = 0.05). Infarct-free survival in LM/LMEQ with RCA disease was also lower than that in LM/LMEQ without RCA disease. Thus although patients with LM and LMEQ were similar in terms of survival and exercise responses, the presence of RCA stenosis was associated with significantly greater ST-segment depression, a prolonged recovery time until normalization of the ST segment, a fivefold increase in the death rate, and higher morbidity from myocardial infarction over a 5-year period of follow-up. Involvement of the RCA should be considered when making decisions concerning medical-surgical management of patients with severe coronary artery disease.


Effects of chronic oral administration of L-deprenyl in the dog.
Dogs were administered capsules containing L-deprenyl daily over 3 weeks at dose levels of 0, 0.1, 0.5, and 1.0 mg/kg. Spontaneous behavior was measured using a canine open field test, and was not significantly affected by L-deprenyl. Plasma levels of amphetamine showed a clear dose-dependent elevation 2 h and was not significantly affected by L-deprenyl. Plasma levels of amphetamine showed a clear dose-dependent elevation 2 h following treatment, but were markedly lower after 24 h, and were undetectable 5 days following the last treatment. Plasma levels of phenylethylamine were increased, but were highly variable. Animals sacrificed 1 day following the last treatment showed a dose-dependent inhibition of monoamine oxidase B in the brain, liver, and kidney, whereas monoamine oxidase A was unaffected in these tissues. L-Deprenyl also caused an increase in phenylethylamine in the striatum and hypothalamus, but not in the neocortex. Brain levels of DA, DOPAC, 3-MT, HVA, 5-HT, and 5-HIAA were unaffected. The pharmacological profile for the dog is distinct from that of other species in that long-term treatment did not produce any significant inhibition of MAO-A activity. The absence of an effect on biogenic amines or metabolites suggests that the metabolism of dopamine is mediated at least in part through pathways other than MAO-B in the normal adult dog.


Survival and growth of goat primordial follicles after in vitro culture of ovarian cortical slices in media containing coconut water.
The development of culture systems to support the initiation of growth of primordial follicles is important to the study of the factors that control the earliest stages of folliculogenesis. We investigated the effectiveness of five culture media, two supplements and three culture periods on the survival and growth of goat primordial follicles after culturing ovarian cortex. The media were based on minimal essential minimum (MEM) and coconut water solution (CWS) added in the proportion of 0, 25, 50, 75 or 100%. The two supplements were none versus supplemented with insulin-transferrin-selenium, pyruvate, glutamine, hypoxanthine, and BSA. Pieces of goat ovarian cortex were cultured in the media for 1, 3 or 5 days and representative samples were evaluated at day 0 as non-cultured controls. The replicates were the two ovaries of five mixed breed goats. The number of primordial, intermediate, primary and secondary follicles at each period of culture and the number of degenerated follicles were evaluated. Mitotic activity of granulosa cells was studied by immunolocalization of proliferating cell nuclear antigen (PCNA). The number of follicles in each stage and degenerated follicles were statistically analyzed by ANOVA using a factorial design and the significance of differences assessed using Tukey test. Chi-square test was used to compare the percentage of follicles with PCNA positive granulosa cells. As the culture period progressed, the number of primordial follicles fell and there was a significant increase in the number of primary follicles. The fall in the number of primordial follicles was particularly marked after 1 day culture. No effect of media on the number of primordial and primary follicles was observed after culture, but MEM as well as supplements increased the number of intermediate follicles. Follicular degeneration was kept at the same level after culture in the media tested, except for pure CWS that increased the number of degenerated follicles. In contrast, addition of supplements to culture media reduced follicular degeneration. In non-cultured tissue, PCNA was expressed in granulosa cells of 31.6% of the growing follicles. This percentage had not significantly changed after 5 days culture in the various media, indicating the maintenance of proliferation activity of granulosa cells during culture. In conclusion, it is shown that goat primordial follicles may be successfully activated after in vitro culture in all media tested. However, when pure CWS is used the follicular degeneration is enhanced, but the addition of supplements to culture media decrease follicular degeneration.


Monoclonal antibodies for malaria prevention.
Monoclonal antibodies are highly specific proteins that are cloned from a single B cell and bind to a single epitope on a pathogen. These laboratory-made molecules can serve as prophylactics or therapeutics for infectious diseases and have an impressive capacity to modulate the progression of disease, as demonstrated for the first time on a large scale during the COVID-19 pandemic. The high specificity and natural starting point of monoclonal antibodies afford an encouraging safety profile, yet the high cost of production remains a major limitation to their widespread use. While a monoclonal antibody approach to abrogating malaria infection is not yet available, the unique life cycle of the malaria parasite affords many opportunities for such proteins to act, and preliminary research into the efficacy of monoclonal antibodies in preventing malaria infection, disease, and transmission is encouraging. This review examines the current status and future outlook for monoclonal antibodies against malaria in the context of the complex life cycle and varied antigenic targets expressed in the human and mosquito hosts, and provides insight into the strengths and limitations of this approach to curtailing one of humanity's oldest and deadliest diseases.


Homeostatic matching and nonlinear amplification at identified central synapses.
Here we describe the properties of a synapse in the Drosophila antennal lobe and show how they can explain certain sensory computations in this brain region. The synapse between olfactory receptor neurons (ORNs) and projection neurons (PNs) is very strong, reflecting a large number of release sites and high release probability. This is likely one reason why weak ORN odor responses are amplified in PNs. Furthermore, the amplitude of unitary synaptic currents in a PN is matched to the size of its dendritic arbor. This matching may compensate for a lower input resistance of larger dendrites to produce uniform depolarization across PN types. Consistent with this idea, a genetic manipulation that lowers input resistance increases unitary synaptic currents. Finally, strong stimuli produce short-term depression at this synapse. This helps explain why PN odor responses are transient, and why strong ORN odor responses are not amplified as powerfully as weak responses.


Composition and in silico structural analysis of fibroin from liquid silk of non-mulberry silkworm Antheraea assamensis.
Silk is spun from the liquid precursor known as liquid silk secreted from the posterior part and stored in the silk gland lumen with occurrence of many momentary events. The liquid silk in the silk gland is transformed to the spun silk fibre. In this study the elucidation of the protein components of liquid silk from the posterior part of the silk gland (PSG) of saturniid silkworm Antheraea assamensis along with its structural characterization has been reported. The 3D model of the N-terminal amorphous portion with some repeat crystalline motifs (19-255) of core protein fibroin has also been constructed. 1D and 2D electrophoresis revealed the homo-dimeric structure of the silk protein. Secondary structure analysis by Circular dichroism, FTIR spectroscopy showed α helical structural component as predominant conformation in the liquid silk. The crystalline structure investigated through X ray diffraction (XRD) analysis also revealed the presence of less ordered amorphous α helical conformation in the liquid silk. The 3D structural model proposed of the residues from 19 to 255 has revealed structural stability throughout the molecular dynamics simulation process. This study will provide the detailed structural information and in silico analysis of the core protein present in the liquid silk of PSG.


Identification and characterization of a novel light-induced promoter for recombinant protein production in Pleurotus ostreatus.
A lectin gene (plectin) with a high level of expression was previously identified by comparative transcriptome analysis of Pleurotus ostreatus. In this study, we cloned a 733-bp DNA fragment from the start codon of the plectin gene. Sequence analysis showed that the plectin promoter (Plp) region contained several eukaryotic transcription factor binding motifs, such as the TATA-box, four possible CAAT-box, light respon-siveness motifs and MeJA-responsiveness motifs. To deter-mine whether the Plp promoter was a light-regulated promoter, we constructed an expression vector with the fused egfp-hph fragment under the control of the Plp promoter and transformed P. ostreatus mycelia via Agrobacterium tunte-faciens. PCR and Southern blot analyses confirmed the Plp-egfp-hph fragment was integrated into the chromosomal DNA of transformants. qRT-PCR, egfp visualization, and intracellular egfp determination experiments showed the Plp promoter could be a light-induced promoter that may be suitable for P. ostreatus genetic engineering. This study lays the foundation for gene homologous expression in P. ostreatus.


Cocaine-related myocardial infarction: concomitant heroin use can cloud the picture.
Cocaine-related myocardial infarction is a well-known phenomenon. Concurrent heroin use can mask signs and symptoms of myocardial infarction. We discuss an unusual presentation of myocardial infarction, associated with both cocaine and heroin ("speedball") self-injection, that initially went undiagnosed.


Lung macrophages and dendritic cells express HLA-G molecules in pulmonary diseases.
HLA-G is selectively expressed in extravillous trophoblast of human placenta, which does not express classical HLA-A and -B molecules. Several studies report the role of HLA-G as a molecule involved in immune tolerance. By interacting with NK and T cells inhibitory receptors, HLA-G may downregulate their cytotoxicity functions. To appreciate the biologic and clinical relevance of HLA-G expression in lung diseases, HLA class I and HLA-G expression were analyzed in a panel of 36 ex vivo neoplastic tissues and 8 non-neoplastic lung tissues. Immunohistochemical analysis was performed using a pan-HLA class I antibody (W6/32) and three different specific anti-HLA-G antibodies (87G, MEMG/9 and 4H84). These findings demonstrated that HLA-G products were not expressed in pulmonary structural cells. However, HLA-G molecules were detected in activated macrophages and dendritic cells infiltrating lung carcinomas (33%) and nontumoral pulmonary diseases (25%). HLA-G expression was not correlated with classical HLA alterations. No statistical correlation was found between HLA-G expression and clinical or biologic parameters except high tumor size. The expression of HLA-G in myelo-monocytic cells infiltrating lung pathologic tissues could alter antigenic presentation and contribute to decrease immune response efficiency, subsequently favoring the progression of tumoral or inflammatory processes.


Salinomycin sensitizes antimitotic drugs-treated cancer cells by increasing apoptosis via the prevention of G2 arrest.
Here, we investigated whether Sal could sensitize cancer cells to antimitotic drugs. We demonstrated that Sal sensitized paclitaxcel (PAC)-, docetaxcel (DOC)-, vinblastin (VIN)-, or colchicine (COL)-treated cancer cell lines, suggesting that Sal has the ability to sensitize the cells to any form of microtubule-targeting drugs. Sensitization to the antimitotic drugs could be achieved with very low concentrations of Sal, suggesting that there is a possibility to minimize Sal toxicity associated with human cancer patient treatments. Sensitization by Sal increased apoptosis, which was observed by C-PARP production. Sal sensitized the cancer cells to antimitotic drugs by preventing G2 arrest, suggesting that Sal contributes to the induction of mitotic catastrophe. Sal generally reduced cyclin D1 levels in PAC-, DOC-, and VIN-treated cells. In addition, Sal treatment increased pH2AX levels and reduced p21 levels in antimitotic drugs-treated cells. These observations suggest that the mechanisms underlying Sal sensitization to DNA-damaging compounds, radiation, and microtubule-targeting drugs are similar. Our data demonstrated that Sal sensitizes cancer cells to antimitotic drugs by increasing apoptosis through the prevention of G2 arrest via conserved Sal-sensitization mechanisms. These results may contribute to the development of Sal-based chemotherapy for cancer patients treated with antimitotic drugs.


Are the Naranjo criteria reliable and valid for determination of adverse drug reactions in the intensive care unit?
The Naranjo criteria are frequently used for determination of causality for suspected adverse drug reactions (ADRs); however, the psychometric properties have not been studied in the critically ill. To evaluate the reliability and validity of the Naranjo criteria for ADR determination in the intensive care unit (ICU). All patients admitted to a surgical ICU during a 3-month period were enrolled. Four raters independently reviewed 142 suspected ADRs using the Naranjo criteria (review 1). Raters evaluated the 142 suspected ADRs 3-4 weeks later, again using the Naranjo criteria (review 2). Inter-rater reliability was tested using the kappa statistic. The weighted kappa statistic was calculated between reviews 1 and 2 for the intra-rater reliability of each rater. Cronbach alpha was computed to assess the inter-item consistency correlation. The Naranjo criteria were compared with expert opinion for criterion validity for each rater and reported as a Spearman rank (r(s)) coefficient. The kappa statistic ranged from 0.14 to 0.33, reflecting poor inter-rater agreement. The weighted kappa within raters was 0.5402-0.9371. The Cronbach alpha ranged from 0.443 to 0.660, which is considered moderate to good. The r(s) coefficient range was 0.385-0.545; all r(s) coefficients were statistically significant (p < 0.05). Inter-rater reliability is marginal; however, within-rater evaluation appears to be consistent. The inter-item correlation is expected to be higher since all questions pertain to ADRs. Overall, the Naranjo criteria need modification for use in the ICU to improve reliability, validity, and clinical usefulness.


V/Q mismatches unassociated with pulmonary embolism: case report and review of the literature.
A case is reported in which an intrathoracic stomach produced a ventilation/perfusion (V/Q) mismatch on lung scan. Causes of V/Q mismatch other than pulmonary embolism are reviewed.


Toxicity of polystyrene nanoplastics in Ctenopharyngodon idella juveniles: A genotoxic, mutagenic and cytotoxic perspective.
The increased contamination of surface water with plastic waste is proportional to the increased consumption of products that use them as raw material. However, the impact of these residues on aquatic biota remains limited, mainly when it comes to nanoplastics (NPs). Thus, the aim of the current study is to test the hypothesis that the exposure of Ctenopharyngodon idella juveniles to polystyrene nanoplastics (PS NPs) at low concentrations (0.04 ng/L, 34 ng/L and 34 μg/L), for 20 days, leads to DNA damage and has mutagenic and cytotoxic effects on their erythrocytes. Comet assay enabled observing that DNA damage (inferred from the greater tail length, DNA percentage in the tail and Olive tail moment) induced by PS NPs has increased as the pollutant concentrations have increased, as well as that the formation of micronuclei and other nuclear abnormalities was equitable in animals exposed to this pollutant. On the other hand, there were significant changes in erythrocyte shape and size, oxidative stress generation (NO levels, lipid peroxidation, hydrogen peroxide), antioxidant system inhibition (mediated by total hepatic glutathione) and PS NPs accumulation in the liver and brain of animals exposed to higher concentrations of it. Therefore, the current study has confirmed the initial hypothesis and enhanced the knowledge about the genotoxic, mutagenic and cytotoxic potential of PS NPs in freshwater fish at early developmental stage, relating these effects to biochemical changes and significant accumulation of these nanomaterials. Besides, it is a warning about the (eco) toxicological risk represented by these nanopollutants in aquatic environments. CAPSULE: Polystyrene nanoplastics are capable of inducing DNA damage, mutagenic and cytotoxicity changes in fish.


[Analysis of the internationalized highly cited segment of national surgery publications].
The internationalized segment of manuscripts on surgery published in top-rated journals indexed in the Web of Science Core Collection (WoS CC) was analyzed. Presence of national publications in surgical journals of different quartiles was estimated. It was shown that 59.6% of surgical articles of Russian authors, indexed in the WoS CC, were published in high-ranking journals (Q1 and Q2). The number of such articles has been increased by more than 3 times (from 23 in 2010 to 86 in 2018) on the background of no growth in the fourth quartile. We formed a rating of national educational and academic organizations, which have made the greatest contribution to a portfolio of publications on surgery, indexed in Q1-Q2 quartiles of WoS CC, as well as in the segment of highly cited publications.


Effects of heavy metals on sex inversion of the mussel Mytilus galloprovincialis Lam., 1819 in coastal zone of the Black Sea.
Sex inversion in the mussel Mytilus galloprovincialis under the influence of heavy metals as one of the reasons for the shift in the sex ratio in the mussel population on the Black Sea coastal zone of Crimea were considered in the work. The present study is the first to directly show that heavy metals can cause females of the mussel M. galloprovincialis to change into males during post-spawning development of gonads. The degree of impact of heavy metals on the sex change in mussel females was different and decreased in the following sequence: Cu2+ → Cd2+ → Hg2+ → Pb2+ → Zn2+. Copper ions had the greatest effect, which caused a sex inversion in 54 % of females. The heavy metals Hg2+ and Pb2+ were also quite toxic causing mortality in 13 % and 10 % of individuals, respectively. It is possible to use M. galloprovincialis as a model organism in the study of mechanism of environmental sex reversal in bivalves.


Kinetic and energetic characterization of solute flux through the reconstituted aspartate/glutamate carrier from beef heart mitochondria after modification with mercurials.
The functional switch from specific, coupled antiport to unspecific unidirectional transport (efflux) of the reconstituted aspartate/glutamate carrier from mitochondria after chemical modification with mersalylic acid was investigated in kinetic and energetic terms. The rate of mercurial-induced efflux was determined for a number of solutes which differ from the physiological substrate aspartate in structure, size and charge, namely oxoglutarate, sulfate, glucose, lysine and arginine. These values were compared to the rates of efflux as well as antiport of aspartate. Measurement of the temperature dependence of all rates led to evaluation of the activation energy of the different substrates. The activation energy was similar for all substrates and for both transport modes, whereas the efflux rates could be ordered in the following sequence: anions > uncharged solutes > cations. When extrapolating to Vmax conditions, the resulting turnover numbers for uniport substrates become similar and exceed the turnover numbers for aspartate and glutamate antiport. Trans-inhibition of efflux was only observed in the case of externally added aspartate or glutamate and only for internal anionic substrates (at the cis side), thus indicating that after efflux induction the specificity of the external binding site is fully and that of the internal site is partially retained. The consequence of these results for understanding the transport function of the aspartate/glutamate carrier in the slippage mode (uniport) is discussed in energetic and kinetic terms.


Behavioral and cellular responses to pulses of low doses of estradiol-17 beta.
The effectiveness of single vs. separate pulses of low doses of free estradiol on the induction of sexual receptivity in ovariectomized female rats was examined. Two separate subcutaneous pulses of low doses of free estradiol at 0 and 6 hours induced high levels of progesterone facilitated receptivity at 24 hours. However, a single pulse of the same total dose of estradiol induced little or no receptivity at 24 hours (or at 18 hours). In fact, approximately 10 times as much estradiol was required in a single pulse to induce comparable receptivity. The smaller behavioral response to a single pulse was not likely due to a ceiling effect or an unutilized excess of the hormone after one injection. This suggestion is based on measurements of the redistribution of estrogen receptors from the cytoplasm to cell nuclei as an index of an initial cellular stimulus. Doses of estradiol used in the behavioral studies included several doses that were subsaturating with regard to hypothalamic estrogen receptors. The greatly enhanced behavioral response to two separated pulses of estradiol is consistent with the hypothesis that an initial action of estradiol may be to sensitize target tissues to further stimulation by the hormone.


An in vivo study of voltage-dependent renal tubular acidosis induced by amiloride.
It has been proposed that most forms of hyperkalemic distal renal tubular acidosis (dRTA) result from a voltage-dependent acidification defect in the cortical collecting tubule (CCT) in which hydrogen and potassium secretion are decreased secondary to a reduced, transepithelial potential difference (PD) arising from impaired sodium reabsorption. The present in vivo study examines one model of hyperkalemic dRTA, induced by chronic amiloride administration, to examine the relationship between urinary excretion of hydrogen and potassium ions and CCT PD in the rat kidney. Chronic administration of amiloride produced a significant metabolic acidosis with a plasma bicarbonate of 21.3 mmol/liter compared to 25.9 mmol/liter in control rats. Plasma potassium was higher in experimental animals (4.9 mmol/liter vs. 3.3 mmol/liter in controls) and was associated with a significantly reduced fractional excretion of potassium of 11.2% versus 37.4% in controls. When animals were loaded with DOCA and infused with 4% sodium sulphate to maximize urine acidification, urine pH was significantly higher in the experimental group (6.35 vs. 5.55 in controls) while the mean PD in cortical collecting tubules was markedly lower at -21.1 mV versus -58.9 mV in controls. These results support a voltage dependent mechanism to explain the defect in hydrogen and potassium ion secretion induced by amiloride.


Overcoming leukemia heterogeneity by combining T cell engaging bispecific antibodies.
Leukemia represents about 5% of all human cancers. Despite advances in therapeutics, a substantial number of patients succumb to the disease. Several subtypes of leukemia are inherently more resistant to treatment despite intensive chemotherapy or targeted therapy. Here we describe the generation of T cell engaging (CD3) bispecific antibodies (BsAbs) built on humanized IgG frameworks using the IgG(L)-scFv format against two targets expressed on acute lymphoblastic leukemia (ALL) and on acute myeloid leukemia (AML). Each BsAb mediated potent anti-leukemia effect against ALL (CD19) and AML (CD33) in vitro and in xenograft models. Importantly, the CD19-specific BsAb (BC250) was effective against hematogenous spread preventing metastases to liver and kidney in mice bearing ALL and Burkitt's lymphoma xenografts. BC250 was more potent than the The Food and Drug Administration (FDA)-approved BsAb blinatumomab against ALL xenografts in vivo as measured by tumor bioluminescence and mouse survival. Furthermore, the combination of the CD19 and CD33 BsAbs in two xenograft models of mixed phenotype acute leukemia (biphenotypic and bilineal leukemia) was far superior than monotherapy with either of the BsAbs alone. Selective combinations of these leukemia-specific BsAb offer the potential to overcome tumor heterogeneity or clonal escape in the modern era of antibody-based T cell-driven immunotherapy.


Danish multicenter randomized study on fibrinolytic therapy versus acute coronary angioplasty in acute myocardial infarction: rationale and design of the DANish trial in Acute Myocardial Infarction-2 (DANAMI-2).
Randomized trials have indicated that primary coronary angioplasty performed in patients admitted directly to highly-experienced angioplasty centers offers certain advantages over intravenous fibrinolytic therapy. However, the large majority of patients with acute myocardial infarction are submitted to hospitals without a catheterization laboratory. This means that additional transportation will be necessary for many patients if a strategy of acute coronary angioplasty is to be introduced as routine treatment. The delay of treatment caused by transportation might negate (part of) the benefits of primary angioplasty compared to fibrinolytic therapy given immediately at the local hospital. The DANish trial in Acute Myocardial Infarction-2 (DANAMI-2) is the first large-scale study to clarify, in a whole community, which of the 2 treatment strategies is best. A total of 1900 patients with ST-elevation myocardial infarction are to be randomized: 800 patients will be admitted to invasive hospitals and 1100 patients will be admitted to referral hospitals. Half of the 1100 patients admitted to referral hospitals will immediately be transferred to an invasive center to be treated with primary angioplasty. If acute transfer from a local hospital to an angioplasty center is the superior strategy, primary angioplasty should be offered to all patients as routine treatment on a community basis.


Rewarding Effects of Optical Stimulation of Ventral Tegmental Area Glutamatergic Neurons.
Ventral tegmental area (VTA) neurons play roles in reward and aversion. The VTA has three major neuronal phenotypes: dopaminergic, GABAergic, and glutamatergic. VTA glutamatergic neurons--expressing vesicular glutamate transporter-2 (VGluT2)--project to limbic and cortical regions, but also excite neighboring dopaminergic neurons. Here, we test whether local photoactivation of VTA VGluT2 neurons expressing Channelrhodopsin-2 (ChR2) under the VGluT2 promoter causes place preference and supports operant responding for the stimulation. By using a Cre-dependent viral vector, ChR2 (tethered to mCherry) was expressed in VTA glutamatergic neurons of VGluT2::Cre mice. The mCherry distribution was evaluated by immunolabeling. By confocal microscopy, we detected expression of mCherry in VTA cell bodies and local processes. In contrast, VGluT2 expression was restricted to varicosities, some of them coexpressing mCherry. By electron microscopy, we determined that mCherry-VGluT2 varicosities correspond to axon terminals, forming asymmetric synapses on neighboring dopaminergic neurons. These findings indicate that ChR2 was present in terminals containing glutamatergic synaptic vesicles and involved in local synaptic connections. Photoactivation of VTA slices from ChR2-expressing mice induced AMPA/NMDA receptor-dependent firing of dopaminergic neurons projecting to the nucleus accumbens. VTA photoactivation of ChR2-expressing mice reinforced instrumental behavior and established place preferences. VTA injections of AMPA or NMDA receptor antagonists blocked optical self-stimulation and place preference. These findings suggest a role in reward function for VTA glutamatergic neurons through local excitatory synapses on mesoaccumbens dopaminergic neurons.


Evidence for a neurotransmitter role of glutamate in guinea pig myenteric plexus neurons.
Longitudinal muscle-myenteric plexus strips of the guinea pig ileum were used to investigate a possible transmitter role of glutamate (Glu) in the enteric nervous system. Glu was released from this nerve muscle preparation by high K(+)-depolarization in a Ca2(+)-dependent manner, by electrical field stimulation and by the ganglionic stimulant dimethylphenylpiperazinium which indicates its neural origin. Contractions of the longitudinal muscle evoked by electrical stimulation of the myenteric nerves or by Glu, were significantly reduced by the N-methyl-D-aspartate (NMDA)-receptor antagonist FR115427 (9 and 18 microM), whereas contractions induced by histamine were unaffected. The results show that the amino acid Glu is likely to play an excitatory neurotransmitter role via NMDA receptors in the myenteric plexus of the guinea pig.


[Prenatal diagnosis of upper limb reduction deficiencies].
Ultrasonography has become an indispensable tool in prenatal care providing a throughout screening of the morphological abnormalities of the foetus. The examination of the upper limbs is now part of a routine screening checklist available in France since 2005. Recent progress in past years has focused on the early detection of reductional anomalies. As early as the first trimester scan, the three segments of the upper limb are apparent and transversal anomalies can be easily detected. Early diagnosis of malformations may lead to ethical considerations since women may request for medical termination of pregnancy. Apart from transversal anomalies of the limb which remain most of the time accidental, genetic syndromes may also lead to longitudinal reductions of the upper limb. In such cases, ultrasound may be helpful in genetic counselling by detecting other associate malformations. The search for associate malformations in favour of a genetic syndrome is therefore mandatory before referral to a prenatal consultation with the surgeon. Three-dimensional ultrasound and multi detector computed tomography (MDCT) are being increasingly used as additional procedures to improve diagnosis and long-term prognosis.


Effects of 2-alkynyladenosine derivatives on intraocular pressure in rabbits.
We evaluated the activities of 2-alkynyladenosine derivatives, relatively selective adenosine A2 receptor agonists, in the intraocular pressure regulation in rabbits. An adenosine A2 receptor agonist 2-[p-(2-carboxyethyl)phenylethylamino]-5'-N-ethylcarboxamidoadenosine (CGS-21680) decreased intraocular pressure, while another A2 receptor agonist 2-(phenylamino)adenosine transiently increased it. The first group of 2-alkynyladenosine derivatives (1-hexyn-1-yl derivatives) caused a transient increase followed by decrease in intraocular pressure, while the second group (1-octyn-1-yl and 6-cyano-1-hexyn-1-yl derivatives) only decreased it. The second group is also effective in the ocular hypertensive models induced by water-loading and alpha-chymotrypsin. The outflow facility was increased by a 1-octyn-1-yl derivative. Both increase and decrease in intraocular pressure induced by 2-alkynyladenosine derivatives were inhibited by an adenosine A2 receptor antagonist 3,7-dimethyl-1-propargylxanthine, but not by an adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dipropyl xanthine. These findings suggest that 2-alkynyladenosine derivatives may affect intraocular pressure via adenosine A2 receptor, and 2-alkynyladenosine derivative-induced ocular hypotension is due to the increase of outflow facility.


A Rare Case of Median Nerve Entrapment within the Bone After Surgical Treatment of a Pediatric Supracondylar Humerus Fracture: A Case Report.
We present the rare event of median nerve bony entrapment after a supracondylar distal humerus fracture in a child. The median nerve was both clinically and electrically still, partially intact at 2 years after the injury. The nerve was surgically extracted from the bone. Follow-up evaluation a year later showed motor and sensory improvement. We found only 2 similar reports in the literature and one similar postmortem example. We hope that this case brings awareness of an unusual complication after a commonly encountered injury.


Thermophilic anaerobic digestion of source-sorted organic fraction of municipal solid waste.
The influence of different organic fraction of municipal solid wastes during anaerobic thermophilic (55 degrees C) treatment of organic matter was studied in this work: food waste (FW), organic fraction of municipal solid waste (OFMSW) and shredded OFMSW (SH_OFMSW). All digester operated at dry conditions (20% total solids content) and were inoculated with 30% (in volume) of mesophilic digested sludge. Experimental results showed important different behaviours patterns in these wastes related with the organic matter biodegradation and biogas and methane production. The FW reactor showed the smallest waste biodegradation (32.4% VS removal) with high methane production (0.18 LCH4/gVS); in contrast the SH_OFMSW showed higher waste biodegradation (73.7% VS removal) with small methane production (0.05 LCH4/g VS). Finally, OFMSW showed the highest VS removal (79.5%) and the methane yield reached 0.08 LCH4/g VS. Therefore, the nature of organic substrate has an important influence on the biodegradation process and methane yield. Pre-treatment of waste is not necessary for OFMSW.


Effects of temperature, pH elevators, and energy production inhibitors on horseradish peroxidase transport through endocytic vesicles.
We investigated the effects of reduced temperature, the pH elevators NH4Cl, monensin, and HEPES (N-2-hydroxy-ethylpiperazine-N'-2-ethanesulfonic acid) buffer, as well as the metabolic poisons NaF/KCN on transport of the fluid phase pinocytic marker, horseradish peroxidase (HRP), to lysosomes in Chinese hamster ovary (CHO) cells. In cell fractionation experiments, these agents appeared to block HRP transit at specific point(s) from "early" to "late" (i.e., low to high density) prelysosomal vesicles and lysosomes. Reduced temperature (17 degrees C) most strongly inhibited HRP transport from low density, early endosomes to lysosomes. In long-term HRP uptakes at 17 degrees C, marked peroxidase accumulation occurred both in early endosomes and in lysosomes. Loss (reversible pinocytosis) of HRP from "very early" endosomes occurred at 17 degrees C. All three pH elevators including the common media supplement HEPES buffer inhibited transit of internalized HRP into lysosomes. For all three pH elevators, inhibition was most pronounced at the "early" endosome stage. The respiratory inhibitors NaF/KCN also inhibited transport most strongly at the early endosome stage. Together these results suggest that "early" steps in the endocytic transport of HRP are the most sensitive and that the conditions tested may exert direct effects on the processing of endocytic vesicles.


Effects of enhanced cerebrospinal fluid levels of vasopressin, vasopressin antagonist or vasoactive intestinal polypeptide on circadian sleep-wake rhythm in the rat.
Several endogenous peptides have been implicated in the regulation of sleep and wakefulness. The present study was carried out in order to determine whether the light-dark rhythm of vasopressin (VP) in the cerebrospinal fluid (CSF) had functional significance in relaying information from the circadian pacemaker, i.e. the suprachiasmatic nuclei (which synthesize VP as well as vasoactive intestinal polypeptide (VIP], to the centra regulating sleep. After constant delivery of VP in the CSF via an Accurel/collodion implant in the lateral ventricle, the VP CSF level was raised from 20-35 pg/ml to ca. 265 pg/ml whereby a VP rhythm in the CSF could no longer be detected. Under these conditions VP was found to increase the arousal state of the rat in the dark period, which resulted in a higher amplitude of the circadian sleep-wake rhythm. Application of the VP antagonist d(CH2)5[Tyr(Me)2]VP partly had opposite effects. A similar approach with central application of VIP resulted in an increase in rapid eye movement and quiet sleep but did not affect the amplitude of the circadian rhythm. It was concluded that although peptide levels in the CSF may show clear temporal variations with the light-dark cycle, this rhythmicity is not causally related to the circadian aspect of sleep-wakefulness. However, both VP and VIP contribute to the regulation of the amount of time spent in sleep and wakefulness and the level of VP in the CSF is correlated with the amplitude of the rhythm.


Recovery of Patients with Pure Diffuse Axonal Injury Who Remained in a Coma for 6 Hours or More.
Diffuse axonal injury (DAI) is a traumatic brain injury and one of the most common causes of unfavorable outcome and death. The aim of this study was to investigate the recovery of patients with pure DAI who remained in a coma for 6 hours or longer after brain injury. This was a follow-up study of 75 patients diagnosed with pure DAI, aged 18-60 years, with a Glasgow Coma Scale score ≤8 at hospital admission. Patient data were collected at hospital admission, hospital discharge, and 3 and 6 months after DAI. Recovery was assessed by score changes in the Katz Index of Independence in Activities of Daily Living and Extended Glasgow Outcome Scale. The percentage of patients in a coma for 6-24 hours, >24 hours without brainstem signs, and >24 hours with brainstem signs was 42.7%, 20%, and 37.3%, respectively. The 6-month mortality rate was 32.0%, and the mean Extended Glasgow Outcome Scale score among survivors decreased from 3.8 at discharge (SD = 1.2) to 2.1 at 3 months (SD = 1.6) and 1.2 at 6 months (SD = 1.6). The mean Katz Index of Independence in Activities of Daily Living scores were 8.5 (SD = 5.5), 3.5 (SD = 5.8), and 1.8 (SD = 4.5) at discharge and 3 and 6 months after trauma, respectively. Statistically significant differences were observed among the 3 evaluation periods. Mortality was high among patients with DAI, but almost all survivors had favorable outcomes at 6 months. Functional improvement was more pronounced in the first 3 months.


Practice strategies to improve primary care for chronic disease patients under a pay-for-value program.
Improving primary care for patients with chronic illness is critical to advancing healthcare quality and value. Yet, little is known about what strategies are successful in helping primary care practices deliver high-quality care for this population under value-based payment models. Double-blind interviews in 14 primary care practices in the state of Michigan, stratified based on whether they did (n = 7) or did not (n = 7) demonstrate improvement in primary care outcomes for patients with at least one reported chronic disease between 2010 and 2013. All practices participate in a statewide pay-for-performance program run by a large commercial payer. Using an implementation science framework to identify leverage points for effecting organizational change, we sought to identify, describe and compare strategies among improving and non-improving practices across three domains: (1) organizational learning opportunities, (2) approaches to motivating staff, and (3) acquisition and use of resources. We identified 10 strategies; 6 were "differentiating" - that is, more prevalent among improving practices. These differentiating strategies included: (1) participation in learning collaboratives, (2) accessing payer tools to monitor quality performance, (3) framing pay-for-performance as a practice transformation opportunity, (4) reinvesting earned incentive money in equitable, practice-centric improvement, (5) employing a care manager, and (6) using available technical support from local hospitals and provider organizations to support performance improvement. Implementation of these strategies varied based on organizational context and relative strengths. Practices that succeeded in improving care for chronic disease patients pursued a mix of strategies that helped meet immediate care delivery needs while also creating new adaptive structures and processes to better respond to changing pressures and demands. These findings help inform payers and primary care practices seeking evidence-based strategies to foster a stronger delivery system for patients with significant healthcare needs.


EU mitigation potential of harvested wood products.
The new rules for the Land Use, Land Use Change and Forestry sector under the Kyoto Protocol recognized the importance of Harvested Wood Products (HWP) in climate change mitigation. We used the Tier 2 method proposed in the 2013 IPCC KP Supplement to estimate emissions and removals from HWP from 1990 to 2030 in EU-28 countries with three future harvest scenarios (constant historical average, and +/-20% in 2030). For the historical period (2000-2012) our results are consistent with other studies, indicating a HWP sink equal on average to -44.0 Mt CO2 yr-1 (about 10% of the sink by forest pools). Assuming a constant historical harvest scenario and future distribution of the total harvest among each commodity, the HWP sink decreases to -22.9 Mt CO2 yr-1 in 2030. The increasing and decreasing harvest scenarios produced a HWP sink of -43.2 and -9.0 Mt CO2 yr-1 in 2030, respectively. Other factors may play an important role on HWP sink, including: (i) the relative share of different wood products, and (ii) the combined effect of production, import and export on the domestic production of each commodity. Maintaining a constant historical harvest, the HWP sink will slowly tend to saturate, i.e. to approach zero in the long term. The current HWP sink will be maintained only by further increasing the current harvest; however, this will tend to reduce the current sink in forest biomass, at least in the short term. Overall, our results suggest that: (i) there is limited potential for additional HWP sink in the EU; (ii) the HWP mitigation potential should be analyzed in conjunction with other mitigation components (e.g. sink in forest biomass, energy and material substitution by wood).


Endoscopic endonasal transpterygoid nasopharyngectomy.
Describe our technique for endoscopic transpterygoid nasopharyngectomy and support its feasibility with our early clinical outcomes. Our endoscopic technique comprises an extended inferomedial maxillectomy, mobilization of the pterygopalatine fossa, removal of the pterygoid plates and Eustachian tube to access the posterolateral nasopharynx. Control of the parapharyngeal and petrous segments of the internal carotid artery is the keystone of the approach. Various histopathologies were treated, including epidermoid carcinomas (n = 9), lymphoepithelioma (n = 1), adenoid cystic carcinoma (n = 5), adenocarcinoma (n = 2), mucoepidermoid carcinoma (n = 2), and sarcoma (n = 1). Negative microscopic margins were obtained in 95% (19/20) of patients. No perioperative mortality, cerebral spinal fluid (CSF) leak, meningitis, or cerebrovascular accident was encountered; however, one patient suffered an internal carotid artery (ICA) injury, without permanent sequelae. All but one patient received adjuvant therapy (external and/or stereotactic radiotherapy with or without chemotherapy). Follow-up ranged from 15 to 68 months (mean = 33). Overall survival was 45% (9/20) and local control was 65% (13/20). Endoscopic transpterygoid nasopharyngectomy for primary and recurrent nasopharyngeal malignancies is feasible and safe in properly selected patients. Preliminary outcomes compare to that of conventional techniques. Endoscopic resections, however, are demanding; they require specialized equipment and a team versed in endoscopic oncologic surgery. Long-term follow-up and reproducibility remain undefined.


GSTM1 and GSTT1 polymorphisms and colorectal cancer risk in Chinese population: a meta-analysis.
Studies investigating the associations between GSTM1 and GSTT1 polymorphisms and colorectal cancer (CRC) risk in Chinese population have reported controversial results. Thus, a meta-analysis was performed. Four hundred and seven relevant records were identified through a literature search up to September 7, 2011, and 19 studies were finally included, involving a total of 3,130 CRC cases and 6,423 controls. Subgroup analyses were performed by language and study design. Statistical analysis was performed with the software programs Review Manager (version 5.1.2) and STATA (version 11.0). For the GSTM1 polymorphism, the null genotype of GSTM1 was not associated with CRC risk in Chinese population (OR = 1.12, 95% CI = 0.97-1.28). Similar associations were found for GSTT1 polymorphism (OR = 1.10, 95% CI = 0.94-1.29) and the dual null genotype of GSTM1/GSTT1 (OR = 1.26, 95% CI = 0.93-1.71). For subgroup analyses, studies published in English and population-based studies further identified these associations for the three aspects above in Chinese population. This meta-analysis suggests that the null genotypes of GSTM1 and GSTT1 and the dual null genotype of GSTM1/GSTT1 were all not risk factors in CRC in Chinese population.


Autophagy: cells SNARE selves.
Autophagosomes sequester cytosolic constituents and deliver this cargo to lysosomes for destruction. Two groups now report that autophagosome maturation requires homotypic membrane fusion catalyzed by SNARE proteins.


Evaluation of the Elements of Short Hairpin RNAs in Developing shRNA-Containing CAR T Cells.
Short hairpin RNAs (shRNAs) have emerged as a powerful tool for gene knockdown in various cellular systems, including chimeric antigen receptor (CAR) T cells. However, the elements of shRNAs that are crucial for their efficacy in developing shRNA-containing CAR T cells remain unclear. In this study, we evaluated the impact of different shRNA elements, including promoter strength, orientation, multiple shRNAs, self-targeting, and sense and antisense sequence composition on the knockdown efficiency of the target gene in CAR T cells. Our findings highlight the importance of considering multiple shRNAs and their orientation to achieve effective knockdown. Moreover, we demonstrate that using a strong promoter and avoiding self-targeting can enhance CAR T cell functionality. These results provide a framework for the rational design of CAR T cells with shRNA-mediated knockdown capabilities, which could improve the therapeutic efficacy of CAR T cell-based immunotherapy.


Use of Vicryl (polyglactin 910) sutures in general surgical and cardiothoracic procedures.
The satisfactory substitute for catgut suture, Vicryl (polyglactin 910) suture, was used in fifty-three patients who underwent general and thoracic surgical procedures. Theoretical advantages of increased strength, controlled absorption by slow depolymerization and dissolution, and superior handling characteristics were confirmed. No suture-related complications were observed.


Biological environmental specimen banking in Slovakia.
Biological environmental specimens, including samples of human tissues, were stored for 5-10 years after solubilizing by mineralization in boiling nitric acid. The sampling procedure, transport treatment and storing was standardized. Documentation identifying the sample and its origin were used. Data on toxic metals in dust-fall, in the individual components of the environment as soil, air, ground and surface water, plants, animals, food and human tissues (liver, kidney, lung, brain, heart and plasma) are reported for the 6 most heavily contaminated regions of Slovakia. In some areas xenobiotics in the environment seriously affected the flora and fauna, including man. Banking of specimens has been stressed as the necessity for future analyses.


Characterization of the NF-?B signaling triggered by doxorubicin.
Doxorubicin (DOX) is an antibiotic used in the treatment of various cancers. However, its clinical use is limited due to the toxic effects it causes. In several biological systems reactive oxygen species (ROS) derived from DOX metabolism have been associated with its toxicity because they can alter several signal transduction pathways. One of the major signal transduction pathways activated in response to oxidant stress is that of the nuclear transcription factor ?B (NF-?B), which is crucial for cell survival, cell proliferation, and immune responses. Previous studies from our laboratory have described that DOX triggersthe activation of the MAPK (ERK, p38, and JNK) pathways, NF-?B mobilization and caspase activation in rat hepatocytes. These events were indirectly ascribed to ROS generation by pharmacological approaches. Although NF-?B mobilization is usually accompanied by up-regulation of the genes with regulatory ?B elements, our gene expression analysis rendered a quite different scenario. The aim of this work was to verify the implication of ROS in the DOX-mediated signaling and to explore the transcriptional regulatory behaviour of NF-?B mobilized by DOX. Results showed that DOX treatment induces ROS generation, particularly H2O2. DOX-induced caspase-3 activation was ROS dependent, whereas the NF-?B mobilization was a process independent of H2O2. Furthermore, DOX-mobilized NF-?B complexes were dimmers formed by p65 with all the members of the Rel family, excepting Rel B. The analysis of the NF-?B transcriptional activity performed by reporter gene assays suggests that these DOX-mobilized NF-?B complexes are not transcriptionally competent.


Increased Abdominal Perimeter Differently Affects Respiratory Function in Men and Women.
Obesity is a worldwide epidemic being the main cause of cardiovascular, metabolic disturbances and chronic pulmonary diseases. The increase in body weight may affect the respiratory system due to fat deposition and systemic inflammation. Herein, we evaluated the sex differences in the impact of obesity and high abdominal circumference on basal ventilation. Thirty-five subjects, 23 women and 12 men with a median age of 61 and 67, respectively, were studied and classified as overweight and obese according to body mass index (BMI) and were also divided by the abdominal circumference. Basal ventilation, namely, respiratory frequency, tidal volume, and minute ventilation, was evaluated. In normal and overweight women, basal ventilation did not change, but obese women exhibited a decrease in tidal volume. In men, overweight and obese subjects did not exhibit altered basal ventilation. In contrast, when subjects were subdivided based on the abdominal perimeter, a higher circumference did not change the respiratory frequency but induced a decrease in tidal volume and minute ventilation in women, while in men these two parameters increased. In conclusion, higher abdominal circumference rather than BMI is associated with alterations in basal ventilation in women and men.


Applicability of thermography for cancer diagnosis in small animals.
Medical thermography is an imaging test used to monitor skin surface temperature. Although it is not a recent technique, significant advances have been made since the 2000s with the equipment modernization, leading to its popularization. In cancer diagnosis, the application of thermography is supported by the difference in thermal distribution between neoplastic processes and adjacent healthy tissue. The mechanisms involved in heat production by cancer cells include neoangiogenesis, increased metabolic rate, vasodilation, and the release of nitric oxide and pro-inflammatory substances. Currently, thermography has been widely studied in humans as a screening tool for skin and breast cancer, with positive results. In veterinary medicine, the technique has shown promise and has been described for skin and soft tissue tumors in felines, mammary gland tumors, osteosarcoma, mast cell tumors, and perianal tumors in dogs. This review discusses the fundamentals of the technique, monitoring conditions, and the role of thermography as a complementary diagnostic tool for cancer in veterinary medicine, as well as future perspectives for improvement.


Mastectomy options for the treatment of ipsilateral breast cancer recurrence after lumpectomy.
Mastectomy is the recommended treatment for ipsilateral breast tumor recurrence (IBTR) in patients who initially received breast conservation surgery (BCS) and radiation. We evaluated the 3 types of mastectomies performed for the surgical treatment of IBTR (nipple sparing (NSM), skin sparing (SSM) and total mastectomy (TM)) to assess surgical complications and local control outcomes among groups. Patients who developed IBTR after BCS and received mastectomy from 2011 to 2019 were reviewed. Patient characteristics and treatment were analyzed. The incidence of postoperative complications and second breast cancer recurrence were compared. Mastectomy was performed in 113 patients presenting with isolated IBTR (17 NSM, 48 SSM and 48 TM). There was no difference in post-operative complications between groups. At 3-year follow-up, 5 (4%) patients had a second recurrence. Tumor size at IBTR was the only predictor for second recurrence and not mastectomy type or receipt of reconstruction. In patients initially treated with BCS who experienced an IBTR, NSM or SSM mastectomy with immediate reconstruction had low complication rates and no increase in local recurrence compared to the TM group.


[Surgical anatomy of the lumbar spine].
The success and risks of spinal surgery depend on a correct diagnosis and detailed knowledge of anatomy. This report provides information on relevant structures of the lumbar spine and possible surgical complications. Anatomical topography and different surgical approaches are described step by step.


Ablation of Gadd45β ameliorates the inflammation and renal fibrosis caused by unilateral ureteral obstruction.
The growth arrest and DNA damage-inducible beta (Gadd45β) protein have been associated with various cellular functions, but its role in progressive renal disease is currently unknown. Here, we examined the effect of Gadd45β deletion on cell proliferation and apoptosis, inflammation, and renal fibrosis in an early chronic kidney disease (CKD) mouse model following unilateral ureteral obstruction (UUO). Wild-type (WT) and Gadd45β-knockout (KO) mice underwent either a sham operation or UUO and the kidneys were sampled eight days later. A histological assay revealed that ablation of Gadd45β ameliorated UUO-induced renal injury. Cell proliferation was higher in Gadd45β KO mouse kidneys, but apoptosis was similar in both genotypes after UUO. Expression of pro-inflammatory cytokines after UUO was down-regulated in the kidneys from Gadd45β KO mice, whereas UUO-mediated immune cell infiltration remained unchanged. The expression of pro-inflammatory cytokines in response to LPS stimulation decreased in bone marrow-derived macrophages from Gadd45β KO mice compared with that in WT mice. Importantly, UUO-induced renal fibrosis was ameliorated in Gadd45β KO mice unlike in WT mice. Gadd45β was involved in TGF-β signalling pathway regulation in kidney fibroblasts. Our findings demonstrate that Gadd45β plays a crucial role in renal injury and may be a therapeutic target for the treatment of CKD.


[Radical prostatectomy in clinically localized prostate carcinoma. Pro laparoscopic approach].
Systematic development of laparoscopy during the last decade has led to establishing laparoscopic radical prostatectomy (LRP) as a surgical procedure. On the basis of extensive experience at our center, the advantages of the minimally invasive method are described as well as the problems still in existence. Reduced trauma caused by laparoscopic access in combination with clearly reduced blood loss has resulted in less morbidity after laparoscopic procedures. This is reflected in a shorter postoperative stay in hospital and faster convalescence. LRP as an ambitious and complex procedure has an average complication rate of 12%, which shows that the method has surpassed the stage of experimental surgery. By direct comparison, the costs of LRP are higher than for the open surgical procedure, but on the whole this is economically balanced by the lower morbidity, shorter hospital stay, and faster convalescence. The progress in technology to be expected in the field of laparoscopy will further increase quality, precision, and safety of LRP and thus contribute to the establishment of laparoscopic radical prostatectomy as a surgical method of choice.


Liver homing in the rat of 111Indium labelled beef and neuraminidase-treated rat erythrocytes (studies with a gamma camera).
The rate of liver homing of 111In-labelled erythrocytes has been measured under a Gamma Camera. Homing of neuraminidase-treated or xenogeneic erythrocytes is delayed by preinjection of glycolipids or glycopeptides.


(E)-N-Aryl-2-oxo-2-(3,4,5-trimethoxyphenyl)acetohydrazonoyl cyanides as tubulin polymerization inhibitors: Structure-based bioisosterism design, synthesis, biological evaluation, molecular docking and in silico ADME prediction.
A series of (E)-N-Aryl-2-oxo-2-(3,4,5-trimethoxyphenyl)acetohydrazonoyl cyanides have been synthesized and evaluated for their anticancer activity in human hepatocellular liver carcinoma HepG2 and breast adenocarcinoma MCF-7 cell lines. Among all the tested compounds, compound 3a, 3e and 3n displayed more activity than lead compound with IC50 value of 0.26-0.61 μM. Meanwhile, these compounds (3a, 3e and 3n) showed potent antiproliferative activity against a panel of cancer cells and the HCT-8/T multidrug resistant cell line with IC50 values in the range of 0.077- 7.44 μM. Flow cytometric analyses revealed that compound 3n induced cell cycle arrest in G2/M phases in a dose dependent manner. The compound 3n also displayed potent tubulin polymerization inhibition with an IC50 value of 0.9 µM, with ten folds more active than colchicine (IC50 = 9 μM). Molecular docking studies revealed that compound 3n efficiently interacted with the colchicine binding site of tubulin through hydrophobic, cation-π and hydrogen bond interaction. Furthermore, in silico pharmacokinetic prediction shown that these compounds have a good ADME-related physicochemical parameters. These results demonstrate that 3n exhibits potent cytotoxicity in cancer cells by targeting the colchicine binding site of tubulin and potentially acts as a therapeutic lead compound for the development of anticancer drugs.


Centrosomes in the DNA damage response--the hub outside the centre.
Here, we review how DNA damage affects the centrosome and how centrosomes communicate with the DNA damage response (DDR) apparatus. We discuss how several proteins of the DDR are found at centrosomes, including the ATM, ATR, CHK1 and CHK2 kinases, the BRCA1 ubiquitin ligase complex and several members of the poly(ADP-ribose) polymerase family. Stereotypical centrosome organisation, in which two centriole barrels are orthogonally arranged in a roughly toroidal pericentriolar material (PCM), is strongly affected by exposure to DNA-damaging agents. We describe the genetic dependencies and mechanisms for how the centrioles lose their close association, and the PCM both expands and distorts after DNA damage. Another consequence of genotoxic stress is that centrosomes undergo duplication outside the normal cell cycle stage, meaning that centrosome amplification is commonly seen after DNA damage. We discuss several potential mechanisms for how centrosome numbers become dysregulated after DNA damage and explore the links between the DDR and the PLK1- and separase-dependent mechanisms that drive centriole separation and reduplication. We also describe how centrosome components, such as centrin2, are directly involved in responding to DNA damage. This review outlines current questions on the involvement of centrosomes in the DDR.


Calmodulin regulates the post-anaphase reposition of centrioles during cytokinesis.
A transient postanaphase repositioning of the centriole is found to control the completion of cytokinesis. Using a green fluorescent protein-calmodulin fusion protein as a living cell probe, we have previously found that calmodulin is associated with the initiation and progression of cytokinesis. In this study, we further studied the effect of calmodulin on the repositioning of the centriole and subsequent cell cycle progression. When activity of calmodulin is inhibited, the regression of the centriole from the intercellular bridge to the cell center is blocked, and thus the completion of cell division is repressed and two daughter cells are linked by longer cell bridge in perturbed cells. W7 treatment during cytokinesis also results in unfinished cytokinesis and stopped G1 phase. These results suggest that calmodulin activity is required for centriole repositioning and can affect the completion of cytokinesis and cell cycle progression.


Phase I dose-escalating study of TAS-106 in combination with carboplatin in patients with solid tumors.
TAS-106 was designed to inhibit RNA synthesis by blocking RNA polymerases I, II, and III. This was a single-center, open-label, phase I study to identify the maximum tolerated dose (MTD), pharmacokinetics, and biologic effects of the combination of TAS-106 and carboplatin, following a standard 3 + 3 design. This phase I trial was comprised of a regimen of a 60-min IV infusion of carboplatin on day 1 of each 21-day cycle followed by a 24-h infusion of TAS-106, also on day 1 of each cycle. 39 patients were treated (21 male, 18 female, median age 62 years, range 21-80 years). Median number of prior therapies was 4. Maximum Tolerated Dose (MTD) was 3 mg/m(2) TAS-106 with AU 4 carboplatin. Dose-limiting toxicities were neutropenia and thrombocytopenia, with and without growth factor support. While no patients achieved a complete or partial response, four patients had stable disease lasting ≥4 months, including one patient each with ovarian, non-small cell lung, basal cell and colorectal cancer. In summary, the combination of TAS-106 and carboplatin was well-tolerated, and further studies in non-small cell lung and ovarian cancer are warranted to assess the efficacy of this drug combination.


Serum erythropoietin in rheumatoid arthritis and other inflammatory arthritides: relationship to anaemia and the effect of anti-inflammatory treatment.
Serum erythropoietin (s-Epo) was measured with a sensitive radioimmunoassay method in 58 patients with classical rheumatoid arthritis (n = 41) or seronegative spondyloarthropathies (n = 17). Epo was significantly (P less than 0.001) increased and on an average two times higher than in a healthy population. A correlation was found between Hb and s-Epo (r = -0.46, P less than 0.005), indicating that these patients respond to anaemia with an increase in s-Epo. In order to investigate if inflammation has a direct influence on s-Epo levels a short period of corticosteroid treatment was given to rapidly decrease inflammatory activity. No increase in s-Epo was seen after 1 week. Furthermore, there was a correlation between s-Epo and ESR in all patients (r = 0.59, P less than 0.01). These results indicate that s-Epo is directed by the Hb level, which in turn is influenced by the inflammatory activity: a higher inflammatory activity gives a lower Hb and an increase in s-Epo. In comparison to previously published figures for the relation between Hb and s-Epo these patients seem to have an ordinary Epo response. We conclude that the anaemia of patients with chronic inflammatory joint disease is not caused by a diminished Epo production.


MicroRNA-25-3p regulates osteoclasts through nuclear factor I X.
Osteoporosis is a bone metabolic disease, characterized by loss of bone density leading to fractures. Its incidence increases with age and affects patient quality of life. Although osteoclasts play a significant role in osteoporosis, their underlying regulatory mechanisms remain unclear. In this study, we found that microRNA (miR)-25-3p negatively regulates osteoclast function through nuclear factor I X (NFIX). Overexpression of NFIX promoted osteoclast proliferation and increased the expression of the osteoclast differentiation and activity markers tartrate-resistant acid phosphatase and cathepsin K. MiR-25-3p transfection inhibited NFIX expression, which in turn inhibited osteoclast proliferation. Collectively, our results suggest that miR-25-3p promotes osteoclast activity by regulating the expression of NFIX. Therefore, targeting miR-25-3p in osteoclasts could be a promising strategy for treating skeletal disorders involving reduced bone formation.


Pulse-generated runoff: a new method of determining calf vessel patency.
A non-invasive method of determining calf vessel patency before femorodistal bypass has been developed. This pulse-generated runoff (PGR) system generates blood flow in patent calf arteries by means of a pulsatile cuff even if the existing Doppler signal is inaudible. PGR was compared with pre-operative arteriography in 95 ischaemic limbs and both were compared with the peripheral resistance measured at operation in 62 limbs. There was a highly significant correlation between the PGR and arteriogram scores (rs = 0.74, P less than 0.001) but PGR tended to detect more patent vessels than arteriography. The peripheral resistance correlated better with PGR than arteriography (rs = -0.71 and -0.54 respectively, P less than 0.001). PGR is a simple, non-invasive method of determining calf and foot vessel patency pre-operatively.


Comparison of procedural times for ultrasound-guided perineural catheter insertion in obese and nonobese patients.
Perineural catheter insertion with ultrasound guidance alone has been described, but it remains unknown whether this new technique results in the same procedural time and success rate for obese and nonobese patients. We therefore tested the hypothesis that obese patients require more time for perineural catheter insertion compared to nonobese patients despite using ultrasound. Data from 5 previously published randomized clinical trials comparing ultrasound- and stimulation-guided perineural catheter insertion techniques were reviewed, and patients who received ultrasound-guided catheters were divided into 2 groups: obese (body mass index ≥30 kg/m(2)) and nonobese (body mass index <30 kg/m(2)). A standardized ultrasound-guided nonstimulating catheter technique was used with mepivacaine, 1.5% (40 mL), as the initial bolus via the placement needle for the primary surgical nerve block. The primary outcome was the procedural time for perineural catheter insertion. Secondary outcomes included block efficacy, procedure-related pain, fluid leakage, vascular puncture, and catheter dislodgment. A sample of 120 patients was identified: 51 obese and 69 nonobese. All obese patients had successful catheter placement compared to 68 of 69 (98%) nonobese patients (P = .388). The time for perineural catheter insertion [median (10th-90th percentiles)] was 7 (4-12) minutes for obese patients versus 7 (4-15) minutes for nonobese patients (P = .732). There were no statistically significant differences in other secondary outcomes. On the basis of this retrospective analysis, perineural catheter insertion is not prolonged in obese patients compared to nonobese patients when an ultrasound-guided technique is used. However, these results are only suggestive and require confirmation through prospective study.


Neighborhood context and acculturation among Central American immigrants.
Years in the US is often used as a proxy for acculturation, and level of acculturation may be an important predictor of differential health outcomes for immigrants. Some studies have examined the interaction between community level factors and acculturation, but not among Latinos. Level of acculturation and neighborhood concentration of Latinos was assessed in a sample of 194 Spanish-speaking, immigrant, pregnant Latinas. Neighborhood concentration of Latinos moderated the association between years living in the US and acculturation level. For individuals living in a high concentration of Latinos, longer time in the US was less related to higher levels of acculturation. In contrast, among Latinas living in a low concentration of other Latinos, the amount of time since immigrating to the US was strongly associated with level of acculturation. These findings have implications for health outcomes research done with immigrant groups, particularly Latinos.


[Brain tumors and pregnancy].
Despite not being a common fact, the occurrence of brain tumors during pregnancy poses a risk to both the mother and infant. To identify the best medical procedure to be followed for a pregnant patient harboring a brain tumor. The records of 6 patients with brain tumors, diagnosed during pregnancy were examined. Several types of brain tumors have been associated with pregnancy, but the meningioma is, by far, the most frequent. It seems that pregnancy aggravates the clinical course of intracranial tumors. There were no operative mortality in these series. In 2 patients the labor occurred before the craniotomy and in others, the delivery occurred after the surgery. The best moment to recommend the craniotomy and the neurosurgical removal of the tumor will depend of the mothers neurological condition, the tumor histological type as well as the gestational age.


Chemical-specific determinants for pre-conceptional exposure to emerging and legacy per- and polyfluoroalkyl substances.
The exposure of preconception women to per- and polyfluoroalkyl substances (PFASs) could negatively affect her reproductive health. However, chemical-specific determinants for pre-conceptional exposure to PFASs, particularly the emerging ones, remain poorly understood. In the present study, it was found that the total PFAS concentration ranged from 8.9 to 440.3 ng/mL (median: 49.6 ng/mL) in 1060 preconception women. The PFAS exposure profile was dominated by PFOA (16.8 ng/mL), followed by PFOS (13.3 ng/mL), 6:2 Cl-PFESA (8.9 ng/mL), PFDA (2.4 ng/mL), PFNA (2.1 ng/mL), and others. The pre-conceptional exposure to the selected PFASs was significantly associated, in a chemical-specific pattern, with multiple demographic characteristics and the consumption frequency of different types of food. In particular, the exposure to 6:2 Cl-PFESA was associated with age, parity, alcohol drinking, educational level, household income, and the consumption frequency of red meat, marine and freshwater fish, shellfish, and shrimp. However, our analysis revealed that the investigated sociodemographic and diet variables only explained a relatively small proportion (1.3%-18.7%) of PFAS concentration variations, raising the need of exploring additional factors critical to pre-conceptional PFAS exposure. Overall, the identification of chemical-specific determinants would greatly facilitate the understanding of the link between pre-conceptional exposure and health outcomes, and the mitigation of human exposure to PFAS, particularly the emerging ones.


Neutrophil activation during hemodialysis.
Oxidative metabolism of PMNs of uremic patients is enhanced due to unknown serum (plasma) factors which are removed during hemodialysis. Respiratory burst activity is diminished in both PMA-stimulated and unstimulated states compared to healthy controls. Hemodialysis normalizes stimulated and decreases unstimulated hydrogen peroxide production. Several authors found that resting and stimulated chemiluminescence (CL) during hemodialysis correlates with complement activation, whereas other authors describe CL using dialyzer membranes with only mild anaphylatoxin formation. Alterations of PMN carbohydrate metabolism in uremic patients improves during HD with polysulfone. HD with PMMA, however, activates glycogenolysis. These alterations may be responsible for disturbance in phagocytosis. Degranulation during HD also occurs in absence of complement activation. Calcium channel blockers decrease activation of PMNs using dialyzers with only little anaphylatoxin formation.


Multicomponent Droplet Drying Modeling Based on Conservation and Population Balance Equations.
The aim of this work is to present a modeling tool to describe drying kinetics and delineate evolving physical and chemical behavior of multicomponent droplets during drying. Conservation equations coupled with population balance equations (PBE) are used to achieve this goal. Modeling results are gauged with single salt-water droplet drying from literature and show congruent trends. This model is then extended to a more complex system: various droplet sizes containing methanol (solvent), Felodipine (active ingredient), and PVP (polyvinylpyrrolidone as excipient). The FIB-SEM (Focused-Ion Beam Scanning Electron Microscopy) imaging results from spray-dried particles produced with similar formulation and processing conditions are consistent with phase behavior predicted by the model. The results show competing impacts of transport phenomena on the intermittent shell formation process and final particle structure and chemical heterogeneity. Solute diffusion, solvent efflux, and intra-drop flow impact the model system. It is found that shell formation follows a fluctuating profile where the initial precipitation of the dissolved species on the droplet surface is dampened, and nucleated particles become dispersed periodically until the shell becomes strong enough to withstand internal circulations. These internal effects are dependent on droplet size and are pronounced for larger droplets. That is, the particle phase behavior and physical nature are functions of the atomized droplet size. Stemming understating from this study would inform an optimized unit, operating in target design space. This would provide better product quality control and minimize discrepancies observed in process development during the early phase vs. commercial scale.


Increased chemosensitivity via targeting testicular nuclear receptor 4 (TR4)-Oct4-interleukin 1 receptor antagonist (IL1Ra) axis in prostate cancer CD133+ stem/progenitor cells to battle prostate cancer.
Prostate cancer (PCa) stem/progenitor cells are known to have higher chemoresistance than non-stem/progenitor cells, but the underlying molecular mechanism remains unclear. We found the expression of testicular nuclear receptor 4 (TR4) is significantly higher in PCa CD133(+) stem/progenitor cells compared with CD133(-) non-stem/progenitor cells. Knockdown of TR4 levels in the established PCa stem/progenitor cells and the CD133(+) population of the C4-2 PCa cell line with lentiviral TR4 siRNA led to increased drug sensitivity to the two commonly used chemotherapeutic drugs, docetaxel and etoposide, judging from significantly reduced IC50 values and increased apoptosis in the TR4 knockdown cells. Mechanism dissection studies found that suppression of TR4 in these stem/progenitor cells led to down-regulation of Oct4 expression, which, in turn, down-regulated the IL-1 receptor antagonist (IL1Ra) expression. Neutralization experiments via adding these molecules into the TR4 knockdown PCa stem/progenitor cells reversed the chemoresistance, suggesting that the TR4-Oct4-IL1Ra axis may play a critical role in the development of chemoresistance in the PCa stem/progenitor cells. Together, these studies suggest that targeting TR4 may alter chemoresistance of PCa stem/progenitor cells, and this finding provides the possibility of targeting TR4 as a new and better approach to overcome the chemoresistance problem in PCa therapeutics.


Radiotherapy for cerebral metastases.
Whole brain radiotherapy (WBRT) for patients with unresected brain metastases results in symptomatic response in about 50% of patients and improvement in median survival to 3 to 6 months. Most patients with brain metastases are appropriately treated with a conventional palliative course of 30 Gy in 10 fractions over 2 weeks, although accelerated hyperfractionation with 32 Gy to the whole brain plus a boost to at least 54.4 Gy at 1.6 Gy twice daily yields better results for patients with solitary metastases. Patients with a life-expectancy of greater than 6 months should receive at most that or equal to 2.0 Gy per fraction to minimize the risk of radiation-induced leukoencephalopathy and dementia. Patients with good performance status, absent or controlled primary tumor, and no extracranial metastases might benefit from surgical resection or radiosurgery (with or without adjunctive WBRT) to improve local control.


Geographically variable selection in Ambystoma tigrinum virus (Iridoviridae) throughout the western USA.
We investigated spatially variable selection in Ambystoma tigrinum virus (ATV) which causes frequent and geographically widespread epizootics of the tiger salamander, Ambystoma tigrinum. To test for evidence of selection, we sequenced several coding and noncoding regions from virus strains isolated from epizootics throughout western North America. Three of the sequenced regions contained homologues for genes putatively involved in host immune evasion and virulence: eIF-2alpha, caspase activation and recruitment domain (CARD) and beta-OH-steroid oxidoreductase. Selection analysis showed evidence of very strong purifying selection on eIF-2alpha, purifying selection within certain viral clades on CARD and positive selection on beta-OH-steroid oxidoreductase within certain clades. Analysis using MULTIDIVTIME and Tajima's relative rate tests indicate accelerated rates of evolution within clades associated with anthropogenic movement. These clades also demonstrate greater spatial variability in selection, suggesting a lack of local adaptation (i.e. locally adapted populations should exhibit little to no selection because of absent or reduced variation in fitness once a fitness optimum is reached). Increased transfer of non-native viral strains to naïve salamander populations, in conjunction with local maladaptation as a result of local selection pressures, may explain the spread and emergence of ATV epizootics in A. tigrinum in western North America.


Acute Opioid Withdrawal Mimicking Postoperative Joint Infection Following anterior cruciate ligament (ACL) Reconstruction: A Case Report.
BACKGROUND A short course of opioid narcotics is often prescribed for postoperative anterior cruciate ligament (ACL) reconstruction pain management. Unfortunately, there is a well-documented incidence of opioid withdrawal syndrome (OWS) following short-term use of these medications. OWS can present with symptoms such as influenza-like illness. It is important to differentiate OWS from infectious illnesses, especially after surgery. CASE REPORT We present a case of OWS in a patient who underwent ACL reconstruction 7 days prior. The patient's OWS symptoms were similar to symptoms of a postoperative infection. The knee was aspirated, and the analysis of the aspirate was not concerning for an infection. The patient's symptoms spontaneously resolved on postoperative day 10. This is the first documented case of OWS mimicking ACL reconstruction joint infection. CONCLUSIONS OWS after surgery may present with symptoms similar to joint infection. It is important to consider OWS as a potential complication after surgery and differentiate it from infection to avoid any further unnecessary invasive treatments for the patient.


Genome-wide characterization of circRNA expression profile in overexpression of RIP2 chicken macrophages associated with avian pathogenic E.coli infection.
Avian pathogenic E. coli (APEC) can cause localized and systemic diseases in poultry, threatening human health via meat or egg contamination and resulting in considerable economic losses to the poultry industry globally. Increasing evidence shows circRNAs were widely involved in various biological processes. However, the role of circRNAs in the host response against APEC infection, especially correlated with the regulation of RIP2, remains unclear. Herein, the RNAseq technology was used to identify the circRNA expression profiles in the overexpression of RIP2 macrophages with or without APEC infection. A total of 256 and 287 differentially expressed (DE) circRNAs were identified in the overexpression of RIP2 group (oeRIP2) vs. the wild-type group (WT) and oeRIP2 + APEC vs. APEC, respectively, whose parental genes were involved in MAPK signalling pathway, Wnt signalling pathway, focal adhesion, tight junction, and VEGF signalling pathways. Specifically, the key circRNAs, such as 5:814443-825127, 10:18922360-18928461, 2:8746306-8750639, and 2:124177751-124184063 might play a critical role in APEC infection and the regulation of RIP2. As a whole, these findings will facilitate understanding the molecular mechanism underlying circRNAs, especially related to the regulation of the RIP2 gene. Meanwhile, the study may offer new ideas to improve host immune and inflammatory response against APEC infection.


Identification of mono-ubiquitinated LDH-A in skeletal muscle cells exposed to oxidative stress.
We previously reported that oxidative stress is associated with unloading-mediated ubiquitination of muscle proteins. To further elucidate the involvement of oxidative stress in ubiquitination, we examined the ubiquitination profile in rat myoblastic L6 cells after treatment with hydrogen peroxide. Hydrogen peroxide induced many ubiquitinated proteins with low molecular masses (less than 60 kDa) as well as high molecular masses (more than 160 kDa). Among them, a 42-kDa-ubiquitinated protein was abundantly accumulated and immediately disappeared after the treatment. Microsequencing revealed that the 42-kDa-protein was identical to the mono-ubiquitinated form of rat lactate dehydrogenase A (LDH-A), and we confirmed that hydrogen peroxide induced the mono-ubiquitination of LDH-A in COS7 cells overexpressing LDH-A and ubiquitin. Under unloading conditions, such as tail-suspension and spaceflight, mono-ubiquitinated LDH was accumulated in gastrocnemius muscle. Interestingly, E-64-d plus pepstatin, lysosomal protease inhibitors, further accumulated mono-ubiquitinated LDH-A in the cells after treatment with hydrogen peroxide, while they did not affect the amount of poly-ubiquitinated LDH. In contrast, epoxomicin, a potent proteasome inhibitor, did not change the amount of mono-ubiquitinated LDH-A in L6 cells treated with hydrogen peroxide, although it significantly increased the amount of poly-ubiquitinated LDH. Our results suggest that oxidative stress induces not only poly-ubiquitination but also mono-ubiquitination of LDH-A, which may be involved in its lysosomal degradation during unloading.