Factors associated with empathy among community pharmacists in Lebanon.
Empathy is the cornerstone of the relationship between the healthcare provider and the patient. In Lebanon, no studies have investigated the factors associated with empathy among community pharmacists. Hence, the importance of this research to better understand empathy and help community pharmacists with this vital aspect of their practice. This study aimed to evaluate empathy and possible factors associated with it among Lebanese community pharmacists. This cross-sectional study was carried out between March and July 2018. It enrolled a proportionate random sample of 435 community pharmacists from all Lebanese districts. The Epi info software calculated the minimum sample size, based on a total number of 3762 community pharmacists, with an expected frequency of 50% of pharmacists with low empathy, and a 95% confidence interval. The minimal sample size required was 350 community pharmacists; our sample size was 435 to account for missing values. Our results revealed that 228 (53.4%) pharmacists had low empathy. Lower empathy was significantly associated with more physical (Beta = - 0.331) and mental (Beta = - 0.126) work fatigue, higher age (Beta = - 0.125) and a practice experience between 3 years and less than 6 years compared to less than 6 months (Beta = - 2.440). This study shed the light on some factors associated with empathy among Lebanese community pharmacists. Low empathy levels were significantly associated with factors such as age, practice experience, and mental and physical work fatigue, all of which impact the practice, as the accepted model of pharmacy practice requires that pharmacists establish effective communication and use interpersonal skills. Therefore, developing empathetic communication skills is considered essential. Furthermore, increased mental and physical work fatigue should not hinder community pharmacists' access to self-care, whether for their mental or physical health.


SMX degradation by ozonation and UV radiation: a kinetic study.
The rate constants of sulfamethoxazole (SMX) degradation by ozonation and UV(254) radiation were investigated under various parameters including influent ozone gas concentration, initial SMX concentration, UV light intensity, ionic strength, water quality in terms of varying anions (bicarbonate, sulfate and nitrate), humic acid (HA) and pH. The results indicated that the removal of SMX by ozonation and UV(254) radiation fitted well to a pseudo first-order kinetic model and the rate constants were in the range of (0.9-9.8)×10(-3) and (1.7-18.9)×10(-3) s(-1), respectively. The second-order rate constants of SMX with ozone (ko(3)), under varying operational parameters, were also determined and varied in the range of (0.60-3.38)±0.13×10(5)M(-1) s(-1). In addition, SMX degradation through UV pretreatment followed by ozonation in the presence of HA was proved to be an effective method which can remove SMX with a low ozone dose. The results suggested that ozonation of SMX was more affected by concentration of influent ozone gas, alkalinity, and HA, while incident UV light intensity, pH, and HA were the dominant factors influencing UV degradation of SMX.


Qualitative and quantitative analysis of endocytic recycling.
Endocytosis, which encompasses the internalization and sorting of plasma membrane (PM) lipids and proteins to distinct membrane-bound intracellular compartments, is a highly regulated and fundamental cellular process by which eukaryotic cells dynamically regulate their PM composition. Indeed, endocytosis is implicated in crucial cellular processes that include proliferation, migration, and cell division as well as maintenance of tissue homeostasis such as apical-basal polarity. Once PM constituents have been taken up into the cell, either via clathrin-dependent endocytosis (CDE) or clathrin-independent endocytosis (CIE), they typically have two fates: degradation through the late-endosomal/lysosomal pathway or returning to the PM via endocytic recycling pathways. In this review, we will detail experimental procedures that allow for both qualitative and quantitative assessment of endocytic recycling of transmembrane proteins internalized by CDE and CIE, using the HeLa cervical cancer cell line as a model system.


Analysis of recombinat glycoproteins by mass spectrometry.
The advent of new technologies for analysis of biopolymers by mass spectrometry has revolutionised strategies for recombinant protein characterization. The principal recent developments have been matrix-assisted laser desorption/ionization and electrospray ionization mass spectrometry. Using these tools, accurate molecular mass determinations can now be obtained routinely-often using minute (picomole-femtomole) quantities of protein or protein fragments. These techniques have proved indispensible for detailed characterization of the post-translational modifications of recombinant proteins produced by eukaryotic systems. Glycosylation is arguably the most important and complex of these modifications and has prompted widespread use of these new techniques. In this mini-review article I describe recent advances in the use of mass spectrometry for analysis of recombinant glycoproteins.


Cryoelectron microscopy of vitreous sections: a step further towards the native state.
Nuclear architecture has been investigated intensively by various electron microscopy (EM) methods. Most of these require chemical fixation of the sample, although cryofixation has also been used in combination with cryosubstitution and resin embedding. This approach allowed one to considerably increase the knowledge about the structural features of different nuclear domains and their involvement in nuclear functions. Cryoelectron microscopy of vitreous sections (CEMOVIS) has added a new dimension to the ultrastructural analysis of the cell nucleus, especially thanks to the possibility of observing the specimen in its hydrated state. In this way one can analyse, at high resolution, cellular structures as close as possible to their native state. In this chapter we describe in detail the different steps of the CEMOVIS method, which should allow an electron microscopist to perform cryosectioning and cryoelectron microscopy of vitrified biological material.


Movement velocity during high- and low-velocity resistance exercise protocols in older adults.
The primary aim of the present study was to determine the actual movement velocity of high-velocity, low-load (HVLL) and low-velocity, high-load (LVHL) resistance exercise in a group of older adults. The secondary aim was to examine the differences in velocities produced between male and females. In a crossover study design, four males (age: 67±3years) and five females (age: 68±2years) completed three sets of leg press, calf raise, leg curl, leg extension, chest press, seated row, bicep curl and tricep extension on six separate occasions (three HVLL and three LVHL sessions). The command "as fast as possible" was given for the concentric phase of HVLL, and 2s using a 60-bpm metronome controlled the concentric phase during LVHL. Participants had three days of recovery between each session, and a 7-day period before crossing over to the other protocol. Movement velocity was measured during the concentric and eccentric phases of resistance exercise using two-dimensional video analysis. The concentric phases for all exercises were significantly faster (P<0.001) during HVLL compared to LVHL. Furthermore, males produced significantly greater velocities than females during the concentric phase of the chest press, seated row, bicep curl, and tricep extension for both HVLL and LVHL (P<0.05). These protocols provide a simple solution for exercise professionals to ensure that older adults are training at desired velocities when carrying out resistance exercise, without the need for equipment that measures velocity.


Autoradiography of 32P and 14C incorporation into protoplasts as a means of determining the percentage of virus infected protoplasts.
Stripping Film Autoradiography (SFA) was used to measure percentage protoplast infection. Control and infected protoplasts were incubated in the presence of [32P]orthophosphate or [14C]leucine fixed onto glass slides and placed in contact with a sensitive photographic emulsion. Infected protoplasts were distinguished by blackened areas of exposed film which coincided with protoplasts containing labelled virus products. The use of SFA is demonstrated for two different virus/protoplast systems, namely tobacco mosaic virus (TMV) in tobacco and turnip yellow mosaic virus (TYMV) in rape. The method detects infection as early as 12-16 h post-inoculation and UV irradiation is not necessary for reducing background interference from labelled host proteins.


Development of microemulsion of tamsulosin and dutasteride for benign prostatic hyperplasia therapy.
Benign prostatic hyperplasia (BPH) is a condition characterized by a benign enlargement of the prostate that interferes with the normal flow of urine. This disease is treated with the oral administration of combination therapy comprising α-blockers (tamsulosin) and 5α-reductase inhibitors (dutasteride). However, these compounds have low bioavailability. Thus, transdermal microemulsions aimed at promoting permeation and efficient targeted drug delivery through the skin are used. The objectives of this study were to obtain microemulsions of the combined doses of dutasteride and tamsulosin and evaluate their anti-hyperplastic activity in vivo. A phase diagram (4:1) was obtained for the choice of microemulsions. The microemulsions were characterized in terms of the droplet size, rheology, pH, conductivity, refractive index, in vitro release profile, and antihyperplastic effect in vivo. A method for the simultaneous quantification of drugs was developed using UV-vis spectroscopy. The microemulsions had an average size less than 116 nm, an acidic pH and low viscosity. The conductivity ranged from 6.18 to 185.2 μS/cm. The in vitro release profile was sustained for 6 h. Microemulsions promoted the reduction in the size of testosterone-dependent organs (prostate and seminal vesicles). Transdermal formulations for the treatment of BPH were obtained as a therapeutic alternative to conventional treatments.


Clinical evaluation of a new bilayer "artificial skin" composed of collagen sponge and silicone layer.
A bilayer "artificial skin" composed of an outer layer of silicone and an inner sponge layer of collagen and chondroitin sulphate has been developed by modifying the technique proposed by Yannas et al. (1980). Following experimental successes, the "artificial skin" was applied clinically. It was placed on the skin defects of 10 patients. Three weeks after application the outer layer of silicone sheet was peeled off and thin split thickness skin was grafted onto the newly synthesised dermis-like tissue. Secondary skin grafts took perfectly in all cases and postoperative appearance was satisfactory.


Alterations of Mg2+ After Hemorrhagic Shock.
Hemorrhagic shock is generally characterized by hemodynamic instability with cellular hypoxia and diminishing cellular function, resulting from an imbalance between systemic oxygen delivery and consumption and redistribution of fluid and electrolytes. Magnesium (Mg) is the fourth most abundant cation overall and second most abundant intracellular cation in the body and an essential cofactor for the energy production and cellular metabolism. Data for blood total Mg (tMg; free-ionized, protein-bound, and anion-bound forms) and free Mg2+ levels after a traumatic injury are inconsistent and only limited information is available on hemorrhagic effects on free Mg2+ as the physiologically active form. The aim of this study was to determine changes in blood Mg2+ and tMg after hemorrhage in rats identifying mechanism and origin of the changes in blood Mg2+. Hemorrhagic shock produced significant increases in blood Mg2+, plasma tMg, Na+, K+, Cl-, anion gap, partial pressures of oxygen, glucose, and blood urea nitrogen but significant decreases in RBC tMg, blood Ca2+, HCO3-, pH, partial pressures of carbon dioxide, hematocrit, hemoglobin, total cholesterol, and plasma/RBC ATP. During hemorrhagic shock, K+, anion gap, and BUN showed significant positive correlations with changes in blood Mg2+ level, while Ca2+, pH, and T-CHO correlated to Mg2+ in a negative manner. In conclusion, hemorrhagic shock induced an increase in both blood-free Mg2+ and tMg, resulted from Mg2+ efflux from metabolic damaged cell with acidosis and ATP depletion.


Drug resistant parasites and fungi from a one-health perspective: A global concern that needs transdisciplinary stewardship programs.
Antimicrobials including antibiotics, antiparasitic, and antifungals, are subjected to resistance. In this context, Public Health Organizations called for a One Health approach because antimicrobials used to treat different infectious diseases in animals and plants may be the same than those used in humans. Whereas mechanisms of resistance transmission from animals or environment to humans should be considered differently if related to prokaryotic or eukaryotic pathogens, their impact can be considered as a whole. In that respect, we discussed the use of anti-parasitic in animals including anticoccidials, anthelmintics, and insecticides-acaricides, and the use of azoles in the environment that may both favor the development of drug resistance in humans. In light of the current situation, there is an urgent need for a transdisciplinary approach through anti-parasitic and antifungal stewardship programs in humans, animals, and environment, especially in the era of COVID-19 pandemic that will probably aggravate antimicrobial resistance.


Choleretic and cholestatic effects of infused bile salts in the rat.
In rats, at low infusion rates taurocholate (TC), taurochenodeoxycholate (TCDC) and taurodeoxycholate (TCD) each produced an increase in bile flow of 20-50%. However, at high infusion rates (5-20 mumoles min-1kg-1) the cholestatic effects of the bile salts were revealed and the relative toxicity of the bile salts was seen to be TDC greater than TCDC greater than TC.


Post-training ethanol disrupts trace conditioned fear in rats: effects of timing of ethanol, dose and trace interval duration.
Ethanol has complex effects on memory performance, although hippocampus-dependent memory may be especially vulnerable to disruption by acute ethanol intoxication occurring during or shortly after a training episode. In the present experiments, the effects of post-training ethanol on delay and trace fear conditioning were examined in adolescent rats. In Experiment 1, 30-day-old Sprague-Dawley rats were given delay or trace conditioning trials in which a 10s flashing light CS was paired with a 0.5 mA shock US. For trace groups, the trace interval was 10 s. On days 31-33, animals were administered ethanol once daily (0.0 or 2.5 g/kg via intragastric intubation), and on day 34 animals were tested for CS-elicited freezing. Results showed that post-training ethanol affected the expression of trace, but had no effect on delay conditioned fear. Experiment 2 revealed that this effect was dose-dependent; doses lower than 2.5 g/kg were without effect. Experiment 3 evaluated whether proximity of ethanol to the time of training or testing was critical. Results show that ethanol administration beginning 24h after training was more detrimental to trace conditioned freezing than administration that was delayed by 48 h. Finally, in Experiment 4 animals were trained with one of three different trace intervals: 1, 3 or 10s. Results indicate that post-training administration of 2.5 g/kg ethanol disrupted trace conditioned fear in subjects trained with a 10s, but not with a 1 or 3s, trace interval. Collectively the results suggest that ethanol administration impairs post-acquisition memory processing of hippocampus-dependent trace fear conditioning.


A Photonic 1 × 4 Power Splitter Based on Multimode Interference in Silicon-Gallium-Nitride Slot Waveguide Structures.
In this paper, a design for a 1 × 4 optical power splitter based on the multimode interference (MMI) coupler in a silicon (Si)-gallium nitride (GaN) slot waveguide structure is presented-to our knowledge, for the first time. Si and GaN were found as suitable materials for the slot waveguide structure. Numerical optimizations were carried out on the device parameters using the full vectorial-beam propagation method (FV-BPM). Simulation results show that the proposed device can be useful to divide optical signal energy uniformly in the C-band range (1530-1565 nm) into four output ports with low insertion losses (0.07 dB).


Inclusive fitness analysis of cumulative cultural evolution in an island-structured population.
The success of humans on the globe is largely supported by our cultural excellence. Our culture is cumulative, meaning that it is improved from generation to generation. Previous works have revealed that two modes of learning, individual learning and social learning, play pivotal roles in the accumulation of culture. However, under the trade-off between learning and reproduction, one's investment into learning is easily exploited by those who copy the knowledge of skillful individuals and selfishly invest more efforts in reproduction. It has been shown that in order to prevent such a breakdown, the rate of vertical transmission (i.e. transmission from parents to their offspring) of culture must be unrealistically close to one. Here we investigate what if the population is spatially structured. In particular, we hypothesize that spatial structure should favor highly cumulative culture through endogenously arising high kinship. We employ Wright's island model and assume that cultural transmission occurs within a local island. Our inclusive fitness analysis reveals combined effects of direct fitness of the actor, indirect fitness through relatives in the current generation, and indirect fitness through relatives in future generations. The magnitude of those indirect benefits is measured by intergenerational coefficients of genetic relatedness. Our result suggests that the introduction of spatial structure raises the stationary level of culture in the population, but that the extent of its improvement compared with a well-mixed population is marginal unless spatial localization is extreme. Overall, our model implies that we need an alternative mechanism to explain highly cumulative culture of modern humans.


NAG level differences in panic disorder and agoraphobia.
It is not clear if panic disorder (PD) and agoraphobia are variants of the same disorder or distinct diseases. A laboratory test could help resolve this issue. Research has shown that levels of the urinary lysosomal enzyme N-acetyl-beta-glusosaminidase (NAG) differ between patients with various psychiatric disorders. This study examined whether NAG levels would be similar in PD and agoraphobia, suggesting the two disorders may be the same disorder, or different, suggesting they may be distinct diseases. Differences found could suggest either qualitative or quantitative distinctions between these disorders. Ninety-one agoraphobics were compared to 24 patients with panic disorder. NAG levels were significantly lower in panic patients compared to agoraphobic patients 9.7+/- 8 versus 22+/- 21; P< .005. These data provide limited support for the hypothesis that PD and agoraphobia may be distinct diseases.


Prognostic significance of Versican expression in gastric adenocarcinoma.
Gastric cancer (GC) is the leading malignancy in the digestive system. Versican is a ubiquitous component of the extracellular matrix and has a role in tumor progression. We aim to examine the expression of Versican in GC and the relationship between Versican levels and patient survival. We detected the mRNA expression of Versican in tumorous pairs and adjacent normal tissues (ANTs) of 78 GC patients by quantitative real-time polymerase chain reaction. The protein expression of Versican in 101 cases of matched GC and ANT, as well as in 27 intraepithelial neoplastic (IN) samples, was evaluated by immunohistochemistry. We analyzed the correlation between Versican levels and clinical outcomes. Finally, we performed CCK-8 cell counting assay and transwell assay in GC cell lines. Versican mRNA expression was significantly greater in tumor tissues (P<0.001) than in ANT. Versican was majorly expressed in the stroma surrounding tumor epithelium and minorly some areas of tumor epithelium. The Versican expression level was higher in GC than in ANT (P=0.004), but no significant difference was observed between ANT and IN (P=0.517). The Versican mRNA and protein levels were consistent in GC. High Versican mRNA and protein expression correlated with greater tumor invasion depth (P=0.030, P=0.027). Univariate and multivariate analysis revealed that patients with high Versican mRNA expression exhibited poor disease-specific survival (P<0.001). In vitro experiments showed that Versican overexpression promoted cell proliferation and invasion. Our data indicate that Versican may be a novel prognostic indicator in GC and may be a potential target for clinical diagnosis.


Local anti-inflammatory activity of Tamus communis.
The effects of an ethanol root extract of Tamus communis were documented on cotton pellet granuloma in rats. The inhibitory effect of the solvent-free extract (5-20 mg/pellet) on granuloma formation was comparable to that of reference drugs benzydamine HCl (5-20 mg/pellet) and hydrocortisone (5 mg/pellet). The local anti-inflammatory activity of T. communis was not accompanied by a decrease in body weight.


Intravesical therapy of superficial bladder cancer.
The aim of treatment of superficial bladder cancer with intravesical therapy is threefold: (1) Eradicate existing disease. (2) Prevention of recurrence. (3) Prevention of tumor progression. The prognostic factors allow differentiation in different risk groups and this is useful in planning treatment. Studies on pharmacokinetics have proved the efficacy of optimized drug delivery. Comparing resection with and without intravesical chemotherapy a short term approximately 15% decrease in tumor recurrence with chemotherapy can be obtained but no effect on progression was proven. No agent has proved more effective than the other. Single, early instillation of chemotherapy has proven effective but the role of maintenance therapy has been controversial. Immunotherapy in the form of Bacillus Calmette-Guerin generally have proven more efficacious than chemotherapy. The results in comparison to mitomycin C have not been as conclusive. Several new approaches are explored to improve the efficacy of this therapy.


Probiotics for the improvement of metabolic profiles in patients with metabolic-associated fatty liver disease: A systematic review and meta-analysis of randomized controlled trials.
This meta-analysis of randomized controlled trials (RCTs) was conducted to assess the efficacy of probiotics in the treatment of metabolic-associated fatty liver disease (MAFLD) mainly in terms of liver function, glucose and lipid metabolism, and inflammation. RCTs were searched on PubMed, Web of Science, Embase, and the Cochrane Library until June 2022. A meta-analysis was performed on the therapeutic efficacy of probiotics on liver function, glucose and lipid metabolism, and inflammatory biomarkers by using RevMan 5.4 software. A total of 772 patients from 15 studies were included in the analysis. The methodological quality varied across studies. We found that adding probiotic therapies could reduce the levels of alanine aminotransferase [mean difference (MD): -11.76 (-16.06, -7.46), p < 0.00001], aspartate aminotransferase (MD: -9.08 (-13.60, -4.56), p < 0.0001], γ-glutamyltransferase [MD: -5.67 (-6.80, -4.54), p < 0.00001] and homeostasis model assessment-insulin resistance [MD: -0.62 (-1.08, -0.15), p = 0.01], in patients with MAFLD compared with those in control individuals. However, there was no statistically significant improvement in the levels of total cholesterol, triglycerides, low-density lipoprotein cholesterol, C-reactive protein and tumor necrosis factor α among patients with MAFLD. Subgroup analyses showed that other key factors, such as age, participants' baseline body mass index, and the duration of intervention, may influence probiotic therapy outcomes. There is promising evidence that probiotic supplementation can reduce liver enzyme levels and regulate glycometabolism in patients with MAFLD. Further rigorous and long-term trials exploring these novel therapeutic perspectives are warranted to confirm these results.


Phase II trial of hypomethylating agent combined with nivolumab for acute myeloid leukaemia relapse after allogeneic haematopoietic cell transplantation-Immune signature correlates with response.
Acute myeloid leukaemia (AML) relapse after allogeneic haematopoietic cell transplantation (allo-HCT) is often driven by immune-related mechanisms and associated with poor prognosis. Immune checkpoint inhibitors combined with hypomethylating agents (HMA) may restore or enhance the graft-versus-leukaemia effect. Still, data about using this combination regimen after allo-HCT are limited. We conducted a prospective, phase II, open-label, single-arm study in which we treated patients with haematological AML relapse after allo-HCT with HMA plus the anti-PD-1 antibody nivolumab. The response was correlated with DNA-, RNA- and protein-based single-cell technology assessments to identify biomarkers associated with therapeutic efficacy. Sixteen patients received a median number of 2 (range 1-7) nivolumab applications. The overall response rate (CR/PR) at day 42 was 25%, and another 25% of the patients achieved stable disease. The median overall survival was 15.6 months. High-parametric cytometry documented a higher frequency of activated (ICOS+ , HLA-DR+ ), low senescence (KLRG1- , CD57- ) CD8+ effector T cells in responders. We confirmed these findings in a preclinical model. Single-cell transcriptomics revealed a pro-inflammatory rewiring of the expression profile of T and myeloid cells in responders. In summary, the study indicates that the post-allo-HCT HMA/nivolumab combination induces anti-AML immune responses in selected patients and could be considered as a bridging approach to a second allo-HCT. Trial-registration: EudraCT-No. 2017-002194-18.


Using classification and regression tree modelling to investigate treatment response to a single low-dose ketamine infusion: Post hoc pooled analyses of randomized placebo-controlled and open-label trials.
Evidence suggests that clinical markers, such as comorbid anxiety, body weight, and others can assist in predicting response to low-dose ketamine infusion in treatment resistant depression patients. However, whether a composite of clinical markers may improve the predicted probability of response is uncertain. The current study investigated the results of our previous randomized placebo-controlled and open-label trials in which 73 patients with treatment-resistant depression (TRD) received a single ketamine infusion of 0.5 mg/kg. Clinical characteristics at baseline, including depression severity, duration of the current episode, obesity, comorbidity of anxiety disorder, and current suicide risk, were assessed as potential predictors in a classification and regression tree model for treatment response to ketamine infusion. The predicted probability of a composite of age at disease onset, depression severity, duration of current episode, and obesity/overweight was significantly greater (area under curve = .736, p = .001) than that of any one marker (all p > .05). The most powerful predictors of treatment response to ketamine infusion were younger age at disease onset and obesity/overweight. The strongest predictors of treatment nonresponse were longer duration of the current episode and greater depression severity at baseline. Depression severity, duration of the current episode, obesity, and age at disease onset may predict treatment response versus nonresponse to low-dose ketamine infusion. However, whether our predicted probability for a single infusion may be applied to repeated infusions would require further investigation. UMIN Clinical Trials Registry (UMIN000023581 and UMIN000016985).


Histomorphometric analysis of bone in idiopathic hypercalciuria before and after treatment with thiazide.
Twenty-seven normocalcemic patients aged 11-69 yrs with recurrent renal stone formation and idiopathic hypercalciuria were studied before and after treatment with hydrochlorthiazide (TD) 50 mg twice a day for 6 months. Hypercalciuria was defined as a 24 h renal calcium excretion of more than 7.5 mmol for males and 6.3 mmol for females. Quantitative histomorphometric analysis of iliac crest bone biopsies were performed before and after treatment. TD treatment increased the adjusted serum calcium level (p less than 0.01), whereas no significant effects on the serum levels of phosphorous, alkaline phosphatase or iPTH were found. The urinary calcium/creatinine ratio decreased (p less than 0.01) during TD treatment, whereas no change in the urinary phosphorous/creatinine ratio was found. The histomorphometric analysis revealed a reduction in the extent of eroded surfaces (p less than 0.05) and bone formation rate (p less than 0.05) as well as a decrease in the osteoid thickness (p less than 0.05) during TD treatment. No effect on the trabecular bone volume was found. A reduction in the activation frequency of new remodeling sites and thereby a reduced bone turnover during TD treatment can explain the observed histomorphometric changes. The decrease in osteoid thickness may be related to the increased serum calcium concentration leading to better conditions for mineralization.


Mysterious oil spill on the Brazilian coast - Part 2: A probabilistic approach to fill gaps of uncertainties.
Over 5000 tons of spilled oil reached the northeast coast of Brazil in 2019. The Laboratory for Computational Methods in Engineering (LAMCE/COPPE/UFRJ) employed time-reverse modeling and identify multiple potential source areas. As time-reverse modeling has many uncertainties, this article carried out a methodology study to mitigate them. A probabilistic modeling using Monte Carlo approach was developed to test these source areas with the Spill, Transport, and Fate Model (STFM) and a scenario tree methodology was used to select possible spill scenarios. To estimate the performance of Lagrangian models, two new model performance evaluations were added to Chang and Hanna (2004). The combination of probabilistic simulations, scenario tree analysis, and model performance evaluation proved to be a powerful tool for mitigating the uncertainties of time-reverse modeling, yielding good results and simple implementation.


[Linguistic portrait of a Russian-German speaking woman with dementia : Longitudinal observations from a German language nursing home].
The advantages of an individual use of the linguistic resources of multilingual persons in need of care are obvious, but quite often an implementation is hardly possible. This leads to a reduction of the linguistic abilities of those concerned. This case study shows the differences in the abilities of a Russian-German bilingual woman suffering from dementia in expressing herself in two languages and traces the longitudinal changes. Data material from 4 years of observation (including conversation recordings, linguistic tests and interviews with nursing personnel) was used to create the linguistic portrait. The expression abilities and changes in the languages were different. In German, the receptive abilities at word level and sentence level and productive abilities at word level remained unchanged over the entire period. In Russian, the situation was less stable; at the beginning, she was an interested interlocutor who could express herself fluently at all levels. Over time, her syntactic complexity and willingness to interact decreased; nevertheless, better and productive Russian skills remained. The asymmetrical distribution of the two languages entails the danger of a one-sided assessment of the general abilities of the person concerned. This underlines the need for a differentiated view of the languages.


Whole exome sequencing identifies novel germline variants of SLC15A4 gene as potentially cancer predisposing in familial colorectal cancer.
About 15% of colorectal cancer (CRC) patients have first-degree relatives affected by the same malignancy. However, for most families the cause of familial aggregation of CRC is unknown. To identify novel high-to-moderate-penetrance germline variants underlying CRC susceptibility, we performed whole exome sequencing (WES) on four CRC cases and two unaffected members of a Polish family without any mutation in known CRC predisposition genes. After WES, we used our in-house developed Familial Cancer Variant Prioritization Pipeline and identified two novel variants in the solute carrier family 15 member 4 (SLC15A4) gene. The heterozygous missense variant, p. Y444C, was predicted to affect the phylogenetically conserved PTR2/POT domain and to have a deleterious effect on the function of the encoded peptide/histidine transporter. The other variant was located in the upstream region of the same gene (GRCh37.p13, 12_129308531_C_T; 43 bp upstream of transcription start site, ENST00000266771.5) and it was annotated to affect the promoter region of SLC15A4 as well as binding sites of 17 different transcription factors. Our findings of two distinct variants in the same gene may indicate a synergistic up-regulation of SLC15A4 as the underlying genetic cause and implicate this gene for the first time in genetic inheritance of familial CRC.


[Immune system and allergies-An unholy alliance].
Various factors affect the maturation of the infantile immune system both prenatally and postnatally, including risk and protective factors from the environment, nutrition, genetics and epigenetics. The microbiome seems to play a substantial role. The complex interaction and regulation of all these factors is ultimately decisive for whether a child develops an allergy during the course of development of the immune system. The genetic components play a decisive role in the development of allergic diseases. The epigenetic regulation could represent a mechanism where environmental influences act upon the immune regulation in the emergence of allergic diseases. The main factors in the pathophysiology of allergic reactions are a dysregulation of various cells of the innate and acquired immune systems as well as their interaction. This review describes the role of various T helper cell types in allergic diseases. The incidence and duration of airway infections are clearly increased in allergic patients compared to nonallergic controls. In addition to functional aspects, the reason for the more frequent infections is an impairment of the immune defence by the allergy-related persisting inflammation of the mucous membranes. These mechanisms must be differentiated from a true immunodeficiency. Allergic rhinitis (AR) and bronchial asthma are nowadays no longer defined as separate diseases but as two forms of expression of an atopic entity with a similar pathology. Both diseases can be mediated by immunoglobulin E and be elicited by identical triggers. A bronchial hyperreactivity is detectable in the majority of patients with AR but without clinical asthma.


Mindfulness in the focus of the neurosciences - The contribution of neuroimaging to the understanding of mindfulness.
Mindfulness affects human levels of experience by facilitating the immediate and impartial perception of phenomena, including sensory stimulation, emotions, and thoughts. Mindfulness is now a focus of neuroimaging, since technical and methodological developments in magnetic resonance imaging have made it possible to observe subjects performing mindfulness tasks. We set out to describe the association between mental processes and characteristics of mindfulness, including their specific cerebral patterns, as shown in structural and functional neuroimaging studies. We searched the MEDLINE databank of references and abstracts on life sciences and biomedical topics via PubMed using the keywords: "mindfulness," "focused attention (FA)," "open monitoring (OM)," "mind wandering," "emotional regulation," "magnetic resonance imaging (MRI)" and "default mode network (DMN)." This review extracted phenomenological experiences across populations with varying degrees of mindfulness training and correlated these experiences with structural and functional neuroimaging patterns. Our goal was to describe how mindful behavior was processed by the constituents of the default mode network during specific tasks. Depending on the research paradigm employed to explore mindfulness, investigations of function that used fMRI exhibited distinct activation patterns and functional connectivities. Basic to mindfulness is a long-term process of learning to use meditation techniques. Meditators progress from voluntary control of emotions and subjective preferences to emotional regulation and impartial awareness of phenomena. As their ability to monitor perception and behavior, a metacognitive skill, improves, mindfulness increases self-specifying thoughts governed by the experiential phenomenological self and reduces self-relational thoughts of the narrative self. The degree of mindfulness (ratio of self-specifying to self-relational thoughts) may affect other mental processes, e.g., awareness, working memory, mind wandering and belief formation. Mindfulness prevents habituation and the constant assumptions associated with mindlessness. Self-specifying thinking during mindfulness and self-relational thinking in the narrative self relies on the default mode network. The main constituents of this network are the dorsal and medial prefrontal cortex, and posterior cingulate cortex. These midline structures are antagonistic to self-specifying and self-relational processes, since the predominant process determines their differential involvement. Functional and brain volume changes indicate brain plasticity, mediated by mental training over the long-term.


Nonspecific crossreacting antigen (NCA) is a major member of the carcinoembryonic antigen (CEA)-related gene family expressed in lung cancer.
Carcinoembryonic antigen (CEA) is one of the most important tumour markers in the management of human carcinoma, including lung cancer. So far, however, because of the nonspecificity of anti-CEA antibodies, it remains unclear whether the experimental measurements of CEA expression really reflect genuine CEA. In normal lung, nonspecific cross reacting antigen (NCA) has been described as a major component of CEA-related antigens. Recently isolated CEA and NCA cDNA clones enabled us to analyse CEA and NCA expression of in vivo tumour specimens and tumour cell lines at mRNA levels. NCA-specific mRNA (but not CEA-specific mRNA) was detected in all normal lung tissues examined. Of 21 lung cancer tissue specimens, nine expressed both NCA and CEA and five expressed only NCA. Of 16 tumour cell lines, two expressed only NCA and one expressed both NCA and CEA, although its level of CEA mRNA was weaker than that of NCA mRNA. Therefore, CEA-related mRNA expression was always accompanied by NCA mRNA expression; there were no cases of CEA mRNA expression alone. These findings suggest that NCA is a major member of the CEA-related gene family expressed in lung cancer.


Relationships between measures of fitness, physical activity, body composition and vascular function in children.
The prevalence of obesity and physical inactivity in Western countries has increased rapidly. Both are modifiable risk factors for cardiovascular disease. Atherosclerosis begins in childhood and endothelial dysfunction is its earliest detectable manifestation. We assessed flow-mediated dilation (FMD) in 129 children (75 female; 10.3+0.3 yrs; 54 male; 10.4; 0.3 yrs). FMD was normalised for differences in the eliciting shear rate stimulus between subjects (SR(AUC)). Fitness was assessed as peak oxygen uptake during an incremental treadmill exercise test (V O(2)peak). Body composition was measured using a dual-energy X-ray absorptiometry (DEXA) scan. Physical activity (PA) was assessed using Actigraph accelerometers. The cohort was split into tertiles according to FMD% and also FMD% corrected for SR(AUC) to gain insight into the determinants of vascular function. Across the cohort, significant correlations were observed between FMD%/SR(AUC) and DEXA percentage fat (r=-0.23, p=0.009) and percentage lean mass (r=0.21, p=0.008), and also with PA performed at moderate-to-high intensity (r=0.363, p=0.001). For children in the lowest FMD%/SR(AUC) tertile, a stronger relationship with all PA measures was observed, particularly with high intensity PA (r=0.572, P=0.003). Regression analysis revealed that high intensity PA was the only predictor of impaired FMD%/SR(AUC). These data suggest that traditional risk factors for CHD in adult populations impact upon vascular function in young people. Furthermore, it appears that individuals with impaired FMD may benefit from performing high intensity PA, whereas no relationships exist between FMD and lower intensities of PA or between PA and FMD in those subjects who possess preserved vascular function a priori.


Discussion on Microwave-Matter Interaction Mechanisms by In Situ Observation of "Core-Shell" Microstructure during Microwave Sintering.
This research aims to deepen the understanding of the interaction mechanisms between microwave and matter in a metal-ceramic system based on in situ synchrotron radiation computed tomography. A special internal "core-shell" microstructure was discovered for the first time and used as an indicator for the interaction mechanisms between microwave and matter. Firstly, it was proved that the microwave magnetic field acted on metal particles by way of inducing an eddy current in the surface of the metal particles, which led to the formation of a "core-shell" microstructure in the metal particles. On this basis, it was proposed that the ceramic particles could change the microwave field and open a way for the microwave, thereby leading to selective heating in the region around the ceramic particles, which was verified by the fact that all the "core-shell" microstructure was located around ceramic particles. Furthermore, it was indicated that the ceramic particles would gather the microwaves, and might lead to local heating in the metal-ceramic contact region. The focusing of the microwave was proved by the quantitative analysis of the evolution rate of the "core-shell" microstructure in a different region. This study will help to reveal the microwave-matter interaction mechanisms during microwave sintering.


Effect of interferon therapy on radionuclide imaging in chronic liver diseases due to HCV infection.
Interferon (alpha-IFN) exerts a modulating effect on the immune system. Kupffer cells of the liver play an important immunological role by their uptake of various agents and particles, including colloids. We sought to discover if alpha-IFN could enhance the colloid uptake function of the Kupffer cells. The effect of alpha-IFN therapy on radioisotope scans of the liver was studied in 20 patients with chronic liver disease due to hepatitic C virus (HCV) infection who received therapy at a dose of 3 million IU for 6 mo, in another 20 patients who received the same therapy for 12 mo and in matched control groups (10 patients with HCV infection for each study group) who did not receive alpha-IFN. A 99mTc-sulfur colloid scan of the liver was obtained for each group before and after therapy and, for control subjects, at the start and end of the study periods. The liver-to-spleen geometric mean ratio of colloid uptake was assessed. In the first study group, the mean rate of improvement in the liver-to-spleen ratio was 48% in 70% of patients, compared to 8% in 20% of controls (p < 0.05). In the second study group, mean liver-to-spleen ratio was 88% in 85% of patients, compared to 12% in 40% of controls (p < 0.001). Alpha-IFN therapy appears to enhance the colloidal uptake function of Kupffer cells, which adds a new dimension to the immunomodulatory effect of interferon.


Identification, characterization, and antimicrobial activity of a novel big defensin discovered in a commercial bivalve mollusc, Tegillarca granosa.
Molluscs, the second largest animal phylum on earth, primarily rely on cellular and humoral immune responses to fight against pathogen infection. Although antimicrobial peptides (AMPs) such as big defensin play crucial roles in the humoral immune response, it remains largely unknown in the ecological and economic important blood clam (Tegillarca granosa). In this study, a novel big defensin gene (TgBD) was identified in T. granosa through transcripts and whole genome searching. Bioinformatic analyses were conducted to explore the molecular characteristics of TgBD, and comparisons of TgBD with those reported in other molluscs were performed by multiple alignments and phylogenetic analysis. In addition, the expression patterns of TgBD in various tissues and upon bacterial challenge were investigated while the antimicrobial activity of synthetic N-terminal domain of TgBD was confirmed in vitro by radial diffusion experiment. Results obtained showed TgBD had an open reading frame (ORF) of 369 bp, encoding a prepropeptide containing a signal peptide and a propeptide. Similar to big defensins reported in other species, TgBD consists of a hydrophobic N-terminal domain containing β1-α1-α2-β2 folds and a cysteine-rich cationic C-terminal domain with three disulfide bonds between C1-C5, C2-C4, and C3-C6. Phylogenetic analysis showed that TgBD shared 76.80% similarity to its close relative ark shell (Scapharca broughtoni). In addition, TgBD expression was observed in all tissues investigated under normal conditions and was significantly induced by injection of Vibrio parahaemolyticus. Furthermore, synthetic N-terminal peptide of TgBD exhibited strong antimicrobial activity against Gram-positive bacteria tested. Our results indicated that TgBD is a constitutive and inducible acute phase AMP, which provides a universal and prompt protection for T. granosa.


Effectiveness of two intranasal vaccines for the control of bovine respiratory disease in newborn beef calves: A randomized non-inferiority multicentre field trial.
Bovine respiratory syncytial virus (BRSV) and bovine parainfluenza-3 virus (bPI3V) are major causes of bovine respiratory disease (BRD) in newborn calves worldwide. Vaccination is widely used to prevent BRD, and intranasal vaccines for BRSV and bPI3V were developed to overcome interference from BRSV and bPI3V-specific maternally derived antibodies. Many experimental challenge trials have demonstrated that intranasal vaccines for BRSV and bPI3V are efficacious, but effectiveness under field conditions has been demonstrated less often, especially for newborn beef calves. The objective of this field trial was to compare the effectiveness of a newly available commercial BRSV-bPI3V intranasal vaccine with that of a benchmarked one in newborn beef calves reared in a cow-calf system. A total of 935 calves from 39 farms were randomized into two vaccine groups (Bovalto Respi Intranasal [Vaccine A], n=468; Rispoval RS+PI3 Intranasal [Vaccine B], n=467), and monitored during the in-house risk period up to three months after vaccination. Non-inferiority analysis was performed by calculating the difference in BRD prevalence between the two vaccine groups. No significant differences were observed between vaccines regarding clinical outcomes of morbidity, mortality, duration between vaccination and BRD occurrence, or treatments required. Because the upper limit of the 2-sided 95% confidence interval of the difference in BRD prevalence between the two treatment groups (0.8%) was less than the margin of non-inferiority (δ=5%), a non-inferiority of Vaccine A was concluded. In conclusion, Vaccine A is at least as effective as Vaccine B for the prevention of BRD in newborn beef cattle in a cow-calf system under field conditions.


Generalist seabirds as biomonitors of ocean mercury: The importance of accurate trophic position assignment.
Monitoring mercury concentration in the marine environment is pivotal due to the risks that mercury intake poses to the ecosystem and human health. It is therefore of interest to make reliable, comparative measurements over large geographic areas. Here, the utility of wide-ranging generalist seabirds as mercury biomonitors at an ocean basin scale was assessed, using the Cory's Shearwater as a model species. The mercury concentration in flight feathers moulted at distant non-breeding areas of geolocator-tracked birds was quantified, reflecting contamination in various geographic areas. Compound-specific isotope analysis of amino acids was used to obtain comparable trophic positionestimates controlled for baseline isoscape. Birds that remained resident in the Canary Current integrated less mercury into their feathers than those that migrated to either the Benguela or Agulhas currents. Residents also occupied a significantly lower trophic position during the non-breeding season than migrants, largely explaining the difference in mercury exposure. Both mercury concentration and trophic position were similar in individuals spending the non-breeding period in the Benguela and Agulhas currents. This paper highlights the importance of accurate trophic position calculation in order to understand mercury exposure in wide-ranging predators and for meaningful spatial comparisons.


Transposable element loads in a bacterial symbiont of weevils are extremely variable.
Not only are transposable elements profuse in the bacterial endosymbiont of maize weevils, but we found that their quantities also vary approximately 10-fold among individual weevils. Because multicopy elements can facilitate homologous recombination, this insertion sequence (IS) load variability suggests that these essentially asexual bacteria may exhibit substantial intraspecific genomic variation.


Identifying research priorities in breast cancer surgery: a UK priority setting partnership with the James Lind Alliance.
A James Lind Alliance priority setting partnership was developed to identify research priorities in breast cancer surgery from individuals with lived experience, at high genetic risk of breast cancer, and healthcare professionals (HCPs). 'Uncertainties' were collected using an online survey. Following an evidence check and development of summary questions, an interim survey asked participants to rank their top 10 research priorities from the question list. Top-ranked questions from patient/carer, high-risk and professional groups were carried forward for discussion to a final online prioritisation workshop. 260 participants (101 patients/carers, 156 HCPs) submitted 940 uncertainties via the initial survey. These were analysed thematically into 128 summary questions in six topic areas. Following evidence checking, 59 questions were included in the interim survey which was completed by 572 respondents. Marked differences were seen in questions prioritised by patients/carers, HCPs and women at high-risk. The top eight priorities in patient/carer and professional groups and top two priorities for high-risk women were carried forward to the online workshop at which 22 participants discussed and agreed the final top 10. Key themes included de-escalation of breast and axillary surgery, factors impacting the development/detection of locoregional recurrence and optimal provision of support for informed treatment decision-making. The top 10 research priorities in breast cancer surgery have been agreed. However, the observed differences in research priorities identified by patients and professional groups were not anticipated. Top priorities from both groups should inform future UK breast cancer surgical research, to ensure that it addresses questions that are important to breast cancer community as a whole.


Technique for restoration of mite (Acari) preparations in deteriorated Hoyer's medium.
The Acari Collection of Instituto Butantan (IBSP), São Paulo, Brazil, includes many types and other identified mite specimens that were mounted in Hoyer's medium, mainly in the first part of last century. An effort to restore degraded preparations was initiated in 1996. In this process, an improved technique was developed, allowing the adequate cleaning of specimens mounted up to 50-70 years before. Types and other identified specimens of Trombidiformes (Harpirhynchidae and Trombiculidae), Sarcoptiformes (Acaridae, Atopomelidae, Listrophoridae, and Psoroptidae) and Mesostigmata (Dermanyssidae, Ixodorhynchidae, Laelapidae, Macronyssidae, and Spinturnicidae) deposited at IBSP Collection have been satisfactorily restored.


Two-photon photovoltaic effect in gallium arsenide.
The two-photon photovoltaic effect is demonstrated in gallium arsenide at 976 and 1550 nm wavelengths. A waveguide-photodiode biased in its fourth quadrant harvests electrical power from the optical energy lost to two-photon absorption. The experimental results are in good agreement with simulations based on nonlinear wave propagation in waveguides and the drift-diffusion model of carrier transport in semiconductors. Power efficiency of up to 8% is theoretically predicted in optimized devices.


Hemichorea secondary to isolated temporal infarction with severe middle cerebral artery stenosis: a case report and review of literature.
Hemichorea typically results from a contralateral subthalamic nuclei (STN) lesion, although it has been reported in the cortex in a minority of cases. However, to our best knowledge, there are no documented cases in literature of hemichorea occurring as a secondary condition to an isolated temporal stroke. We present a case of an elderly female who sustained a sudden onset of hemichorea in her right extremities, predominantly in the distal region, lasting over a period of two days. Brain diffuse weighted image (DWI) demonstrated a high signal in the temporal region, while magnetic resonance angiography (MRA) revealed severe stenosis of the middle cerebral artery. During the symptomatic phase, computed tomography perfusion (CTP) revealed delayed perfusion in the left middle cerebral artery territory, characterized by the time-to-peak (TTP) measure. Based on the results of her medical history and laboratory tests, we were able to rule out the possibility of infectious, toxic, or metabolic encephalopathy. Her symptoms gradually improved with antithrombotic and symptomatic treatment. It is important to recognize and consider acute onset hemichorea as an initial symptom of stroke to avoid misdiagnosis and delays in appropriate treatment. Further research on temporal lesion that lead to hemichorea is warranted to gain a better understanding of the underlying mechanisms.


Manganese-Catalyzed Ring Opening of Benzofurans and Its Application to Insertion of Heteroatoms into the C2-O Bond.
A new class of aromatic metamorphosis in which benzofurans are converted into diverse six-membered oxaheterocycles has been developed. This transformation is composed of two reactions in one pot: manganese-catalyzed arylative or alkylative ring-opening of benzofurans affording dianionic intermediates and subsequent trapping with multivalent heteroatom electrophiles. Various electrophiles containing silicon, boron, phosphorus, germanium, and titanium could be applied to this heteroatom insertion.


B(C6F5)3: A New Class of Strong and Bulky Lewis Acid for Exo-Selective Intermolecular Diels-Alder Reactions of Unreactive Acyclic Dienes with α,β-Enals.
Lewis acid B(C6F5)3 catalyzed the Diels-Alder reactions of multisubstituted open-chain dienes and α,β-enals to afford the desired products with high exo-selectivities are reported. The substituent effect of the dienes and dienophiles on the product's stereoselectivity was thoroughly investigated, and it was found that most of the desired exo-Diels-Alder products could be obtained in good yields and with high exo-stereoselectivities.


Production of the copolymer poly(3-hydroxybutyrate-co-3-hydroxyvalerate) with varied composition using different nitrogen sources with Haloferax mediterranei.
The extreme haloarchaea Haloferax mediterranei accumulates poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) without the need for specific precursors. In this study, growth kinetics and PHBV synthesis were characterised under nitrogen-excess and nitrogen-limiting conditions in ammonium and, for the first time, nitrate. With excess nitrogen, ammonium and nitrate cultures generated 10.7 g/L biomass containing 4.6 wt% PHBV and 5.6 g/L biomass with 9.3 wt% PHBV, respectively. Copolymer composition varied with the nitrogen source used: PHBV from ammonium cultures had 16.9 mol% 3-hydroxyvalerate (HV), while PHBV from nitrate cultures contained 12.5 mol% HV. Nitrogen limitation was achieved with carbon-to-nitrogen (C/N) molar ratios of 25 or higher. Nitrogen limitation reduced biomass generation and polymer concentration, but polymer accumulation increased to 6.6 and 9.4% for ammonium and nitrate, respectively, with C/N 42. PHBV composition was also affected and cultures with lower C/N ratios produced richer HV polymers. Copolymer formation was not a uniform process: HV was only detected after a minimum accumulation of 0.45 g/L PHB and lasted for a maximum of 48 h. The understanding of copolymer synthesis and the influence of culture conditions such as the nitrogen source will help in designing novel strategies for the production of PHBV with more regular structure and material properties.


Genetic diversity and multilocus genetic structure in the relictual endemic herb Japonolirion osense (Petrosaviaceae).
Plant clonality may greatly reduce effective population size and influence management strategies of rare and endangered species. We examined genetic diversity and the extent of clonality in four populations of the monotypic herbaceous perennial Japonolirion osense, which is one of the most rare flowering plants in Japan. Allozyme analysis revealed moderate levels of genetic variation, and the proportion of polymorphic loci (P=66.7%) was higher than the value for species with similar life-history traits. With four polymorphic loci, 19 multilocus genotypes were observed among 433 aerial shoot samples and 10 (52%) were found only in single populations. The proportion of distinguishable genotypes (PD=0.10) and Simpson's index of diversity (D=0.52) also exhibited moderate levels of genotypic diversity compared to other clonal plants, with genotype frequencies at Hardy-Weinberg equilibrium. The distributions of genotypes were often localized and they were mostly found within a radius of 5 m. Spatial autocorrelation analysis showed that shoot samples located 4 m apart were expected to be genetically independent. The results suggest that the spatial extent of genets was relatively narrow and thus the clonality was not extensive.


A noncyclopean diagram of binocular vision in strabismology.
Most diagrams concerning binocular vision and squint contain the cyclopean eye, which is a vestige of the 2000-year-old projection theory. The author's previously published diagram is based on a motor theory of spatial localization which has been formulated by Descartes, Lotze, and Roelofs.


Anti-inflammatory pretreatment enables an efficient dendritic cell-based immunotherapy against established tumors.
Although animals can be immunized against the growth of some tumor implants, most of the attempts to use immunotherapy to cause the regression of animal and human tumors once they have become established have been disappointing even when strongly immunogenic tumors were used as target. In this paper, we demonstrate that the failure to achieve an efficient immunological treatment against an established strongly immunogenic murine fibrosarcoma was paralleled with the emergence of a state of immunological unresponsiveness (immunological eclipse) against tumor antigens observed when the tumor surpassed the critical size of 500 mm(3). In turn, the onset of the immunological eclipse was coincidental with the onset of a systemic inflammatory condition characterized by a high number of circulating and splenic polymorphonucleated neutrophils (PMN) displaying activation and Gr1(+)Mac1(+) phenotype and an increasing serum concentration of the pro-inflammatory cytokines TNF-alpha, IL-1beta and IL-6 cytokines and C-reactive protein (CRP) and serum A amyloid (SAA) phase acute proteins. Treatment of tumor-bearing mice with a single low dose (0.75 mg/kg) of the synthetic corticoid dexamethasone (DX) significantly reduced all the systemic inflammatory parameters and simultaneously reversed the immunological eclipse, as evidenced by the restoration of specific T-cell-dependent concomitant immunity, ability of spleen cells to transfer anti-tumor activity and recovery of T-cell signal transduction molecules. Two other anti-inflammatory treatments by using indomethacin or dimeric TNF-alpha receptor, also partially reversed the immunological eclipse although the effect was not as striking as that observed with DX. The reversion of the immunological eclipse was not enough on its own to inhibit the primary growing tumor. However, when we used the two-step strategy of inoculating DX to reverse the eclipse and then dendritic cells loaded with tumor antigens (DC) as an immunization booster, a significant inhibition of the growth of both established tumors and remnant tumor cells after excision of large established tumors was observed, despite the fact that the vaccination alone (DC) had no effect or even enhanced tumor growth in certain circumstances. The two-step strategy of tumor immunotherapy that we present is based on the rationale that it is necessary to eliminate or ameliorate the immunological eclipse as a precondition to allow an otherwise ineffective anti-tumor immunological therapy to have a chance to be successful.


Hyperactive behavioral phenotypes and an altered brain monoaminergic state in male offspring mice with perinatal hypothyroidism.
Thyroid hormone (TH) is essential for normal brain development. TH insufficiency during early stages of development may increase the risk for attention deficit/hyperactivity disorder, in which malfunction of brain monoaminergic systems is likely involved. However, little is known about the effects of perinatal hypothyroidism on behaviors and brain monoaminergic systems in offspring mice. The present study examined in mice (1) whether perinatal hypothyroidism causes hyperactive behavioral phenotypes, (2) how perinatal hypothyroidism influences brain monoaminergic systems, and (3) whether hyperactive behavioral phenotypes are associated with the state of brain monoaminergic systems. When dams were exposed to propylthiouracil, offspring mice developed hypothyroidism during the perinatal period. Offspring mice with perinatal hypothyroidism exhibited hyperactive behavioral phenotypes such as hyper-ambulatory activity and an increased response rate in the two-way active avoidance test in a male-specific manner. Significant decreases in dopamine (DA) and serotonin turnover were observed in the striatum (ST), nucleus accumbens, hypothalamus, and hippocampus in male mice with perinatal hypothyroidism. A significant correlation between ambulatory activity and DA turnover in the ST and an augmented ambulatory response to the DA reuptake inhibitor bupropion suggested that DA in the ST was involved in the hyper-ambulatory activity in mice with perinatal hypothyroidism.


The effect of the communication skills training on the sensitivity and cultural competence of the nurses in the pediatric wards: A quasi-experimental study.
This study aimed to investigate the effect of the communicative training skills on the sensitivity and cultural competence of the nurses in the pediatric wards. The participants included 54 nurses from the pediatric ward of Namazi Hospital affiliated with REDACTED. The sample members entered the study through voluntary registration in the in-service training system. The results showed that cultural sensitivity score was 44.22±11.78 before the intervention, 48.51±13.34 immediately after the intervention, and 55.55±20.20 one month after the intervention. Cultural sensitivity score significantly increased immediately and one month after communication skills training for nurses compared to before the intervention (P < 0.001). The results also showed that cultural competency score was 51.68±9.43 before the intervention and increased significantly immediately after the communication skills training and one month after the intervention (57.64±10.43 and 62.56±11.53, respectively), showing significant improvement (P < 0.001). The communication skills training promoted the nurses' cultural sensitivity and competence in childcare wards. Therefore, the implementation of the theoretical and practical methods of teaching communication skills is suggested to improve nurses' cultural competence and consequently, improve childcare quality in different cultures.


Development of a real-time PCR assay for detection of Plasmodium falciparum, Plasmodium vivax, and Plasmodium ovale for routine clinical diagnosis.
A TaqMan-based real-time PCR qualitative assay for the detection of three species of malaria parasites-Plasmodium falciparum, P. ovale, and P. vivax-was devised and evaluated using 122 whole-blood samples from patients who had traveled to areas where malaria is endemic and who presented with malaria-like symptoms and fever. The assay was compared to conventional microscopy and to an established nested-PCR assay. The specificity of the new assay was confirmed by sequencing the PCR products from all the positive samples and by the lack of cross-reactivity with Toxoplasma gondii and Leishmania infantum DNA. Real-time PCR assay showed a detection limit (analytical sensitivity) of 0.7, 4, and 1.5 parasites/ micro l for P. falciparum, P. vivax, and P. ovale, respectively. Real-time PCR, like nested PCR, brought to light errors in the species identification by microscopic examination and revealed the presence of mixed infections (P. falciparum plus P. ovale). Real-time PCR can yield results within 2 h, does not require post-PCR processing, reduces sample handling, and minimizes the risks of contamination. The assay can therefore be easily implemented in routine diagnostic malaria tests. Future studies are warranted to investigate the clinical value of this technique.


Activation of a ventral hippocampus-medial prefrontal cortex pathway is both necessary and sufficient for an antidepressant response to ketamine.
A single sub-anesthetic dose of ketamine exerts rapid and sustained antidepressant effects. Here, we examined the role of the ventral hippocampus (vHipp)-medial prefrontal cortex (mPFC) pathway in ketamine's antidepressant response. Inactivation of the vHipp with lidocaine prevented the sustained, but not acute, antidepressant-like effect of ketamine as measured by the forced swim test (FST). Moreover, optogenetic as well as pharmacogenetic specific activation of the vHipp-mPFC pathway using DREADDs (designer receptors exclusively activated by designer drugs) mimicked the antidepressant-like response to ketamine; importantly, this was pathway specific, in that activation of a vHipp to nucleus accumbens circuit did not do this. Furthermore, optogenetic inactivation of the vHipp/mPFC pathway at the time of FST completely reversed ketamine's antidepressant response. In addition, we found that a transient increase in TrkB receptor phosphorylation in the vHipp contributes to ketamine's sustained antidepressant response. These data demonstrate that activity in the vHipp-mPFC pathway is both necessary and sufficient for the antidepressant-like effect of ketamine.


Hereditary Pancreatic Cancer Syndromes.
Despite decades of scientific and clinical research, pancreatic ductal adenocarcinoma (PDAC) remains a lethal malignancy. The clinical and pathologic features of PDAC, specifically the known environmental and genetic risk factors, are reviewed here with special emphasis on the hereditary pancreatic cancer (HPC) syndromes. For these latter conditions, strategies are described for their identification, for primary and secondary prevention in unaffected carriers, and for disease management in affected carriers. Nascent steps have been made toward personalized medicine based on the rational use of screening, tumor subtyping, and targeted therapies; these have been guided by growing knowledge of HPC syndromes in PDAC.


Correlation between posterior vaginal wall defects assessed by clinical examination and by defecography.
To estimate the accuracy of clinical examination and the indications for defecography in patients with primary posterior wall prolapse. Fifty-nine patients with primary pelvic organ prolapse were evaluated with a questionnaire, clinical examination and defecography. Defecography was used as reference standard. There was no relation between bowel complaints and posterior wall prolapse evaluated by clinical examination (p = 0.33), nor between bowel complaints and rectocele (p = 0.19) or enterocele (p = 0.99) assessed by defecography. The diagnostic accuracy of clinical examination in diagnosing rectocele was 0.42, sensitivity was 1.0 and specificity was 0.23. The diagnostic accuracy of clinical examination in diagnosing enterocele was 0.73, with a sensitivity of 0.07 and a specificity of 0.95. Clinical examination is not accurate to assess anatomic defects of the posterior vaginal wall. Defecography is recommended as a helpful diagnostic tool in the work-up of patients with posterior vaginal wall prolapse if surgical repair is considered.


From pond to table: Differences in breeding and consumption affect the balance between dietary risk of residual cadmium and uptake benefits of nutrients in Chinese mitten crab (Eriocheir sinensis).
We used a risk-benefit model to evaluate the effects of different farming methods and consumption habits on dietary risk of Chinese mitten crab. In this study, we found that cadmium levels in the total edible parts and brown meat were 0.029-0.462 mg/kg and 0.017-1.694 mg/kg, respectively. Cadmium exposure experiment showed that brown meat was the main enrichment site of cadmium. Fatty acid test found that the EPA + DHA content in total edible parts fed with formulated feed and iced trash fish was 19.64 ± 3.62 mg/g and 28.72 ± 2.30 mg/g (p > 0.05), respectively, and that in brown meat was 27.66 ± 5.16 mg/g and 40.15 ± 3.50 mg/g (p > 0.05), respectively. According to the risk-benefit model analysis, the dietary risk of brown meat under the two breeding methods is relatively high, but the risk quotient is less than 1.


Loss of pirenzepine regional selectivity following solubilization and partial purification of the putative M1 and M2 muscarinic receptor subtypes.
Pirenzepine inhibition of [3H]N-methylscopolamine ([3H]NMS) binding was studied in membranous, digitonin-solubilized, and partially purified muscarinic receptors from bovine cortex, an area of the brain rich in the putative M1 muscarinic receptor subtype, and from pons-medulla, an area rich in the putative M2 subtype. In accord with previous work, we found that pirenzepine bound to membranous receptors from cortex with an IC50 that was over one order of magnitude lower than to receptors from pons-medulla. After digitonin solubilization, however, this regional selectivity was significantly reduced. In receptors from pons-medulla, the IC50 for pirenzepine inhibition of [3H]NMS was reduced from 2.1 +/- 0.7 X 10(-6) M in membrane-bound receptors, to 4.3 +/- 0.3 X 10(-7) M after solubilization, whereas in receptors from cortex, the IC50 remained unchanged after solubilization. The solubilized receptors from both brain areas maintained their binding characteristics after partial purification over an ABT-Sepharose affinity column and a hydroxylapetite column. These findings raise the possibility that the different pirenzepine binding characteristics used to define M1 and M2 receptor subtypes are not inherent in the receptor protein itself, but may be due to coupling factors such as effector proteins, phospholipids or cytoskeletal proteins which could be associated with the membranous receptor and become dissociated from the receptor after solubilization.


Relative peripheral hyperopia leads to greater short-term axial length growth in White children with myopia.
Controversy exists regarding the influence of peripheral visual experience on the onset and progression of childhood myopia. This longitudinal, observational study evaluated the relationship between relative peripheral refraction (RPR) and changes in refractive error and axial length (AL) over 12 months in White children aged 6-7 and 12-13 years with a range of baseline refractive errors. Cycloplegic baseline autorefraction at horizontal retinal eccentricities of 0° and ±30° were recorded with the Shin-Nippon NVision-K 5001 while AL was measured using the Zeiss IOLMaster 700. Measurements were repeated after 12 months on a subgroup. Refractive data were transposed into power vectors as mean spherical equivalent (M), J0 and J45 . RPR was calculated by subtracting central from peripheral measurements. Participants were defined as myopic (M ≤ -0.50 D), premyopic (-0.50 D < M ≤ +0.75 D), emmetropic (+0.75 D < M < +2.00 D) or hyperopic (M ≥ +2.00 D). Data were collected from 222 and 245 participants aged 6-7 and 12-13 years, respectively. Myopic eyes demonstrated, on average, more hyperopic RPR. Emmetropes and premyopes displayed emmetropic RPR, and hyperopes showed a myopic RPR. Fifty-six 6- to 7-year-olds and seventy 12- to 13-year-olds contributed 12-month repeated measures. Longitudinal data demonstrated a significant relationship between a more hyperopic RPR in the nasal retina and greater short-term axial elongation in teens with myopia at baseline (β = 0.69; p = 0.04). Each dioptre of relative peripheral hyperopia in the nasal retina was associated with an additional 0.10 mm (95% CI: 0.02-0.18 mm) annual increase in AL. Hyperopic RPR in the nasal retina of myopic children is indicative of increased risk for rapid axial elongation and may be a useful metric to support decision-making in myopia management.


Comparison of nerve stimulation vs. ultrasound-guided lateral sagittal infraclavicular block.
A nerve stimulation-guided lateral sagittal infraclavicular block (LSIB) has been proven to be an effective block. The purpose of this study was to evaluate whether the use of ultrasound (US) guidance would further improve the block quality of LSIB. In a prospective manner, 80 adult patients scheduled for hand, wrist and forearm surgery were randomly allocated to US or nerve stimulation (NS) groups. A needle was inserted into a sagittal plane, 20 degrees dorsally, until muscle twitches were observed in synchrony with the stimulation. In the US group, the block was performed using the same puncture site but under ultrasonic guidance. The final position of the needle was verified with the use of a nerve stimulator. A local anesthetic mixture of 20 ml of levobupivacaine, 5 mg/ml and 20 ml of lidocaine and 20 mg/ml with 5 microg/ml epinephrine (total 40 ml) was administered in both groups. The block was successful in 37 patients in the NS group and 38 patients in the US group. Block efficacy was better in the US group than the group NS in radial nerve distribution at 20 min (P<0.05). In the US group, there was a slight tendency toward better block density in other nerve areas also but these differences were not significant. Vascular puncture was noted in three patients in the NS group and none in the US group. The block success rate was high and comparable in both groups. There was a trend toward improved block quality in the US group, although not significant.


Correction: Li et al. m6A mRNA Methylation Regulates LKB1 to Promote Autophagy of Hepatoblastoma Cells through Upregulated Phosphorylation of AMPK. Genes 2021, 12, 1747.
In the original publication [...].


Acinetobacter oleivorans IRS14 alleviates cold stress in wheat by regulating physiological and biochemical factors.
Climate change is responsible for extreme cold winters, causing a significant loss in crop yield and productivity due to chilling stress. This study aims to investigate the potential of psychrotrophic plant growth-promoting rhizobacteria (PGPR) strain to promote wheat growth under cold stress and explore the adaptive responses of wheat. Wheat seeds and seedlings were inoculated with the psychrotrophic strain IRS14 and the plants were cultivated for five weeks at 6°C ± 2°C. The genetic, biochemical, physiological, and molecular analysis of the bacterium and plant was done to evaluate the effect of the PGPR strain in alleviating chilling stress. IRS14 possesses antioxidant activity and produced multiple phytohormones, which enhanced seed germination (∼50%) and plant growth (∼50%) during chilling stress. Here, we reported that the application of IRS14 helps to regulate the biochemical and metabolic pathways in wheat plants. It alleviates chilling stress and increases plant growth rate and biomass. Strain IRS14 in wheat effectively increased chlorophyll content, antioxidants, carotenoid, proline, and endogenous phytohormones compared with untreated wheat.


The autopsy: its role in the evaluation of patient care.
To determine whether autopsies improve the detection of major clinical errors. Retrospective chart review of all deaths for a 30-month period to detect major clinical errors when a correct diagnosis and institution of proper therapy would have prolonged the patient's life, with comparison of autopsied patients with those without an autopsy. Small government hospital inpatient medical service. 335 consecutive deaths with 141 [42%] autopsies. Review of the clinical records of cases without autopsy led to the discovery of only two major clinical errors [1%], whereas 19 major clinical errors [13%] were detected in autopsy cases. Three of the 19 errors in autopsy patients would have been detected by chart review alone. Thirteen of the 19 clinical errors in autopsied patients were related to infections that were missed or were not treated appropriately because of misdiagnosis. Autopsies continue to reveal unanticipated and important information that is essential for internal medicine residency training and for the evaluation of the quality of medical care.


Carcinoembryonic antigen: function in metastasis by human colorectal carcinoma.
Carcinoembryonic antigen (CEA) is a glycoprotein that has been useful as a tumor marker to predict recurrence in gastrointestinal malignancies, but whose biological function has not been elucidated. With the recent evidence that CEA is a member of the immunoglobulin supergene family, CEA may be involved in intercellular recognition and binding. This review examines the role that CEA plays in the development of metastases by colorectal carcinoma.


Effect of standing desk use on cognitive performance and physical workload while engaged with high cognitive demand tasks.
It is clear that the cognitive resources invested in standing are greater than in sitting, but six of eight previous studies suggested that there is no difference in cognitive performance. This study investigated the effects of sitting and standing workstations on the physical workload and cognitive performance under variable cognitive demand conditions. Fifteen participants visited two times for testing sitting and standing workstations, and were asked to play two difficulty levels of Tetris game for 40 min while kinematic variables, CoP regularity, CoP SD, and cognitive performances were captured every 5 min. Results revealed a more neural posture in standing than in sitting, but using the standing workstation degraded attention and executive function. The CoP SD was 7 times greater in standing, but the CoP regularity was 1/4 in sitting, denoting greater attentional investment while engaged at the standing workstation.


Goal-directed program after sleeve gastrectomy improves weight loss.
The aim of our study is to determine if a goal-directed program improves weight loss after sleeve gastrectomy. Our goal-directed program involves setting excess weight loss targets at fixed intervals after sleeve gastrectomy. We identified patients in 3 bariatric centers between April 2010 and July 2013 and compared the center that has a goal-directed weight loss program (goal-directed program) with the other 2 centers (standard program). A total of 211 patients were included, with 129 patients in the goal-directed weight loss program. The 2 groups were similar in terms of gender distribution, ethnicity distribution, age, and preoperative weight, preoperative body mass index, and surgical technique. The follow-up rates at 3, 6, 9, and 12 months for patients in the goal-directed program was 84.5%, 75.2%, 59.7%, and 82.2%, respectively, compared with 65.9%, 68.3%, 51.2%, and 68.3% for the standard program. The percentage total weight loss at 3, 6, 9, and 12 months was 17.1%, 23.3%, 26.8%, and 28.6%, respectively, for the goal-directed program, compared with 15.3%, 21.8%, 24.4%, and 25.4%, respectively, for the standard program. The mean excess weight loss at 3, 6, 9, and 12 months were 40%, 54%, 62%, and 67%, respectively, for the goal-directed program group, and 36%, 50%, 54%, and 55%, respectively, for the standard program, where statistical significance (P<.005) was achieved at 12 months. Our results suggest that a goal-directed protocol may improve weight loss outcomes after laparoscopic sleeve gastrectomy.


Mouse betaine-homocysteine S-methyltransferase deficiency reduces body fat via increasing energy expenditure and impairing lipid synthesis and enhancing glucose oxidation in white adipose tissue.
Betaine-homocysteine S-methyltransferase (BHMT) catalyzes the synthesis of methionine from homocysteine. In our initial report, we observed a reduced body weight in Bhmt(-/-) mice. We initiated this study to investigate the potential role of BHMT in energy metabolism. Compared with the controls (Bhmt(+/+)), Bhmt(-/-) mice had less fat mass, smaller adipocytes, and better glucose and insulin sensitivities. Compared with the controls, Bhmt(-/-) mice had increased energy expenditure, with no changes in food intake, fat uptake or absorption, or in locomotor activity. The reduced adiposity in Bhmt(-/-) mice was not due to hyperthermogenesis. Bhmt(-/-) mice failed to maintain a normal body temperature upon cold exposure because of limited fuel supplies. In vivo and ex vivo tests showed that Bhmt(-/-) mice had normal lipolytic function. The rate of (14)C-labeled fatty acid incorporated into [(14)C]triacylglycerol was the same in Bhmt(+/+) and Bhmt(-/-) gonadal fat depots (GWAT), but it was 62% lower in Bhmt(-/-) inguinal fat depots (IWAT) compared with that of Bhmt(+/+) mice. The rate of (14)C-labeled fatty acid oxidation was the same in both GWAT and IWAT from Bhmt(+/+) and Bhmt(-/-) mice. At basal level, Bhmt(-/-) GWAT had the same [(14)C]glucose oxidation as did the controls. When stimulated with insulin, Bhmt(-/-) GWAT oxidized 2.4-fold more glucose than did the controls. Compared with the controls, the rate of [(14)C]glucose oxidation was 2.4- and 1.8-fold higher, respectively, in Bhmt(-/-) IWAT without or with insulin stimulus. Our results show for the first time a role for BHMT in energy homeostasis.


Isolated trapezoid fractures: a case report with compilation of the literature.
Isolated fractures of the trapezoid bone have been rarely reported in the literature, the mechanism of injury being an axial or bending load transmitted through the second metacarpal. We report a case of an isolated, nondisplaced trapezoid fracture that was sustained by direct trauma and subsequently treated successfully in a short-arm cast. Diagnostic and treatment strategies for isolated fractures of the trapezoid bone are reviewed as well as the results of operative and nonoperative treatment.


Drought-tolerant Desmodium species effectively suppress parasitic striga weed and improve cereal grain yields in western Kenya.
The parasitic weed Striga hermonthica Benth. (Orobanchaceae), commonly known as striga, is an increasingly important constraint to cereal production in sub-Saharan Africa (SSA), often resulting in total yield losses in maize (Zea mays L.) and substantial losses in sorghum (Sorghum bicolor (L.) Moench). This is further aggravated by soil degradation and drought conditions that are gradually becoming widespread in SSA. Forage legumes in the genus Desmodium (Fabaceae), mainly D. uncinatum and D. intortum, effectively control striga and improve crop productivity in SSA. However, negative effects of climate change such as drought stress is affecting the functioning of these systems. There is thus a need to identify and characterize new plants possessing the required ecological chemistry to protect crops against the biotic stress of striga under such environmental conditions. 17 accessions comprising 10 species of Desmodium were screened for their drought stress tolerance and ability to suppress striga. Desmodium incanum and D. ramosissimum were selected as the most promising species as they retained their leaves and maintained leaf function for longer periods during their exposure to drought stress conditions. They also had desirable phenotypes with more above ground biomass. The two species suppressed striga infestation, both under controlled and field conditions, and resulted in significant grain yield increases, demonstrating the incremental capability of Desmodium species in striga suppression. These results demonstrate beneficial effects of Desmodium species in enhancing cereal productivity in dry areas.


Correlation between free platinum AUC and total platinum measurement 24 h after i.v. bolus injection of cisplatin in humans.
The plasma kinetics of platinum after i.v. bolus administration of cisplatin was determined for 17 patients with advanced cancer. Statistical analysis of individual values revealed a high correlation between the area under the plasma concentration-time curve (AUC) of free platinum (unbound to proteins) and the concentration of platinum bound to plasma proteins 24 h after drug administration (Cp24). A similar correlation was found between the peak plasma values of ultrafiltrable platinum (Cp0) and Cp24. When studied in the same patient, increases in free platinum AUC and Cp0 were also found to result in increased Cp24. It is suggested that a single measurement of plasma platinum concentration 24 h after i.v. infusion of cisplatin could be a simple method either of detecting patients with extreme values of AUC and Cp0 or of studying the evolution of these parameters during multiple courses of treatment, although it cannot be used to give precise values for AUC and Cp0.


Exopolysaccharide production from Sclerotium glucanicum NRRL 3006 and Botryosphaeria rhodina DABAC-P82 on raw and hydrolysed starchy materials.
Evaluation of fermentative usage of raw starchy materials for exopolysaccharide (EPS) production by Sclerotium glucanicum NRRL 3006 and Botryosphaeria rhodina DABAC-P82. Non-hydrolysed corn starch, soft wheat flour, potato flour, cassava flour, sweet and industrial potato flours, and corn starch hydrolysed to different dextrose equivalent (DE) were tested in shaken culture for EPS production. Both fungal strains produced EPS on all tested materials but the production was maximum on hydrolysed corn starch (30.5 and 19.8 g l(-1) by B. rhodina and S. glucanicum on corn starch at 100 and 62 DE, respectively). Raw starchy materials as such and, in particular, partially or totally hydrolysed corn starch could be used profitably for EPS production by S. glucanicum and B. rhodina. The excellent EPS production, productivity and yield of B. rhodina DABAC-P82 when grown on 60 g l(-1) of totally hydrolysed corn starch.


Oral Zn-DTPA treatment reduces cadmium absorption and retention in rats.
This work was performed to evaluate the possibility of using early oral diethylenetriaminepentaacetate (DTPA) therapy for decreasing absorption and retention of cadmium. Albino rats (6 days and 6 weeks old) were used. 115mCd was administered orally. Zn-DTPA was also given orally (3.64 mmol/kg) immediately after 115mCd and 24 h thereafter. Radioactivity in body and organs was determined 6 days later. In sucklings this treatment decreased whole body and gut retention 7-9 times and kidney and liver retention 2-3 times. In older rats it decreased whole body, gut and organ retention 4-5 times. This finding deserves attention since it is generally believed that DTPA is not indicated for early treatment, i.e. while the toxic metals or radionuclides are still in the gastrointestinal tract.


Angiopoietin signaling in the vasculature.
The angiopoietin (Ang) growth factors and the endothelial Tie receptors regulate blood and lymphatic vessel development, and vascular permeability, inflammation, angiogenic remodeling and tumor vascularization in adult tissues. The angiopoietins activate the Tie receptors in unique in trans complexes at endothelial cell-cell and cell-matrix contacts. In addition, integrins have been implicated in the regulation of Ang-Tie signaling. Recent interest has focused on the function of angiopoietin-2 and its inhibition in the tumor vasculature and also in other pathological conditions associated with endothelial dysfunction. Here we review the current understanding of the signaling functions of the Ang-Tie pathway and its potential for future development of targeted vascular therapeutics.


In Silico Prediction of hPXR Activators Using Structure-Based Pharmacophore Modeling.
The activation of pregnane X receptor (PXR), a member of the nuclear receptor superfamily, can mediate potential drug-drug interactions by regulating the expression of several drug-mediated enzymes and transporters, resulting in reduced therapeutic efficacy or increased toxicity by producing reactive metabolites. Therefore, in the early stage of drug development, it is important to predict these risks using an in silico approach. We constructed a human PXR (hPXR) pharmacophore model based on known structural information of compounds that activate PXR. We evaluated the prediction accuracy of the model using data sets generated on 68 original synthetic compounds from the Mitsubishi Tanabe Pharma Corporation and over 2500 drugs from the National Institutes of Health Chemical Genomics Center Pharmaceutical Collection for their ability to activate hPXR. The prediction accuracies of the PXR pharmacophore model were 0.78 and 0.86 for the Mitsubishi Tanabe Pharma Corporation and National Institutes of Health Chemical Genomics Center Pharmaceutical Collection, respectively. The compounds resulting in the smallest root-mean square deviation hit by pharmacophore search were the well-known PXR inducers such as Bosentan. These results suggest that using the in silico approach developed in this study is useful to identify potential hPXR activators and modify the drug design during the early stage of drug development.


Novel concept of enzyme selective nicotinamide adenine dinucleotide (NAD)-modified inhibitors based on enzyme taxonomy from the diphosphate conformation of NAD.
The dihedral angle θ of the diphosphate part of NAD(P) were investigated to distinguish the differences in the binding-conformation of NAD(P) to enzymes and to create an enzyme taxonomy. Furthermore, new inhibitors with fixed dihedral angles showed that enzymes could recognize the differences in the dihedral angle θ. We suggest the taxonomy and the dihedral angle θ are important values for chemists to consider when designing inhibitors and drugs that target enzymes.


Pioglitazone for primary stroke prevention in Asian patients with type 2 diabetes and cardiovascular risk factors: a retrospective study.
Studies assessing the efficacy of pioglitazone solely for primary stroke prevention in Asian patients with type 2 diabetes mellitus (DM) and present multiple cardiovascular (CV) risk factors are rare. Thus, we aimed to assess the effect of pioglitazone on primary stroke prevention in Asian patients with type 2 DM without established CV diseases but with risk factors for CV diseases. Between 2000 and 2012, we enrolled patients aged ≥ 18 years, who were newly diagnosed with type 2 diabetes and had at least one of the following CV risk factors: hypertension and hyperlipidemia. Patients with a history of stroke and those using insulin or glucagon-like peptide-1 agonist for more than 3 months were excluded. Patients were divided into the pioglitazone and non-pioglitazone groups based on their receipt of pioglitazone during the follow-up period. Propensity-score matching (1:1) was used to balance the distribution of the baseline characteristics and medications. Follow-up was terminated upon ischemic stroke development, withdrawal from the insurance system, or on December 31, 2013, whichever occurred first. The overall incidence of new-onset ischemic stroke in the two groups was subsequently compared. The subgroup analyses of ischemic stroke were conducted using different baseline features. Additionally, the effect of pioglitazone exposure dose on the occurrence of ischemic stroke was evaluated. Chi square test, Student's t-test, competing risk regression models, Kaplan-Meier method, and log-rank test were some of the statistical tests conducted. A total of 13 078 patients were included in the pioglitazone and non-pioglitazone groups. Compared with patients who did not receive pioglitazone, those administered pioglitazone had a lower risk of developing ischemic stroke (adjusted hazard ratio: 0.78; 95% confidence interval: 0.62-0.95). The subgroup analyses defined by different baseline features did not reveal significant alterations in the observed effect of pioglitazone. Moreover, a significant decreasing trend in ischemic stroke risk with an increase in pioglitazone dose (p-value for trend = 0.04) was observed. Pioglitazone use decreased the risk of new-onset ischemic stroke in Asian patients with type 2 DM and CV risk factors. Trial registration number CMUH104-REC2-115-CR4.


Rotational stability test for the diagnosis of radial collateral ligament rupture in the fingers: Anatomical study.
Diagnosing rupture of the radial collateral ligament (RCL) of the finger metacarpophalangeal (MCP) joints is difficult. The aim of this cadaver study was to validate a rotational test for the MCP after RCL transection. With the MCP and proximal interphalangeal joints in flexion, rotation along the axis of the proximal phalanx was applied through an extended distal interphalangeal joint to 36 cadaver fingers. Each finger's pulp described an arc of pronation and supination that was noted on the palm. The test was repeated three times: before transection, after transection of the proper collateral ligament (CL) and after transection of both the proper and accessory CLs. Rotational arcs were measured in pronation and supination. Mean length of the pronation arc after transection of the main RCL was 17.53mm, while it was only 12.41mm before transection for the supination arc. Mean length of the pronation arc after transection of both CLs was 22.83mm compared to only 11.93mm before transection. Our results show a significant difference in pronation stability of the MCP joint after transection of the RCL proper. We can conclude that this rotational stability test is a valid test for diagnosing RCL rupture in MCP joints.


Hypothermia attenuates the severity of oxidative stress development in asphyxiated newborns.
This retrospective case-control study aimed to examine the development of oxidative stress in asphyxiated infants delivered at more than 37 weeks of gestation. Thirty-seven neonates were stratified into 3 groups: the first group experienced hypothermia (n = 6); the second received hypothermia cooling cup treatment for 3 days, normothermia (n = 16); and the third was the control group (n = 15). Serum total hydroperoxide (TH), biological antioxidant potential, and oxidative stress index (OSI) (calculated as TH/biological antioxidant potential) were measured within 3 hours after birth. Serum TH and OSI levels gradually increased after birth in hypothermia and normothermia cases. At all time points, serum TH and OSI levels were higher in hypothermia and normothermia cases than in control cases. Serum TH and OSI levels were higher in normothermia cases than in hypothermia cases at days 3, 5, and 7. This study demonstrated that hypothermia attenuated the development of systemic oxidative stress in asphyxiated newborns.


Oncogenes as novel targets for cancer therapy (part II): Intermediate signaling molecules.
This is the second part of a four-part review on potential therapeutic targeting of oncogenes. The previous part introduced the new technologies responsible for the advancement of oncogene identification, target validation, and drug design. Because of such advances, new specific and more efficient therapeutic agents can be developed for cancer. This part of the review continues the exploration of various oncogenes, which we have grouped within seven categories: growth factors, tyrosine kinases, intermediate signaling molecules, transcription factors, cell cycle regulators, DNA damage repair genes, and genes involved in apoptosis. Part I included a discussion of growth factors and tyrosine kinases. This portion of the review covers intermediate signaling molecules and the various strategies used to inhibit their expression or decrease their activities.


Dermatologic manifestations of gastrointestinal disorders.
Many disorders of the gastrointestinal tract have cutaneous manifestations. Thus, a careful examination of the skin may uncover clues to underlying diseases of the liver, gastrointestinal tract, and pancreas. This article explores the alimentary-cutaneous relationship.


Type b capsular polysaccharide as a virulence factor of Haemophilus influenzae.
The capsular polysaccharide of Haemophilus influenzae serotype b [(3)-beta-D-ribose-(1-1)-ribitol-5-phosphate] is a major virulence factor and a target for serum antibodies which protect individuals against invasive infections. Studies in an experimental rat model of meningitis, using genetically defined H. influenzae transformants, provide evidence that chromosomal genes within or limited to a region (cap b) containing genes necessary for type b capsule are critical for efficient intravascular survival of H. influenzae. Within cap b there is a duplication of a 17 kb region organized as direct repeats separated by a smaller (1-2 kb) region of non-repeated DNA. Homologous recombination between the direct repeats is rec dependent and results in high-frequency loss of capsule expression and virulence.