Paleoenvironmental inferences on the Late Miocene hominoid-bearing site of Can Llobateres (NE Iberian Peninsula): An ecometric approach based on functional dental traits.
Hispanopithecus laietanus from the Late Miocene (9.8 Ma) of Can Llobateres 1 (CLL1; Vallès-Penedès Basin, NE Iberian Peninsula) represents one of the latest occurrences of fossil apes in Western mainland Europe, where they are last recorded at ∼9.5 Ma. The paleoenvironment of CLL1 is thus relevant for understanding the extinction of European hominoids. To refine paleoenvironmental inferences for CLL1, we apply ecometric models based on functional crown type (FCT) variables-a scoring scheme devised to capture macroscopic functional traits of occlusal shape and wear surfaces of herbivorous large mammal molars. Paleotemperature and paleoprecipitation estimates for CLL1 are provided based on published regional regression models linking average FCT of large herbivorous mammal communities to climatic conditions. A mapping to Whittaker's present-day biome classification is also attempted based on these estimates, as well as a case-based reasoning via canonical variate analysis of FCT variables from five relevant biomes. Estimates of mean annual temperature (25 °C) and mean annual precipitation (881 mm) classify CLL1 as a tropical seasonal forest/savanna, only in partial agreement with the canonical variate analysis results, which classify CLL1 as a tropical rainforest with a higher probability. The former biome agrees better with previous inferences derived from fossil plants and mammals, as well as preliminary isotopic data. The misclassification of CLL1 as a tropical forest is attributed to the mixture of forest-adapted taxa with others adapted to more open environments, given that faunal and plant composition indicates the presence of a dense wetland/riparian forest with more open woodlands nearby. The tested FCT ecometric approaches do not provide unambiguous biome classification for CLL1. Nevertheless, our results are consistent with those from other approaches, thus suggesting that FCT variables are potentially useful to investigate paleoenvironmental changes through time and space-including those that led to the extinction of European Miocene apes.


Wilms' tumors in adults.
Four cases of adult Wilms' tumor are reported comparing their diagnoses, treatment, and survival with the world literature. The oldest recorded patient is herein described at age 84. Aggressive surgical and medical therapy is necessary to improve survival. Surgical exploration should be through a transperitoneal approach with the patient positioned such that access to the chest can be obtained for maximum exposure and resection. Chemotherapy consisting of actinomycin D and vincristine should be instituted in all patients. Radiation therapy must also be considered in any patient with the diagnosis of nephroblastoma.


Primary calvarial tuberculosis.
Tuberculosis is a very common disease in India. Its prevalence, capacity to affect every other organ, and atypical presentations make it an important part of the differential diagnosis for cases presenting in the rural setup. Primary tuberculous caries of the calvarium is a rare manifestation of this common entity. A young lady presented with headache and discharging sinus of the scalp. Imaging revealed epidural abscess with midline shift. She underwent surgery, and histopathological diagnosis of tuberculous etiology was made. The pre and intraoperative images, radiological images, and histopathological images are reported and discussed. Tuberculosis should be included in the differential diagnosis of the osteolytic lesions of skull with discharging sinus. A high degree of suspicion, especially in patients from low socioeconomic status, is warranted in managing such cases.


Hepatitis A outbreak among men who have sex with men (MSM) predominantly linked with the EuroPride, the Netherlands, July 2016 to February 2017.
Between July 2016 and February 2017, 48 male cases of hepatitis A were notified in the Netherlands. Of these, 17 identified as men who have sex with men (MSM). Ten of the 13 cases for whom sequencing information was available, were infected with a strain linked with the EuroPride that took place in Amsterdam in 2016. This strain is identical to a strain that has been causing a large outbreak among MSM in Taiwan.


Renal carcinoma associated with a novel succinate dehydrogenase A mutation: a case report and review of literature of a rare subtype of renal carcinoma.
Renal cell carcinoma (RCC) linked to germline mutation of succinate dehydrogenase subunits A, B, C, and D (SDHA, SDHB, SDHC, and SDHD, respectively) has been recently included as a provisional entity in the 2013 International Society of Urological Pathology Vancouver classification. Most SDH-deficient tumors show SDHB mutation, with only a small number of RCC with SDHC or SDHD having been reported to date. Only one case of SDH-deficient renal carcinoma known to be SDHA mutated has been previously reported. Here we report an additional RCC harboring an SDHA mutation occurring in a 62-year-old man with right flank pain and nodal metastasis. The tumor was characterized by an infiltrative pattern with solid, acinar, and papillary components. Loss of SDHA and SDHB protein by immunohistochemistry confirmed the diagnosis. Hybrid capture-based comprehensive genomic profiling identified 3 genomic alterations in tumor tissue: (i) a novel single-nucleotide splice site deletion in SDHA gene, (ii) single-nucleotide deletion in NF2 gene, and (iii) EGFR gene amplification of 19 copies. This is the second report of SDHA-mutated RCC. With increased awareness, this rare tumor can be recognized on the basis of distinctive morphology and confirmation by immunohistochemistry and genomic profiling.


[Personal genomics: are we debating the right Issues?].
The debate about personal genomics and their role in personalized medicine has been, to some extent, hijacked by the controversy about commercially available genomic tests sold directly to consumers. The clinical validity and utility of such tests are currently limited and most medical associations recommend that consumers refrain from testing. Conversely, DTC genomics proponents and particularly the DTC industry argue that there is personal utility in acquiring genomic information. While it is necessary to debate risks and benefits of DTC genomics, we should not lose sight of the increasingly important role that genomics will play in medical practice and public health. Therefore, and in anticipation of this shift we also need to focus on important implications from the use of genomics information such as genetic discrimination, privacy protection and equitable access to health care. Undoubtedly, personal genomics will challenge our social norms maybe more than our medicine. Sticking to the polarization of «to have or not to have DTC genomics» risks to takes us away from the critical issues we need to be debating.


A molting chemical cue (N-acetylglucosamine-6-phosphate) contributes to cannibalism of Chinese mitten crab Eriocheir sinensis.
Under high-density culture, cannibalism occurs frequently during the molting of the Chinese mitten crabs Eriocheir sinensis, resulting in a large reduction in production. We found that the leakage of molting fluid from sexually immature crabs informs conspecifics that they are in a molting process. This hypothesis was verified through metabolomics analyses combined with behavioral experiments. The GlcNAc-6-P was identified as a molting biomarker from the differential metabolites by non-targeted metabolomics. In addition, we found that the concentration of GlcNAc-6-P in the molting fluid was significantly higher than other molting metabolites at different molting stages, reaching 5.84 μmol L-1, indicating that the molting fluid was the source of GlcNAc-6-P. Moreover, the behavioral experiments showed that crabs were actively approached to high concentrations of GlcNAc-6-P (1 μmol L-1), but had no obvious choice tendency at different concentrations of UTP, 20-HE and low concentrations of GlcNAc-6-P (0.1 μmol L-1, 0.01 μmol L-1) compared with the control groups. In conclusion, that E. sinensis by sensing the concentration change of GlcNAc-6-P can locate the source of GlcNAc-6-P release and actively approach the high concentration GlcNAc-6-P area and attack the molting crab, causing cannibalism. Blocking the reception pathway of molting chemical cues in E. sinensis, thereby preventing the perception of signals originating from conspecifics' molting in the vicinity, could lead to a reduction in cannibalistic behavior and an increase in overall production. Additionally, this method presents a prospective solution for addressing cannibalism in other crustacean species where such behavior is prevalent.


Computer-managed instruction: an alternative teaching strategy.
Computer-managed instruction is an instructional strategy whereby the computer is used to provide learning objectives, learning resources, and assessment of learner performance. Computer-managed instruction (CMI) aids the instructor in instructional management without actually doing the teaching. Central CMI themes discussed in the literature are individualization, behavioral objectives, and educational technology. The main objective of this study was to compare the outcomes of two teaching strategies: CMI versus the traditional lecture method. The learning objectives were based on specified theoretical content from a Health Assessment course for baccalaureate nursing students. The design of the study was quasi-experimental incorporating two experimental treatments applied to two groups on two occasions. Data analysis addresses differences between groups using CMI and the traditional lecture method. The variables examined were the cognitive performance of learners, the learner's attitude toward the instructional strategy, the learner's retention of knowledge, the time involved in mastering the learning objectives, and the relationship between learner characteristics and the effectiveness of the instructional strategy. No significant mean difference (p less than 0.05) was found between groups on cognitive performance as measured by written and practical examination scores. For these first-year baccalaureate nursing students, CMI did not prove to be a positive instructional method as assessed by the Attitude Questionnaire. The majority of students preferred a combination of instructional methods. There was no significant difference between groups in the time spent meeting the learning objectives by either teaching strategy. The findings suggested that these students preferred learning strategies that are traditional in nature and teacher directed.(ABSTRACT TRUNCATED AT 250 WORDS)


Estradiol Has Differential Effects on Acute Colonic Inflammation in the Presence and Absence of Estrogen Receptor β Expression.
Inflammatory bowel disease (IBD) increases the risk of developing colon cancer. This risk is higher in men compared to women, implicating a role for female hormones in the protection against this disease. Studies from our laboratory demonstrated that estradiol (E2) protects against inflammation-associated colon tumor formation when administered following chemical carcinogen and induction of chronic colitis. This study seeks to better understand the effect of E2 on acute colitis in the presence and absence of estrogen receptor β (ERβ). Inflammation was induced by 2,4,6-trinitrobenzenesulfonic acid in wild-type (WT) and ERβ knockout (ERβKO) mice implanted with a control or E2-containing pellet and killed 5 days later. Inflammation and injury were scored by a pathologist. Apoptosis and proliferation were assessed by immunohistochemistry. Cytokines were measured by multiplex analysis. E2 treatment reduced inflammation in the middle colon in WT mice and the distal colon in ERβKO mice compared to control mice. WT mice had reduced IL-6, IL-12, IL-17, GM-CSF, IFN-γ, MCP-1, MIP-1α, and TNF-α, and ERβKO had reduced IL-6 and IFN-γ expression in response to E2. Injury scores were lower in E2-treated ERβKO mice compared to control ERβKO mice. ERβKO mice had increased proliferation in the basal third of crypts in the distal colon and decreased apoptosis in the proximal colon. These data suggest that E2 has differential protective effects against acute colitis in the presence or absence of ERβ and provide insight into how E2 may protect against IBD.


Dietary intake and nutritional treatment in childhood Crohn's disease.
Dietary intake was assessed in 24 children with active Crohn's disease. Seventeen of the children were sex and height matched with healthy siblings of other patients. The mean energy intake was 1,764 KJ/day (420 kcal/day) lower in patients during relapse than controls (p < 0.05). All 24 children entered a randomised controlled trial of high-dose steroids compared to an elemental diet. The elemental diet was well tolerated orally in most cases; only one patient required nasogastric administration. There was a similar improvement in disease activity and duration of remission in both groups regardless of the site of disease. Subsequent growth velocity was significantly better in the group treated with the elemental diet despite a greater and more sustained increase in energy intake in the group treated with steroids. Reintroduction of specific foods in the elemental diet group initially caused symptoms in three children but were subsequently tolerated. During remission, there was no significant difference in energy intake, but vegetables were consumed significantly less frequently (p < 0.01) and confectionery significantly more frequently (p < 0.05) when patients were compared with their own siblings.


[Analysis of optic nerve head by confocal scanning laser ophthalmoscope in ocular hypertension].
To analyze optic nerve head topography using confocal the scanning laser ophthalmoscope (CSLO) in ocular hypertension in comparison to normal eyes. We examined 25 patients with ocular hypertension and 27 normal controls. All of them had a complete ophthalmic examination. Optic nerve head analysis was performed by using a CSLO-type Heidelberg retina tomograph (HRT). The following stereometric parameters were evaluated: disc area, area and volume of cup, cup/disc ratio, area and volume of neuroretinal rim, mean and maximal cup depth, cup shape measure, height variation contour, mean retinal nerve fiber layer thickness, and retinal nerve fiber layer (RNFL) cross-section area. In ocular hypertension eyes, rim volume, height variation contour and RNFL thickness showed a statistically significant reduction compared to normal eyes. HRT appears to be an important tool in detecting early damage of retinal nerve fiber layer in ocular hypertension.


Phase II Trial of Nilotinib in Patients With Metastatic Malignant Melanoma Harboring KIT Gene Aberration: A Multicenter Trial of Korean Cancer Study Group (UN10-06).
KIT has been suggested to be a potential therapeutic target for malignant melanoma. We evaluated the antitumor activity and safety of the KIT inhibitor nilotinib in metastatic melanoma patients harboring KIT gene mutations or amplifications. We conducted a phase II multicenter trial of nilotinib in metastatic malignant melanoma with KIT mutations or amplifications. Patients received 400 mg oral nilotinib twice daily. The primary endpoint was response rate, and if seven or more responders were observed from the cumulative 36 patients, nilotinib would be considered worthy of further testing in this study population. Between October 2009 and June 2013, 176 patients underwent molecular screening for KIT gene aberrations, and 42 patients harboring KIT gene mutations and/or amplification were enrolled in the study. Overall, 25 (59.5%), 15 (35.7%), and 2 (4.8%) patients had KIT mutations, KIT amplifications, and both KIT mutations and amplification, respectively. Of the 42 enrolled patients, 1 patient achieved complete response, 6 patients achieved partial response, and 17 patients achieved stable disease, resulting in an overall response rate of 16.7% (95% confidence interval [CI]: 5.4%-28.0%) and a disease control rate of 57.1% (95% CI: 42.1%-72.1%). The median duration of response was 34 weeks (range: 5-55 weeks). Of the 7 responders, 6 patients had KIT mutations (exon 11: 5 patients; exon 17: 1 patient), and 1 patient had KIT amplification only. Although this study did not meet its primary endpoint of response rate, nilotinib showed durable response in a subset of metastatic melanoma patients with specific KIT mutations. KIT aberration can be detected in a subset of metastatic melanoma patients. This phase II trial showed that nilotinib demonstrates durable response in a subset of patients with KIT mutations. The safety profile was very tolerable. This study suggests that a KIT inhibitor may benefit a small subset of metastatic melanoma patients with KIT mutations.


COPD in cancer patients: higher prevalence in the elderly, a different treatment strategy in case of primary tumours above the diaphragm, and a worse overall survival in the elderly patient.
The purpose of this study was to document the influence of chronic obstructive pulmonary diseases (COPD) on stage at diagnosis, treatment strategy, and survival for unselected cancer patients (35 years and older) diagnosed between 1995 and 2004 in the Eindhoven Cancer Registry. Follow-up of all patients was complete up to January 1st, 2006. Twelve percent of all cancer patients had COPD at the time of cancer diagnosis, being about 15% in elderly patients (65+) and up to 30% among lung cancer patients, middle-aged males and all females with oesophageal and laryngeal cancer, and middle-aged women with renal cancer. Stage at diagnoses was not significantly different between cancer patients with or without COPD, except for lung cancer patients who were diagnosed at an earlier stage. Nevertheless, non-small cell lung cancer (NSCLC) patients with COPD less frequently underwent surgery, and chemotherapy, and more often radiotherapy. In the presence of COPD, women with oesophageal cancer underwent surgery less often, and patients with laryngeal cancer received radiotherapy more often. The effect of COPD on the type of oncological treatment was not different for middle-aged (35-64 years) and elderly cancer patients. In a multivariate Cox-regression model, COPD was associated with a significantly worse survival, especially for elderly patients with colon, rectum, larynx, prostate or urinary bladder cancer. In conclusion, not surprisingly, COPD is related with age and smoking-associated tumours. Therapy of cancer patients with COPD was different for head and neck tumours and primary tumours in the chest organs (above the diaphragm), for whom radiotherapy, as an alternative treatment option, was available. As COPD, especially at older age, is frequently associated with a worse prognosis, further prospective investigation of interactions seems warranted. Further, closer involvement of pulmonologists and COPD nurses in elderly cancer patients might be warranted.


Histological subtypes of hepatocellular carcinoma are related to gene mutations and molecular tumour classification.
Our increasing understanding of hepatocellular carcinoma (HCC) biology holds promise for personalized care, however its translation into clinical practice requires a precise knowledge of its relationship to tumour phenotype. We aimed at investigating molecular-phenotypic correlations in a large series of HCC. To this purpose, 343 surgically resected HCC samples were investigated by pathological review, immunohistochemistry, gene expression profiling and sequencing. CTNNB1 (40%) and TP53 (21%) mutations were mutually exclusive and defined two major groups of HCC characterized by distinct phenotypes. CTNNB1 mutated tumours were large (p=0.002), well-differentiated (p<0.001), cholestatic (p<0.001), with microtrabecular (p<0.001) and pseudoglandular (p<0.001) patterns and without inflammatory infiltrates (p<0.001). TP53 mutated tumours were poorly differentiated (p<0.001) with a compact pattern (p=0.02), multinucleated (p=0.01) and pleomorphic (p=0.02) cells and frequent vascular invasion (p=0.02). World Health Organization (WHO) classification of histological subtypes were also strongly related to molecular features. The scirrhous subtype was associated with TSC1/TSC2 mutations (p=0.005), epithelial-to-mesenchymal transition and a progenitor expression profile. The steatohepatitic subtype showed frequent IL-6/JAK/STAT activation without CTNNB1, TERT and TP53 pathway alterations (p=0.01). Pathological review identified a novel subtype, designated as "macrotrabecular-massive" associated with poor survival (p<0.001), high alpha-fetoprotein serum level (p=0.02), vascular invasion (p<0.001), TP53 mutations (p<0.001) and FGF19 amplifications (p=0.02), features also validated in The Cancer Genome Atlas (TCGA) data. Finally, integration of HCC pathological characteristics with its transcriptomic classification showed phenotypically distinct tumour subclasses closely related to G1-G6 subgroups. HCC phenotypes are tightly associated with gene mutations and transcriptomic classification. These findings may help in translating our knowledge of HCC biology into clinical practice. Lay summary: HCC is a very heterogenous tumour, both at the pathological and molecular levels. We show here that HCC phenotype is tightly associated to its molecular alterations and underlying oncogenic pathways.


Vital Signs: Prevalence of Doctor-Diagnosed Arthritis and Arthritis-Attributable Activity Limitation - United States, 2013-2015.
In the United States, doctor-diagnosed arthritis is a common and disabling chronic condition. Arthritis can lead to severe joint pain and poor physical function, and it can negatively affect quality of life. CDC analyzed 2013-2015 data from the National Health Interview Survey, an annual, nationally representative, in-person interview survey of the health status and behaviors of the noninstitutionalized civilian U.S. adult population, to update previous prevalence estimates of arthritis and arthritis-attributable activity limitations. On average, during 2013-2015, 54.4 million (22.7%) adults had doctor-diagnosed arthritis, and 23.7 million (43.5% of those with arthritis) had arthritis-attributable activity limitations (an age-adjusted increase of approximately 20% in the proportion of adults with arthritis reporting activity limitations since 2002 [p-trend <0.001]). Among adults with heart disease, diabetes, and obesity, the prevalences of doctor-diagnosed arthritis were 49.3%, 47.1%, and 30.6%, respectively; the prevalences of arthritis-attributable activity limitations among adults with these conditions and arthritis were 54.5% (heart disease), 54.0% (diabetes), and 49.0% (obesity). The prevalence of arthritis is high, particularly among adults with comorbid conditions, such as heart disease, diabetes, and obesity. Furthermore, the prevalence of arthritis-attributable activity limitations is high and increasing over time. Approximately half of adults with arthritis and heart disease, arthritis and diabetes, or arthritis and obesity are limited by their arthritis. Greater use of evidence-based physical activity and self-management education interventions can reduce pain and improve function and quality of life for adults with arthritis and also for adults with other chronic conditions who might be limited by their arthritis.


Local unfolding and the stepwise loss of the functional properties of tubulin.
Tubulin exhibits a number of characteristic functions that can be used to identify it. They include the ability to polymerize to microtubules, GTPase activity, and the binding of numerous antimitotic drugs and fluorophores. These functions can be differentially modified by low (0.1-1.0M) urea concentrations, and such urea-induced modifications are stable over time periods of minutes to hours. These intermediate states suggest the existence of restricted regions in the protein each of which is associated with a function and its own urea sensitivity. In order of decreasing sensitivity to urea these effects are decreased rate of polymerization of tubulin to microtubules > decreased extent of polymerization approximately decreased GTPase activity > enhanced fluorescence of a rapidly binding analogue of colchicine-MTPT [2-methoxy-5-(2',3',4'-trimethoxyphenyl)tropone] approximately decreased proteolysis by trypsin (after alpha Arg339) and by chymotrypsin (after beta Tyr281) > enhanced fluorescence of 1-anilino-8-naphthalenesulfonic acid (ANS). Additional evidence for the independent behavior of the restricted regions stems from the markedly different time dependence of the response to urea. These low urea concentrations do not induce significant changes in tryptophan fluorescence, suggesting that the observed effects are due to local unfolding. At higher urea concentrations (2-4 M), the enhanced fluorescence of the ligands is abolished; MTPT fluorescence decreases at lower urea concentrations than ANS fluorescence. Moreover, tubulin becomes highly susceptible to proteolysis at multiple sites, and tryptophan emission shows a red-shift, as expected. Multistep unfolding in response to denaturants has been reported for some other proteins. Tubulin appears to be an extreme example of such local responses that proceed under milder conditions than the global transition to the unfolded state.


Construction of a biomechanical head and neck motion model as a guide to evaluation of deformable image registration.
The use of deformable image registration methods in the context of adaptive radiotherapy leads to uncertainties in the simulation of the administered dose distributions during the treatment course. Evaluation of these methods is a prerequisite to decide if a plan adaptation will improve the individual treatment. Current approaches using manual references limit the validity of evaluation, especially for low-contrast regions. In particular, for the head and neck region, the highly flexible anatomy and low soft tissue contrast in control images pose a challenge to image registration and its evaluation. Biomechanical models promise to overcome this issue by providing anthropomorphic motion modelling of the patient. We introduce a novel biomechanical motion model for the generation and sampling of different postures of the head and neck anatomy. Motion propagation behaviour of the individual bones is defined by an underlying kinematic model. This model interconnects the bones by joints and thus is capable of providing a wide range of motion. Triggered by the motion of the individual bones, soft tissue deformation is described by an extended heterogeneous tissue model based on the chainmail approach. This extension, for the first time, allows the propagation of decaying rotations within soft tissue without the necessity for explicit tissue segmentation. Overall motion simulation and sampling of deformed CT scans including a basic noise model is achieved within 30 s. The proposed biomechanical motion model for the head and neck site generates displacement vector fields on a voxel basis, approximating arbitrary anthropomorphic postures of the patient. It was developed with the intention of providing input data for the evaluation of deformable image registration.


Imaging of photo-oxidative stress responses in leaves.
High resolution digital imaging was used to identify sites of photo-oxidative stress responses in Arabidopsis leaves non-invasively, and to demonstrate the potential of using a suite of imaging techniques for the study of oxidative metabolism in planta. Tissue-specific photoinhibition of photosynthesis in individual chloroplasts in leaves was imaged by chlorophyll fluorescence microscopy. Singlet oxygen production was assessed by imaging the quenching of the fluorescence of dansyl-2,2,5,5-tetramethyl-2,5-dihydro-1H-pyrrole (DanePy) that results from its reaction with singlet oxygen. Superoxide and hydrogen peroxide accumulation were visualized by the reduction of nitroblue tetrazolium (NBT) to formazan deposits and by polymerization with 3,3'-diaminobenzidine (DAB), respectively. Stress-induced expression of a gene involved with antioxidant metabolism was imaged from the bioluminescence from leaves of an Arabidopsis APX2-LUC transformant, which co-expresses an ascorbate peroxidase (APX2) with firefly luciferase. Singlet oxygen and superoxide production were found to be primarily located in mesophyll tissues whereas hydrogen peroxide accumulation and APX2 gene expression were primarily localized in the vascular tissues.


Selective forgetting of aversive memories cued in the right hemisphere.
Several writers have suggested that there is selective inhibition of aversive right hemisphere processes from reaching the left hemisphere, thus reducing reportable awareness, although the right hemisphere processes might still affect behavior. Two similar experiments are reported supporting this theory. In the first of three phases, subjects learned a paired associate list to a criterion of one perfect trial. Second, distant associates of some of the words learned in phase 1 were punished. Third, subjects attempted to recall the first word list, with recall cued sometimes in the left visual field and sometimes in the right. Associates of punished words were more likely to be forgotten than control words, when cued in the left visual field so they had to cross from right to left hemisphere to be vocalized. Surprisingly, associates of punished words were remembered better when cued in the right visual field.


Investigation of Pictet-Spengler type reactions of secologanin with histamine and its benzyl derivative.
The reaction of secologanin (1) (mainly in its tetraacetylated form 1a) with histamine (2) and its benzyl derivative (2b) was investigated. With the benzylated amine (2b), the main product was the normal, tetraacetylated benzyl derivative of histeloside having the R configuration at the new center of chirality, C-1 (5b), with a small amount of an unidentified minor component (probably the 1S epimer 5a). In a slightly acidic medium, the reaction with histamine (2) gave two products in an approximately 6:4 ratio. The main compound proved to be the normal, tetraacetylated derivative of the lactam histelosamide with R configuration at C-1 (7b), and the minor product was the tetraacetylisohisteloside with S configuration at the same C-1 center (3a). When the reaction was carried out under acid-free conditions, in addition to the epimeric pair of the normal tetraacetylated lactam (7a, 7b) and the tetraacetylisohisteloside with 1S configuration (3a), tetraacetylneohistelosamide (8b) was also isolated, in which the cyclization took place at one of the cyclic nitrogens of the imidazole ring. Probably, this latter compound is an intermediate also in the formation of the normal isomers, but under slightly acidic conditions it rapidly isomerized into the normal alkaloid. The tendencies experienced previously in the tryptamine and dopamine series were observed also in the histamine series; that is, at C-1, the R configuration is favored over the S one, and lactamization is faster in the former than in the latter case. The structure of the products and their stereoschemistry were established by NMR spectroscopy.


Prevalence of and risk factors for diabetic ketosis in Chinese diabetic patients with random blood glucose levels >13.9 mmol/L: Results from the CHina study in prEvalence of diabetiC Ketosis (CHECK) study.
The aim of the present study was to investigate the prevalence of diabetic ketosis (DK) and its risk factors in Chinese diabetes patients with severe hyperglycemia. The present multicenter cross-sectional study was performed on patients aged >16 years with diabetes mellitus (DM) and random blood glucose levels >13.9 mmol/L (>250 mg/dL). Blood ketones (β-hydroxybutyric acid) and urinary ketones (acetoacetic acid) were measured and information on patient demographic and clinical characteristics was collected. Of 1235 patients enrolled in the study (93 with type 1 DM [T1DM]), 1142 with type 2 DM [T2DM]), 242 (19.6%) had DK (blood ketone levels ≥0.6 mmol/L). Proportionately, DK was more frequent and more severe in patients with T1DM than T2DM (55.9% vs 16.6%, respectively), but in absolute terms occurred in more patients with T2DM (52 vs 190). In patients with blood ketone levels ≥3 mmol/L, the cut-off point of blood glucose levels was 19.05 mmol/L. Risk factors significantly associated with higher blood ketone levels in T2DM included younger age, a shorter duration of diabetes, and not using antidiabetic medication within 12 months prior to the hyperglycemic episode. The prevalence of DK is lower in patients with T2DM than T1DM, but the number of patients with DK is higher for those with T2DM because of more T2DM patients in China. Patients with T2DM who have a younger age, shorter duration of diabetes, and a lack of antidiabetic treatment will suffer from DK more often than older patients with longer T2DM duration and receiving antidiabetic treatment.


Evil lurks in the heart of man: cardiac paraganglioma presenting as recurrent dyspnoea and chronic cough.
A man in his 60s presents with chronic dyspnoea and cough for 3 years. EKG and nuclear stress test were not diagnostic. An echocardiogram revealed moderate pericardial effusion. His symptoms improved with ibuprofen temporarily and a repeat echocardiogram showed resolution of the effusion. However, when his symptoms recurred, re-imaging showed a large intracardiac tumour causing right ventricular outflow obstruction. Subsequent histological examination revealed metastatic paraganglioma. He was found to carry a germline mutation in the SDHB gene which is associated with higher malignant risk. Knowledge of his underlying mutation allowed the patient and his family to receive appropriate gene-specific counselling and surveillance.


Footprints and Ootheca of Lycorma delicatula Influence Host-Searching and -Acceptance of the Egg-Parasitoid Anastatus orientalis.
The spotted lanternfly, Lycorma delicatula White (1845) (Hemiptera: Fulgoridae), is an invasive insect that was first reported in North America in Berks County, Pennsylvania, in 2014. It is a polyphagous phloem feeder that attacks over 70 plant species, threatening the agricultural, lumber, and ornamental industries of North America. Infestations of the pest have been reported in several U.S. counties, and a lack of endemic predators and parasitoids feeding on L. delicatula suggests a release from natural enemies in the invaded range. An egg-parasitoid Anastatus orientalis (Hymenoptera: Eupelmidae) was reported attacking L. delicatula at high rates in its native range and may play a key role in reducing its populations there. To better understand the foraging behavior of A. orientalis, a series of behavioral experiments were conducted to determine successful parasitism and behavioral responses to traces left by adult L. delicatula and to the oothecae which cover their eggs. Our results suggest that wasps detected chemical traces left by L. delicatula adults while walking on surfaces and exhibited a strong arrestment response. Moreover, wasps preferred to oviposit in egg masses with intact oothecae. The implications of these findings are herein discussed with regard to the exploitation of host kairomones by foraging wasps, as well as to its ability to overcome host structural defenses.


Biophysical insights into the membrane interaction of the core amyloid-forming Aβ40 fragment K16-K28 and its role in the pathogenesis of Alzheimer's disease.
The aggregation of amyloid-β (Aβ) on neuronal membranes is implicated in both neuronal toxicity and the progression of Alzheimer's disease. Unfortunately, the heterogeneous environment that results from peptide aggregation in the presence of lipids makes the details of these pathways difficult to interrogate. In this study, we report an investigation of the membrane interaction of an Aβ fragment (K16LVFFAEDVGSNK28, KK13), which maintains the amyloidogenic nature of the full-length peptide and is implicated in membrane-mediated folding, through a combination of NMR spectroscopy and molecular dynamics simulations. Despite KK13's ability to form amyloids in solution, the monomer remains unstructured in the presence of lipid bilayers, unlike its full-length parent peptide. Additionally, NMR and molecular dynamics simulation results support that the presence of GM1 ganglioside, a lipid which strongly promotes binding between Aβ and lipid bilayers, promotes KK13 binding to but not folding on the membrane. Finally, we show that the peptide partitions between the membrane and aqueous solution based on the hydrophobicity of the N-terminal residues, regardless of lipid composition. These results support previous discoveries suggesting the importance of GM1 ganglioside in exacerbating membrane-driven aggregation while identifying the potential importance of C-terminal residues in membrane binding and folding, which has previously been unclear.


Flower development and sex specification in wild grapevine.
Wild plants of Vitis closely related to the cultivated grapevine (V. v. vinifera) are believed to have been first domesticated 10,000 years BC around the Caspian Sea. V. v. vinifera is hermaphrodite whereas V. v. sylvestris is a dioecious species. Male flowers show a reduced pistil without style or stigma and female flowers present reflexed stamens with infertile pollen. V. vinifera produce perfect flowers with all functional structures. The mechanism for flower sex determination and specification in grapevine is still unknown. To understand which genes are involved during the establishment of male, female and complete flowers, we analysed and compared the transcription profiles of four developmental stages of the three genders. We showed that sex determination is a late event during flower development and that the expression of genes from the ABCDE model is not directly correlated with the establishment of sexual dimorphism. We propose a temporal comprehensive model in which two mutations in two linked genes could be players in sex determination and indirectly establish the Vitis domestication process. Additionally, we also found clusters of genes differentially expressed between genders and between developmental stages that suggest a role involved in sex differentiation. Also, the detection of differentially transcribed regions that extended existing gene models (intergenic regions) between sexes suggests that they may account for some of the variation between the subspecies. There is no evidence of differences of expression levels in genes from the ABCDE model that could explain the shift from hermaphroditism to dioecy. We propose that sex specification occurs after floral organ identity has been established and therefore, sex determination genes might be having an effect downstream of the ABCDE model genes.For the first time a full transcriptomic analysis was performed in different flower developmental stages in the same individual. Our experimental approach enabled us to create a comprehensive catalogue of transcribed genes across developmental stages and genders that will contribute for future work in sex determination in seed plants.


Study on the mechanical parameters of neuromuscular joint facilitation rehabilitation techniques for lumbar intervention.
[Purpose] To measure the reliability of and quantify the force on the spinous process during lumbar neuromuscular joint facilitation using mechanical measuring gloves. [Participants and Methods] We recruited 12 healthy participants. The operator wore a mechanical measuring glove and performed evaluations in the four modes of neuromuscular joint facilitation of the lumbar spine. The mechanical glove was used to measure the force applied by the fingers on the spinous process during the intervention. [Results] The reliability of measuring the supraspinous force during lumbar neuromuscular joint facilitation with mechanical gloves was found to be good; the force was 30.9 ± 6.6 N for front lifting, 37.1 ± 9.1 N for rear descent, 36.8 ± 9.0 N for forward descent, and 24.6 ± 4.7 N for rear lifting. Overall, the average force was 32.3 ± 9.0 N. No statistical difference was observed between passive and resistance motion. [Conclusion] This study confirmed that the measurement of the force on the spinous process in lumbar neuromuscular joint facilitation using mechanical measurement gloves has good reliability. Furthermore, we determined the average force exerted on the spinous process during lumbar neuromuscular joint facilitation and quantified the operation specifications of this manipulation were.


Different levels of polybrominated diphenyl ethers (PBDEs) and chlorinated compounds in breast milk from two U.K. Regions.
Polybrominated diphenyl ether (PBDE) congeners are constituents of flame retardants, and there is growing concern regarding their persistence, bioaccumulation, and toxicity. We collected breast milk samples between late 2001 and early 2003 from 54 U.K.-resident mothers. Of these, 27 originated from southeast England (London), and the other 27 originated from northwest England (Lancaster). Analysis of milk-fat extracts by gas chromatography-mass spectrometry was performed to determine the levels of 15 PBDE congeners, 15 polychlorinated biphenyl (PCB) congeners, and other selected chlorinated compounds. PCB and organochlorine (OC) levels in southeast samples were consistently higher, and significant differences (p < 0.05) were observed. Sigma PBDE levels ranged from 0.3 to 69 ng/g lipid (geometric mean, 6.6 ng/g), and PBDE-47 was the most abundant congener. Sigma PCB levels ranged from 26 to 530 ng/g lipid (geometric mean, 150 ng/g) and were composed mainly of PCB-153 (26%), PCB-138 (20%), and PCB-180 (13%). OC levels for 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane (p,p'-DDT) and its metabolites (Sigma DDX) ranged from 24 to 2,300 ng/g lipid (geometric mean, 160 ng/g);Sigma hexachlorocyclohexane levels ranged from 1.2 to 1,500 ng/g lipid (geometric mean, 16 ng/g). Using nuclear magnetic resonance-based metabonomics, samples (n = 7) containing the highest contaminant levels were compared with samples (n = 7) containing the lowest levels. Excellent separation along the first principal component implied that the chemical constituents of the two groups were significantly different. Although reasons for such differences remain obscure, lifestyle factors associated with a more heterogeneous London cohort could be responsible. Identifying primary routes of contaminant exposures and their biologic effects is of great importance. Key words: breast milk, flame retardants, gas chromatography-mass spectrometry, milk-fat extracts, organochlorines, PBDE-47, persistent contaminants, polybrominated diphenyl ethers, polychlorinated biphenyls, United Kingdom.


Assessment of psoriatic plaque in vivo with correlation mapping optical coherence tomography.
Vascular abnormalities play an acute role in the pathogenesis of psoriasis. In order to characterize vascular involvement in psoriasis and its regular clinical assessment in vivo, non-invasive high speed imaging with high resolution and high sensitivity is needed. The correlation mapping optical coherence tomography (cmOCT) technique was used for in vivo microcirculation imaging of human forearm under normal and psoriatic conditions. The cmOCT technique developed by our group uses dense scanning OCT image acquisition and post-processing software based on correlation statistics. The frequency domain OCT system was used for imaging which acquires a 3D volume of 1024 × 1024 A-scans, each of 512 pixels deep in approximately 70 s. The cmOCT technique processes the resulting OCT volume within 116 s using a 7 × 7 kernel. 3D structural and functional (microcirculation) maps of the healthy tissue and the psoriatic plaque were obtained using the cmOCT technique. The presented results indicate that cmOCT allows not only the identification of the microvessels, but also produces more detailed microvascular networks showing how the blood vessels relate to each other in healthy tissue and within the plaque. The microcirculation pattern within the plaque is totally different from the healthy tissue. The distinct changes are also observed in vessel density, tortuosity, and orientation. The cmOCT provides high sensitivity and imaging speed for in vivo microcirculation imaging within the human skin under normal and diseased conditions.


Rituximab in autoimmune hematologic diseases: not just a matter of B cells.
Rituximab, a chimeric monoclonal antibody that depletes B cells by binding to the CD20 cell-surface antigen, has been investigated extensively in autoimmune disorders. Following the encouraging results in immune thrombocytopenia (ITP), the use of this agent was explored in other autoimmune hematologic diseases, most notably autoimmune hemolytic anemia (AIHA) and thrombotic thrombocytopenic purpura (TTP), characterized by the presence of pathogenetic autoantibodies. Although randomized clinical trials are lacking, the cumulative data would suggest that rituximab has a beneficial role in their treatment. Response to B-cell-depleting therapy is actually associated with a significant decrease of circulating autoantibodies. However, several lines of evidence indicate that the T-cell compartment may also be modulated by these interventions. The doses and the duration of rituximab treatment in patients with autoimmune diseases are still unclear. The incidence of severe side effects is low but not insignificant. In particular, the risk of systemic infections and viral reactivation is a major concern.


Detection of Entangled States Supported by Reinforcement Learning.
Discrimination of entangled states is an important element of quantum-enhanced metrology. This typically requires low-noise detection technology. Such a challenge can be circumvented by introducing nonlinear readout process. Traditionally, this is realized by reversing the very dynamics that generates the entangled state, which requires a full control over the system evolution. In this Letter, we present nonlinear readout of highly entangled states by employing reinforcement learning to manipulate the spin-mixing dynamics in a spin-1 atomic condensate. The reinforcement learning found results in driving the system toward an unstable fixed point, whereby the (to be sensed) phase perturbation is amplified by the subsequent spin-mixing dynamics. Working with a condensate of 10 900 ^{87}Rb atoms, we achieve a metrological gain of 6.97_{-1.38}^{+1.30} dB beyond the classical precision limit. Our work will open up new possibilities in unlocking the full potential of entanglement caused quantum enhancement in experiments.


Liver transplantation in children: maternal and family stress, coping, and adaptation.
This study examined the relationship of family stress, severity of the stressor, uncertainty, coping, and family adaptation from pretransplantation to posttransplantation. A descriptive, longitudinal study of 15 mothers whose children were at least 5 years posttransplantation. Maternal stress, coping, and uncertainty demonstrated significant changes over time, whereas family stress did not. Pretransplantation family stress, anger, and confusion were related to poorer family adaptation. Interventions for mothers pretransplantation should account for the coping, levels of stress, and uncertainty present at each phase of the transplantation process. Interventions need to be tailored to the transplantation phase. Long-term interventions remain necessary and should be directed at reinforcement of teaching, as well as assessment and provision of parental support relevant to the long-term needs of the family.


Effect of sex hormones on the tissue localization of nuclear estrogen receptor positively stained cells in the seminal vesicle of immature castrated rats.
We studied the changes in the tissue localization of nuclear estrogen receptor (ER) positively stained cells in the seminal vesicle of immature castrated rats under various environmental conditions of sex hormones by immunohistochemical methods. In castrated rats of 6 weeks of age, the percentage of nuclear ER positively stained cells showed remarkable increase in the periglandular stroma region, but not in the epithelium and the peripheral stroma region. Estrogen administration to castrated rats dramatically increased the percentage of nuclear ER positively stained cells in both the epithelium and the peripheral stroma region, whereas cessation of estrogen treatment caused a significant percentile decrease. These results suggest that the nuclear ER expression in both the epithelial cells and the peripheral stromal cells seems to respond to estrogen. The concomitant treatment of estradiol-17 beta (E2) with 5 alpha-dihydrotestosterone (DHT) completely inhibited these E2 mediated ER expression in the epithelium and the stroma. This result suggests that ER works only when E2 is given in the absence of DHT in the seminal vesicle of immature castrated rats.


Spatial Clusters of Diabetes and Physical Inactivity: Do Neighborhood Characteristics in High and Low Clusters Differ?
This study aims to find spatial clusters of diabetes and physical inactivity among a sample population in Kerala, India, and evaluate built environment characteristics within the high and low spatial clusters. Spatial clusters with a higher and lower likelihood of diabetes and physical inactivity were identified using spatial scan statistic at various radii. Built environment characteristics were captured at panchayat level and 1600 m buffer around participant location using Geographical Information Systems. Comparison of sociodemographic and built environment factors was carried out for participants within high and low spatial clusters using t tests. Ten high and 8 low spatial clusters of diabetes and 17 high and 23 low spatial clusters of physical inactivity were identified in urban and rural areas of Kerala. Significant differences in built environment characteristics were consistent for low spatial clusters of diabetes and physical inactivity in the urban scenario. Built environment characteristics were found to be relevant in both urban and rural areas of Kerala. There is an urgent call to explore spatial clustering of non-communicable diseases in Kerala and undo the one-size-fits-all approach for prevention and control of non-communicable diseases.


Prognostic and treatment factors affecting pelvic control of Stage IB and IIA-B carcinoma of the intact uterine cervix treated with radiation therapy alone.
This is a retrospective analysis of 264 patients with Stage IB and IIA-B carcinoma of the cervix treated with curative intent at the University of Florida from October 1964 through April 1980. There is a minimum 2-year follow-up. Patients dead of distant metastases (13), dead from intercurrent disease (14), or lost to follow-up (1) less than 24 months from treatment with pelvic disease controlled were excluded from analysis of pelvic control. All patients were included in analysis of complications and survival. Tumor size and hematocrit were noted to be significant prognostic factors with regard to control of disease in the pelvis in Stage IB and IIA cancers. Tumor size and hematocrit also influenced pelvic control in Stage IIB, but to a lesser extent than in Stages IB and IIA. Patient age was a weak prognostic factor for control of disease in the pelvis for Stages IB, IIA, and IIB, but more strongly influenced pelvic control when considered in conjunction with tumor size and hematocrit. Overall treatment time influenced pelvic control in all cases when the size of the lesion was greater than or equal to 6 cm. In lesions greater than or equal to 6 cm in diameter, the amount of tumor regression noted at the time of the radium application after 3500 to 4000 rad external beam irradiation was a predictor of pelvic control. Data on treatment complications and survival are included, and future treatment strategies discussed.


Pathogenic Characteristics of Staphylococcus aureus Endovascular Infection Isolates from Different Clonal Complexes.
Staphylococcus aureus is a major cause of bacteremia and, even with appropriate clinical management, causes high morbidity, and mortality due to its involvement in endovascular complications and metastatic infections. Through different pathogenic in vivo and in vitro models we investigated the behavior of S. aureus most relevant clonal complexes (CCs) causing endovascular complications. We analyzed 14 S. aureus strains representing CC5, CC8, CC15, CC30, and CC45 that caused endovascular complications, including methicillin susceptible and resistant isolates and strains with different functionality of the agr global regulator. Their adherence to collagen, interaction with the endothelium, resistance to immune attack, capacity to form biofilm and virulence in the Galleria mellonella model were analyzed. CC30 and CC45 showed greater adhesion to collagen and CC8 showed a trend towards higher rate of intracellular persistence in endothelial cells. All CCs exhibited similar tolerance to neutrophil antimicrobial peptide hNP-1 and were capable of forming biofilms under static conditions. The virulence assay in the G. mellonella model demonstrated that CC15 and CC30 were the most and least virulent, respectively. The analysis of the genomic sequences of the most relevant virulence genes identified some CC15 specific gene patterns (absence of enterotoxins and sak gene) and variants (mainly in leucocidins and proteases), but did not reveal any gene or variant that could be responsible for the increased virulence detected for CC15 strains. Even though all the CCs were capable of causing endovascular complications, our results showed that different CCs are likely to produce these complications through different mechanisms which, if confirmed in more sophisticated models, would indicate the need to more specific management and therapeutic approaches.


Cross-cultural adaptation and validation of the Protective Nursing Advocacy Scale for Brazilian nurses.
to adapt culturally and validate the Protective Nursing Advocacy Scale for Brazilian nurses. methodological study carried out with 153 nurses from two hospitals in the South region of Brazil, one public and the other philanthropic. The cross-cultural adaptation of the Protective Nursing Advocacy Scale was performed according to international standards, and its validation was carried out for use in the Brazilian context, by means of factor analysis and Cronbach's alpha as measure of internal consistency. by means of evaluation by a committee of experts and application of pre-test, face validity and content validity of the instrument were considered satisfactory. From the factor analysis, five constructs were identified: negative implications of the advocacy practice, advocacy actions, facilitators of the advocacy practice, perceptions that favor practice advocacy and barriers to advocacy practice. The instrument showed satisfactory internal consistency, with Cronbach's alpha values ranging from 0.70 to 0.87. it was concluded that the Protective Nursing Advocacy Scale - Brazilian version, is a valid and reliable instrument for use in the evaluation of beliefs and actions of health advocacy, performed by Brazilian nurses in their professional practice environment.


Molecular clip and tweezer introduce new mechanisms of enzyme inhibition.
Artificial molecular clips and tweezers, designed for cofactor and amino acid recognition, are able to inhibit the enzymatic activity of alcohol dehydrogenase (ADH). IC50 values and kinetic investigations point to two different new mechanisms of interference with the NAD(+)-dependent oxidoreductase: While the clip seems to pull the cofactor out of its cleft, the tweezer docks onto lysine residues around the active site. Both modes of action can be reverted to some extent, by appropriate additives. However, while cofactor depletion by clip 1 was in part restored by subsequent NAD(+) addition, the tweezer (2) inhibition requires the competitive action of lysine derivatives. Lineweaver-Burk plots indicate a competitive mechanism for the clip, with respect to both substrate and cofactor, while the tweezer clearly follows a noncompetitive mechanism. Conformational analysis by CD spectroscopy demonstrates significant ADH denaturation in both cases. However, only the latter case (tweezer-lysine) is reversible, in full agreement with the above-detailed enzyme switch experiments. The complexes of ADH with clips or tweezer can be visualized in a nondenaturing gel electrophoresis, where the complexes migrate toward the anode, in contrast to the pure enzyme which approaches the cathode. Supramolecular chemistry has thus been employed as a means to control protein function with the specificity of artificial hosts opening new avenues for this endeavor.


Clinical laboratories: production industry or medical services?
The current failure to evidence any link between laboratory tests, clinical decision-making and patient outcomes, and the scarcity of financial resources affecting healthcare systems worldwide, have put further pressure on the organization and delivery of laboratory services. Consolidation, merger, and laboratory downsizing have been driven by the need to deliver economies of scale and cut costs per test while boosting productivity. Distorted economics, based on payment models rewarding volume and efficiency rather than quality and clinical effectiveness, have underpinned the entrance of clinical laboratories into the production industry thus forcing them to relinquish their original mission of providing medical services. The sea change in laboratory medicine in recent years, with the introduction of ever newer and ever more complex tests, including 'omics', which impact on clinical decision-making, should encourage clinical laboratories to return to their original mission as long as payments models are changed. Rather than being considered solely in terms of costs, diagnostic testing must be seen in the context of an entire hospital stay or an overall payment for a care pathway: the testing process should be conceived as a part of the patient's entire journey.


"What do you mean I can't write?".
The ability to communicate in writing is a critical component of effective leadership. Yet, available "helpful hints" about business writing are often oversimplified, unspecific, or even misleading. This article, abridged from Harvard Business Review, identifies all the elements of business writing and provides a practical, commonsense discussion of each, to help you improve both upward and downward written communications in your organization.


The use of interactive media for HIV/AIDS prevention in the military community.
Over 50 years of risk-reduction efforts for sexually transmitted diseases (STD) exist as a foundation for Acquired Immunodeficiency Disease Syndrome (AIDS) prevention programs in the military, yet very few innovative prevention concepts have been generated. However, the military has used interactive media successfully in medical education to supplement instructional lessons, demonstrate surgical procedures, and train soldiers in mass casualty and combat trauma. The Department of Defense plans to use interactive media in the military's STD clinics for AIDS education. The media combines the visual flexibility of an interactive videodisc with the storage and retrieval capabilities of a computer to display text, graphics, photos, and full-motion media. Rather than a completely descriptive or didactic approach to STD and AIDS prevention activities, a novice user can see and interact with an immediate-motion video representation on the screen. This is important in modifying behavior patterns and demonstrating their relationship to the transmission of the AIDS virus. The development of an interactive videodisc on HIV prevention for use in the military's STD clinics will be discussed, as well as the expedience of their multifaceted use in delivering AIDS information.


Immunization with pneumococcal neuraminidases NanA, NanB and NanC to generate neutralizing antibodies and to increase survival in mice.
Purpose. Pneumococcal virulence protein-based vaccines can provide serotype-independent protection against pneumococcal infections. Many studies, including clinical observational studies on Thomsen-Friedenrich antigen exposure and haemolytic uremic syndrome, defined the role of neuraminidases NanA, NanB and NanC in host-pneumococcus interaction. Since neuraminidases are major virulence proteins, they are potential targets for both vaccines and small molecule inhibitors. Here we explored the utility of three neuraminidases as protein vaccine antigens to generate neutralizing antibodies and to increase survival following pneumococcal infections.Methodology. Rabbits and mice were immunized subcutaneously with enzymatically active recombinant NanA, NanB and NanC as individual or a combination of the three neuraminidases. Antisera titres were determined by ELISA. Neuraminidase activity inhibition by antiserum was tested by peanut lectin and flow cytometry. Clinical isolates with serotype 3, 6B, 14, 15B, 19A and 23F were used to infect immunized mice by tail vein injection.Results/Key findings. Presence of high levels of IgG antibodies in antisera against NanA, NanB and NanC indicates that all of the three neuraminidases are immunogenic vaccine antigens. To generate potent NanA neutralizing antibodies, both lectin and catalytic domains are essential, whereas for NanB and NanC a single lectin domain is sufficient. Immunization with triple neuraminidases increased the survival of mice when intravenously challenged with clinical isolates of serotype 3 (40 %), 6B (60 %), 15B (60 %), 19A (40 %) and 23F (30 %).Conclusion. We recommend the inclusion of three pneumococcal neuraminidases in future protein vaccine formulations to prevent invasive pneumococcal infection caused by various serotypes.


Involvement of brain mineralocorticoid receptor in salt-enhanced hypertension in spontaneously hypertensive rats.
We recently showed that brain mineralocorticoid receptors (MRs) are involved in blood pressure and kidney function control in normotensive Wistar rats. We now assessed the involvement of brain MRs in spontaneously hypertensive rats (SHR), in which the presence of adrenocorticoids has been shown to be required for the development of hypertension. The effect of a single intracerebroventricular (ICV) injection of an MR antagonist (RU28318) on systolic blood pressure (SBP) and renal function was examined in conscious adult SHR and Wistar-Kyoto rats (WKY) maintained on a standard-sodium diet (0.4% Na(+)). In WKY, a long-lasting decrease in SBP was caused by the ICV injection of 10 ng RU28318 as previously reported in Wistar rats, associated with increased urinary excretion of water and electrolytes. In SHR maintained on the standard diet, the ICV injection of RU28318 (10 or 100 ng) had no effect on cardiovascular and renal functions. However, the ICV injection of 10 ng RU28318 in SHR after 3 weeks of high sodium intake (8% Na(+)) caused a long-lasting decrease in SBP. The effect was present at 8 hours (DeltaSBP 34+/-2 mm Hg), persisted at 24 hours (DeltaSBP 29+/-1 mm Hg), and disappeared at 48 hours after the injection. The hypotension was not associated with changes in heart rate, urinary excretion of water and electrolytes, and plasma renin activity, whereas renal denervation did not affect the decrease in SBP. A more pronounced decrease in SBP (49+/-3 mm Hg at 8 hours) was observed with 100 ng RU28318. This dose of the antagonist was without effect after subcutaneous administration. Thus, brain MRs appear to participate in the maintenance of hypertension in conscious adult SHR sensitized by sodium loading.


Oral mini-pulse therapy in vitiligo: a systematic review.
There is limited evidence supporting the use of alternative treatments for patients with nonstable vitiligo. This study aimed to review the effects of oral mini-pulse (OMP) therapy in the management of nonsegmental vitiligo. The following databases were searched between inception and May 2020 for relevant studies: Scopus, Web of Science, MEDLINE, and Embase. All randomized controlled trials that compared OMP therapy with any other active treatment or placebo for nonstable vitiligo were included. The Cochrane's risk of bias tool was used to evaluate the risk of bias (ROB) in selected studies, and the overall quality of evidence of each outcome was assessed using the Grading Recommendations, Assessment, Development, and Evaluations (GRADE) system. Four studies met our selection criteria. All of them were conducted in India and included 246 patients. OMP therapy included betamethasone or dexamethasone. The duration of treatment was 6 months in all studies. Up to 32% of patients achieved a repigmentation rate of >75% when OMP therapy was administered as monotherapy. No difference was observed between OMP therapy and other treatments in arresting the disease, and weight gain was the most frequent adverse effect. The overall ROB in all included studies was relatively high because of the randomization process, outcome measurement and informed selection of outcomes. Based on the findings of these studies, OMP therapy did not demonstrate additional value compared with other treatments. Hence, there is an urgent need to conduct high-quality clinical trials to evaluate this therapy.


A validated LC-MS/MS assay for simultaneous quantification of methotrexate and tofacitinib in rat plasma: application to a pharmacokinetic study.
A highly sensitive, specific and rapid LC-ESI-MS/MS method has been developed and validated for simultaneous quantification of methotrexate (MTX) and tofacitinib (TFB) in rat plasma (50 μL) using phenacetin as an internal standard (IS), as per the US Food and Drug Administration guidelines. After a solid-phase extraction procedure, the separation of the analytes and IS was performed on a Chromolith RP₁₈e column using an isocratic mobile phase of 5 m m ammonium acetate (pH 5.0) and acetonitrile at a ratio of 25:75 (v/v) using flow-gradient with a total run time of 3.5 min. The detection was performed in multiple reaction monitoring mode, using the transitions of m/z 455.2 → 308.3, m/z 313.2 → 149.2 and m/z 180.3 → 110.2 for MTX, TFB and IS, respectively. The calibration curves were linear over the range of 0.49-91.0 and 0.40-74.4 ng/mL for MTX and TFB, respectively. The intra- and interday accuracy and precision values for MTX and TFB were <15% at low quality control (QC), medium QC and high QC and <20% at lower limit of quantification. The validated assay was applied to derive the pharmacokinetic parameters for MTX and TFB post-dosing of MTX and TFB orally and intravenously to rats.


Interactions between subunits of Saccharomyces cerevisiae RNase MRP support a conserved eukaryotic RNase P/MRP architecture.
Ribonuclease MRP is an endonuclease, related to RNase P, which functions in eukaryotic pre-rRNA processing. In Saccharomyces cerevisiae, RNase MRP comprises an RNA subunit and ten proteins. To improve our understanding of subunit roles and enzyme architecture, we have examined protein-protein and protein-RNA interactions in vitro, complementing existing yeast two-hybrid data. In total, 31 direct protein-protein interactions were identified, each protein interacting with at least three others. Furthermore, seven proteins self-interact, four strongly, pointing to subunit multiplicity in the holoenzyme. Six protein subunits interact directly with MRP RNA and four with pre-rRNA. A comparative analysis with existing data for the yeast and human RNase P/MRP systems enables confident identification of Pop1p, Pop4p and Rpp1p as subunits that lie at the enzyme core, with probable addition of Pop5p and Pop3p. Rmp1p is confirmed as an integral subunit, presumably associating preferentially with RNase MRP, rather than RNase P, via interactions with Snm1p and MRP RNA. Snm1p and Rmp1p may act together to assist enzyme specificity, though roles in substrate binding are also indicated for Pop4p and Pop6p. The results provide further evidence of a conserved eukaryotic RNase P/MRP architecture and provide a strong basis for studies of enzyme assembly and subunit function.


DotU expression is highly induced during in vivo infection and responsible for virulence and Hcp1 secretion in avian pathogenic Escherichia coli.
Type VI secretion systems (T6SSs) contribute to pathogenicity in many pathogenic bacteria. Three distinguishable T6SS loci have been discovered in avian pathogenic Escherichia coli (APEC). The sequence of APEC T6SS2 locus is highly similar to the sequence of the newborn meningitis Escherichia coli (NMEC) RS218 T6SS locus, which might contribute to meningitis pathogenesis. However, little is known about the function of APEC T6SS2. We showed that the APEC T6SS2 component organelle trafficking protein (DotU) could elicit antibodies in infected ducks, suggesting that DotU might be involved in APEC pathogenicity. To investigate DotU in APEC pathogenesis, mutant and complemented strains were constructed and characterized. Inactivation of the APEC dotU gene attenuated virulence in ducks, diminished resistance to normal duck serum, and reduced survival in macrophage cells and ducks. Furthermore, deletion of the dotU gene abolished hemolysin-coregulated protein (Hcp) 1 secretion, leading to decreased interleukin (IL)-6 and IL-8 gene expression in HD-11 chicken macrophages. These functions were restored for the complementation strain. Our results demonstrated that DotU plays key roles in the APEC pathogenesis, Hcp1 secretion, and intracellular host response modulation.


Bidirectional transfer from a 24 bp border repeat of Agrobacterium tumefaciens.
T-region transfer from wild-type Agrobacterium strains is thought to be an orientated process, starting at the right border repeat and terminating at the left border repeat of the T-region. Here we demonstrate that a right border repeat in the inverted orientation relative to the onc-genes can also mediate transfer of the T-region to the plant cell, although with lower efficiency as a border repeat in the native orientation. Transfer mediated by an inverted right border repeat is stimulated by the presence of the T-region transfer enhancer. Similar single stranded molecules, comprising the bottom strand of the T-DNA, were isolated from acetosyringone induced bacteria, irrespective of the orientation of the right border. These findings show that border repeats work bidirectionally to some extent.


Discriminability effect on Garner interference: evidence from recognition of facial identity and expression.
Using Garner's speeded classification task existing studies demonstrated an asymmetric interference in the recognition of facial identity and facial expression. It seems that expression is hard to interfere with identity recognition. However, discriminability of identity and expression, a potential confounding variable, had not been carefully examined in existing studies. In current work, we manipulated discriminability of identity and expression by matching facial shape (long or round) in identity and matching mouth (opened or closed) in facial expression. Garner interference was found either from identity to expression (Experiment 1) or from expression to identity (Experiment 2). Interference was also found in both directions (Experiment 3) or in neither direction (Experiment 4). The results support that Garner interference tends to occur under condition of low discriminability of relevant dimension regardless of facial property. Our findings indicate that Garner interference is not necessarily related to interdependent processing in recognition of facial identity and expression. The findings also suggest that discriminability as a mediating factor should be carefully controlled in future research.


Alterations in prednisolone disposition as a result of time of administration, gender and dose.
The disposition of total and free prednisolone has been studied in four male and four female volunteers, each of whom received an intravenous dose of 0.075 mg/kg (low) and 1.5 mg/kg (high) of prednisolone at both 06.00 h and 18.00 h. For the low dose, free prednisolone clearance was 14% lower (P = 0.012) and time-averaged prednisolone free fraction was 22% higher (P less than 0.001) in the morning, there being no circadian difference in total prednisolone clearance. There was no circadian differences in prednisolone disposition at the high dose. These findings are consistent with a mechanism in which cortisol causes a simultaneous competitive inhibition of prednisolone clearance and plasma protein binding at low, but not at high prednisolone doses. Prednisolone clearance was higher in female than in male subjects, the mean increase being 18% (P = 0.022) for total prednisolone and 21% (P = 0.036) for free prednisolone. Mean total prednisolone clearance and steady-state distribution volume were two-fold higher at the high vs the low dose (P less than 0.001), but free prednisolone clearance showed a dose dependent decrease of 11% (P = 0.019). There was no change in free prednisolone steady-state distribution volume.


Evaluation of the effect of trimetazidine on Tc-99m methoxyisobutyl isonitrile gated scintigraphy in patients with coronary artery ectasia.
Coronary artery ectasia (CAE) is the abnormal dilatation of a segment of the coronary artery to a diameter of at least 1.5 times that of normal adjacent segments. Symptoms are variable, and its prognosis and treatment modalities are unclear. The aim of this study is to evaluate the effect of trimetazidine (TMZ) on ischemic left ventricular function by rest-stress Tc-99m methoxyisobutyl isonitrile (Tc-99m MIBI) myocardial scintigraphy in symptomatic patients with CAE. We included patients with ectasia admitted to our Cardiology Department, Turkey, between 2003 and 2004 in this study. All patients underwent coronary angiography and diagnosed with CAE, before and 4 weeks after TMZ administration. Seventeen patients (9 men, 8 women) underwent gated single-proton emission tomographic (SPECT) using Tc-99m MIBI. We performed quantitative global and regional ventricular functional analysis using quantitative gated SPECT software. The global ejection fraction increased from 59.9%+/-8.9% to 62.6%+/-8.3% after therapy (p=0.033). In addition, the end systolic volume and the end diastolic volume decreased after therapy (101.7+/-23.5 ml to 95.1+/-22.9 ml, p=0.002; from 41.1+/-14.3 to 36.4+/-13.6, p=002). In all segments, we observed significant post-therapy increases in relative tracer uptake. Percentage of MIBI uptake was 71.2+/-15.3 at baseline stress and 73.2+/-15 post-TMZ (p=0.001). As global function parameters, the total wall motion normal areas changed significantly (67-74% p=0.01) after therapy, but the total wall thickness did not changed significantly(49-45%, p=0.21). The results of this study demonstrate that TMZ improves myocardial function by rest-stress Tc-99m MIBI gated SPECT during stress-induced ischemia in patients with CAE. Also, the outcomes revealed improvement in functional parameters, and percentage of MIBI uptake post TMZ administration. We can use this procedure to monitor the effect of TMZ in CAE patients.


Specific removal of proteins from the envelope of Escherichia coli by protease treatments.
When the envelope fraction of Escherichia coli was treated by trypsin, about 40% of total envelope proteins were removed from the fraction without changing its phospholipid content. Analysis of envelope proteins by acrylamide gel electrophoresis in 0.5% sodium dodecyl sulfate revealed that trypsin treatment was very specific; one of the major proteins (molecular weight, 38,000) and all proteins of molecular weight greater than 70,000 were completely removed by the treatment. On the other hand, three other major proteins were found to be resistant to the treatment, including protein Y, which was previously shown to be related to deoxyribonucleic acid replication. The trypsin treatment of the envelope fractions composed of a five electron-dense layered structure formed vesicles with a triple-layered membrane (two electron-dense layers). Pronase treatment of the envelope fraction removed about 60% of the envelope proteins without changing its phospholipid content. A major protein of molecular weight of 58,000 was found to be the only protein resistant to the Pronase treatment. Application of these treatments is useful for purification and structural studies of envelope proteins.


Mycobacterium abscessus subsp. abscessus Is Capable of Degrading Pseudomonas aeruginosa Quinolone Signals.
Pseudomonas aeruginosa employs 2-heptyl-3-hydroxy-4(1H)-quinolone (the Pseudomonas quinolone signal, PQS) and 2-heptyl-4(1H)-quinolone (HHQ) as quorum sensing signal molecules, which contribute to a sophisticated regulatory network controlling the production of virulence factors and antimicrobials. We demonstrate that Mycobacterium abscessusT and clinical M. abscessus isolates are capable of degrading these alkylquinolone signals. Genome sequences of 50 clinical M. abscessus isolates indicated the presence of aqdRABC genes, contributing to fast degradation of HHQ and PQS, in M. abscessus subsp. abscessus strains, but not in M. abscessus subsp. bolletii and M. abscessus subsp. massiliense isolates. A subset of 18 M. a. subsp. abscessus isolates contained the same five single nucleotide polymorphisms (SNPs) compared to the aqd region of the type strain. Interestingly, representatives of these isolates showed faster PQS degradation kinetics than the M. abscessus type strain. One of the SNPs is located in the predicted promoter region of the aqdR gene encoding a putative transcriptional regulator, and two others lead to a variant of the AqdC protein termed AqdCII, which differs in two amino acids from AqdCI of the type strain. AqdC, the key enzyme of the degradation pathway, is a PQS dioxygenase catalyzing quinolone ring cleavage. While transcription of aqdR and aqdC is induced by PQS, transcript levels in a representative of the subset of 18 isolates were not significantly altered despite the detected SNP in the promoter region. However, purified recombinant AqdCII and AqdCI exhibit different kinetic properties, with approximate apparent Km values for PQS of 14 μM and 37 μM, and kcat values of 61 s-1 and 98 s-1, respectively, which may (at least in part) account for the observed differences in PQS degradation rates of the strains. In co-culture experiments of P. aeruginosa PAO1 and M. abscessus, strains harboring the aqd genes reduced the PQS levels, whereas mycobacteria lacking the aqd gene cluster even boosted PQS production. The results suggest that the presence and expression of the aqd genes in M. abscessus lead to a competitive advantage against P. aeruginosa.


Developing a conceptual model of coach concussion communication by adapting the theory of planned behavior and the social ecological model.
Objective: Acknowledging that coach communication about concussion increases the likelihood of athletes reporting concussive symptoms, the goal of this study was to examine factors affecting such communication, in order to develop a conceptual model that would inform the design of future educational interventions.Participants: Division I contact sport coaches.Methods: We conducted structured qualitative interviews with coaches and analyzed interviews using Thematic Analysis, viewed through the lens of the Theory of Planned Behavior nested within the Social Ecological Model.Results: Coaches had good knowledge of concussion and understood the dangers of playing with symptoms. However, they also discussed the lack of objective criteria for concussion diagnosis, and pressure to win in order to remain employed, both of which created barriers to concussion communication. Ultimately, most coaches reported not engaging in significant concussion communication as they did not feel this was their role, instead deferring to medical staff.Conclusions: Educational interventions might benefit from a focus on the importance of coach concussion safety-supportive coach communication, with a goal of increasing the likelihood of athlete concussion reporting.


The expression of CD4 and CD8 molecules conditions the behavior of V beta + murine thymocytes upon superantigenic challenge.
We investigated the capacity of the Staphylococcal enterotoxin (SE) B, a superantigen (SAg) specific for TCR V beta domain, to modulate V beta 8+ thymocytes selection in adult mice. Thymocytes were collected at various time intervals after SEB injection (10 and 100 micrograms) and V beta 8+ modulation was analysed by three color flow cytometry. SEB failed to affect V beta 8+ thymocytes comprised in the less mature compartments, namely, CD4+8+ and CD4-CD8-, whereas it selectively affected V beta 8+CD4+8+ (downward modulation) and V beta 8+CD4-8+ thymocytes (upward modulation). The different response to SEB challenge between CD4+8- and CD4-8+ thymocytes appeared dependent on the CD4/MHC class II interaction, as V beta 8+CD4-8+ thymocytes carrying a transgenic CD4 molecule capable of interacting with MHC class II showed the same response of V beta 8+CD4+8- thymocytes. At variance with thymocytes, however, V beta 8+CD4+8- and V beta 8+CD4-8+ splenic T lymphocytes responded to SAg challenge in identical manner (upward modulation) highlighting the importance of maturation status and/or microenvironment in SAg response. V beta 8+ thymocytes remaining in the thymus were assessed for their capacity to respond to a SAg challenge. Thus, thymocytes were obtained at various time intervals after SEB injection and cultured in the presence of SEB or SEA, a Sag specific for V beta 10 as control. A reduced mitotic response to SEB but not to SEA was noticed irrespective of the number of V beta 8+ responding cells present in culture. It is concluded that SAgs affect TCR specific thymocytes by conditioning their redistribution and inducing an anergic status.


Working women and breastfeeding in Israel.
Two-hundred and ninety-one working women in Israel were interviewed 7-9 months after childbirth. The mean number of months that they had breastfed was 2.03. The duration of breastfeeding increased with religiousity and higher education. Women born in Europe, primiparas and grandparas (4 + children) and those over the age of 40 breastfed longer. Most of the women returned to work only after completing breastfeeding. Duration of breastfeeding was reduced when the mother suffered from stress, tiredness, encountered feeding problems, or if the baby cried excessively.


COVID-19: The Dysregulated Response to Infection - Why Consider Polymethylmethacrylate Membrane in Hemodialysis Patients?
Since SARS-CoV-2 spread through China at the end of 2019, COVID-19 has been probably the most difficult challenge in the last decades for healthcare systems all around the world, still representing a danger for fragile patients with different comorbidities. Chronic dialysis patients affected by COVID-19 experienced severe disease with a higher mortality rate compared to the general population. Morbidity and mortality of this severe acute respiratory syndrome depend on both acute respiratory failure and systemic immunological involvement with consequent inflammation-mediated injury. Indeed, the most important determining factor of COVID-19 severity is the strength of the so-called "cytokine storm" associated with SARS-CoV-2 infection. Therefore, this severe infection varies clinically from an asymptomatic condition to a generalized and violent inflammatory response and acute respiratory distress syndrome, with consequent pulmonary interstitial edema and a high risk of multi-organ failure. The use of extracorporeal therapies targeting cytokine clearance to improve patients' outcomes has been widely debated, especially in end-stage kidney disease's patients on maintenance dialysis or in individuals affected by acute kidney injury admitted to intensive care units. Different studies were conducted to demonstrate how specific dialyzers could decrease the COVID-19 inflammatory state. The aim of this narrative review was to summarize main studies about this topic, focusing primarily on the role of polymethylmethacrylate dialyzer and underlining pros and cons of this sorbent.


Modification of a fiber protein in an adenovirus vector improves in vitro gene transfer efficiency to the mouse microglial cell line.
In microglia, it is difficult to introduce exogenous genes of interest even by recombinant adenovirus vectors (Ad) which can infect with high efficiency only to the cells expressing coxackievirus and adenovirus receptors (CAR). We found a lack of CAR expression in primary cultured murine microglia (PCMG) and its immortalized cell line MG5 by reverse transcription-polymerase chain reaction. In order to improve the efficiency of gene transfer, we generated a novel Ad (Ad-RGD) by an incorporation of the Arg-Gly-Asp motif (RGD) containing peptide in the HI loop of the viral fiber knob domain, which enables the virus to contact target cells through alpha V integrins which are known to be ubiquitously expressed on the surface of mammalian cells. Ad-RGD showed a remarkable improvement (13-18-fold) in the delivery of Escherichia coli LacZ gene in MG5 cells and a moderate increase in PCMG cells under the treatment with granulocyte-macrophage colony stimulating factor. These results suggest that Ad-RGD may be a potent tool for the delivery of genes to microglia activated by optimum stimulation, and thus analyzing the function of microglia with utilization of MG5 and PCMG cells.


The roles of Groucho/Tle in left-right asymmetry and Kupffer's vesicle organogenesis.
The heart is the first organ to form and function in the vertebrate embryo. Furthermore, differences between the left and right sides of the embryo become first detectable during cardiac development. We observed strong cardiac laterality phenotypes in medaka embryos by manipulating Groucho protein activity. The phenotypes produced by misexpressing Tle4 and the dominant-negative Aes reveal a general effect of these corepressor proteins on left-right (LR) development. With the help of an inducible expression system, we were able to define temporally different phases for these effects. In an early phase during gastrulation, Groucho proteins regulate Brachyury expression in the dorsal forerunner cells, which later gives rise to the Kupffer's vesicle (KV). The interference of endogenous Groucho proteins by misexpression of Aes leads to KVs of reduced size, whereas overexpression of Tle4 results in enlarged KVs. The expression level of the cilia marker Lrd was also affected both positively and negatively from these treatments. In the late phase during somitogenesis, Groucho proteins regulate the asymmetric activities of Nodal and Lefty genes. Altering canonical Wnt signaling produced similar results in late embryos, however, this did not affect KV morphogenesis or Lrd expression in early embryos. Therefore, changes in Kupffer's vesicle morphogenesis and the laterality of visceral organs following alterations in Groucho corepressor levels demonstrate two distinct phases in which Groucho proteins help establish LR asymmetry in medaka fish.


An appraisal of pancreatectomy for advanced cancer of the pancreas based on survival rate and postoperative physical performance.
The follow-up results of surgical procedures for cancer of the pancreas at three affiliated hospitals during the past 15 years (1974-1989) were retrospectively analyzed to evaluate the merit of pancreatectomy in surgical treatment of advanced stages of this disease. Included were 4 cases of stage I, 14 cases of stage II, 19 cases of stage III, 43 cases of localized stage IV, and 35 cases of generalized stage IV. Pancreatectomy was performed in 67 cases; 100%, 92.9%, 89.5%, 67.4%, and 11.4% of the stage I, II, III, localized IV, and generalized IV cases, respectively. For the localized stage IV cases, in which the cancerous lesions were advanced but limited to the peripancreatic region, 29 pancreatectomies, 12 bypass operations, and 2 exploratory laparotomies were performed. This group included 17 curative and 12 noncurative pancreatectomies. The 50% survival periods were 257 days after curative pancreatectomy, 226 days after noncurative pancreatectomy, 120 days after bypass operation, and 33 days after exploratory laparotomy. The difference in overall survival rate between curative and noncurative pancreatectomies was not significant. The overall survival rates after both curative and noncurative pancreatectomies were significantly higher than the rate after bypass operation. The postoperative physical performance status after pancreatectomy was significantly better than after the palliative procedures. No significant difference in the status was found between patients after standard and extended pancreatectomies. There was no significant difference in the survival rates or the physical performance status between the pancreatectomy group and the palliative surgery group for the generalized stage IV cases, in which the cancerous lesions extended beyond the peripancreatic region. On the basis of these findings, it is concluded that pancreatectomy extends the postoperative survival period without impairment of the physical performance status in patients with advanced cancer of the pancreas. Even when the pancreatectomy proves to be a noncurative resection, this aggressive surgical approach may be of benefit to this group of patients. It should be noted, however, that pancreatectomy is not beneficial to patients whose lesions have already become generalized.


Free paclitaxel-loaded E-selectin binding peptide modified micelle self-assembled from hyaluronic acid-paclitaxel conjugate inhibit breast cancer metastasis in a murine model.
The present work seeks to construct a nanovehicle for the efficient suppression of breast cancer metastasis through targeting E-selectin on tumor vascular endothelial cells and hyaluronic acid-receptor on tumor cells. Herein, a new ligand-PEG-lipid conjugate, E-selectin binding peptide-polyethene glycol-1-octadecylamine (Esbp-PEG-OA), was used as the targeting molecule of micelle self-assembled form hyaluronic acid-paclitaxel (HA-PTX) conjugate. When loaded with free PTX, the micelles (Esbp-HA-PTX/PTX) exhibited nanoscale particle size with high drug-loading capacity (up to 31.5%). In vitro release study showed that the conjugated and entrapped PTX released simultaneously. Cellular uptake of micelles confirmed that Esbp-HA-PTX micelles could be specifically and efficiently internalized into E-selectin expressing human umbilical vein endothelial cells (HUVEC) and 4T1 breast cancer cells via receptor-meditated endocytosis. In vitro cytotoxicity assay further revealed that Esbp-HA-PTX/PTX micelles significantly improved the selectivity of PTX for killing the two cell types compared with PTX solution formulation. More importantly, Esbp-HA-PTX micelles raised the accumulation of payload in tumor through targeting two cell types in the tumor microenvironment simultaneously, resulting in marked in vivo inhibition of tumor growth, intratumoral microvessel density and metastasis, and decreased systemic toxicity over solution formulation. Overall, Esbp-HA-PTX/PTX micelle is promising in therapy of breast cancer metastasis.


Shifts in functional traits elevate risk of fire-driven tree dieback in tropical savanna and forest biomes.
Numerous predictions indicate rising CO2 will accelerate the expansion of forests into savannas. Although encroaching forests can sequester carbon over the short term, increased fires and drought-fire interactions could offset carbon gains, which may be amplified by the shift toward forest plant communities more susceptible to fire-driven dieback. We quantify how bark thickness determines the ability of individual tree species to tolerate fire and subsequently determine the fire sensitivity of ecosystem carbon across 180 plots in savannas and forests throughout the 2.2-million km(2) Cerrado region in Brazil. We find that not accounting for variation in bark thickness across tree species underestimated carbon losses in forests by ~50%, totaling 0.22 PgC across the Cerrado region. The lower bark thicknesses of plant species in forests decreased fire tolerance to such an extent that a third of carbon gains during forest encroachment may be at risk of dieback if burned. These results illustrate that consideration of trait-based differences in fire tolerance is critical for determining the climate-carbon-fire feedback in tropical savanna and forest biomes.


Molecular dynamics simulations of the Escherichia coli HPPK apo-enzyme reveal a network of conformational transitions.
6-Hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK) catalyzes the first reaction in the folate biosynthetic pathway. Comparison of its X-ray and nuclear magnetic resonance structures suggests that the enzyme undergoes significant conformational change upon binding to its substrates, especially in three catalytic loops. Experimental research has shown that even when confined by crystal contacts, loops 2 and 3 remain rather flexible when the enzyme is in its apo form, raising questions about the putative large-scale induced-fit conformational change of HPPK. To investigate the loop dynamics in a crystal-free environment, we performed conventional molecular dynamics simulations of the apo-enzyme at two different temperatures (300 and 350 K). Our simulations show that the crystallographic B-factors considerably underestimate the loop dynamics; multiple conformations of loops 2 and 3, including the open, semi-open, and closed conformations that an enzyme must adopt throughout its catalytic cycle, are all accessible to the apo-enzyme. These results revise our previous view of the functional mechanism of conformational change upon MgATP binding and offer valuable structural insights into the workings of HPPK. In this paper, conformational network analysis and principal component analysis related to the loops are discussed to support the presented conclusions.


Ethanol production from eucalyptus wood hemicellulose hydrolysate by Pichia stipitis.
Ethanol production was evaluated from eucalyptus wood hemicellulose acid hydrolysate using Pichia stipitis NRRL Y-7124. An initial lag phase characterized by flocculation and viability loss of the yeast inoculated was observed. Subsequently, cell regrowth occurred with sequential consumption of sugars and production of ethanol. Polyol formation was detected. Acetic acid present in the hydrolysate was an important inhibitor of the fermentation, reducing the rate and the yield. Its toxic effect was due essentially to its undissociated form. The fermentation was more effective at an oxygen transfer rate between 1.2 and 2.4 mmol/L h and an initial pH of 6.5. The hydrolysate used in the experiences had the following composition (expressed in grams per liter): xylose 30, arabinose 2.8, glucose 1.5, galactose 3.7, mannose 1.0, cellobiose 0.5, acetic acid 10, glucuronic acid 1.5, and galacturonic acid 1.0. The best values obtained were maximum ethanol concentration 12.6 g/L, fermentation time 75 h, fermentable sugar consumption 99% ethanol yield 0.35 g/g sugars consumed, and volumetric ethanol productivity 4 g/L day. (


Study of energetic properties of different tree organs in six Olea europaea L. cultivars.
Pruning is an important horticultural practice for the management of olive orchards (Olea europaea L.) that generates a considerable amount of residues every year. Olive orchards are increasingly expanding beyond the Mediterranean Basin to new growing Countries (Australia, California, Argentina, Chile and Uruguay) and this will certainly lead to larger availability of pruning material. Currently, the interest in use of olive tree pruning residues for energy purposes is increasing but unfortunately, the information on the differences among organs of the tree, in terms of calorific value and ash content, is scarce. Another unknown aspect is the effect of cultivar vigour on dry matter partition among different tree organs, these are important traits to establish the energetic quality of pruning residues. The aim of this research was to study energetic aspects of six olive cultivars, largely grown in the Sicilian olive industry and characterized by different vigour. The trees taken into consideration in the study were selected in an experimental orchard to avoid any effect due to differences in environmental conditions and management. The energetic characteristics, calorific value and ash content, were evaluated for the various tree organs particularly shoots, leaves and branches; also root system was evaluated, although the roots can only be used once the trees are uprooted. Significant differences were observed in the calorific values among the different tree organs and the cultivars. Regarding the ash, shoots and leaves showed the highest content with respect to the other organs, thus causing a possible tendency in slagging with fouling and corrosion of boiler components.


[Impact of sleep disorders on quality of life in epilepsy].
To study the relationship between sleep disorder symptoms and health-related quality of life (HRQOL) in patients with epilepsy. Three groups of participants were included: patients with epilepsy (EG, n=151), healthy controls (CG, n=130), patients with a confirmed diagnosis of sleep disorder (SDG, n=69). HRQOL was assessed with SF-36 containing 8-domains (D1-D8). EG, CG, SDG groups as well as subgroups with- or without sleep disturbance (SD) and partial (PE) or generalized (GE) epilepsy were compared. When comparing quantitative HRQOL data between EG and CG groups, SF-36 scores were significantly lower in EG. In the EG group, the scores on each domain were lower compared to the group with SD (p<0,001). While in CG the impact of SD decreased, with the difference being significant (p<0,05) in only half of SF-36 domains, there was no difference in HRQOL levels between EG with SD and SDG. Also, the lowest HRQOL was seen in patients with PE compared to GE with SD. Patients with epilepsy with SD report lower HRQOL, also disordered sleep impacts HRQOL more in patients with PE than with GE. The results indicate that sleep disorders should be addressed during management of patients with epilepsy.