Chronic graft-versus-host disease: long-term results from a randomized trial on graft-versus-host disease prophylaxis with or without anti-T-cell globulin ATG-Fresenius.
Previous randomized graft-versus-host disease (GVHD)-prophylaxis trials have failed to demonstrate reduced incidence and severity of chronic GVHD (cGVHD). Here we reanalyzed and updated a randomized phase 3 trial comparing standard GVHD prophylaxis with or without pretransplantation ATG-Fresenius (ATG-F) in 201 adult patients receiving myeloablative conditioning before transplantation from unrelated donors. The cumulative incidence of extensive cGVHD after 3 years was 12.2% in the ATG-F group versus 45.0% in the control group (P < .0001). The 3-year cumulative incidence of relapse and of nonrelapse mortality was 32.6% and 19.4% in the ATG-F group and 28.2% and 33.5% in the control group (hazard ratio [HR] = 1.21, P = .47, and HR = 0.68, P = .18), respectively. This nonsignificant reduction in nonrelapse mortality without increased relapse risk led to an overall survival rate after 3 years of 55.2% in the ATG-F group and 43.3% in the control group (HR = 0.84, P = .39, nonsignificant). The HR for receiving immunosuppressive therapy (IST) was 0.31 after ATG-F (P < .0001), and the 3-year probability of survival free of IST was 52.9% and 16.9% in the ATG-F versus control, respectively. The addition of ATG-F to standard cyclosporine, methotrexate GVHD prophylaxis lowers the incidence and severity of cGVHD, and the risk of receiving IST without raising the relapse rate. ATG-F prophylaxis reduces cGVHD morbidity.


Analysis of cathepsin and furin proteolytic enzymes involved in viral fusion protein activation in cells of the bat reservoir host.
Bats of different species play a major role in the emergence and transmission of highly pathogenic viruses including Ebola virus, SARS-like coronavirus and the henipaviruses. These viruses require proteolytic activation of surface envelope glycoproteins needed for entry, and cellular cathepsins have been shown to be involved in proteolysis of glycoproteins from these distinct virus families. Very little is currently known about the available proteases in bats. To determine whether the utilization of cathepsins by bat-borne viruses is related to the nature of proteases in their natural hosts, we examined proteolytic processing of several viral fusion proteins in cells derived from two fruit bat species, Pteropus alecto and Rousettus aegyptiacus. Our work shows that fruit bat cells have homologs of cathepsin and furin proteases capable of cleaving and activating both the cathepsin-dependent Hendra virus F and the furin-dependent parainfluenza virus 5 F proteins. Sequence analysis comparing Pteropus alecto furin and cathepsin L to proteases from other mammalian species showed a high degree of conservation; however significant amino acid variation occurs at the C-terminus of Pteropus alecto furin. Further analysis of furin-like proteases from fruit bats revealed that these proteases are catalytically active and resemble other mammalian furins in their response to a potent furin inhibitor. However, kinetic analysis suggests that differences may exist in the cellular localization of furin between different species. Collectively, these results indicate that the unusual role of cathepsin proteases in the life cycle of bat-borne viruses is not due to the lack of active furin-like proteases in these natural reservoir species; however, differences may exist between furin proteases present in fruit bats compared to furins in other mammalian species, and these differences may impact protease usage for viral glycoprotein processing.


Locoregional therapy.
Even after complete surgical resection of pulmonary metastases, many patients develop recurrent disease in the thorax despite the use of systemic chemotherapy, dosage of which is limited because of systemic toxicity. Although subsequent operations are feasible and good long-term results have been reported, sufficient functional lung parenchyma must remain. For this reason, new treatment strategies are explored. Similar to isolated limb and liver perfusion, isolated lung perfusion (ILuP) is a promising surgical technique for the delivery of high-dose chemotherapy with minimal systemic toxicity. The use of biologic response modifiers, such as tumor necrosis factor, is also feasible. ILuP with high-dose chemotherapy has proven to be highly effective in the experimental models of pulmonary metastases with a superior survival advantage compared with systemic treatment. Lung levels are significantly higher after ILuP compared with intravenous therapy without systemic exposure. Phase I human studies have shown that ILuP is technically feasible with low morbidity and without compromising the patient's pulmonary function. Further clinical studies are necessary to determine its definitive effect on local recurrence, long-term toxicity, pulmonary function, and survival.


Myocardial salvage after ST-segment-elevation myocardial infarction: comparison between prasugrel and clopidogrel in the presence or absence of high-residual platelet reactivity.
The effect of prasugrel over clopidogrel on myocardial salvage in ST-segment-elevation myocardial infarction (STEMI) patients undergoing primary percutaneous coronary intervention (p-PCI) is not fully elucidated. Among 854 consecutive STEMI patients who underwent p-PCI, 446 patients were evaluated by two-phase (7 days and 3 months) single-photo emission computed tomography (SPECT). Patients were divided into two groups based on the loading P2Y12 inhibitor. The clopidogrel group was further divided based on the result of platelet function testing. Thus, the prasugrel group included 227 patients; the clopidogrel without high-residual platelet reactivity (HRPR) group, 109 patients; and the clopidogrel with HRPR group, 107 patients. The primary endpoint was the Myocardial Salvage Index (MSI), determined by SPECT. The incidence of final TIMI 0/1 and TIMI myocardial perfusion grade 0/1 was higher in the clopidogrel with HRPR group (0.9%, 1.8%, and 7.5%, P = .002; 19.8%, 29.4%, and 41.1%, P = .0002, in the prasugrel, clopidogrel without HRPR, and clopidogrel with HRPR groups, respectively). The MSI was significantly lower in the clopidogrel with HRPR group (48% [27-66], 44% [30-72], and 36% [15-55], P = .006, respectively). Prasugrel in STEMI patients was associated with an increased MSI compared with clopidogrel in the presence of HRPR.


Organization and expression of multiple actin genes in the sea urchin.
A set of at least 11 actin genes has been isolated from genomic recombinant deoxyribonucleic acid libraries of the sea urchin Strongylocentrotus purpuratus. Most of the isolates derive from a library which represents the genome of a single animal. There are at least five distinct types of sea urchin actin gene, some of which are represented by multiple copies in the genome. The actin gene types are distinguished by nonhomologous flanking sequences and intervening sequences, though the protein coding sequences appear in most cases to be quite similar. Eight of the 11 genes isolated have been recovered in lambda recombinants that contain two actin genes, linked at 5- to 9-kilobase distances. Restriction map overlaps suggest that the genome contains an array of at least three of these genes spaced over about 30 kilobases of deoxyribonucleic acid. In the linkage patterns observed, actin genes of diverse types were linked to each other. In early embryos, actin messenger ribonucleic acid (RNA) transcripts of 1.8 and 2.2 kilobases were found, and the longer of these transcripts was more prevalent in the maternal RNA of the egg. From RNA gel blot experiments, we conclude that the two transcripts derive from different actin gene types. Different repetitive sequences were located to either side of most of the actin genes, and in most observed cases the repeat sequences which were adjacent to actin genes of a given type were similar. The repeat sequences flanking the actin genes belonged to families which were transcribed, but those repeats in the neighborhood of the actin genes which have been investigated were not themselves represented in the stable RNAs of eggs or early embryos.


Association of PAI-1 and fibrinogen with diabetic retinopathy in the Veterans Affairs Diabetes Trial (VADT).
To test the hypothesis that high levels of plasminogen-activating inhibitor (PAI)-1 and fibrinogen at baseline were associated with the onset or progression of diabetic retinopathy (DR) during the Veterans Affairs Diabetes Trial (VADT). The VADT was an open-label, prospective, randomized controlled trial to test the effect of standard glycemic control (STD) compared with intensive control (INT) on cardiovascular events in patients with advanced type 2 diabetes mellitus (T2DM). Diabetic retinopathy (DR) outcomes were also collected. Incidence and progression of DR were assessed by grading seven-field stereoscopic fundus photographs at baseline and 5 years later taken in 858 of a total of 1,791 participants who completed both eye examinations. Assignment to INT was not independently associated with decreased risk of onset of DR. However, after adjustment for multiple covariates, baseline level of PAI-1 was an independent risk factor for the onset of DR. The risk for incidence of DR increased by 12% for each 10 ng/dL increase in baseline PAI-1 concentration (odds ratio [OR] 1.012 [95% CI 1.00-1.024], P = 0.042). Assignment to INT was not independently associated with decreased risk of progression of DR. However, there was an interaction between glycemic treatment assignment and fibrinogen level at baseline. INT was associated with decreased progression of retinopathy in those with fibrinogen <296 mg/dL (OR 0.55 [95% CI 0.31-1.00], P = 0.03). The results require confirmation but are consistent with greater hypercoagulabilty and inflammation, as measured by higher levels of PAI-1 and fibrinogen, being related to DR and responsiveness to INT.


Testing a Smartphone App (Young with Diabetes) to Improve Self-Management of Diabetes Over 12 Months: Randomized Controlled Trial.
Young people often struggle to self-manage type 1 diabetes during the transition from childhood to adulthood. Mobile health (mHealth) apps may have the potential to support self-management, but evidence is limited and randomized controlled trials are needed. We assessed whether the mHealth app "Young with Diabetes" improved young people's self-management measured by glycated hemoglobin (HbA1c) and three self-reported psychometric scales. Young people (14-22 years) with inadequate glycemic control and their parents were enrolled in a randomized controlled trial and assigned either to Young with Diabetes and usual care (Young with Diabetes group) or to usual care alone (control). Young with Diabetes use was monitored; functions included a chat room, contact the health care provider, reminders, tips, information about the diabetes department and type 1 diabetes topics, carbohydrate counting, and a parents' section. Outcomes included HbA1c and three self-reported psychometric scales: Perceived Competence in Diabetes Scale; Health Care Climate Questionnaire; and Problem Areas In Diabetes care survey. Data were collected at baseline and at 2, 7, and 12 months. A total of 151 young people were randomized (Young with Diabetes group=76, control=75) and 49 parents agreed to participate. At 12 months, HbA1c was significantly higher (4.1 mmol/mol; 0.4 %) in the Young with Diabetes group, compared to the control group (P=.04); this finding did not occur when comparing app users (Young with Diabetes use ≥5 days) with nonusers. Young people used Young with Diabetes on a mean of 10.5 days. They spent the most time chatting about alcohol and searching for information about sex. Most young people and half of the parents reported that Young with Diabetes helped them. More than 80% would recommend Young with Diabetes to peers. Young with Diabetes did not improve HbA1c, but it may be a useful complement to self-management. Qualitative evaluation is needed to explore benefits and shortcomings of Young with Diabetes. Health care providers should address young peoples' knowledge about sensitive topics, provide them with peer support, and be aware of parents' need for information about how to support. ClinicalTrials.gov NCT02632383; https://clinicaltrials.gov/ct2/show/NCT02632383 (Archived by WebCite at http://www.webcitation.org/6zCK2u7xM).


Obesity inhibits lymphangiogenesis in prostate tumors.
Lymphangiogenesis is the process that leads to new lymphatic vessels formation from preexisting blood vessels in the presence of appropriate inducing signals, which in pathologic conditions such as cancer, may contribute to tumor cells dissemination. The aim of the present study was to study the role of obesity, leptin and insulin in tumor lymphangiogenesis. For that, we have quantified the lymphatic vessels in prostate tumors through their immunohistochemistry staining by Lyve-1 in RM1 prostate tumors induced in different obese mice models (ob/ob, db/db and diet induced obese (DIO) and in normal weight C57BL/6J mice (control). Lymph vessels density was determined by Lyve-1 immunohistochemistry of prostate adenocarcinomas, while the percentage of the Lyve-1 stained area and lymphatic vessels number were obtained using a morphometric computerized tool. Obese ob/ob and DIO mice presented prostate tumors that were significantly larger (p<0.001) than controls, while tumors of db/db mice were significantly smaller (p=0.047). Lyve-1 expression was significantly higher in prostate tumors of DIO mice compared to tumors of db/db mice (p<0.05); furthermore Lyve-1 expression was negatively correlated with the percentage of the epididymal fat and body weight (p<0.01). No significantly correlations were found between Lyve-1 expression and tumor weight and leptin or insulin plasma levels. Our results suggest that obesity may have a protective effect against prostate cancer dissemination by inhibiting lymphangiogenesis through a still unidentified mechanism that appears not to involve leptin or insulin.


ABL-N-induced apoptosis in human breast cancer cells is partially mediated by c-Jun NH2-terminal kinase activation.
The present study was designed to determine the possibility of acetylbritannilactone (ABL) derivative 5-(5-(ethylperoxy)pentan-2-yl)-6-methyl-3-methylene-2-oxo-2,3,3a,4,7,7a-hexahydrobenzofuran-4-yl 2-(6-methoxynaphthalen-2-yl)propanoate (ABL-N) as a novel therapeutic agent in human breast cancers. We investigated the effects of ABL-N on the induction of apoptosis in human breast cancer cells and further examined the underlying mechanisms. Moreover, tumor growth inhibition of ABL-N was done in xenograft models. ABL-N induced the activation of caspase-3 in estrogen receptor (ER)-negative cell lines MDA-MB-231 and MDA-MB-468, as evidenced by the cleavage of endogenous substrate Poly (ADP-ribose) polymerase (PARP). Pretreatment of cells with pan-caspase inhibitor z-VAD-fmk or caspase-3-specific inhibitor z-DEVD-fmk inhibited ABL-N-induced apoptosis. ABL-N treatment also resulted in an increase in the expression of pro-apoptotic members (Bax and Bad) with a concomitant decrease in Bcl-2. Furthermore, c-Jun-NH2-terminal kinase (JNK) and p38 mitogen-activated protein (MAP) kinase (p38) were activated in the apoptosis induced by ABL-N and JNK-specific inhibitor SP600125 and JNK small interfering RNA (siRNA) antagonized ABL-N-mediated apoptosis. However, the p38-specific inhibitor SB203580 had no effect upon these processes. Moreover, neither of the caspase inhibitors prevented ABL-N-induced JNK activation, indicating that JNK is upstream of caspases in ABL-N-initiated apoptosis. Additionally, in a nude mice xenograft experiment, ABL-N significantly inhibited the tumor growth of MDA-MB-231 cells. ABL-N induces apoptosis in breast cancer cells through the activation of caspases and JNK signaling pathways. Moreover, ABL-N treatment causes a significant inhibition of tumor growth in vivo. Therefore, it is thought that ABL-N might be a potential drug for use in breast cancer prevention and intervention.


Detection of Xylella fastidiosa in potential insect vectors by immunomagnetic separation and nested polymerase chain reaction.
A sensitive and specific assay for detecting Xylella fastidiosa in potential insect vectors was developed. This assay involves immunomagnetic separation of the bacteria from the insect, followed by a two-step, nested polymerase chain reaction (PCR) amplification using previously developed oligonucleotide primers specific to X. fastidiosa. A total of 347 leafhoppers representing 16 species were captured and sampled from American elm (Ulmus americana L.) trees growing in a nursery where bacterial leaf scorch caused by X. fastidiosa occurs. Two of these leafhopper species, Graphocephala coccinea and G. versuta, regularly tested positive for X. fastidiosa using this technique. These insects are therefore potential vectors of X. fastidiosa. Using immunocapture and nested PCR, it was possible to detect as few as five bacteria per sample.


Pattern recognition algorithm reveals how birds evolve individual egg pattern signatures.
Pattern-based identity signatures are commonplace in the animal kingdom, but how they are recognized is poorly understood. Here we develop a computer vision tool for analysing visual patterns, NATUREPATTERNMATCH, which breaks new ground by mimicking visual and cognitive processes known to be involved in recognition tasks. We apply this tool to a long-standing question about the evolution of recognizable signatures. The common cuckoo (Cuculus canorus) is a notorious cheat that sneaks its mimetic eggs into nests of other species. Can host birds fight back against cuckoo forgery by evolving highly recognizable signatures? Using NATUREPATTERNMATCH, we show that hosts subjected to the best cuckoo mimicry have evolved the most recognizable egg pattern signatures. Theory predicts that effective pattern signatures should be simultaneously replicable, distinctive and complex. However, our results reveal that recognizable signatures need not incorporate all three of these features. Moreover, different hosts have evolved effective signatures in diverse ways.


Inhibitory effects of lupane‑type triterpenoid saponins from the leaves of Acanthopanax gracilistylus on lipopolysaccharide-induced TNF‑α, IL‑1β and high‑mobility group box 1 release in macrophages.
Acanthopanax gracilistylus (AGS) has long been used in traditional Chinese medicine for the treatment of various inflammatory diseases. 3‑O‑β‑D‑glucopyranosyl 3α, 11α‑dihydroxylup‑20(29)‑en‑28‑oic acid, acantrifoside A, acankoreoside D, acankoreoside B and acankoreoside A are major lupane‑type triterpenoid saponins derived from AGS. In the present study, these five saponins were isolated from AGS by chromatography and their anti‑inflammatory activities were investigated in lipopolysaccharide (LPS)‑treated RAW264.7 macrophages. Cell viability was evaluated by MTT assay. Tumor necrosis factor (TNF)‑α, interleukin (IL)‑1β and NF‑κB p65 were measured by ELISA. The gene expression levels of TNF‑α and IL‑1β was detected by reverse‑transcription polymerase chain reaction. And high‑mobility group box 1 (HMGB1) were analyzed by western blotting. The results demonstrated that these five saponins significantly suppressed LPS‑induced expression of TNF‑α and IL‑1β at the mRNA and protein level in RAW264.7 cells. Further analysis revealed that acankoreoside A and acankoreoside B were able to reduce the secretion of HMGB1 and NF‑κB activity induced by LPS in RAW264.7 macrophages. Taken together, these results suggested that the anti‑inflammatory activity of AGS‑derived saponins may be associated with the downregulation of TNF‑α and IL‑1β, and the 'late‑phase' proinflammatory cytokine HMGB1, via negative regulation of the NF‑κB pathway in RAW264.7 cells.


Resistin: molecular history and prognosis.
Obesity and diabetes have reached epidemic proportions worldwide. The antidiabetic thiazolidinedione (TZD) drugs are insulin-sensitizing agents now widely used in the treatment of type 2 diabetes. TZDs are ligands for the nuclear hormone receptor peroxisome proliferator activated receptor gamma, which is a master regulator of adipogenesis and adipocyte metabolism. The molecular mechanisms by which TZDs improve insulin sensitivity have not been fully identified. Here we consider a novel secreted factor first identified as a TZD-suppressible gene in mouse adipocytes, called resistin, and discuss what is currently known about resistin regulation and function in mouse and human.


Use of changes in ST segment elevation for prediction of infarct artery recanalization in acute myocardial infarction.
The role of the ECG in evaluating reperfusion status after thrombolytic treatment in acute myocardial infarction is not clear. Dramatic ST segment changes have been observed during recanalization of an infarct-related artery, but ST criteria have not been definitively established for prediction of coronary artery patency. Differences in ST segment changes in relation to infarct localization have not been evaluated, and further investigation is required into reciprocal ST depression, which provides information independent from ST elevation. Therefore, the aim of this study was to evaluate how early changes in ST segment elevations and depressions predict vessel patency after fibrinolysis for patients with anterior and inferior/lateral infarcts. Two hundred patients with a Pardee wave in the ECG and chest pain of less than 6 h duration were given thrombolytic treatment. The result of the therapy was assessed simultaneously with coronary angiography. Patients were divided into two groups: I (50 patients) without recanalization (TIMI grade 0, 1 or 2), and II (150 patients) with successful recanalization (TIMI grade 3). Before and after therapy, analysis of the 12 lead ECG included maximum ST elevation measurement (H1, H2 respectively), the sum of ST elevations (sigma H1, sigma H2), the sum of ST segment depressions (sigma h1, sigma h2), and the ratios of ST segment changes (R1 = H2:H1, R2 = sigma H2:sigma H1, R3 = sigma h2:sigma h1). The mean interval from the first to the second ECG was 3.5 +/- 1 h. Successive values of R1 and R2 were examined to find that which best distinguished between the two groups. The best values for prediction of reperfusion were: (1) For anterior wall infarct [table: see text] (2) For inferior and lateral infarct [table: see text] In 13 patients with a complete right or left bundle branch block in the first or second ECG, the result of treatment was predicted in 11 patients using criteria for factor R1 and in 12 patients using criteria for R2. Analysis of ST segment depressions revealed a significant correlation between normalization of ST segment depressions and elevations (R3 vs R1: r = 0.60, P < 0.05; R3 vs R2 r = 0.59, P < 0.05). Multivariate discriminant analysis showed an independent value of R3 for discrimination between the two groups, but only in patients with inferior/lateral infarcts. The overall accuracy of the common algorithm in predicting reperfusion was significantly better in patients with inferior/lateral infarcts (Chi2 test, P = 0.0078). When separate algorithms were used, there was no significant difference between patients with anterior or inferior/lateral infarcts because of the significant improvement in prediction of reperfusion in patients with anterior infarcts (McNemar's test: P = 0.041). We conclude that analysis of ST segments on the standard 12-lead ECG offers valuable help in the early identification of successful recanalization of infarct-related arteries after thrombolytic therapy in patients with acute myocardial infarction. Use of the ratio of ST segment normalization according to the separate criteria for anterior and inferior/lateral infarcts gives the test a high sensitivity and specificity, even in the presence of interventricular conduction disturbances.


Target-specific mutations efficiency at multiple loci of CRISPR/Cas9 system using one sgRNA in soybean.
Soybean has a palaeopolyploid genome with nearly 75% of the genes present in multiple copies. Although the CRISPR/Cas9 system has been employed in soybean to generate site-directed mutagenesis, a systematical assessment of mutation efficiency of the CRISPR/Cas9 system for the multiple-copy genes is still urgently needed. Here, we successfully optimize one sgRNA CRISPR/Cas9 system in soybean by testing the efficiency, pattern, specificity of the mutations at multiple loci of GmFAD2 and GmALS. The results showed that simultaneous site-directed mutagenesis of two homoeologous loci by one sgRNA, the mutation frequency in the T0 generation were 64.71% for GmPDS, 60.0% for GmFAD2 and 42.86% for GmALS, respectively. The chimeric and heterozygous mutations were dominant types. Moreover, association of phenotypes with mutation pattern at target loci of GmPDS11 and GmPDS18 could help us further demonstrate that the CRISPR/Cas9 system can efficiently generate target specific mutations at multiple loci using one sgRNA in soybean, albeit with a relatively low transformation efficiency.


Representing the location of manipulable objects in shape-selective occipitotemporal cortex: Beyond retinotopic reference frames?
When interacting with objects, we have to represent their location relative to our bodies. To facilitate bodily reactions, location may be encoded in the brain not just with respect to the retina (retinotopic reference frame), but also in relation to the head, trunk or arm (collectively spatiotopic reference frames). While spatiotopic reference frames for location encoding can be found in brain areas for action planning, such as parietal areas, there is debate about the existence of spatiotopic reference frames in higher-level occipitotemporal visual areas. In an extensive multi-voxel pattern analysis (MVPA) fMRI study using faces, headless bodies and scenes stimuli, Golomb and Kanwisher (2012) did not find evidence for spatiotopic reference frames in shape-selective occipitotemporal cortex. This finding is important for theories of how stimulus location is encoded in the brain. It is possible, however, that their failure to find spatiotopic reference frames is related to their stimuli: we typically do not manipulate faces, headless bodies or scenes. It is plausible that we only represent body-centred location when viewing objects that are typically manipulated. Here, we tested for object location encoding in shape-selective occipitotemporal cortex using manipulable object stimuli (balls and cups) in a MVPA fMRI study. We employed Bayesian analyses to determine sample size and evaluate the sensitivity of our data to test the hypothesis that location can be encoded in a spatiotopic reference frame in shape-selective occipitotemporal cortex over the null hypothesis of no spatiotopic location encoding. We found strong evidence for retinotopic location encoding consistent with previous findings that retinotopic reference frames are common neural representations of object location. In contrast, when testing for spatiotopic encoding, we found evidence that object location information for small manipulable objects is not decodable in relation to the body in shape-selective occipitotemporal cortex. Post-hoc exploratory analyses suggested that spatiotopic aspects might modulate retinotopic location encoding. Overall, our findings provide evidence that there is no spatiotopic encoding that is independent of retinotopic location in shape-selective occipitotemporal cortex.


Experience sampling reveals the role that covert goal states play in task-relevant behavior.
Cognitive neuroscience has gained insight into covert states using experience sampling. Traditionally, this approach has focused on off-task states. However, task-relevant states are also maintained via covert processes. Our study examined whether experience sampling can also provide insights into covert goal-relevant states that support task performance. To address this question, we developed a neural state space, using dimensions of brain function variation, that allows neural correlates of overt and covert states to be examined in a common analytic space. We use this to describe brain activity during task performance, its relation to covert states identified via experience sampling, and links between individual variation in overt and covert states and task performance. Our study established deliberate task focus was linked to faster target detection, and brain states underlying this experience-and target detection-were associated with activity patterns emphasizing the fronto-parietal network. In contrast, brain states underlying off-task experiences-and vigilance periods-were linked to activity patterns emphasizing the default mode network. Our study shows experience sampling can not only describe covert states that are unrelated to the task at hand, but can also be used to highlight the role fronto-parietal regions play in the maintenance of covert task-relevant states.


Umami and appetite: effects of monosodium glutamate on hunger and food intake in human subjects.
Subjects consumed soup (beef consomme) preloads of a fixed size containing different concentrations of monosodium L-glutamate (MSG). Effects on appetite following these preloads, and when no soup was consumed, were assessed in 3 studies. The soups supplemented with MSG were rated as more "pleasant," more "savoury" and more "satisfying" than soup with no added MSG. Compared with the no preload condition, consumption of the soups initially reduced appetitive motivational ratings and increased fullness ratings, but did not alter food intake in a test meal begun either 2 or 30 minutes later. This immediate inhibition of subjective motivation to eat was unaffected by MSG concentration. The failure of the soups to reduce subsequent food intake is presumably due to their low energy content (less than 10 kcal) and indicates that sensory stimulation alone is insufficient to reduce appetite. Indeed, the most important finding concerning MSG showed that motivation to eat recovered more rapidly following a lunchtime meal in which MSG-supplemented soup was served as the first course (compared both with the effect of unsupplemented soup and no preload). It is suggested tentatively that MSG through its stimulation of orosensory receptors and/or by improving the palatability of the soup may have influenced the metabolic disposal of nutrients consumed in the previous meal.


The safety of pegylated interferon alpha-2b in the treatment of chronic hepatitis B: predictive factors for dose reduction and treatment discontinuation.
Treatment with interferon-alpha has been shown to be effective in one-third of hepatitis B e antigen-positive chronic hepatitis B patients, but is clinically associated with relevant adverse events. To investigate the safety of pegylated interferon alpha-2b in 300 hepatitis B e antigen-positive patients with compensated liver disease. Patients were treated with pegylated interferon alpha-2b for 52 weeks combined with either lamivudine 100 mg/day or placebo. Pegylated interferon alpha-2b was administered for 100 microg once a week for 32 weeks; thereafter, the dose was reduced to 50 microg once a week. Adverse events and their effect on study medication were reported at monthly visits in a standardized way. The most frequently reported side-effects were flu-like syndrome (68%), headache (40%), fatigue (39%), myalgia (29%) and local reaction at the injection site (29%). These symptoms typically occurred within the first month of therapy and subsided during the course of therapy. Neutropenia and thrombocytopenia induced by pegylated interferon alpha-2b increased the risk of infections and bleeding complications, but these complications were rare and mild. The frequency of all side-effects was not different between patients treated with pegylated interferon alpha-2b combined with lamivudine or placebo. In 69 (22%) patients the dose of pegylated interferon alpha-2b was reduced prematurely. Of these dose reductions, 36 (52%) were because of neutropenia. Therapy was discontinued in 28 (8%) patients. The most frequent reasons for early discontinuation were psychiatric side-effects (depression, psychosis) and flu-like symptoms. Multivariate Cox regression analysis showed that low neutrophil count at baseline and cirrhosis were independent predictors of dose reduction or therapy discontinuation. We conclude that in patients with chronic hepatitis B and compensated liver disease prolonged pegylated interferon alpha-2b therapy is safe, and that pre-existent cirrhosis and neutropenia are the most important predictors of dose reduction or early treatment discontinuation.


Ramucirumab in elderly patients with hepatocellular carcinoma and elevated alpha-fetoprotein after sorafenib in REACH and REACH-2.
Limited data on treatment of elderly patients with hepatocellular carcinoma (HCC) increase the unmet need. REACH and REACH-2 were global phase III studies of ramucirumab in patients with HCC after prior sorafenib, where patients with alpha-fetoprotein (AFP) ≥400 ng/mL showed an overall ssurvival (OS) benefit for ramucirumab. These post-hoc analyses examined efficacy and safety of ramucirumab in patients with HCC and baseline AFP ≥ 400 ng/mL by three prespecified age subgroups (<65, ≥65 to <75 and ≥75 years). Individual patient data were pooled from REACH (baseline AFP ≥400 ng/mL) and REACH-2. Kaplan-Meier and Cox proportional hazards regression methods (stratified by study) assessed OS, progression-free survival (PFS), time to progression (TTP) and patient-reported outcomes (Functional Hepatobiliary System Index-8 [FHSI-8] score). A total of 542 patients (<65 years: n = 302; ≥65 to <75 years: n = 160; ≥75 years: n = 80) showed similar baseline characteristics between ramucirumab and placebo. Older subgroups had higher hepatitis C and steatohepatitis incidences, and lower AFP levels, than the <65 years subgroup. Ramucirumab prolonged OS in patients <65 years (hazard ratio [HR], 0.753; 95% CI 0.581-0.975), ≥65 to <75 years (0.602; 0.419-0.866) and ≥75 years (0.709; 0.420-1.199), PFS and TTP irrespective of age. Ramucirumab showed similar overall safety profiles across subgroups, with a consistent median relative dose intensity ≥97.8%. A trend towards a delay in symptom deterioration in FHSI-8 with ramucirumab was observed in all subgroups. In this post-hoc analysis, ramucirumab showed a survival benefit across age subgroups with a tolerable safety profile, supporting its use in advanced HCC with elevated AFP, irrespective of age, including ≥75 years.


Inhibition of neuronal nitric oxide synthase by 4-amino pteridine derivatives: structure-activity relationship of antagonists of (6R)-5,6,7,8-tetrahydrobiopterin cofactor.
The family of nitric oxide synthases (NOS) catalyzes the conversion of L-arginine to L-citrulline and nitric oxide (NO), an important cellular messenger molecule which has been implicated in the pathophysiology of septic shock and inflammatory and neurodegenerative disease states. NOS can be maximally activated by the ubiquitous cofactor, (6R)-5,6,7,8-tetrahydrobiopterin (H(4)Bip), and antagonists of H(4)Bip may be of therapeutic importance to inhibit pathologically high NO formation. The 4-amino substituted analogue of H(4)Bip was reported to be a potent NOS inhibitor. Therefore, we developed a series of novel 4-amino pteridine derivatives, anti-pterins, to pharmacologically target the neuronal isoform of nitric oxide synthase (NOS-I). To functionally characterize the pterin/anti-pterin interaction and establish a structure-activity relationship (SAR), we systematically altered the substituents in the 2-, 4-, 5-, 6-, and 7-position of the pteridine nucleus. Varying the substitution pattern in the 2-, 5-, and 7-position resulted in no significant inhibitory effect on enzyme activity. In contrast, bulky substituents in the 6-position, such as phenyl, markedly increased the inhibitory potency of the reduced 4-amino-5,6,7,8-tetrahydropteridines, possibly as a consequence of hydrophobic interactions within NOS-I. However, this was not the case for the aromatic 4-amino pteridines. Interestingly, chemical modification of the 4-amino substituent by dialkyl/diaralkylation together with 6-arylation of the aromatic 2,4-diamino pteridine resulted in potent and efficacious inhibitors of NOS-I, suggesting possible hydrophilic and hydrophobic interactions within NOS-I. This SAR agrees with (a) the recently published crystal structure of the oxygenase domain of the inducible NOS isoform (NOS-II) and (b) the comparative molecular field analysis of selected NOS-I inhibitors, which resulted in a 3D-QSAR model of the pterin binding site interactions. Further optimization should be possible when the full length structure of NOS-I becomes available.


The citrus flavonoids hesperetin and nobiletin differentially regulate low density lipoprotein receptor gene transcription in HepG2 liver cells.
Reduction of plasma cholesterol by citrus flavonoids is associated with effects on specific liver functions related to lipid handling. In previous in vivo studies, polymethoxylated flavones (PMF) reduced plasma cholesterol levels at lower doses than required for flavanones. To delineate hepatic mechanisms that underlie this differential potency, we used HepG2 cells to quantitate effects on expression of the LDL receptor (LDLR) gene. A dose-response analysis showed that 200 micromol/L hesperetin, a flavanone present as a disaccharide in oranges, increased LDLR mRNA levels 3.6- to 4.7-fold of the untreated control. In contrast, nobiletin, a PMF found at the highest concentration in oranges and tangerines, achieved maximal stimulation of 1.5- to 1.6-fold of control at only 5 micromol/L. Transcriptional regulation of the LDLR gene by citrus flavonoids has been implicated but, to our knowledge, not directly demonstrated. Here, using transfection vector constructs containing the upstream region of the LDLR gene, we show differences in both potency and efficacy in the induction of transcription, with peak stimulation of 5.3- to 7.5-fold of control at 150-160 micromol/L hesperetin and 3- to 3.8-fold of control at 10-20 micromol/L nobiletin. Hesperetin sustains induction, whereas nobiletin is inhibitory at high doses, resulting in an inverted-U dose response. The sterol regulatory element (SRE) in the LDLR gene upstream region plays a crucial role, because mutation of this site strongly attenuated induction in response to hesperetin or nobiletin. Thus, citrus flavonoids are likely to act through the SRE-binding proteins, with PMF initially activating these mechanisms at considerably lower concentrations than flavanones.


Role of hormone-controlled T-cell cytokines in the maintenance of pregnancy.
Human CD4 T helper lymphocytes can be subdivided into at least three distinct functional subsets on the basis of their cytokine secretion profiles. One type of CD4+ lymphocyte, T helper 1 (Th1), produces interferon (IFN)-gamma and tumour necrosis factor beta, a second type (Th2) produces interleukin (IL)-4 and IL-5 and a third type (Th0) produces both Th1 and Th2 cytokines. The apparent paradox that embryos are not rejected by the maternal immune system despite the presence of paternal MHC histocompatibility antigens has been explained in mice by a Th2 switch at the level of the materno-fetal interface. We showed that some hormones enhanced during pregnancy can affect the development of Th1 and Th2 responses. Indeed, we found that progesterone promotes the production of IL-4 and IL-5, whereas relaxin promotes the production of IFN-gamma by T-cells. In addition, we showed that leukaemia inhibitory factor (LIF), which is essential for embryo implantation, associates with Th2 cells and is upregulated by IL-4 and progesterone. We also showed that LIF is down-regulated by Th1 inducers [IL-12, IFN-gamma and IFN-alpha]. Furthermore, we found a decreased production of LIF, IL-4 and IL-10 by decidual T-cells in women with unexplained recurrent abortions in comparison with women with normal gestation at the moment of voluntary abortion. The decreased production of LIF, IL-4 and IL-10 was not found in peripheral-blood T-cells. These results suggest that the local production of LIF and/or Th2 cytokines may contribute to the maintenance of pregnancy.


Real-world utility of HCV core antigen as an alternative to HCV RNA testing: Implications for viral load and genotype.
Following positive serology, the gold standard confirmatory test of hepatitis C virus (HCV) infection is detection of HCV RNA by PCR. We assessed the utility of HCV core antigen testing to identify active infection among those positive for anti-HCV antibodies, when introduced to routine testing. We identified serum samples that were tested at a single laboratory in Scotland from June 2011to December 2017. Serum samples testing positive for HCV antibodies (HCV Ab positive) followed by reflex HCV core antigen (Ag) testing during the study period were identified. Those patients for whom a PCR test was requested on the baseline sample were also identified. For this group, the sensitivity and specificity of HCV Ag as a diagnostic tool were assessed using HCV PCR as gold standard. In our cohort of 744 patients, we demonstrated a sensitivity of 82.1% (95% CI 77.1%-86.2%) and a specificity of 99.8% (95% CI 98.6%-100%). Genotype 3 was associated with increased odds of a false-negative result (OR = 3.59, 95% CI: 1.32-9.71), and reduced odds of a false negative were associated with older age (odds ratio (OR)=0.92, 95% CI: 0.88-0.97 per year) and viral load (OR = 0.10, 95% CI: 0.05-0.21 per log10 IU/ml). While the implementation of HCV core antigen testing for diagnosis could lead to significant cost savings in national screening programmes, our data suggest that a significant proportion of HCV-infected individuals may be missed. These findings have implications for HCV diagnosis and determination of viral clearance after treatment, particularly in low- and middle-income regions, where genotype 3 is prevalent.


Does age influence normal gastro-oesophageal reflux?
Prolonged oesophageal pH monitoring is being used increasingly to detect abnormal gastro-oesophageal reflux. To assess the influence of age on normal reflux patterns, a group of 13 young asymptomatic subjects (mean age 22 years) was compared with a group of 14 middle aged asymptomatic subjects (mean age 49 years). An ambulatory system using a radiotelemetry capsule and a portable receiving system was used, oesophageal pH being recorded for at least 16 hours during an overnight hospital stay under standardised conditions. There was no significant difference in the duration or frequency of reflux episodes as defined by pH less than 5, less than 4, less than 3, or as a fall in pH of more than two units. It is concluded that it is an acceptable practice to use young volunteers to establish normal values in reflux studies of young and middle aged patients.


Effects of itraconazole and terbinafine on Leishmania major lesions in BALB/c mice.
The effects of two antifungal compounds, the azole itraconazole and the allylamine terbinafine, on Leishmania major infections in mice are reported. Sixty BALB/c mice were each inoculated subcutaneously with metacyclic promastigotes of L. major at the base of the tail. From 4 weeks post-inoculation, 40 of the mice were treated for 4 weeks (20 with itraconazole and 20 with terbinafine) and the rest were left untreated. Lesion sizes were estimated weekly for 10 weeks post-infection. Both drugs appeared effective in treating the cutaneous lesions but response to itraconazole was faster and, at the end of the experiment, the mean size of the lesions on the mice treated with itraconazole was smaller than that of the lesions on the terbinafine-treated mice.


Physician perceptions of the role and value of basic science knowledge in daily clinical practice.
The role of basic science education in a clinical setting remains unclear. Research to understand how academic clinicians perceive and use this part of their education can aid curricular development. To assess physician's attitudes toward the value of science knowledge in their clinical practice. Academic physicians from three medical schools completed a questionnaire about the utility of basic science education in core clinical tasks and in practice-based learning and improvement. A total of 109 clinical faculty returned the survey. Overall, 89% of the respondents indicated that basic science education is valuable to their clinical practice. When asked about the utility of basic science information in relation to direct patient care, greater than 50% of the doctors felt they use this when diagnosing and communicating with patients. This rose to greater than 60% when asked about choosing treatment options for their patients. Individuals also responded that basic science knowledge is valuable when developing evidence-based best practices. Specifically, 89% felt that they draw upon this information when training students/residents and 84% use this information when reading journal articles. This study shows that basic science education is perceived by responding academic physicians to be important to their clinical work.


Promoting collaborative practice with culturally diverse populations.
Practicing nurses in multiple health care settings must be prepared to manage a diverse, multicultural patient population and work collaboratively with co-workers representing different cultural backgrounds. To prepare professional nurses to practice effectively with our increasingly diverse population, frontline managers and nursing service administrators must act jointly to increase their knowledge of cultural diversity, share that knowledge, and combine forces to promote cultural awareness and sensitivity in practice settings.


Influence of iron on growth, morphology, outer membrane protein composition, and synthesis of siderophores in Campylobacter jejuni.
Three human isolates of Campylobacter jejuni were grown in a biphasic culture medium with and without the addition of a synthetic chelator to induce iron limitation. Cells grown in low-iron medium exhibited slower growth rates and altered cellular morphology. Increased numbers of longer, more filamentous forms were seen in Gram-stained smears. Three proteins, with apparent Mrs of 82,000, 76,000, and 74,000, were consistently present in the outer membrane of cells grown in low-iron medium. At least one of these proteins (76,000 to 74,000) was exposed on the cell surface. A bioassay was used to look for the production of siderophores by these and other strains of C. jejuni. Seven of 26 strains tested produced detectable amounts of siderophores. Growing strains at 42 degrees C failed to suppress siderophore synthesis or to alter the outer membrane protein profiles of iron-starved cells. The ability of three strains to utilize exogenously supplied siderophores for growth in low-iron medium was also examined. All three strains were able to utilize enterochelin and ferrichrome, but none utilized aerobactin, rhodotorulic acid, or desferrioxamine B. The effect of iron on the virulence of C. jejuni for 11-day-old chicken embryos inoculated via the chorioallantoic membrane was also determined.


Performance of FibroScan in grading steatosis and fibrosis in patients with nonalcoholic fatty liver disease: A meta-analysis.
Biopsy remains the gold standard for the diagnosis of Non-alcoholic fatty liver disease (NAFLD). To investigate the diagnostic value of FibroScan based on biopsy and range of cut-offs for steatosis and fibrosis, we explored the grade of steatosis and fibrosis. A simultaneous search was performed on cohort studies published earlier than October 8, 2020,in the PubMed, Web of Science, Sinomed, CNKI, VIP, and WanFang databases. Next,we screened qualified studies. The data were mainly analysed in RevMan and complemented in STATA. The area under the receiver operating characteristic of FibroScan in identifying the stage of steatosis for ≥ S1 was 0.90 (sensitivity:89%; specificity:92%), that for ≥ S2 was 0.82 (sensitivity:89%;specificity:70%) and that for S3 was 0.79 (sensitivity:83%; specificity:63%).The area under the receiver operating characteristic of FibroScan in identifying the stage of fibrosis for ≥ F1 was 0.86 (sensitivity:81%;specificity:77%),that for ≥ F2 was 0.80 (sensitivity: 75%; specificity:82%), that for ≥ F3 was 0.94 (sensitivity:87%; specificity: 89%) and that for F4 was 0.97 (sensitivity: 94%; specificity:91%). FibroScan, a promising and cost-effective technique, can provide an accurate noninvasive approach for quantifying and staging hepatic steatosis and fibrosis in NAFLD, particularly for advanced fibrosis and cirrhosis. Further studies are needed to explore the relationship between steatosis and fibrosis based on the same group. Additionally, NASH is the key stage of NAFLD. Early diagnosis and intervention can help reduce the incidence of liver cirrhosis. However, no large study has investigated the significance of FibroScan in the diagnosis of NASH confirmed by pathology.


Physical Fitness in Young Men between 1975 and 2015 with a Focus on the Years 2005-2015.
The purpose of the present study was to investigate changes in physical fitness and anthropometry of young men entering the military service in Finland during the years 1975-2015. The study included the fitness test results of 627,142 healthy young male conscripts (age 19.1 ± 0.4 yr). Data included results of aerobic capacity, muscle fitness tests, and anthropometric characteristics. The results show that the increase in mean body mass of young men has slowed down during the last 10 yr. However, the total increase in body mass was 6.8 kg (8.8%, P ≤ 0.001) between 1993 and 2015. The mean distance achieved in the 12-min running test decreased by 337 m (12.2%, P ≤ 0.001) between the peak in 1980 and 2015. The relative number of conscripts who ran less than 2200 m increased from 3.6% to 25.9% (P ≤ 0.001) between 1980 and 2015, and the proportion who ran more than 3000 m decreased from 25.1% to 6.5% (P ≤ 0.001). The relative number of conscripts who achieved an excellent or good muscle fitness index decreased from 66.8% to 40.1% (P ≤ 0.001) between 1992 and 2000, and remained unchanged between 2000 and 2010. However, the proportion who achieved a poor muscle fitness index increased from 8.1% to 31.4% (P ≤ 0.001) between 1992 and 2010. The present study shows that the increase in mean body mass of young male conscripts has slowed down during the last 10 yr. However, their aerobic capacity has still decreased during recent decades. In addition, the proportion of conscripts with poor muscle fitness has increased. From the national defense and health perspective, more initiatives are needed to encourage young men to increase their level of daily physical activity to be fit and ready for operations.


Th1 and Th2 cytokine secretion patterns in murine candidiasis: association of Th1 responses with acquired resistance.
Two chemically mutagenized agerminative variants of Candida albicans were used to immunize mice against challenge with highly virulent cells of the parent strain. Although both mutants (Vir- 3 and Vir- 13) resulted in nonlethal infection and could be recovered from mouse organs for many days after the intravenous inoculation of 10(7) to 10(6) cells, significant protection to systemic challenge with virulent C. albicans was induced by only one (Vir- 3) of the two variants. Anticandidal resistance in Vir- 3-infected mice was associated with the occurrence in vivo of strong delayed-type hypersensitivity to Candida antigen, detection in vitro of highly fungicidal effector macrophages, and presence in the serum of a large proportion of Candida-reactive antibodies of the immunoglobulin G2a isotype. Bulk cultures of purified CD4+ lymphocytes from mice infected with either mutant were compared for their ability to produce gamma interferon (IFN-gamma), interleukin-2 (IL-2), IL-4, and IL-6 in vitro. After stimulation with specific antigen, CD4+ cells from Vir- 3-immunized mice released large amounts of the Th1-specific cytokines, IFN-gamma and IL-2, at a time when CD4+ cells from Vir- 13-infected mice predominantly secreted the characteristic Th2 cytokines, IL-4 and IL-6. These results were confirmed by quantitative analysis of cytokine-producing Th1 and Th2 cells. In addition, only mice infected with Vir- 3 displayed a high frequency of CD8+ cells with the potential for in vitro lysis of yeast-primed bone marrow macrophages. Purified CD4+ cells from Vir- 3-infected mice, but not a mixture of these cells with CD4+ lymphocytes from mice infected with Vir- 13, could adoptively transfer delayed-type hypersensitivity reactivity onto naive mice. Taken together, these data suggest that both Th1 and Th2 CD4+ lymphocytes may be activated during experimental C. albicans infection in mice.


Precision medicine for psychopharmacology: a general introduction.
Precision medicine is an emerging medical model that can provide accurate diagnoses and tailored therapeutic strategies for patients based on data pertaining to genes, microbiomes, environment, family history and lifestyle. Here, we provide basic information about precision medicine and newly introduced concepts, such as the precision medicine ecosystem and big data processing, and omics technologies including pharmacogenomics, pharamacometabolomics, pharmacoproteomics, pharmacoepigenomics, connectomics and exposomics. The authors review the current state of omics in psychiatry and the future direction of psychopharmacology as it moves towards precision medicine. Expert commentary: Advances in precision medicine have been facilitated by achievements in multiple fields, including large-scale biological databases, powerful methods for characterizing patients (such as genomics, proteomics, metabolomics, diverse cellular assays, and even social networks and mobile health technologies), and computer-based tools for analyzing large amounts of data.


Kankuamo, a new theraphosid genus from Colombia (Araneae, Mygalomorphae), with a new type of urticating setae and divergent male genitalia.
A new monotypic Theraphosidae genus, Kankuamo Perafán, Galvis & Pérez-Miles, gen. n., is described from Colombia, with a new type of urticating setae. These setae differ from others principally by having a small distal oval patch of lanceolate reversed barbs. Males of Kankuamo gen. n. additionally differ by having a palpal bulb organ very divergent from all known species, with many conspicuous keels dispersed across the median tegulum to the tip, mostly with serrated edges. Females differ by having spermathecae with a single notched receptacle, with two granulated lobes and several irregular sclerotized longitudinal striations. The new urticating setae, type VII, is characterized, illustrated and its releasing mechanism is discussed. It is hypothesized that these setae are the first in Theraphosinae subfamily whose release mechanism is by direct contact. Kankuamo gen. n. is described and illustrated on the basis of the type species Kankuamo marquezi Perafán, Galvis & Gutiérrez, sp. n., and their remarkable characteristics, morphological affinities and cladistic relationship are analyzed.


'Feeling younger, remembering better': the effect of experimentally induced subjective age on memory performance among Chinese older adults.
Objectives: This study aimed to explore whether experimentally induced younger subjective age can lead to better memory performance among Chinese older adults.Method: A total of 203 participants aged 60-84 years were randomly assigned to three groups. In the positive and neutral feedback groups, participants were told that their memory performance was better than and equivalent to the same-aged peers after an initial memory task, respectively, in contrast to no feedback in the control group. Participants then completed a second memory measure.Results: The results revealed that participants in the positive feedback group felt younger and showed a significant increase in memory performance, whereas participants in the neutral feedback group felt older but also showed a significant increase in memory performance. For participants in the control group, no significant changes in memory performance were observed.Conclusion: It seems that experimentally induced younger subjective age can lead to better memory performance among older adults, providing a promising strategy to maintain memory functioning in old age.


Respite care on a children's ward.
In March 1984 a short term respite care facility for handicapped children was opened in a children's ward catering primarily for acute medical and surgical problems. The facility was based on a four bedded room designed so that if beds became short in the main ward it could revert immediately to the care of acutely sick children. Three nurses were appointed specifically to staff the facility, the nursing budget for the rest of the ward being reduced proportionately. Conversions were funded by charities and some of the conversion work done by volunteers. The main users were totally dependent children aged under 5 with severe mental and physical handicaps. Parents found the service invaluable, and in addition to planned admissions it was usually possible to accept a child at short notice--for example, when some domestic crisis occurred. Only very rarely was admission impossible because of the needs of acutely ill children. A short term respite care facility not only helps parents cope and may provide beneficial experience for a handicapped child but is also a useful training ground for medical students and junior staff.


Association of serum 25-hydroxyvitamin D levels with aggressiveness of papillary thyroid cancer.
Serum 25-hydroxyvitamin D (25(OH)D) deficiency has been known to be associated with the risk and mortality of several cancers. However, the role of 25(OH)D in papillary thyroid cancer (PTC) remains controversial. This study aimed to investigate the association between 25(OH)D and clinicopathologic features of PTC. Patients who underwent thyroidectomy were retrospectively reviewed. Serum 25(OH)D levels were measured within a week prior to surgery. The patients were categorized into four quartiles according to season-specific 25(OH)D levels. The association between 25(OH)D levels and clinicopathologic features of PTC was analyzed. A total of 2932 patients were enrolled in the study. The 25(OH)D levels were significantly higher in patients with lymph node metastasis (LNM; P < 0.001), lateral LNM (P < 0.001), and multifocal tumors (P < 0.001). Compared to the first quartile (Q1) of 25(OH)D level, the third quartile (Q3) and the fourth quartile (Q4) showed an unadjusted OR of 1.36 (95% CI: 1.09-1.69; P = 0.006) and 1.76 (95% CI: 1.42-2.19; P < 0.001) for LNM (P for trend < 0.001), respectively. An increased risk of multifocal tumors was strongly associated with high 25(OH)D concentration (P for trend <0.001). Similar results were obtained after adjusting for confounding factors. High 25(OH)D levels are associated with aggressive features of PTC, such as lymph node metastasis and multifocality.


Oral pamidronate prevents high-dose glucocorticoid-induced lumbar spine bone loss in premenopausal connective tissue disease (mainly lupus) patients.
Glucocorticoid (GC)-induced osteoporosis contributes to chronic damage in patients suffering from connective tissue diseases (CTD) such as systemic lupus erythematosus (SLE). In this study, performed in an highly selected cohort of premenopausal female CTD (mostly lupus) patients, given high-dose GC therapy for severe disease, we show that lumbar spine bone loss can be averted by treatment with oral disodium pamidronate combined with calcium salts and vitamin D3 supplements and not by calcium salts and vitamin D3 supplements alone. We stress the need for optimal GC-induced bone loss prevention therapy in premenopausal patients, a too often neglected issue in patients whose survival has dramatically improved over the last decades.


Effects of angiotensin converting enzyme inhibitor cilazapril and angiotensin II antagonist saralasin in ovarian hyperstimulation syndrome in the rabbit.
We investigated the possible effects of the angiotensin converting enzyme (ACE) inhibitor cilazapril and angiotensin II antagonist saralasin on ovulation, ovarian steroidogenesis and ascites formation in the ovarian hyperstimulation syndrome (OHSS) in the rabbit model. OHSS was induced in rabbits by human menopausal gonadotropin (hMG) and intermittent human chorionic gonadotropin (hCG). In the cilazapril group (n = 10), animals also received cilazapril 2 mg/kg intraperitoneally daily for 7 days. In the saralasin group (n = 8), animals received saralasin intraperitoneally 1 h before or 1 h after hCG administration. Control animals (n = 8), received intraperitoneal saline solution. Serial blood samples were drawn on days 1, 5, 7 and 9 to measure serum estradiol and progesterone levels. On day 9, all rabbits underwent surgical exploration. Peritoneal and pleural fluid formation, ovarian weights and number of ovulations were determined. The volume of the ascitic and pleural fluids after hyperstimulation were not statistically different between the control, cilazapril and saralasin groups. The weight gains and ovarian weights of animals were similar between treatment and control groups. Saralasin significantly (p < 0.05) inhibited ovulation, but cilazapril did not. Cilazapril and saralasin did not affect progesterone production. Only cilazapril significantly decreased estradiol production (p < 0.05). In conclusion, the ACE inhibitor cilazapril and angiotensin II antagonist saralasin did not prevent ascites formation in OHSS. The ovarian renin-angiotensin system may not be the only factor acting in ascites formation in the OHSS.


A review on PARP1 inhibitors: Pharmacophore modeling, virtual and biological screening studies to identify novel PARP1 inhibitors.
A tremendous research on Poly (ADP-ribose) polymerase (PARP) pertaining to cancer and ischemia is in very rapid progress. PARP's are a specific class of enzymes that repairs the damaged DNA. Recent findings suggest also that PARP-1 is the most abundantly expressed nuclear enzyme which involves in various therapeutic areas like inflammation, stroke, cardiac ischemia, cancer and diabetes. The current review describes the overview on clinical candidates of PARP1 and its current status in clinical trials. This paper also covers identification of potent PARP1 inhibitors using structure and ligand based pharmacophore models. Finally 36 potential hits were identified from the virtual screening of pharmacophore models and screened for PARP1 activity. 15 actives were identified as potent PARP1 inhibitors and further optimization of these analogues are in progress.


Doppler assessment of aortic regurgitation. Correlation with hemodynamics and angiography.
The Doppler method by permitting assessment of transvalvular blood flow velocity has provided a direct means to interrogate aortic regurgitant flow. Pulsed Doppler permits detection of disturbed diastolic flow by sampling proximal to the aortic valve in the outflow tract and is highly sensitive for diagnosis of aortic regurgitation (AR). For semi-quantitative assessment of the severity, left ventricular (LV) mapping can be performed and a ratio of the area of retrograde diastolic to antegrade systolic flow in the descending aorta can be used. According to the continuity principle, it should be possible to estimate regurgitant fraction by examination of forward flows from two different sites, one representative of forward output and one of total left ventricular output, but this method has not yet been sufficiently validated. Continuous wave (CW) Doppler is nearly as sensitive for detection of aortic regurgitation as pulsed wave (PW) Doppler. Signal strength of regurgitant jet provides an indirect clue to its severity: generally a strong signal indicates moderate to severe degree, a weak signal is associated with mild degrees of regurgitation. The spectral outline of regurgitant jet velocity is determined by instantaneous pressure difference between aortic root and the left ventricle during diastole and an indirect clue to severity of aortic regurgitation is provided by the slope of the curve. A steeper slope or shorter velocity half-time is associated with more severe degrees of regurgitation and vice versa. However, there is considerable scatter in this correlation for any given grade of severity of aortic regurgitation, providing a limited predictive value.(ABSTRACT TRUNCATED AT 250 WORDS)


Biosorption of copper(II) by Marrubium globosum subsp. globosum leaves powder: effect of chemical pretreatment.
The study was aimed at determining the effect of chemical pretreatment on copper(II) biosorption by Marrubium globosum subsp. globosum leaves. The uptake capacity of the biomass was increased by chemical pretreatment when compared with the raw biomass. The results of biosorption experiments, carried out at the conditions of 50 mg l(-1) initial metal concentration and pH 5.5, showed that pretreating the biomass with alkali solutions (laundry detergent, sodium hydroxide and sodium bicarbonate, 0.5 M) improved the biosorption capacity of biomass (45.90, 45.78 and 43.91%, respectively) compared with raw biomass. Pretreatment with sulfuric and nitric acid solutions, 0.5 M, increased the biosorption capacity of biomass by 11.82 and 10.18%, respectively, while there was no considerable change in the biosorption capacity of biomass (0.35%) after pretreatment with formic acid solution, 0.5 M. Furthermore, sodium chloride and calcium chloride, 0.5 M, pretreatments resulted in the improvement in biosorption capacity of biomass (31.38 and 26.69%, respectively). FT-IR analysis revealed that hydroxyl and carboxyl functional groups were mainly responsible for copper(II) biosorption.


Western-style diet modulates contractile responses to phenylephrine differently in mesenteric arteries from senescence-accelerated prone (SAMP8) and resistant (SAMR1) mice.
The influence of two known cardiovascular risk factors, aging and consumption of a high-fat diet, on vascular mesenteric artery reactivity was examined in a mouse model of accelerated senescence (SAM). Five-month-old SAM prone (SAMP8) and resistant (SAMR1) female mice were fed a Western-type high-fat diet (WD; 8 weeks). Mesenteric arteries were dissected, and vascular reactivity, protein and messenger RNA expression, superoxide anion (O 2 (·-) ) and hydrogen peroxide formation were evaluated by wire myography, immunofluorescence, RT-qPCR, ethidium fluorescence and ferric-xylenol orange, respectively. Contraction to KCl and relaxation to acetylcholine remained unchanged irrespective of senescence and diet. Although similar contractions to phenylephrine were observed in SAMR1 and SAMP8, accelerated senescence was associated with decreased eNOS and nNOS and increased O 2 (·-) synthesis. Senescence-related alterations were compensated, at least partly, by the contribution of NO derived from iNOS and the enhanced endogenous antioxidant capacity of superoxide dismutase 1 to maintain vasoconstriction. Administration of a WD induced qualitatively different alterations in phenylephrine contractions of mesenteric arteries from SAMR1 and SAMP8. SAMR1 showed increased contractions partly as a result of decreased NO availability generated by decreased eNOS and nNOS and enhanced O 2 (·-) formation. In contrast, WD feeding in SAMP8 resulted in reduced contractions due to, at least in part, the increased functional participation of iNOS-derived NO. In conclusion, senescence-dependent intrinsic alterations during early stages of vascular senescence may promote vascular adaptation and predispose to further changes in response to high-fat intake, which may lead to the progression of aging-related cardiovascular disease, whereas young subjects lack the capacity for this adaptation.


Possible value of galectin-3 on follow-up of cardiac remodeling during glucocorticoid treatment.
Glucocorticoids are among the most prescribed drugs globally due to their potent anti-inflammatory and immunosuppressive properties. Although they have positive effects on the treatment of various disease states; long-term administration is associated with high blood pressure, insulin resistance, and susceptibility to type 2 diabetes. The heart attempts to cope with increased blood pressure and a decrease in glucose utilization by developing pathological cardiac remodeling. However, in this process, cardiac fibrosis formation and deterioration in heart structure and functions occur. Galectin-3, a member of the β-galactoside binding lectins, is consistently associated with inflammation and fibrosis in the pathogenesis of various disease states including insulin resistance and heart failure. Galectin-3 expression is markedly increased in activated macrophages and a subset of activated fibroblasts and vascular cells. Also, failing and remodeling myocardium show increased Gal-3 expression and elevated Gal-3 levels are related to heart failure severity and prognosis. Furthermore, Gal-3-related pathways are recently suggested as therapeutic targets both pharmacologically and genetically to increase insulin sensitivity in vivo. The objective of this review is to provide a summary of our current understanding of the role of glucocorticoid-associated insulin resistance, which is important for some cardiac events, and the potential role of galectin in this pathophysiological process.


Potential pitfalls of mass spectrometry to uncover mutations in childhood soft tissue sarcoma: A report from the Children's Oncology Group.
Mass spectrometry-based methods have been widely applied - often as the sole method - to detect mutations in human cancer specimens. We applied this approach to 52 childhood soft tissue sarcoma specimens in an attempt to identify potentially actionable mutations. This analysis revealed that 25% of the specimens harbored high-confidence calls for mutated alleles, including a mutation encoding FLT3(I836M) that was called in four cases. Given the surprisingly high frequency and unusual nature of some of the mutant alleles, we carried out ultra-deep next generation sequencing to confirm them. We confirmed only three mutations, which encoded NRAS(A18T), JAK3(V722I) and MET(R970C) in three specimens. Beyond highlighting those mutations, our findings demonstrate potential pitfalls of primarily utilizing a mass spectrometry-based approach to broadly screen for DNA sequence variants in archived, clinical-grade tumor specimens. Duplicate mass spectrometric analyses and confirmatory next generation sequencing can help diminish false positive calls, but this does not ameliorate potential false negatives due in part to evaluating a limited panel of sequence variants.


PPARs: Key Regulators of Airway Inflammation and Potential Therapeutic Targets in Asthma.
Asthma affects approximately 300 million people worldwide, significantly impacting quality of life and healthcare costs. While current therapies are effective in controlling many patients' symptoms, a large number continue to experience exacerbations or treatment-related adverse effects. Alternative therapies are thus urgently needed. Accumulating evidence has shown that the peroxisome proliferator-activated receptor (PPAR) family of nuclear hormone receptors, comprising PPARα, PPARβ/δ, and PPARγ, is involved in asthma pathogenesis and that ligand-induced activation of these receptors suppresses asthma pathology. PPAR agonists exert their anti-inflammatory effects primarily by suppressing pro-inflammatory mediators and antagonizing the pro-inflammatory functions of various cell types relevant to asthma pathophysiology. Experimental findings strongly support the potential clinical benefits of PPAR agonists in the treatment of asthma. We review current literature, highlighting PPARs' key role in asthma pathogenesis and their agonists' therapeutic potential. With additional research and rigorous clinical studies, PPARs may become attractive therapeutic targets in this disease.


Dental Subphenotypes in Infants With Orofacial Clefts-A Longitudinal Population-Based Retrospective Radiographic Study of the Primary and Secondary Dentitions.
To determine the developmental patterns of primary and secondary dentitions in infants with orofacial clefts. Retrospective, longitudinal, population-based cohort study. Longitudinal records and radiographs of 192 nonsyndromic Northern European infants with isolated unilateral cleft lip (UCL, n = 111) and isolated cleft palate (CP, n = 81). Radiographic assessments of primary and secondary dentition anomalies and dental maturation, by gender and cleft severity for comparisons between the groups and with historical controls. In infants with UCL, the frequencies of dental anomalies were high in both primary (38.7%) and secondary (18.0%) dentitions. Primary and secondary dentition anomalies were not observed in infants with CP and different in the UCL group (P = .003). Risk differences involved primary supernumerary teeth (P = .0001) and talon cusp formation (P = .0001), and secondary tooth agenesis (P = .001) of the maxillary lateral incisor on the side of the cleft lip. Delayed primary and secondary dental maturation occurred in the UCL and CP groups, greater in infants with UCL (P < .0001). Primary and secondary dental maturation featured sexual dimorphism with greater delay in males (UCL, P < .0001; CP, .0001 > P = .001). The effect of cleft severity on dental maturation was significant in infants with UCL (P = .0361) and CP (P = .0175) in the primary but not in the secondary dentition. There were different dental anomalies in the primary and secondary dentitions in operated infants with UCL and no dental anomalies in unoperated infants with CP. Dental maturation was delayed in infants with UCL and CP with greater delay in males compared to females.


Positron emission tomography-based imaging of transgene expression mediated by replication-conditional, oncolytic herpes simplex virus type 1 mutant vectors in vivo.
To evaluate the efficiency of gene delivery in gene therapy strategies for malignant brain tumors, it is important to determine the distribution and magnitude of transgene expression in target tumor cells over time. Here, we assess the time- and vector dose-dependent kinetics of recombinant herpes simplex virus (HSV)-1 vector-mediated gene expression and vector replication in culture and in vivo by a recently developed radiotracer method for noninvasive imaging of gene expression (J. G. Tjuvajev et al., Cancer Res., 55: 6126-6132, 1995). The kinetics of viral infection of rat 9L gliosarcoma cells by the replication-conditional HSV-1 vector, hrR3, was studied by measuring the accumulation rate of 2-[14C]-fluoro-5-iodo-1-beta-D-arabinofuranosyl-uracil (FIAU), a selective substrate for viral thymidine kinase (TK). The level of viral TK activity in 9L cells was monitored by the radiotracer assay to assess various vector doses and infection times, allowing vector replication and spread. In parallel, viral yields and levels of Escherichia coli beta-galactosidase activity were assessed quantitatively. To study vector replication, spread and HSV-1-tk and lacZ gene coexpression in vivo, first- or second-generation recombinant HSV-1 vectors (hrR3 or MGH-1) were injected into s.c. growing rat 9L or human U87 deltaEGFR gliomas in nude rats at various times (8 h to 8 days) and at various vector doses [1 x 10(6) to 2 x 10(9) plaque-forming units (PFUs)] prior to imaging. For noninvasive assessment of HSV-1-tk gene expression (124I-labeled FIAU % dose/g), 0.15 mCi of 124I-labeled FIAU was injected i.v. 8 h after the last vector administration, and FIAU positron emission tomography (PET) was performed 48 h later. For the assessment of HSV-1-tk and lacZ gene coexpression, 0.2 mCi of 131I-labeled FIAU was injected i.v. 24 h after the last vector administration. Forty-eight h later, animals were killed, and tumors were dissected for quantitative autoradiographical and histochemical assessment of regional distribution of radioactivity (TK expression measured as 131I-labeled FIAU % dose/g) and coexpressed lacZ gene activity. The rates of FIAU accumulation (Ki) in hrR3-infected 9L cells in culture, which reflect the levels of HSV-1-tk gene expression, ranged between 0.12 and 3.4 ml/g/min. They increased in a vector dose- and infection time-dependent manner and correlated with the virus yield (PFUs/ml), where the PFUs:Ki ratios remained relatively constant over time. Moreover, a linear relationship was observed between lacZ gene expression and FIAU accumulation 5-40 h after infection of 9L cells with a multiplicity of infection of 1.5. At later times (> 52 h postinjection), high vector doses (multiplicity of infection, 1.5) led to a decrease of FIAU accumulation rates, viral yield, and cell pellet weights, indicating vector-mediated cell toxicity. Various levels of HSV-1-tk gene expression could be assessed by FIAU-PET after in vivo infection of s.c. tumors. The levels of FIAU accumulation were comparatively low (approximately ranging from 0.00013 to 0.003% injected dose/g) and were spatially localized; this may reflect viral-induced cytolysis of infected tumor cells and limited lateral spread of the virus. Image coregistration of tumor histology, HSV-1-tk related radioactivity (assessed by autoradiography), and lacZ gene expression (assessed by beta-galactosidase staining) demonstrated a characteristic pattern of gene expression around the injection sites. A rim of lacZ gene expression immediately adjacent to necrotic tumor areas was observed, and this zone was surrounded by a narrow band of HSV-1-tk-related radioactivity, primarily in viable-appearing tumor tissue. These results demonstrate that recombinant HSV-1 vector-mediated HSV-1-tk gene expression can be monitored noninvasively by PET, where the areas of FIAU-derived radioactivity identify the viable portion of infected tumor tissue that retains FIAU accumulation ability, and that the accumulation rate of FIAU in culture, Ki, reflects the number of HSV-1 viral particles in the infected tumor cell population [4.1 +/- 0.6 x 10(6) PFUs/Ki unit (PFUs divided by ml/min/g)]. Moreover, time-dependent and spatial relationships of HSV-1-tk and lacZ gene coexpression in culture and in vivo indicate the potential for indirect in vivo imaging of therapeutic gene expression in tumor tissue infected with any recombinant HSV-1 vector where a therapeutic gene is substituted for the lacZ gene.


Tumor necrosis factor-alpha suppresses hematopoiesis in children with myelodysplasia.
The term myelodysplasia (MDS) refers to a group of bone marrow failure syndromes which are relatively rare in childhood. The pathogenesis of MDS is unknown, but a variety of chromosomal, molecular, and cytochemical abnormalities have been reported. We describe a 4-month-old female with MDS who presented with severe neutropenia and refractory anemia with excess blasts (RAEB). Bone marrow progenitor cell assays showed decreased erythroid and myeloid colony formation as compared to normal marrow, and the patient's serum further diminished colony formation of both her own and control marrow. These observations suggested the presence of a soluble factor inhibitory to hematopoiesis. Reverse transcriptase-polymerase chain reaction (RT-PCR) analysis of total RNA derived from the patient's bone marrow mononuclear cells revealed highly elevated tumor necrosis factor-alpha (TNF-alpha) mRNA levels. Using a similar RT-PCR profile, TNF-alpha mRNA levels were found to be elevated in two other children with myelodysplasia. We conclude that TNF-alpha is produced in large amounts by bone marrow mononuclear cells of children with MDS, and we hypothesize that TNF-alpha plays an important role in the pathophysiology of the ineffective hematopoiesis observed in MDS.


Diurnal activity patterns and habitat use of juvenile Pastinachus ater in a coral reef flat environment.
Stingrays are thought to play important ecological roles in coral reef ecosystems. However, little is known about juvenile stingray movement patterns and habitat use in coral reefs. This study used active acoustic telemetry to determine fine-scale diel movement patterns and habitat use of juvenile cowtail stingrays (Pastinachus ater) in a coral reef flat environment. Seven cowtail stingrays (4 males and 3 females) were manually tracked between April and December 2016. Each individual was tracked over 2 days, generating a total of 14 active tracks ranging from 4.91 to 9 h. Specimens moved at an average speed of 2.44 m min-1 ± 0.87 SE, with minimum distances travelled ranging from 546 to 1446 m. Tracking data showed that juvenile cowtail stingrays move in response to tidal cycles, moving faster and in straighter pathways during incoming and outgoing tides. Juvenile cowtail stingrays also showed a strong affinity to sand flat areas and mangrove edge areas. These areas provide food resources and potential refuges for juvenile rays to avoid predators. Coral reef flats were identified as secondary refuge for juveniles during the lowest tides. Future research is necessary to fully unveil the major drivers of juvenile cowtail stingray seasonal and ontogenetic movement patterns and habitat use within coral reef flat environments. This information is important to establish a full understanding of juvenile cowtail stingray ecology, but could also improve management and conservation policies.


Abrogation of SRC homology region 2 domain-containing phosphatase 1 in tumor-specific T cells improves efficacy of adoptive immunotherapy by enhancing the effector function and accumulation of short-lived effector T cells in vivo.
T cell expression of inhibitory proteins can be a critical component for the regulation of immunopathology owing to self-reactivity or potentially exuberant responses to pathogens, but it may also limit T cell responses to some malignancies, particularly if the tumor Ag being targeted is a self-protein. We found that the abrogation of Src homology region 2 domain-containing phosphatase-1 (SHP-1) in tumor-reactive CD8(+) T cells improves the therapeutic outcome of adoptive immunotherapy in a mouse model of disseminated leukemia, with benefit observed in therapy employing transfer of CD8(+) T cells alone or in the context of also providing supplemental IL-2. SHP-1(-/-) and SHP-1(+/+) effector T cells were expanded in vitro for immunotherapy. Following transfer in vivo, the SHP-1(-/-) effector T cells exhibited enhanced short-term accumulation, followed by greater contraction, and they ultimately formed similar numbers of long-lived, functional memory cells. The increased therapeutic effectiveness of SHP-1(-/-) effector cells was also observed in recipients that expressed the tumor Ag as a self-antigen in the liver, without evidence of inducing autoimmune toxicity. SHP-1(-/-) effector CD8(+) T cells expressed higher levels of eomesodermin, which correlated with enhanced lysis of tumor cells. Furthermore, reduction of SHP-1 expression in tumor-reactive effector T cells by retroviral transduction with vectors that express SHP-1-specific small interfering RNA, a translatable strategy, also exhibited enhanced antitumor activity in vivo. These studies suggest that abrogating SHP-1 in effector T cells may improve the efficacy of tumor elimination by T cell therapy without affecting the ability of the effector cells to persist and provide a long-term response.


Molecular structures of the S124A, S124T, and S124V site-directed mutants of UDP-galactose 4-epimerase from Escherichia coli.
UDP-galactose 4-epimerase plays a critical role in sugar metabolism by catalyzing the interconversion of UDP-galactose and UDP-glucose. Originally, it was assumed that the enzyme contained a "traditional" catalytic base that served to abstract a proton from the 4'-hydroxyl group of the UDP-glucose or UDP-galactose substrates during the course of the reaction. However, recent high-resolution X-ray crystallographic analyses of the protein from Escherichia coli have demonstrated the lack of an aspartate, a glutamate, or a histidine residue properly oriented within the active site cleft for serving such a functional role. Rather, the X-ray crystallographic investigation of the epimerase.NADH.UDP-glucose abortive complex from this laboratory has shown that both Ser 124 and Tyr 149 are located within hydrogen bonding distance to the 4'- and 3'-hydroxyl groups of the sugar, respectively. To test the structural role of Ser 124 in the reaction mechanism of epimerase, three site-directed mutant proteins, namely S124A, S124T, and S124V, were constructed and crystals of the S124A.NADH.UDP, S124A.NADH.UDP-glucose, S124T. NADH.UDP-glucose, and S124V.NADH.UDP-glucose complexes were grown. All of the crystals employed in this investigation belonged to the space group P3221 with the following unit cell dimensions: a = b = 83.8 A, c = 108.4 A, and one subunit per asymmetric unit. X-ray data sets were collected to at least 2.15 A resolution, and each protein model was subsequently refined to an R value of lower than 19.0% for all measured X-ray data. The investigations described here demonstrate that the decreases in enzymatic activities observed for these mutant proteins are due to the loss of a properly positioned hydroxyl group at position 124 and not to major tertiary and quaternary structural perturbations. In addition, these structures demonstrate the importance of a hydroxyl group at position 124 in stabilizing the anti conformation of the nicotinamide ring as observed in the previous structural analysis of the epimerase.NADH. UDP complex.


Data-driven ICU management: Using Big Data and algorithms to improve outcomes.
The digitalization of the Intensive Care Unit (ICU) led to an increasing amount of clinical data being collected at the bedside. The term "Big Data" can be used to refer to the analysis of these datasets that collect enormous amount of data of different origin and format. Complexity and variety define the value of Big Data. In fact, the retrospective analysis of these datasets allows to generate new knowledge, with consequent potential improvements in the clinical practice. Despite the promising start of Big Data analysis in medical research, which has seen a rising number of peer-reviewed articles, very limited applications have been used in ICU clinical practice. A close future effort should be done to validate the knowledge extracted from clinical Big Data and implement it in the clinic. In this article, we provide an introduction to Big Data in the ICU, from data collection and data analysis, to the main successful examples of prognostic, predictive and classification models based on ICU data. In addition, we focus on the main challenges that these models face to reach the bedside and effectively improve ICU care.


Automatic Planning of Whole Breast Radiation Therapy Using Machine Learning Models.
Purpose: To develop an automatic treatment planning system for whole breast radiation therapy (WBRT) based on two intensity-modulated tangential fields, enabling near-real-time planning. Methods and Materials: A total of 40 WBRT plans from a single institution were included in this study under IRB approval. Twenty WBRT plans, 10 with single energy (SE, 6MV) and 10 with mixed energy (ME, 6/15MV), were randomly selected as training dataset to develop the methodology for automatic planning. The rest 10 SE cases and 10 ME cases served as validation. The auto-planning process consists of three steps. First, an energy prediction model was developed to automate energy selection. This model establishes an anatomy-energy relationship based on principle component analysis (PCA) of the gray level histograms from training cases' digitally reconstructed radiographs (DRRs). Second, a random forest (RF) model generates an initial fluence map using the selected energies. Third, the balance of overall dose contribution throughout the breast tissue is realized by automatically selecting anchor points and applying centrality correction. The proposed method was tested on the validation dataset. Non-parametric equivalence test was performed for plan quality metrics using one-sided Wilcoxon Signed-Rank test. Results: For validation, the auto-planning system suggested same energy choices as clinical-plans in 19 out of 20 cases. The mean (standard deviation, SD) of percent target volume covered by 100% prescription dose was 82.5% (4.2%) for auto-plans, and 79.3% (4.8%) for clinical-plans (p > 0.999). Mean (SD) volume receiving 105% Rx were 95.2 cc (90.7 cc) for auto-plans and 83.9 cc (87.2 cc) for clinical-plans (p = 0.108). Optimization time for auto-plan was <20 s while clinical manual planning takes between 30 min and 4 h. Conclusions: We developed an automatic treatment planning system that generates WBRT plans with optimal energy selection, clinically comparable plan quality, and significant reduction in planning time, allowing for near-real-time planning.


Transcatheter aortic valve implantation: a revolution in the therapy of elderly and high-risk patients with severe aortic stenosis.
Transcatheter aortic valve implantation (TAVI) represents a real revolution in the field of interventional cardiology for the treatment of elderly or high-risk surgical patients with severe symptomatic aortic valve stenosis. Today, TAVI seems to play a key and a reliable role in the treatment of intermediate and maybe low-risk patients with severe aortic stenosis. TAVI has also evolved from a complex and hazardous procedure into an effective and safe therapy by the development of new generation devices. This article aims to review the background and future of TAVI, clinical trials and registries with old and new generation TAVI devices and to focus on some open issues related to post-procedural outcomes.


Accuracy of Two-Dimensional Transvaginal Sonography and Office Hysteroscopy for Detection of Uterine Abnormalities in Patients with Repeated Implantation Failures or Recurrent Pregnancy Loss.
We sought to compare diagnostic values of two-dimensional transvaginal sonography (2D TVS) and office hysteroscopy (OH) for evaluation of endometrial pathologies in cases with repeated implantation failure (RIF) or recurrent pregnancy loss (RPL). This prospective study was performed at Royan Institute from December 2013 to January 2015. TVS was performed before hysteroscopy as part of the routine diagnostic work-up in 789 patients with RIF or RPL. Uterine biopsy was performed in cases with abnormal diagnosis in TVS and/or hysteroscopy. We compared the diagnostic accuracy values of TVS in detection of uterine abnormalities with OH by receiver operating characteristic (ROC) curve analysis. TVS examination detected 545 (69%) normal cases and 244 (31%) pathologic cases, which included 84 (10.6%) endometrial polyps, 15 (1.6%) uterine fibroids, 10 (1.3%) Asherman's syndrome, 9 (1.1%) endometrial hypertrophy, and 126 (15.9%) septate and arcuate uterus. TVS and OH concurred in 163 pathologic cases, although TVS did not detect some pathology cases (n=120). OH had 94% sensitivity, 95% specificity, 62% positive predictive value (PPV), and 99% negative predictive value (NPV) for detection of endometrial polyps. In the diagnosis of myoma, sensitivity, specificity, PPV, and NPV were 100%. TVS had a sensitivity of 50% and specificity of 98% for the diagnosis of myoma. For polyps, TVS had a sensitivity of 54% and specificity of 80%. Area under the ROC curve (AUROC) was 70.69% for the accuracy of TVS compared to OH. TVS had high specificity and low sensitivity for detection of uterine pathologies in patients with RIF or RPL compared with OH. OH should be considered as a workup method prior to treatment in patients with normal TVS findings.


Addressing nuclides not in the CAP88-PC Version-3 library.
Versions of the computer program, CAP88, are widely used to calculate the radiological doses from radionuclides emitted into the air. CAP88-PC Version-3 includes an extensive library of radionuclides, but there are many more that are not included. Surrogates are often used to substitute for nuclides not in the library, though the results are usually overestimates. This paper addresses nuclides that are not in the library and describes methods to obtain more accurate results.


Ginsenoside Rg3 suppresses FUT4 expression through inhibiting NF-κB/p65 signaling pathway to promote melanoma cell death.
Abnormal glycosylation is catalyzed by the specific glycosyltransferases and correlates with tumor cell apoptosis. Increased fucosyltransferase IV (FUT4) is seen in many types of cancer, and manipulating FUT4 expression through specific signaling pathway inhibits cell growth and induces apoptosis. NF-κB is known playing a vital role to control cell growth and apoptosis. Ginsenoside Rg3 is an herbal medicine with strong antitumor activity through inhibiting tumor growth and promoting tumor cell death. However, whether Rg3-induced inhibition on tumor development involves reduced NF-κB signaling and FUT4 expression remains unknown. In the present study, we found that Rg3 suppressed FUT4 expression by abrogating the binding of NF-κB to FUT4 promoter through inhibiting the expression of signaling molecules of NF-κB pathway, reducing NF-κB DNA binding activity and NF-κB transcription activity. NF-κB inhibitor (Bay 11-7082) or knocking down p65 expression by p65 siRNA also led to a significant decreased FUT4 expression. In addition, Rg3 induced apoptosis by activating both extrinsic and intrinsic apoptotic pathways. Moreover, in a xenograft mouse model, Rg3 downregulated FUT4 and NF-κB/p65 expression and suppressed melanoma cell growth and induced apoptosis without any noticeable toxicity. In conclusion, Rg3 induces tumor cell apoptosis correlated with its inhibitory effect on NF-κB signaling pathway-mediated FUT4 expression. Results suggest Rg3 might be a novel therapy agent for melanoma treatment.


Coexpression and secretion of endoglucanase and phytase genes in Lactobacillus reuteri.
A multifunctional transgenic Lactobacillus with probiotic characteristics and an ability to degrade β-glucan and phytic acid (phytate) was engineered to improve nutrient utilization, increase production performance and decrease digestive diseases in broiler chickens. The Bacillus subtilis WL001 endoglucanase gene (celW) and Aspergillus fumigatus WL002 phytase gene (phyW) mature peptide (phyWM) were cloned into an expression vector with the lactate dehydrogenase promoter of Lactobacillus casei and the secretion signal peptide of the Lactococcus lactis usp45 gene. This construct was then transformed into Lactobacillus reuteri XC1 that had been isolated from the gastrointestinal tract of broilers. Heterologous enzyme production and feed effectiveness of this genetically modified L. reuteri strain were investigated and evaluated. Sodium dodecyl sulfate polyacrylamide gel electrophoresis analysis showed that the molecular mass of phyWM and celW was approximately 48.2 and 55 kDa, respectively, consistent with their predicted molecular weights. Endoglucanase and phytase activities in the extracellular fraction of the transformed L. reuteri culture were 0.68 and 0.42 U/mL, respectively. Transformed L. reuteri improved the feed conversion ratio of broilers from 21 to 42 days of age and over the whole feeding period. However, there was no effect on body weight gain and feed intake of chicks. Transformed L. reuteri supplementation improved levels of ash, calcium and phosphorus in tibiae at day 21 and of phosphorus at day 42. In addition, populations of Escherichia coli, Veillonella spp. and Bacteroides vulgatus were decreased, while populations of Bifidobacterium genus and Lactobacillus spp. were increased in the cecum at day 21.


Third-generation cephalosporins: comparative antibacterial activity against routine clinical isolates.
The in vitro antibacterial activity of five third-generation cephalosporins (thienamycin, ceftazidime, cefotaxime, moxalactam and cefoperazone) was compared with that of three second-generation cephalosporins (cefoxitin, cefamandole and cefuroxime) against 313 routine clinical isolates. Thienamycin, ceftazidime, cefotaxime and moxalactam had superior activity against coliform bacilli compared to cefoxitin, cefamandole and cefuroxime. Only three cephalosporins (ceftazidime, thienamycin and cefoperazone) had significant activity against Pseudomonas aeruginosa. Both third-and second-generation cephalosporins had similar activity against gram-positive cocci, except for thienamycin, which was the most active cephalosporin against Staphylococcus aureus and Streptococcus faecalis. No single cephalosporin showed overall superiority in antibacterial activity, but thienamycin and ceftazidime were the most active against the range of bacteria tested.


(2,2'-Biquinoline-kappa2N,N')bis(nitrato-kappa2O,O')copper(II).
In the title monomer, [Cu(NO(3))(2)(C(18)H(12)N(2))], the six-coordinated Cu(II) atom lies on a twofold axis which bisects one of the ligands (a chelating biquinoline) and duplicates the remaining ligand, a chelating nitrate. The latter binds in a very asymmetric way, consistent with a Jahn-Teller distortion in the coordination polyhedron which, due to the triple chelation, is extremely distorted and difficult to describe in terms of any regular model.