Study of formulation variables influencing the drug release rate from matrix tablets by experimental design.
Experimental design was utilized to simultaneously investigate the effect of varying the type of diluent (insoluble Calcium phosphate or water-soluble arabic gum) and the diluent/matrix ratio on the drug release behaviour from both lipophilic (glyceryl behenate, Compritol) or hydrophilic (hydroxypropylmethylcellulose) matrix tablets. Ketoprofen, theophylline and sodium sulphadiazine were selected as model drugs on the basis of their respectively very low, medium and high water-solubility, in order to evaluate the influence of this parameter as well. The selected response variables were the dissolution efficiency (i.e. the area under the dissolution curve) after one and six hours and the time necessary to dissolve 10% drug. Tablets obtained by direct compression of drug-diluent-matrix ternary mixtures prepared according to the experimental plan provided for by an asymmetric screening matrix, were tested for drug release properties using a USP paddle apparatus. Graphic analysis of the effects allowed identification, for each examined drug, of the formulation factors active on the selected responses and determination of the proper level of the variables to be selected for the response improvement. The different results obtained with the three examined drugs pointed out the role of the drug solubility in determining the influence of formulation parameters on drug release rate from matrix tablets.


UGT2B28 accelerates prostate cancer progression through stabilization of the endocytic adaptor protein HIP1 regulating AR and EGFR pathways.
The androgen inactivating UGT2B28 pathway emerges as a predictor of progression in prostate cancer (PCa). However, the clinical significance of UGT2B28 tumoral expression and its contribution to PCa progression remain unclear. Using the Canadian Prostate Cancer Biomarker Network biobank (CPCBN; n = 1512), we analyzed UGT2B28 tumor expression in relation to clinical outcomes in men with localized PCa. UGT2B28 was overexpressed in tumors compared to paired normal adjacent prostatic tissue and was associated with inferior outcomes. Functional analyses indicated that UGT2B28 promoted cell proliferation, and its expression was regulated by the androgen receptor (AR)/ARv7. Mechanistically, UGT2B28 was shown to be a protein partner of the endocytic adaptor protein huntingtin-interacting protein 1 (HIP1), increasing its stability and priming AR/epidermal growth factor receptor (EGFR) pathways, leading to ERK1/2 activation triggering cell proliferation and epithelial-to-mesenchymal transition (EMT). HIP1 knockdown in UGT2B28 positive cells, and dual pharmacological targeting of AR and EGFR pathways, abolished cell proliferative advantages conferred by UGT2B28. In conclusion, UGT2B28 is a prognosticator of progression in localized PCa, regulates both AR and EGFR oncogenic signaling pathways via HIP1, and therefore can be therapeutically targeted by using combination of existing AR/EGFR inhibitors.


Rheology of paraproteinaemias and the plasma hyperviscosity syndrome.
The proper understanding of the causes, pathophysiology, diagnosis and management of the plasma hyperviscosity syndrome is based on good knowledge of malignant paraproteinaemias, properties of immunoglobulins, rheology of blood in the microcirculation, and modern plasma separation techniques. This multifaceted syndrome complicates less than ten per cent of IgA and IgG myelomas, and up to one-third of Waldenström's macroglobulinaemias. A few cases of HVS have also been reported in association with polyclonal hypergammaglobulinaemias. Excessive paraproteinaemia may cause the plasma HVS, especially when paraproteins are extraordinarily large, asymmetrical or cryosensitive, or if they aggregate into hyperviscous macroaggregates. The resultant severe microcirculatory impairment is mainly due to the combined effects of plasma hyperviscosity, significant plasma volume expansion and intense red cell aggregation. The individually variable general symptoms, bleeding tendency, ocular, neurological, cardiovascular, and renal manifestations and laboratory parameters of the HVS are summarized briefly. The majority of patients present hyperviscosity manifestations when the plasma viscosity exceeds 5-6 mPa.s. Plasmapheresis or plasma exchange have established themselves as efficient and safe modes of therapy of hyperviscosity and hypervolaemia. The therapeutic guidelines for the plasma HVS are briefly discussed with regard to recent experience with developing plasma separation techniques. Diagnostic and therapeutic advances combined with increasing haemorheological knowledge have greatly improved the proper management of this potentially lethal complication of paraproteinaemias.


Patients seen in emergency departments who had a prior visit within the previous 72 h-National Hospital Ambulatory Medical Care Survey, 2002.
This study characterized emergency department (ED) visits of patients who had received services in an ED within the previous 72 h. ED data from the National Hospital Ambulatory Medical Care Survey were analysed for: (a) infectious-disease-related visits; (b) infectious-disease-related return visits; and (c) return visits reported within the previous 72 h for all visits. Data were collected from a nationally representative sample of hospital EDs and were weighted to generate national estimates. In 2002, an estimated 20.5 million ED visits occurred in the USA for infectious diseases, for a visit rate of 73/1,000 people. A total of 3.5 million total return visits to EDs occurred within 72 h, and 67% were for follow-up visits. An estimated 625,280 return visits were for infectious diseases (18% of total ED return visits); 72% of these were for follow-up services. For total visits and infectious-disease-related visits, the majority of return visits were reported among those aged 25--44 years and among females. Approximately seven of every 10 return visits to EDs in 2002 were for follow-up services, and no difference existed in the percentage of return visits for infectious diseases compared with total visits. A health services implication exists for treating this percentage of patients in EDs when primary care practitioners should be the point of contact.


The α2-adrenergic receptor pathway modulating depression influences the risk of arterial thrombosis associated with BDNFVal66Met polymorphism.
Depression is associated with thrombotic risk and arterial events, its proper management is strongly recommended in coronary artery disease (CAD) patients. We have previously shown that the Brain-Derived Neurotrophic Factor (BDNF)Val66Met polymorphism, related to depression, is associated with arterial thrombosis in mice, and with an increased risk of acute myocardial infarction in humans. Herein, expanding the previous findings on BDNFVal66Met polymorphism, we show that desipramine, a norepinephrine reuptake-inhibitor, rescues behavioral impairments, reduces the arterial thrombosis risk, abolishes pathological coagulation and platelet hyper-reactivity, normalizes leukocyte, platelet, and bone marrow megakaryocyte number and restores physiological norepinephrine levels in homozygous knock-in BDNF Val66Met (BDNFMet/Met) mice. The in vitro data confirm the enhanced procoagulant activity and the alpha2A-adrenergic receptor (α2A-ADR) overexpression found in BDNFMet/Met mice and we provide evidence that, in presence of Met variant, norepinephrine is crucial to up-regulate procoagulant activity and to enhance platelet generation. The α2-ADR antagonist rauwolscine rescues the prothrombotic phenotype in BDNFMet/Met mice and reduces procoagulant activity and platelet generation in cells transfected with BDNFMet plasmid or exposed to pro-BDNFMet peptide. Finally, we show that homozygous BDNFMet/Met CAD patients have hyper-reactive platelets overexpressing abundant α2A-ADR. The great proplatelet release from their megakaryocytes well reflects their higher circulating platelet number compared to BDNFVal/Val patients. These data reveal an unprecedented described role of Met allele in the dysregulation of norepinephrine/α2A-ADR pathway that may explain the predisposition to arterial thrombosis. Overall, the development of α2A-ADR inhibitors might represent a pharmacological treatment for depression-associated thrombotic conditions in this specific subgroup of CAD patients.


Interruption in the work of nursing professionals: conceptual analysis.
to analyze the concept of "interruption in the work of nursing professionals". conceptual study according to the method proposed by Walker and Avant through integrative literature review. The study searched the databases using the descriptors: "Attention", "Attention Bias", "Health Personnel", "Nurses", "Patient Safety" and "Medical Malpractices". The sample consisted of 36 studies. the antecedents were alarms, answering phone calls, providing patient care, and lack of material/medicine. The defining attributes were pause, suspension, breakage, and intrusion. In relation to the consequences, the study highlighted the increase in frequency and severity of medication errors and change of focus. theconceptual analysis identified the attributes, antecedents, and consequences and allowed to build an operational definition for "interruption in the work of nursing professionals". It will contribute to the improvement of the work process and the creation of strategies that ensure safer care for the patient.


Clinical features and molecular basis of 102 Chinese patients with congenital dysfibrinogenemia.
Congenital dysfibrinogenemia (CD) is a rare qualitative disorder of fibrinogen (Fg) with heterogeneous clinical manifestations. We aimed to analyze clinical phenotype and molecular basis of 102 Chinese CD patients and to evaluate the application of thromboelastography (TEG). Clinical manifestations were recorded and quantified using the consensus ISTH bleeding assessment tool. Kaolin activated TEG and functional Fg TEG were applied in 30 patients. Genetic analysis of Fg genes were performed by direct sequencing. 27.5% patients experienced bleeding, 3.9% had thrombosis and 68.6% were asymptomatic. Females were more prone to experience bleeding (P=0.01). Significant difference (P<0.05) in TEG results were found between patients with hot-spot mutations at AαArg35(16) and γArg301(275), but were not identified between patients with and without bleeding. Normal TEG results were found in patients with mutations at AαArg35(16), AαPro37(18) or AαArg38(19). Six novel mutations were identified, including AαGly33(14)del, AαAsp57(38)_Trp60(41)delIVS2+1_+2GTdel, AαPhe742(723)Tyr, γAsn334(308)Thr, γGly335(309)Cys and γTrp395(369)Leu. CD patients have similar clinical manifestations and hot-spot mutations worldwide with no ethnic difference. TEG results could not indicate the bleeding risk in patients, but priority of mutation screening at thrombin cleavage site or polymerization site on Aа chain may be given if TEG results are normal.


Thermally and field-driven mobility of emergent magnetic charges in square artificial spin ice.
Designing and constructing model systems that embody the statistical mechanics of frustration is now possible using nanotechnology. We have arranged nanomagnets on a two-dimensional square lattice to form an artificial spin ice, and studied its fractional excitations, emergent magnetic monopoles, and how they respond to a driving field using X-ray magnetic microscopy. We observe a regime in which the monopole drift velocity is linear in field above a critical field for the onset of motion. The temperature dependence of the critical field can be described by introducing an interaction term into the Bean-Livingston model of field-assisted barrier hopping. By analogy with electrical charge drift motion, we define and measure a monopole mobility that is larger both for higher temperatures and stronger interactions between nanomagnets. The mobility in this linear regime is described by a creep model of zero-dimensional charges moving within a network of quasi-one-dimensional objects.


Activation of extracellular signal-regulated kinase (ERK) and p38 kinase in shock wave-promoted bone formation of segmental defect in rats.
Extracorporeal shock waves (ESW) have recently been used in bone repair. Extracellular signal-regulated kinase (ERK) and p38 kinase are found to act as important mediators for osteogenic factor and mechanical-stimulated proliferation and differentiation of bone-forming cells. A previous study reported that ESW promoted healing of segmental defects in rats by inducing bone morphogenetic proteins (Bone 32 (2003) 387-396) and stimulating osteogenic differentiation of mesenchymal stem cells. In this study, we found that ERK and p38 activation was involved in ESW-augmented bone regeneration of segmental defects. ESW treatment (0.16 mJ/mm2, 1 Hz, 500 impulses) rapidly promoted [3H]-thymidine uptake in 1 day and progressively increased alkaline phosphatase activity, collagen I, II, and osteocalcin synthesis in callus organ culture within 14 days after treatment. Results of [gamma-32P]-phosphotransferase activity assay showed that ERK and p38 in calluses were rapidly activated 1 day and 7 days after ESW treatment, respectively. Histological observation showed that segmental defects subjected to ESW treatment underwent typical bone formation (mesenchymal cell aggregation, hypertrophic cartilage, and endochondral/intramembrane ossification). Intensive bone formation coincided with evident expression of phosphorylated ERK and p38. Moreover, expression of phosphorylated ERK persisted in mesenchymal, chondral, and osteoblastic cells at newly developed bone and cartilage, and the expression of activated p38 was evident on chondral cells located at hypertrophic cartilage. Our findings suggest that mitogen-activated protein kinases (MAPK) regulate the stimulation of biophysical ESW, triggering mitogenic and osteogenic responses in the defects. ERK phosphorylation is active throughout the period of ESW-induced bone regeneration. p38 activation most likely plays an important role in signaling cartilage formation in callus.


Estimation of the morbidity and mortality of congenital Chagas disease: A systematic review and meta-analysis.
Chagas disease is caused by the parasite Trypanosoma cruzi which can be transmitted from mother to baby during pregnancy. There is no consensus on the proportion of infected infants with clinical signs of congenital Chagas disease (cCD). The objective of this systematic review is to determine the burden of cCD. Articles from journal inception to 2020 reporting morbidity and mortality associated with cCD were retrieved from academic search databases. Observational studies, randomized-control trials, and studies of babies diagnosed with cCD were included. Studies were excluded if they were case reports or series, without original data, case-control without cCD incidence estimates, and/or did not report number of participants. Two reviewers screened articles for inclusion. To determine pooled proportion of infants with cCD with clinical signs, individual clinical signs, and case-fatality, random effects meta-analysis was performed. We identified 4,531 records and reviewed 4,301, including 47 articles in the narrative summary and analysis. Twenty-eight percent of cCD infants showed clinical signs (95% confidence interval (CI) = 19.0%, 38.5%) and 2.2% of infants died (95% CI = 1.3%, 3.5%). The proportion of infected infants with hepatosplenomegaly was 12.5%, preterm birth 6.0%, low birth weight 5.8%, anemia 4.9%, and jaundice 4.7%. Although most studies did not include a comparison group of non-infected infants, the proportion of infants with cCD with clinical signs at birth are comparable to those with congenital toxoplasmosis (10.0%-30.0%) and congenital cytomegalovirus (10.0%-15.0%). We conclude that cCD burden appears significant, but more studies comparing infected mother-infant dyads to non-infected ones are needed to determine an association of this burden to cCD.


Mass spectrometric characterization of full-length rat selenoprotein P and three isoforms shortened at the C terminus. Evidence that three UGA codons in the mRNA open reading frame have alternative functions of specifying selenocysteine insertion or translation termination.
Selenoprotein P is an abundant extracellular glycoprotein. Its mRNA contains 10 UGAs in an open reading frame terminated by a UAA. This predicts that full-length selenoprotein P will contain 10 selenocysteine residues. Full-length selenoprotein P and three smaller isoforms that have identical N termini have been demonstrated. Selenoprotein P was purified from rat plasma, and the four isoforms were separated by heparin chromatography and SDS-PAGE. Mass spectrometric peptide analysis of the full-length isoform verified 357 of its 366 predicted amino acid residues, including its C terminus and all 10 selenocysteines. The C termini of the smaller isoforms were characterized by mass spectrometry. The shortened isoforms terminated where the second, third, and seventh selenocysteine residues were predicted to be. This suggests that all isoforms arise from the same mRNA and that the UGAs that specify the second, third, and seventh selenocysteines in full-length selenoprotein P can alternatively serve to terminate translation, producing the shorter isoforms.


Cell-free activation of a DNA-binding protein by epidermal growth factor.
Growth factors such as platelet-derived growth factor and epidermal growth factor (EGF) bind to and activate cell-surface receptors with intrinsic tyrosine kinase activities. Receptor activation elicits multiple physiological changes in target cells, including alterations in gene expression. Receptor tyrosine kinase signalling involves recruitment of proteins into a signalling complex through interactions between receptor autophosphorylation sites and the src-homology region-2 (SH2) domains on these signalling proteins. Diverse signals can subsequently be generated, depending on the specific receptor and cell type. How such signals are transmitted to the nucleus is poorly understood, but because the transcriptional activation of many genes by growth factors occurs in the absence of new protein synthesis, one or more signals emanating from growth factor receptors must directly affect transcription factors. We report here the activation by EGF of a DNA-binding protein in a cell-free system where activation of DNA binding requires ligand, receptor, ATP and phosphotyrosine-SH2 interactions.


Smart surfaces with reversibly switchable wettability: Concepts, synthesis and applications.
As a growing hot research topic, manufacturing smart switchable surfaces has attracted much attention in the past a few years. The state-of-the-art study on reversibly switchable wettability of smart surfaces has been presented in this systematic review. External stimuli are brought about to render the alteration in chemical conformation and surface morphology to drive the wettability switch. Here, starting from the fundamental theories related to the surfaces wetting principles, highlights on different triggers for switchable wettability, such as pH, light, ions, temperature, electric field, gas, mechanical force, and multi-stimuli are discussed. Different applications that have various wettability requirement are targeted, including oil-water separation, droplets manipulation, patterning, liquid transport, and so on. This review aims to provide a deep insight into responsive interfacial science and offer guidance for smart surface engineering. It ends with a summary of current challenges, future opportunities, and potential solutions on smart switch of wettability on superwetting surfaces.


CD36 deficiency induced by antiretroviral therapy.
The molecular basis of lipodystrophy, a syndrome associated with HIV antiretroviral (ARV) therapy, remains unknown. To examine whether ARV therapy might inhibit the expression of CD36, which is known to play an important role in fatty acid and glucose metabolism, and if this might contribute to the metabolic alterations associated with lipodystrophy. The effects of ARV therapy on CD36 levels was examined in vivo in a prospective cohort of individuals treated with ARV therapy and in vitro in assays of human cell lines exposed to ARV drugs. Monocyte CD36 levels were assessed by flow cytometry at baseline and after 7 days of therapy in five healthy volunteers and 10 treatment-naive HIV-1-infected individuals. ARV therapy included protease inhibitors (ritonavir, nelfinavir or lopinavir/ritonavir). In addition, human cell lines (THP-1 and C32) were assessed for CD36 levels pre and post-ritonavir treatment. Three of four healthy controls (one withdrew because of adverse effects) and 6 of 10 HIV-1-infected individuals had a 50 to > 90% decrease in monocyte CD36 levels after 7 days of therapy. One of ten HIV-infected subjects had a 30% decrease, and the remaining individuals had no change or an increase in CD36 levels. CD36 levels decreased significantly in human cell lines treated with ritonavir but not in those treated with zidovudine. ARV therapy resulted in a marked decrease in CD36 in approximately 70% of our participants. Sustained ARV therapy-induced CD36 deficiency may contribute to insulin resistance and other metabolic complications of lipodystrophy.


The importance of oncogenic transcription factors for oral cancer pathogenesis and treatment.
Oral squamous cell carcinoma is a major cause of morbidity and mortality worldwide. Current experimental evidence shows that most important risk factors for oral cancer include tobacco use and excessive alcohol consumption and less well-defined risks include viral infection and a diet deficient in antioxidants. The positive correlation between various risk/etiologic factors of oral cancer and the activation of various transcription factors (TFs) has been reported in the literature. Although initially, TFs were considered to be very difficult targets for use in clinical treatment, recent technological advances have provided the ability to control these factors of cancer progression. This review focuses on the role of oncogenic transcription factors in oral cancer, their modes of activation through various biological pathways, the promises and pitfalls in viewing them as potent oncotargets, the way they can be controlled based on the current understanding, and the future research to be done in this area.


Development of a protocol for determination of domoic acid in the sand crab (Emerita analoga): a possible new indicator species.
The aim of this study was to begin evaluating the utility of sand crabs (Emerita analoga) as an indicator species for the algal neurotoxin, domoic acid (DA), in Monterey Bay, California, USA, a site of recurrent blooms of the DA-producing diatom, Pseudo-nitzschia. One of the current sentinel organisms, the sea mussel (Mytilus californianus), has shown minimal or undetectable toxicity during some local bloom events. As a critical step in assuring the accuracy of DA determinations in E. analoga, we have developed and validated a highly efficient extraction protocol that yields toxin recoveries of 97+/-2.9%. We also determined by HPLC-UV and receptor binding assay, with confirmation by LC-MS/MS, that sand crabs accumulated measurable amounts of DA during toxic Pseudo-nitzschia blooms, while the sea mussel showed no detectable toxin. In addition, a comparison of inter-animal variability in DA content revealed values ranging from ca. 0.5 to 5 microg DAg(-1) tissue and no consistent trend with size class, based on either animal weight or length. These data on the toxicity of individual animals will be useful in designing an appropriate sampling strategy for monitoring DA and, importantly, indicate that sand crabs do not appear to progressively bioaccumulate DA with age.


Effect of pancuronium bromide on the adrenergic reactivity of the isolated rat vas deferens.
Pancuronium bromide (10(-7) to 10(-4) M) failed to produce contraction of the isolated rat vas deferens. Also, no contractions were seen when the animals were pretreated with an MAO inhibitor (iproniazid 80 mg/kg, p.o.). On the other hand, pancuronium bromide (10(-6) to 10(-4) M) produced 1.62- to 2.65-fold increases in the sensitivity of the vas deferens to noradrenaline. This rules out an indirect adrenergic effect in this preparation and suggests an inhibitory effect on catecholamine uptake.


Prise en charge médicale de la récidive du cancer épithélial de l'ovaire: Medical management of recurrent epithelial ovarian cancer.
The panel of therapeutic options available for medical treatment of relapsed ovarian cancer increased over the last years. In late, platinum-sensitive relapse, standard treatment remains platinum-based polychemotherapy. The choice between bevacizumab added to chemotherapy followed by maintenance and inhibitors of poly-(ADP-riboses) polymerases (PARPi) after response to platinum-based therapy should be discussed, taking into account prior treatment, contraindications, and disease characteristics (biology, symptoms…). The addition of bevacizumab at first platinum-sensitive relapse can be considered if it has not been administered in first line, and it is optional (rechallenge) if previously administered (but without Marketing Authorization in this setting). PARPi are indicated for maintenance therapy after response to platinum-based chemotherapy (whatever the treatment line), regardless of BRCA mutational status, in case of no prior administration. Early relapses are associated with poor prognosis and therapeutic options are more limited. They are treated by monochemotherapy without platinum agents, associated with bevacizumab if not administered previously. Beyond first early relapse, there is no standard and inclusion in a clinical trial should be proposed if possible. Several clinical studies assessing associations of immunotherapy and chemotherapy and/or antiangiogenic drugs and/or targeted therapies (such as PARPi) are ongoing in early or late relapse.


A case of multiple trauma following a motor cycle accident.
This paper reports a fractured femur, jejunal laceration and a torn aorta in a young man who appeared reasonably well on admission to hospital. The diagnostic problems and treatment of this case are discussed.


Multicenter Study of Intravenous Recombinant Tissue Plasminogen Activator Infusion around Hiroshima, Japan: The Hiroshima Acute Stroke Retrospective and Prospective Registry Study.
Approximately 10 years have passed since intravenous (IV) recombinant tissue plasminogen activator therapy was approved in Japan. The aim of this retrospective study was to identify the effectiveness and safety of IV alteplase therapy with the Japanese original dose around Hiroshima via consideration of the patients' backgrounds, examination findings, and outcomes. All consecutive patients with ischemic stroke who received IV alteplase therapy between October 2005 and October 2010 were registered. Four hundred twenty-nine patients with ischemic stroke (172 female [40.1%], mean age 73.7 ± 11.8 years) were registered. The proportion of patients over 75 years old was 51.5% (221 patients). The median National Institutes of Health Stroke Scale (NIHSS) scores at admission were 13 (interquartile range, 9-19), and the NIHSS scores 24 hours after alteplase infusion were 8 (interquartile range, 3-15). The proportion of intracerebral hemorrhage within the initial 36 hours was 20.2% (86 patients). After the multivariate regression analysis, a history of hypertension (odds ratio = 4.14; 95% confidence interval, 1.32-14.79; P = .01) and no recanalization (odds ratio = 10.10; 95% confidence interval, 3.03-39.33; P < .0001) were independently associated with a modified Rankin Scale (mRS) score of 2 or higher at 3 months. Patients over 75 years old were not significantly associated with an intracerebral hemorrhage within the initial 36 hours and an mRS score of 2 or higher at 3 months. The results of our study demonstrated that IV alteplase therapy with the Japanese original dose was effective and exhibited a safety profile similar to other studies. Moreover, we should not hesitate to IV alteplase therapy simply because of advanced age.


[Studies on chemical constituents in root of Phlomis medicinalis I].
To study the chemical constituents in root of Phlomis medicinalis. The compounds were isolated and repeatedly purified on macroporous resin, silica gel column chromatography, TLC and Prep-HPLC and the structures were elucidated by physico-chemical properties and NMR spectra. Eight compounds were obtained and elucidated as 5-Hydroxy-7-methoxy-4, 6-dimethylphthalide (1), 4-hydroxymethyl-2-furaldehyde (2) and six iridoid glucosides: 6-O-acetyl-shanzhiside methyl ester (3), 8-O-acetyl-shanzhiside methyl ester (4), shanzhiside methyl ester (5), sesamoside (6), phloyoside II (7) and dehydropentstemoside (8). All the compounds were isolated from the plant for the first time and 1 and 3 were obtained from the plants of Phlomis for the first time.


The felt presence of other minds: Predictive processing, counterfactual predictions, and mentalising in autism.
The mental states of other people are components of the external world that modulate the activity of our sensory epithelia. Recent probabilistic frameworks that cast perception as unconscious inference on the external causes of sensory input can thus be expanded to enfold the brain's representation of others' mental states. This paper examines this subject in the context of the debate concerning the extent to which we have perceptual awareness of other minds. In particular, we suggest that the notion of perceptual presence helps to refine this debate: are others' mental states experienced as veridical qualities of the perceptual world around us? This experiential aspect of social cognition may be central to conditions such as autism spectrum disorder, where representations of others' mental states seem to be selectively compromised. Importantly, recent work ties perceptual presence to the counterfactual predictions of hierarchical generative models that are suggested to perform unconscious inference in the brain. This enables a characterisation of mental state representations in terms of their associated counterfactual predictions, allowing a distinction between spontaneous and explicit forms of mentalising within the framework of predictive processing. This leads to a hypothesis that social cognition in autism spectrum disorder is characterised by a diminished set of counterfactual predictions and the reduced perceptual presence of others' mental states.


Telehealth interventions for primary prevention of cardiovascular disease: a systematic review and meta-analysis.
To assess the effectiveness of telehealth interventions in the primary prevention of cardiovascular disease in adult patients in community settings. Systematic literature review of randomised controlled trials comparing the effectiveness of telehealth interventions to reduce overall cardiovascular disease (CVD) risk and/or to reduce multiple CVD risk factors compared with a non-telehealth control group was conducted in June 2013. Study quality was assessed using the Cochrane Risk of Bias tool. Fixed and random effects models were combined with a narrative synthesis for meta-analysis of included studies. Three of 13 included studies measured Framingham 10-year CVD risk scores, and meta-analysis showed no clear evidence of reduction in overall risk (SMD -0.37%, 95% CI -2.08, 1.33). There was weak evidence for a reduction in systolic blood pressure (SMD -1.22 mmHg 95% CI -2.80, 0.35) and total cholesterol (SMD -0.07 mmol/L 95% CI -0.19, 0.06). There was no change in High-Density Lipoprotein cholesterol or smoking rates. There is insufficient evidence to determine the effectiveness of telehealth interventions in reducing overall CVD risk. More studies are needed that consistently measure overall CVD risk, directly compare different telehealth interventions, and determine cost effectiveness of telehealth interventions for prevention of CVD.


Chromosome 5 allele loss at the glucocorticoid receptor locus in human colorectal carcinomas.
Matched normal/tumor DNA pairs from sporadic colon carcinoma patients were examined for chromosome 5 allele loss using a probe for a functional gene (glucocorticoid receptor = GRL) locus. This locus maps (5q11-q13) close to one of two alternative sites recently reported for a constitutional deletion in a familial adenomatous polyposis (FAP) patient. Tumor-specific allele loss of at least 27% at GRL supports the hypothesis that both hereditary and sporadic forms of colon cancer result from mutations of the same gene. The proximity of the GRL locus to the region of 5q affected in FAP and the observed tumor-specific allele loss at this locus suggest that further research is needed regarding whether genetic alterations in the glucocorticoid receptor may be associated with colon carcinogenesis.


Personal and family attributes of pregnant teenagers: findings from a community-based study in Sri Lanka.
Teenage pregnancies are associated with negative outcomes. Prevention requires understanding them and their families. This study aimed to describe personal and family attributes of pregnant teenagers in Sri Lanka. This was a community-based study in Sri Lanka among 510 pregnant teenagers. Half (50%) of the subjects were 19 years of age at the time of pregnancy. A majority (79.8%) had studied up to grades 6-11. Confidence in decision-making (80.7%) and in refusing unnecessary requests (88.3%) was "excellent" in a majority. Mean age of marriage/co-habiting was 17.6 years. For 31%, marriage/cohabiting was a sudden decision taken jointly with their partner (81.6%) and 83% reported being "legally" married. Substantial proportions of mothers (17.6%) and fathers (13.9%) had not attended school, and 33.1% mothers had worked abroad. Teenagers reported the death of a parent (14.1%), parental separation (10.9%) and being brought up by relatives (20%). Only a few rated strictness of rules/regulations (32.4%), freedom to discuss problems regarding puberty (25.5%), love affairs (12.7%) and sexuality (26.7%) as excellent/good. Of the spouses, 12.9% were <20 years, 71.9% had low education and 98.8% were employed. A majority had "planned" the pregnancy, and for 79.8%, the reason was "husband's wish to have a baby". Pregnant teenagers were mostly in their late teens, from poor families and with low formal education. Though teenagers showed confidence in decision-making, the decision to have a pregnancy had mostly been their spouses. Parents and spouses of the teenagers were also young, less educated and poor. There was evidence of poor parenting practices.


Light-Triggered Nitric Oxide Release by a Photosensitizer to Combat Bacterial Biofilm Infections.
Bacterial biofilms are a serious global health concern, often responsible for persistent infections. New strategies to prevent and treat bacterial infections by eradication of the biofilms are urgently needed. A novel ruthenium-based compound is reported in this study that functions as both a boronic acid-decorated photosensitizer (PS) and a light-triggered nitric oxide (NO) releasing agent. The compound can selectively attach to the bacterial membrane and biofilms and it is highly potent at eradicating Pseudomonas aeruginosa biofilms through the simultaneous release of NO and reactive oxygen species (ROS). The compound, which is more effective than clinical antibiotic tobramycin, also has excellent bacterial specificity and shows no significant cytotoxicity to human cells. The results reveal potential applications of this innovative dual-functional photoactivated ruthenium compound to combat bacterial biofilm infections.


Elevation of serum IgE level and peripheral eosinophil count during T lymphocyte-directed gene therapy for ADA deficiency: implication of Tc2-like cells after gene transduction procedure.
We have successfully carried out T-cell-directed gene therapy for a boy with severe combined immunodeficiency due to adenosine deaminase deficiency (ADA SCID) and unexpectedly found an elevation of serum IgE level and peripheral eosinophil count during the course. More than 90% of transduced cells cultured for 7-11 days before infusion into the patient were positive for CD8 and expressed Th2-type cytokine genes such as IL-4, IL-5 and IL-13. Furthermore, CD4(+) T-depleted PBMC (peripheral blood mononuclear cells) from the patient synthesized IgE in vitro by stimulation with IL-4. Collectively, these results suggested that Tc2-like cells in the transduced cells have distinct immunological functions to help IgE synthesis and activate eosinophils.


Sequence, expression, and evolutionary conservation of a gene encoding a glycine/tyrosine-rich keratin-associated protein of hair.
In hair differentiation several families of keratin proteins with distinctive amino acid compositions are produced. To study the role and regulation of one of these families, the glycine/tyrosine-rich keratin-associated proteins encoded by the KAP6 gene family, a partial wool follicle cDNA clone encoding a sheep KAP6 protein was sequenced and the corresponding gene isolated from a sheep cosmid library. The KAP6.1 gene encodes a basic protein of 82 amino acids (M(r) = 8,296) with a combined glycine and tyrosine content of approximately 60 mol%. There are several KAP6 genes in the sheep genome, all located within a 1,050-kilobase SfiI fragment. Northern blot analysis demonstrated that at least one member of the KAP6 family is expressed in the wool follicle. A rabbit KAP6 gene was isolated and its sequence and expression patterns were compared with the sheep gene. The sheep and rabbit genes have a nucleotide sequence identity of 89%, suggesting that they are equivalent genes and indicating strong selection pressure during evolution. Both genes contain several conserved sequence motifs of 7-9 nucleotides in their 5'-flanking regions that may be involved in the regulation of their expression. Localization of KAP6 mRNAs in sheep wool and rabbit hair follicles by in situ hybridization suggests that the genes are expressed in the cells of the hair shaft cortex in varying expression patterns. KAP6 expression starts relatively late in hair follicle differentiation, and the proportion of hair cortical cells that express it may change from follicle to follicle.


In vitro culture and in vitro maturation of mouse preantral follicles with recombinant gonadotropins.
To develop an effective method for in vitro maturation of preantral follicles isolated from mice ovarian tissue. Isolated preantral follicles were randomly allocated to designed experimental groups for study. University-based research lab. Healthy, normal mice. Superovulation with pregnant mare serum gonadotropin and hCG. Morphological changes and E(2) production were assessed. To obtain competent oocytes, preantral follicles must be cultured with medium containing insulin and recombinant gonadotropins (i.e., recombinant FSH and recombinant LH), with a change of medium daily. A high initial recombinant LH or recombinant FSH facilitates E(2) secretion, enhances granulosa cell outgrowth, and has earlier antral formation. However, prolonged culture in high-recombinant LH or recombinant FSH triggers early differentiation and luteinization of granulosa cells, which results in low metaphase II oocyte and blastocyst formation. We have developed a culture system that allows the successful maturation of preantral follicles in vitro. The matured follicles are a physiologically functional unit that not only secrete E(2) but also generate competent oocytes. In a special condition, 90% of the cultured follicles survived, 53.5% of them produced MII oocytes, and 50% of the derived MII oocytes were fertilized and reached the blastocyst stage after culture in vitro.


The surface structure of the tegument of Schistosoma haematobium.
The surface structure of the tegument of adult S. haematobium (Egyptian strain) was studied by scanning electron microscopy. Most of the dorsal surface of the male is studded by prominent, spine-covered tubercles, or bosses, not found in the female. Structural details of the oral and ventral suckers and sensory organelles, and local variations in the tegument are described.


[Autologous adoptive immunotherapy without destruction of infected cells during the treatment of chronic hepatitis B].
To investigate the profile of liver histological damage after autologous adoptive immunotherapy with cytokine-induced killer cells (CIK cells) in patients with chronic hepatitis B (CHB). 16 CHB patients were randomly enrolled and received autologous adoptive immunotherapy, then followed up 52 weeks. Liver samples were taken from the patients to evaluate the degree of inflammation and fibrosis. The markers of hepatitis B virus and liver function were also detected. 4 patients had two liver-biopsied samples before therapy and after 52 weeks follow-up. One patient's histological assessment revealed a significant improvement in intralobular necroinflammation (G2 --> G1) and fibrosis (S2 --> S1). The others failed to show obvious changes in liver histology. After 10 days culture in vitro, phenotypic characterization of CIK cells changed significantly by flow cytometry. The percentage of CD4+ cells decreased gradually, while the percentage of CD8+ cells increased from 20% to 60% - 80%. After 52 weeks follow-up, HBV DNA was negative (HBV DNA<4pg/ml in serum) in 6 out of 14 patients. The rates of both HBeAg/anti-HBe seroconversion and alanine aminotransferase normalization were 42.86%(6/14). There was no HBsAg/anti-HBs seroconversion. There was few severe treatment-related adverse events. Autologous adoptive immunotherapy doesn't induce the damage of liver histology in chronic hepatitis B patients, which inhibits hepatitis B virus replication by a certain noncytotoxic mechanism.


Solid Oxide Cell Electrode Nanocomposites Fabricated by Inkjet Printing Infiltration of Ceria Scaffolds.
The enhancement of solid oxide cell (SOC) oxygen electrode performance through the generation of nanocomposite electrodes via infiltration using wet-chemistry processes has been widely studied in recent years. An efficient oxygen electrode consists of a porous backbone and an active catalyst, which should provide ionic conductivity, high catalytic activity and electronic conductivity. Inkjet printing is a versatile additive manufacturing technique, which can be used for reliable and homogeneous functionalization of SOC electrodes via infiltration for either small- or large-area devices. In this study, we implemented the utilization of an inkjet printer for the automatic functionalization of different gadolinium-doped ceria scaffolds, via infiltration with ethanol:water-based La1-xSrxCo1-yFeyO3-δ (LSCF) ink. Scaffolds based on commercial and mesoporous Gd-doped ceria (CGO) powders were used to demonstrate the versatility of inkjet printing as an infiltration technique. Using yttrium-stabilized zirconia (YSZ) commercial electrolytes, symmetrical LSCF/LSCF-CGO/YSZ/LSCF-CGO/LSCF cells were fabricated via infiltration and characterized by SEM-EDX, XRD and EIS. Microstructural analysis demonstrated the feasibility and reproducibility of the process. Electrochemical characterization lead to an ASR value of ≈1.2 Ω cm2 at 750 °C, in the case of nanosized rare earth-doped ceria scaffolds, with the electrode contributing ≈0.18 Ω cm2. These results demonstrate the feasibility of inkjet printing as an infiltration technique for SOC fabrication.


Care rejection and aggression among veterans with dementia with and without posttraumatic stress disorder: A multi-group analysis.
In residential long-term care, military service veterans with co-occurring posttraumatic stress disorder (PTSD) and dementia encounter a range of physical and social stimuli that may serve as triggers of trauma-related distress that manifests as care rejection or aggression. Yet, PTSD rarely has been examined in research to understand behaviors of care rejection and aggression in veterans with dementia. Guided by the need-driven dementia-compromised behavior model, we examined the moderation effect of PTSD on pathways from background factors and interpersonal triggers to rejection of care and aggression among veterans with dementia with and without co-occurring PTSD. Secondary data analysis of the Staff Training in Assisted Living Residences-Veterans Health Administration (STAR-VA) intervention evaluation by the U.S. Veterans Health Administration healthcare system. 76 Veterans Health Administration-operated nursing homes. 315 veterans with dementia who participated in STAR-VA. We converted text data on the occurrence of care rejection and aggression to binary variables, combined them with data on sociodemographic and PTSD status obtained using medical chart review, and measured anxiety, cognition, depression, and function using validated instruments. A multi-group structural equation modeling analysis was then conducted to test the moderating effect of PTSD on rejection of care and aggression. Although multi-group structural equation modeling did not support the hypothesis of overall moderation by PTSD, distinct patterns between the two groups were observed with respect to how background factors and interpersonal triggers related to care rejection and aggression. The magnitude of the direct effects of interpersonal triggers on rejection of care was greater in veterans with PTSD (β = 0.42, p = .014 compared to those without β = 0.29, p = .008). Depression had a statistically significant indirect effect on rejection of care via interpersonal triggers only in veterans with PTSD (β = 0.09, p = .009). Functional status had a statistically significant direct effect on aggression only in the PTSD group (β = 0.28, p = .044). Our study identified similar and distinct patterns of relationships among background factors, interpersonal triggers, and rejection of care and aggression between veterans with dementia with and without PTSD. The indirect effect of depression on care rejection via interpersonal triggers has implications for developing targeted interventions that focus on interpersonal triggers for veterans with dementia with PTSD who have greater depressive symptoms. This study underscores the importance of an enhanced focus on trauma-informed care for veterans with dementia and PTSD.


Microglia and lipids: how metabolism controls brain innate immunity.
Microglia are universal sensors of alterations in CNS physiology. These cells integrate complex molecular signals and undergo comprehensive phenotypical remodeling to adapt inflammatory responses. In the last years, single-cell analyses have revealed that microglia exhibit diverse phenotypes during development, growth and disease. Emerging evidence suggests that such phenotype transitions are mediated by reprogramming of cell metabolism. Indeed, metabolic pathways are distinctively altered in activated microglia and are central nodes controlling microglial responses. Microglial lipid metabolism has been specifically involved in the control of microglial activation and effector functions, such as migration, phagocytosis and inflammatory signaling, and minor disturbances in microglial lipid handling associates with altered brain function in disorders featuring neuroinflammation. In this review, we explore new and relevant aspects of microglial metabolism in health and disease. We give special focus on how different branches of lipid metabolism, such as lipid sensing, synthesis and oxidation, integrate and control essential aspects of microglial biology, and how disturbances in these processes associate with aging and the pathogenesis of, for instance, multiple sclerosis and Alzheimer's disease. Finally, challenges and advances in microglial lipid research are discussed.


Role of corticotropin-releasing factor in the median raphe nucleus in yohimbine-induced reinstatement of alcohol seeking in rats.
The pharmacological stressor yohimbine increases ongoing alcohol self-administration and reinstates alcohol seeking in rats. This effect is attenuated by systemic injections of a corticotropin-releasing factor (CRF) antagonist. The brain sites involved in CRF's role in yohimbine-induced alcohol taking and seeking are unknown. We report that injections of the CRF receptor antagonist d-Phe CRF into the median raphe nucleus (MRN) attenuated yohimbine-induced reinstatement of alcohol seeking but had no effect on yohimbine-induced increases in alcohol intake during ongoing self-administration. Results indicate an important role of MRN CRF receptors in yohimbine-induced reinstatement of alcohol seeking but not yohimbine-induced increases in alcohol intake.


In vitro transformation of the tremorgenic mycotoxin verruculogen.
A quantity of 50 mg of crystalline verruculogen was prepared from batch cultures ofAspergillus fumigatus for the use in thein vitro studies with S-9 liver fractions, feces suspensions, and cultures ofEscherichia coli.Incubation of verruculogen with S-9 liver fractions from swine resulted in the transformation of the parent compound into TR-2 toxin and 3 other more polar.TR-2 toxin was also shown to be the main transformation product when incubat-ing verruculogen with fecal suspensions or pure cultures ofE. coli (0149: K88). Incubation times of more than 2 hours led to a complete degradation of verruculogen as well as TR -2 toxin.


Discrimination of retinal images containing bright lesions using sparse coded features and SVM.
Diabetic Retinopathy (DR) is a chronic progressive disease of the retinal microvasculature which is among the major causes of vision loss in the world. The diagnosis of DR is based on the detection of retinal lesions such as microaneurysms, exudates and drusen in retinal images acquired by a fundus camera. However, bright lesions such as exudates and drusen share similar appearances while being signs of different diseases. Therefore, discriminating between different types of lesions is of interest for improving screening performances. In this paper, we propose to use sparse coding techniques for retinal images classification. In particular, we are interested in discriminating between retinal images containing either exudates or drusen, and normal images free of lesions. Extensive experiments show that dictionary learning techniques can capture strong structures of retinal images and produce discriminant descriptors for classification. In particular, using a linear SVM with the obtained sparse coded features, the proposed method achieves superior performance as compared with the popular Bag-of-Visual-Word approach for image classification. Experiments with a dataset of 828 retinal images collected from various sources show that the proposed approach provides excellent discrimination results for normal, drusen and exudates images. It achieves a sensitivity and a specificity of 96.50% and 97.70% for the normal class; 99.10% and 100% for the drusen class; and 97.40% and 98.20% for the exudates class with a medium size dictionary of 100 atoms.


Intraoperative radiation therapy in the multimodality approach to hepatobiliary tract cancer.
IOERT is a reasonable option to consider in patients who have biliary tract cancers above AJCC or Bismuth stage I disease. Inherent resistance of biliary tract cancer cells to ionizing radiation would indicate that IOERT alone would not eradicate most of the tumor clonagen. EBRT (either preoperatively or postoperatively) should be used in combination with IOERT at experienced institutions that have access to both modalities. The single IOERT dose ranges are 10 to 20 Gy [55,67], whereas the EBRT dose ranges from 45 to 50 Gy in 25 to 28 fractions [67]. The most common energy level used is 8 MeV or less. In addition, IOERT port sizes of less than 6 cm in diameter, and often 4 cm or less, are recommended. Finally, intraoperative reconstruction of severely damaged blood vessels may decrease the clinical manifestation of radiation-induced injury to vessels [68].


Chaperone patterns in vernal keratoconjunctivitis are distinctive of cell and Hsp type and are modified by inflammatory stimuli.
Vernal keratoconjunctivitis (VKC) is a severe ocular allergy with pathogenic mechanism poorly understood and no efficacious treatment. The aims of the study were to determine quantities and distribution of Hsp chaperones in the conjunctiva of VKC patients and assess their levels in conjunctival epithelial and fibroblast cultures exposed to inflammatory stimuli. Hsp10, Hsp27, Hsp40, Hsp60, Hsp70, Hsp90, Hsp105, and Hsp110 were determined in conjunctiva biopsies from nine patients and nine healthy age-matched normal subjects, using immunomorphology and qPCR. Conjunctival epithelial cells and fibroblasts were cultured and stimulated with IL-1β, histamine, IL-4, TNF-α, or UV-B irradiation, and changes in Hsp levels were determined by Western blotting. Hsp27, Hsp40, Hsp70, and Hsp90 levels increased in the patients' conjunctiva, whereas Hsp10, Hsp60, Hsp100, and Hsp105 did not. Double immunofluorescence demonstrated colocalization of Hsp27, Hsp40, Hsp70, and Hsp90 with CD68 and tryptase. Testing of cultured conjunctival cells revealed an increase in the levels of Hsp27 in fibroblasts stimulated with IL-4; Hsp40 in epithelial cells stimulated with IL-4 and TNF-α and in fibroblasts stimulated with IL-4, TNF-α, and IL-1β; Hsp70 in epithelial cells stimulated with histamine and IL-4; and Hsp90 in fibroblasts stimulated with IL-1β, TNF-α, and IL-4. UV-B did not induce changes. VKC conjunctiva displays distinctive quantitative patterns of Hsps as compared with healthy controls. Cultured conjunctival cells respond to cytokines and inflammatory stimuli with changes in the Hsps quantitative patterns. The data suggest that interaction between the chaperoning and the immune systems drives disease progression.


Major structural features of the cell wall arabinogalactans of Mycobacterium, Rhodococcus, and Nocardia spp.
The cell wall arabinogalactans of strains of Mycobacterium, Rhodococcus, and Nocardia were per-O-methylated, partially hydrolyzed with acid, and the resulting oligosaccharides were reduced and per-O-ethylated to yield per-O-alkylated oligoglycosyl alditol fragments. Analyses of these fragments by gas chromatography-mass spectrometry and of the intact solubilized polysaccharides by 1H and 13C NMR revealed the major structural features of the different arabinogalactans from representatives of the different genera. All of the mycobacterial products contained a homogalactan segment of alternating 5-linked alpha-galactofuranosyl (Galf) and 6-linked beta-Galf residues. The arabinan segment consisted of three major domains, linear 5-linked alpha-arabinofuranosyl (Araf) residues and branched (3-->5)-linked Araf units substituted with either 5-linked Araf or the disaccharide beta-Araf-(1-->2)-alpha-Araf at both branched positions. The recognition of these features in in vivo grown Mycobacterium leprae is an important development. The arabinan from strains of Nocardia contains a nonreducing-end motif composed of the linear trisaccharide, beta-Araf-(1-->2)-alpha-Araf-(1-->5)-Araf, attached to linear 5-linked alpha-Araf units. The galactan segment of the arabinogalactan of Nocardia sp. is composed of linear 5-linked beta-Galf units substituted in part at O-6 with terminal beta-glucosyl units. The two representative strains of Rhodococcus also differed in the composition of the galactan moiety; in addition to the 5-linked Galf, 2- and 3-linked beta-Galf units are present. The reducing end of the galactans, and therefore, apparently, of the entire arabinogalactans from all species from all genera, are apparently composed of the unit, rhamnosyl-(1-->3)-N-acetyl-glucosamine, which, in turn, is apparently attached to peptidoglycan via phosphodiester linkage.


Transitions of microbial communities in the solid and liquid phases during high-solids anaerobic digestion of organic fraction of municipal solid waste.
This study presents a microbiological diagnosis of a mesophilic high-solids anaerobic digestion (HSAD) system with percolate recirculation. The results demonstrated a significant decrease in microbial diversity in both the solid digestate and the liquid percolate. Also, the digestate from the top and middle sections of the digester had similar diversity, whereas the digestate from the bottom of the tank had a slightly lower diversity. These results suggest that despite percolate recirculation, substrate gradients might have developed across the system. Archaeal communities showed shifts towards known hydrogenotrophic and ammonia-tolerant methanogens (genera Methanocelleus, Methanolinea, Methanosarcina, vadin CA11, etc.), which was a consequence of decreased volatile fatty acids and increased ammonia-nitrogen levels over time. Compared to initial solid and liquid inoculum, the relative abundances of some bacteria (phyla Proteobacteria and Firmicutes) and archaea of the genus Methanosarcina changed between two phases in the opposite direction, indicating a shift of microbes between two phases.


A novel theory on the origin of the genetic code: a GNC-SNS hypothesis.
We have previously proposed an SNS hypothesis on the origin of the genetic code (Ikehara and Yoshida 1998). The hypothesis predicts that the universal genetic code originated from the SNS code composed of 16 codons and 10 amino acids (S and N mean G or C and either of four bases, respectively). But, it must have been very difficult to create the SNS code at one stroke in the beginning. Therefore, we searched for a simpler code than the SNS code, which could still encode water-soluble globular proteins with appropriate three-dimensional structures at a high probability using four conditions for globular protein formation (hydropathy, alpha-helix, beta-sheet, and beta-turn formations). Four amino acids (Gly [G], Ala [A], Asp [D], and Val [V]) encoded by the GNC code satisfied the four structural conditions well, but other codes in rows and columns in the universal genetic code table do not, except for the GNG code, a slightly modified form of the GNC code. Three three-amino acid systems ([D], Leu and Tyr; [D], Tyr and Met; Glu, Pro and Ile) also satisfied the above four conditions. But, some amino acids in the three systems are far more complex than those encoded by the GNC code. In addition, the amino acids in the three-amino acid systems are scattered in the universal genetic code table. Thus, we concluded that the universal genetic code originated not from a three-amino acid system but from a four-amino acid system, the GNC code encoding [GADV]-proteins, as the most primitive genetic code.


Effects of trans-endocardial delivery of bone marrow-derived CD133+ cells on angina and quality of life in patients with refractory angina: A sub-analysis of the REGENT-VSEL trial.
The REGENT-VSEL trial demonstrated a neutral effect of transendocardial injection of autologous bone marrow (BM)-derived CD133+ in regard to myocardial ischemia. The current sub-analysis of the REGENT VSEL trial aims to assess the effect stem cell therapy has on quality of life (QoL) in patients with refractory angina. Thirty-one patients (63.0 ± 6.4 years, 70% male) with recurrent CCS II-IV angina, despite optimal medical therapy, enrolled in the REGENT-VSEL single center, randomized, double-blinded, and placebo-controlled trial. Of the 31 patients, 16 individuals were randomly assigned to the active stem cell group and 15 individuals were randomly assigned to the placebo group on a 1:1 basis. The inducibility of ischemia, (≥ one myocardial segment) was confirmed for each patient using Tc-99m SPECT. QoL was measured using the Seattle Angina Questionnaire. Each patient completed the questionnaire prior to treatment and at the time of their outpatient follow-up visits at 1, 4, 6, and 12 months after cell/placebo treatment. The main finding of the REGENT-VSEL trial sub-analysis was that transendocardial injection of autologous BM-derived CD133+ stem cells in patients with chronic refractory angina did not show significant improvement in QoL in comparison to the control group. Moreover, there was no significant difference between cell therapy and placebo in a number of patients showing improvement of at least 1 Canadian Cardiovascular Society class during the follow-up period. Intra-myocardial delivery of autologous CD133+ stem cells is safe and feasible but does not show a significant improvement in the QoL or angina pectoris symptoms in patients with chronic myocardial ischemia.


Making high-fidelity simulation relevant to the home setting.
The integration of high-fidelity simulation can prepare nurses to respond to realistic patient situations and be ready for their roles as professional nurses. A learning framework such as Understanding by Design can be used to develop simulations that are cohesive with course and program outcomes. The authors discuss their use of this framework to develop a simulation in a community health course.


General health status of youth with autism with and without intellectual disabilities transitioning from special education, and its relationship to personal and family circumstances: longitudinal cohort study.
Objective: Transition from school to early adulthood incurs many changes and may be associated with deterioration in general health in youth with autism. We aimed to investigate this. Method: The National Longitudinal Transitions Study-2 is a USA nationally representative sample of youth receiving special education services, aged 13-17 at wave 1, followed-up over 10 years in five data collection waves. We conducted random-effects ordered logistic regressions to determine the odds ratios (OR) with 95% confidence intervals of wave, age, sex, ethnicity/race, additional intellectual disabilities, parental/guardian relationship status, and household income being associated with general health status in youth with autism. Results: Across waves, only between 74.3%-69.6% had excellent/very good health (71.7%-58.8% in those with co-occurring intellectual disabilities), but wave was not associated with health status. Associations were with age OR = 1.18 (1.04, 1.33), co-occurring intellectual disabilities OR = 1.56 (1.00, 2.44), and household income OR = 0.61 (0.40, 0.94) at $30,001-$50,000, OR = 0.44 (0.27, 0.72) at $50,001-$70,000, and OR = 0.34 (0.20, 0.56) at $70,001+. Sex, ethnicity/race, and parental/guardian relationship status were not associated with health status. Conclusion: There was little change in general health status longitudinally across the transitional period, but the proportion with excellent/very good health was low at each wave. Transitional planning should consider co-occurring intellectual disabilities, and the wider socioeconomic context in which children/youth with autism are raised. Lack of other longitudinal studies indicates a need for replication.


Emerging concepts for the mechanism of alcoholic pancreatitis from experimental models.
The pathophysiologic mechanisms that underlie acute and chronic pancreatitis arising from alcohol abuse are poorly understood. The reasons for this state of knowledge result historically from a lack of models for experimental investigation. Ethanol feeding alone, even at high doses, has minimal and inconsistent effects on morphologic findings in the pancreas in experimental animals. This experience, plus the fact that alcohol abuse causes pancreatic pathology in only a minority of patients, suggest that ethanol acts to sensitize the pancreas to the deleterious effects of other stimuli. In this article, we discuss findings to support this concept of ethanol as a sensitizing agent and experimental models developed that can be used to investigate the effects of ethanol on the pathologic processes of pancreatitis. These pathologic processes include inflammation, cell death, intrapancreatic digestive enzyme activation, and fibrosis.


Lack of association between juvenile idiopathic arthritis and fas gene polymorphism.
Juvenile idiopathic arthritis (JIA) is a complex genetic disease of autoimmune etiology. Fas is a molecule with a pivotal role in apoptosis and hence in immune regulation. Elevated transcriptional levels of Fas in the synovial fluid of patients with JIA suggest that it might be implicated in disease etiopathogenesis. We investigated whether a polymorphism in the Fas promoter region (-670) confers susceptibility to JIA. In this association study, 342 UK patients with JIA and 255 healthy individuals were genotyped for the polymorphism using polymerase chain reaction restriction fragment length polymorphism. Comparisons of the genotypic frequencies were made using chi-square analysis. No statistically significant differences were found when the genotype frequencies of the -670 Fas polymorphism were compared between the JIA cases and the control panel. Similarly, no differences were seen between the JIA subgroups, or when the patients were divided on the basis of rheumatoid factor or antinuclear antibody positivity. The -670 polymorphism of Fas does not appear to be associated with susceptibility to JIA.


The mechanism of hemolysis of erythrocytes by sodium dodecyl sulfate.
The results of a study of vesicular-hemolytic action of anionic detergent sodium dodecyl sulfate on human erythrocytes are presented. Possible molecular events underlying detergent-induced pore formation in the erythrocyte membrane are discussed.


Amygdala electrical stimulation inducing spatial memory recovery produces an increase of hippocampal bdnf and arc gene expression.
Amygdala seems to promote the consolidation of plastic modification in different brain areas and these long-term brain changes require a rapid de novo RNA and protein synthesis. We have previously shown that basolateral amygdala electrical stimulation produces a partial recovery of spatial memory in fimbria-fornix lesioned animals and it is also able to increase the BDNF protein content in the hippocampus. The emerging question is whether these increased BDNF protein content arises from previously synthesized RNA or from de novo RNA expression. Now we address the question if amygdala electrical stimulation 15min after daily water maze training produces a rapid de novo RNA synthesis in the hippocampus, a critical brain area for spatial memory recovery in fimbria-fornix lesioned animals. In addition, we also study RNA arc expression, a gene which is essential for memory and neural plasticity processes. To this purpose, we study amygdala stimulation effects on the expression of plasticity related-early-genes bdnf and arc in the hippocampus of fimbria-fornix lesioned animals trained in a water-maze for 4days. We also checked on the expression of both genes in non-lesioned, untrained animals (acute condition) at 0.5, 1, 2 and 24h after basolateral amygdala electrical stimulation. Our data from trained animals confirm that daily amygdala electrical stimulation 15min after water maze training produces a partial memory recovery and that is coupled to an increase of bdnf and arc genes expression in the hippocampus. Additionally, the acute study shows that a single session of amygdala stimulation induces a transient increase of both genes (peaking at 30min). These results confirm the memory improving effect of amygdala stimulation in fimbria-fornix-lesioned animals and sustain the assumption that the memory improving effect is mediated by newly synthetized BDNF acting on a memory relevant structure like the hippocampus. The increased amount of BDNF within the hippocampus seems to be locally synthetized by mechanisms activated by the amygdala stimulation.


Changes of hand preference in Parkinson's disease.
This study focused on the difference between pre-morbid and current hand preference of patients with Parkinson's disease (PD). A survey instrument comprised items measuring pre-morbid and current hand preference and question related to the side of occurrence of initial symptoms. These questions were administered to 471 PD patients. The results show a significant change of pre-morbid right hand preference toward using the left when the side of PD onset was on the right hand and vice versa. Disease duration does not predict the amount of hand preference shift.


Bayesian statistical modeling to predict observer-specific optimal windowing parameters in magnetic resonance imaging.
Magnetic resonance (MR) images require a process known as windowing for optimizing the display conditions. However, the conventional windowing process often fails to achieve the preferred display conditions for observers due to various factors. This study proposes a novel framework for predicting the preferred windowing parameters for each observer using Bayesian statistical modeling. MR images obtained from 1000 patients were divided into training and test sets at a 7:3 ratio. The image intensity and windowing parameters were standardized using previously reported methods. Bayesian statistical modeling was utilized to predict the windowing parameters preferred by three MR imaging (MRI) operators. The performance of the proposed framework was evaluated by assessing the mean relative error (MRE), mean absolute error (MAE), and Pearson's correlation coefficient (ρ) of the test set. In addition, the naive method, which presumes that the average value of the windowing parameters for each acquisition sequence and body region in the training set is optimal, was also used for comparison. Three MRI operators and three radiologists conducted visual assessments. The mean MRE, MAE, and ρ values for the window level and width (WL/WW) in the proposed framework were 12.6 and 13.9, 42.9 and 85.4, and 0.98 and 0.98, respectively. These results outperformed those obtained using the naive method. The visual assessments revealed no significant differences between the original and predicted display conditions, indicating that the proposed framework accurately predicts individualized windowing parameters with the additional advantages of robustness and ease of use. Thus, the proposed framework can effectively predict the windowing parameters preferred by each observer.


Sensitivity of a novel stool antigen test for detection of Helicobacter pylori in adult outpatients before and after eradication therapy.
We investigated whether a novel monoclonal stool antigen test for detection of Helicobacter pylori performs with the same accuracy as the (13)C-urea breath test (UBT) for adult outpatients in the setting of a private office. The two tests showed identical levels of sensitivity when used to identify H. pylori-infected patients before and after eradication therapy.


Loss of protein kinase PKR expression in human HeLa cells complements the vaccinia virus E3L deletion mutant phenotype by restoration of viral protein synthesis.
The E3L proteins encoded by vaccinia virus bind double-stranded RNA and mediate interferon resistance, promote virus growth, and impair virus-mediated apoptosis. Among the cellular proteins implicated as targets of E3L is the protein kinase regulated by RNA (PKR). To test in human cells the role of PKR in conferring the E3L mutant phenotype, HeLa cells stably deficient in PKR generated by an RNA interference-silencing strategy were compared to parental and control knockdown cells following infection with either an E3L deletion mutant (DeltaE3L) or wild-type (WT) virus. The growth yields of WT virus were comparable in PKR-sufficient and -deficient cells. By contrast, the single-cycle yield of DeltaE3L virus was increased by nearly 2 log(10) in PKR-deficient cells over the impaired growth in PKR-sufficient cells. Furthermore, virus-induced apoptosis characteristic of the DeltaE3L mutant in PKR-sufficient cells was effectively abolished in PKR-deficient HeLa cells. The viral protein synthesis pattern was altered in DeltaE3L-infected PKR-sufficient cells, characterized by an inhibition of late viral protein expression, whereas in PKR-deficient cells, late protein accumulation was restored. Phosphorylation of both PKR and the alpha subunit of protein synthesis initiation factor 2 (eIF-2alpha) was elevated severalfold in DeltaE3L-infected PKR-sufficient, but not PKR-deficient, cells. WT virus did not significantly increase PKR or eIF-2alpha phosphorylation in either PKR-sufficient or -deficient cells, both of which supported efficient WT viral protein production. Finally, apoptosis induced by infection of PKR-sufficient HeLa cells with DeltaE3L virus was blocked by a caspase antagonist, but mutant virus growth was not rescued, suggesting that translation inhibition rather than apoptosis activation is a principal factor limiting virus growth.


Correlation of developmental differences of nuclear transfer embryos cells to the methylation profiles of nuclear transfer donor cells in Swine.
Methylation of DNA is the most commonly studied epigenetic mechanism of developmental competence and somatic cell nuclear transfer (SCNT). Previous studies of epigenetics and the SCNT procedures have examined the effects of different culture media on donor cells and reconstructed embryos, and the methylation status of specific genes in the fetus or live offspring. Here we used a microarray based approach to identify the methylation profiles of SCNT donor cells including three clonal porcine fetal fibroblast-like cell sublines and adult somatic cells selected from kidney and mammary tissues. The methylation profiles of the donor cells were then analyzed with respect to their ability to direct development to the blastocyst stage after nuclear transfer. Clonal cell lines A2, A7 and A8 had blastocyst rates of 11.7%(a), 16.7%(ab) and 20.0%(b), respectively ((ab) p < 0.05). Adult somatic cells included kidney, mammary (large), and mammary (small) also had different blastocyst rates (ab p < 0.05) of 4.2% (a), 10.7% (ab) and 18.3% (b), respectively. For clonal donor cells and for adult somatic cell groups the donor cells with the highest blastocyst rates also had methylation profiles with the lowest similarity to the methylation profiles of the in vivo-produced blastocysts. Conversely, the donor cells with the lowest blastocyst rates had methylation profiles with the highest similarity to the methylation profiles of the in vivo-produced blastocysts. Our findings show there is an inverse correlation to the similarity of the methylation profiles of the donor cells and the in vivo-produced embryos, and to the blastocyst rates following SCNT.


Left ventricular end-diastolic pressure is a predictor of mortality in cardiac surgery independently of left ventricular ejection fraction.
Several risk factors have been shown to increase mortality in cardiac surgery. However, the importance of left ventricular end-diastolic pressure (LVEDP) as an independent risk factor before cardiac surgery is unclear. Method. This observational study investigated 3024 consecutive adult patients who underwent cardiac surgical procedures at the Montreal Heart Institute from 1996 to 2000. The primary outcome was in-hospital mortality with 99 deaths (3.3%) among these patients. Of the 35 variables subjected to univariate analysis, 23 demonstrated a significant association with mortality. Stepwise multivariate logistic regression identified LVEDP as an independent predictor of mortality after cardiac surgery. The area under the receiver operating characteristic curve of the model predicting mortality was 0.85. Elevated LVEDP is an independent predictor of mortality in cardiac surgery. This variable is independent of left ventricular ejection fraction.


Wilhelm Fabricius von Hilden (Guilhelmus Fabricius Hildanus) 1560-1634: pioneer of early neurosurgery.
Wilhelm Fabricius von Hilden, also known as Guilhelmus Fabricius Hildanus, became known as the father of German surgery. Hildanus had a strong interest in surgery of the adult and pediatric nervous systems and attempted to better understand the brain and its morphology. Moreover, as a surgeon, Hildanus performed many procedures that would be classified today as neurosurgery. These included treatment of empyema and depressed skull fractures. We highlight the life of Hildanus and his contributions to what would become the discipline of neurosurgery. In a broad view, Hildanus should be considered an early pioneer of this field of surgery.


Association of colony morphology with coenzyme Q(10) production and its enhancement from Rhizobium radiobacter T6102W by addition of isopentenyl alcohol as a precursor.
Rhizobium radiobacter T6102 was morphologically purified by the aniline blue agar plates to give two distinct colonies; white smooth mucoid colony (T6102W) and blue rough colony (T6102B). The coenzyme Q(10) (CoQ(10)) was produced just by T6102W, showing 2.0 mg/g of CoQ(10) content, whereas the T6102B did not produce the CoQ(10). All of the used CoQ(10) biosynthetic precursors enhanced the CoQ(10) production by T6102W. Specifically, the supplementation of 0.75 mM isopentenyl alcohol improved the CoQ(10) concentration (19.9 mg/l) and content (2.4 mg/g) by 42% and 40%, respectively.


Factors predicting the response of patients with advanced breast cancer to endocrine (Megace) therapy.
We have treated 238 patients with advanced breast cancer with megestrol acetate (Megace, Bristol-Myers): 221 were assessable for response at 6 months by UICC criteria. Thirty-six (16%) patients responded, 54 (25%) were static and 131 (59%) progressed. Survival from the time of starting Megace calculated by log-rank analysis showed no significant difference in survival between patients showing response and static disease at 6 months. Patients with progression of disease within 6 months survived significantly shorter than patients who showed response or static disease at 6 months. Categorizing response at 6 months appeared to identify patients who had static disease of worthwhile duration. ER status of the primary tumour correlated significantly with survival from the time of commencing Megace. However, when Megace was used as a second-line hormone therapy the assessment of response or static disease on prior hormone therapy was a better predictor of the effect of Megace than ER status of the primary tumour.


Comparative proteomic analysis of non-small-cell lung cancer and normal controls using serum label-free quantitative shotgun technology.
The aim of this study was to distinguish non-small-cell lung cancer from normal controls and explore the new potential biomarkers of lung cancer by serum proteomics technology. Label-free quantitative liquid chromatography tandem mass spectrometry (1D-LC/MS/MS) analysis was performed on eight non-small-cell lung cancer (NSCLC) serum samples and eight normal controls. The proteomic data we obtained was analyzed by normalized, randomly paired t test and integrated bioinformatic methods, including hierarchical clustering analysis, principal-component analysis, and support vector machine. We obtained 931 proteins with at least two peptides identified from the 16 serum samples, and 62 proteins were differentially expressed between non-small-cell lung cancer patients and normal controls. There were 16 proteins expressed much higher in the lung cancer group than in the controls. Two hundred eight proteins were shared in all 16 serum samples. Through hierarchical clustering analysis and principal-component analysis based on the 62 differentially expressed proteins, we could distinguish non-small-cell lung cancer from the normal controls. The prediction accuracy of non-small-cell lung cancer analyzed by the support vector machine algorithm based on 208 proteins which were shared in all serum samples is 93.75%. Protein expression patterns have changed in the serum of non-small-cell lung cancer patients. Label-free quantitative LC/MS/MS may be a good method to improve the diagnostic accuracy for lung cancer and it can help in discovering the new biomarkers.


Comparing condylar positions achieved through bimanual manipulation to condylar positions achieved through masticatory muscle contraction against an anterior deprogrammer: a pilot study.
The condylar position can vary depending on several factors. One factor is the influence of occluding teeth. If the influence from occluding teeth could be eliminated, it might be possible to evaluate the condylar position obtained from masticatory muscle contraction. The purpose of this pilot study was to determine the placement of the condyles by contracted masticatory muscles without influence from occluding teeth. For a group of 11 participants, 3 dentists were assigned, in turn, to fabricate a centric relation interocclusal record using bimanual manipulation on each member of the group. After obtaining the centric relation interocclusal records using bimanual manipulation, the records were stored in room temperature water. Subsequently, each of the 11 patients had an anterior deprogrammer fabricated and were given instructions to wear the anterior deprogrammer for 60 minutes. The anterior deprogrammer was designed with the contacting surface perpendicular to the arc of close of the mandibular incisors. In addition, the anterior deprogrammer was relined to eliminate any movement under force, and the occluding surface of the deprogrammer was free of any indentations. After wearing the deprogrammer, 4 interocclusal records (3 in a reclined position and 1 in an upright position to ensure the condylar position did not change in the upright position) were made by having the patient squeeze and close into a properly adapted, trimmed, and warmed interocclusal record. The condylar position in centric relation recorded in interocclusal records using bimanual manipulation was compared to the condylar position recorded by the contraction of the masticatory muscles against an anterior deprogrammer using a condylar position indicating device. The data were analyzed with a 2-independent-samples test of proportions, alpha=.05 (1-tail). The condylar positions obtained using bimanual manipulation repeated the condylar position within the 0.11-mm tolerance of the Centri-Check instrument in 33 out of 33 opportunities (100%). The condylar positions obtained by using the anterior deprogrammer technique repeated the condylar position within the 0.11-mm tolerance of the Centri-Check in 43/44 opportunities (97.7%). The sample size used in this pilot study was not large enough to detect a very small actual difference (5 percentage points or less) between the 2 methods, should such a difference exist. The results of this pilot study indicate that, without influence from occluding teeth, the contraction of the masticatory muscles places the condyles into the same position as centric relation.


12(S)-hydroperoxyeicosatetraenoic acid (12-HETE) increases mitochondrial nitric oxide by increasing intramitochondrial calcium.
12(S)-hydroxyeicosatetraenoic acid (12-HETE) is one of the metabolites of arachidonic acid involved in pathological conditions associated with mitochondria and oxidative stress. The present study tested effects of 12-HETE on mitochondrial functions. In isolated rat heart mitochondria, 12-HETE increases intramitochondrial ionized calcium concentration that stimulates mitochondrial nitric oxide (NO) synthase (mtNOS) activity. mtNOS-derived NO causes mitochondrial dysfunctions by decreasing mitochondrial respiration and transmembrane potential. mtNOS-derived NO also produces peroxynitrite that induces release of cytochrome c and stimulates aggregation of mitochondria. Similarly, in HL-1 cardiac myocytes, 12-HETE increases intramitochondrial calcium and mitochondrial NO, and induces apoptosis. The present study suggests a novel mechanism for 12-HETE toxicity.


Lipid, phenol and carotenoid changes in 'Bianca' grapevine leaves after mechanical wounding: a case study.
Metabolic changes can occur in plants in response to abiotic stress. Extensive use of leaf discs (mechanical wounding) in studies regarding the effect on the biochemical response of the grapevine to different types of biotic stress makes it necessary to understand metabolic perturbation after injury. In this study, we investigate how mechanical wounding can affect the metabolism of grapevine leaf tissue using Bianca variety as case study. Two sizes of leaf discs (1.1 and 2.8 cm in diameter) were excised from leaves, and phenol, lipid and carotenoid perturbation were investigated 0, 6, 12, 24, 48, 96 and 120 h post cutting. In our study, we found an accumulation of molecules belonging to stilbenoid and stilbene classes such as trans-resveratrol, trans-piceide, Z-miyabenol C, E-cis-miyabenol C and ampelopsin D + quadrangularin A after abiotic stress. The increase in fatty acids such as linoleic acid, linolenic acid and oleic + cis-vaccenic acid during the first 12 h after injury, followed by a return to basal level, allowed us to surmise their role in response to abiotic stress, in particular to mechanical wounding in grapevine leaves. Different-sized discs caused a different response to the tissue, with a higher accumulation in 1.1-cm-diameter discs, especially of phenol compounds. The results of this work can be used to better understand metabolic changes due to biotic stress, having previous knowledge about the perturbation caused by abiotic stress.


Activation of endogenous type-C viral p30 antigen in chemically-induced rat hepatocellular carcinomas.
Chemically induced rat hepatocellular carcinomas were prospectively examined for expression of the major group-specific antigen (p 30) of genetically transmitted rat type-C viruses. Ten primary tumors induced following oral administration of the carcinogen N-2-acetylaminofluorine did not express elevated levels of viral antigen as compared to antigen levels detected in normal liver tissue. By contrast, rapidly growing transplantable hepatocellular carcinomas (THCs) derived from primary tumor expressed increased quantities of viral antigen. The expression of antigen was marginally elevated after only one transplanation, increased to maximal levels after several transplant generations and, once achieved, was stably maintained throughout subsequent transplants. Studies with additional previously established THCs showed that poorly differentiated, rapidly proliferating tumors tended to express elevated levels of viral antigen, while more differentiated, slowly growing tumors did not. The results show that the expression of endogenous type-C viral 30 antigen is a stable phenotypic property of many rat THC lines.


Circulating Tumour DNA in Advanced Melanoma Patients Ceasing PD1 Inhibition in the Absence of Disease Progression.
Immunotherapy is an important and established treatment option for patients with advanced melanoma. Initial anti-PD1 trials arbitrarily defined a two-year treatment duration, but a shorter treatment duration may be appropriate. In this study, we retrospectively assessed 70 patients who stopped anti-PD1 therapy in the absence of progressive disease (PD) to determine clinical outcomes. In our cohort, the median time on treatment was 11.8 months. Complete response was attained at time of anti-PD1 discontinuation in 61 (87%). After a median follow up of 34.2 months (range: 2-70.8) post discontinuation, 81% remained disease free. Using ddPCR, we determine the utility of circulating tumour DNA (ctDNA) to predict progressive disease after cessation (n = 38). There was a significant association between presence of ctDNA at cessation and disease progression (p = 0.012, Fisher's exact test) and this conferred a negative and positive predictive value of 0.82 (95% CI: 0.645-0.930) and 0.80 (95% CI 0.284-0.995), respectively. Additionally, dichotomised treatment-free survival in patients with or without ctDNA at cessation was significantly longer in the latter group (p < 0.001, HR: 0.008, 95% CI: 0.001-0.079). Overall, our study confirms that durable disease control can be achieved with cessation of therapy in the absence of disease progression and undetectable ctDNA at cessation was associated with longer treatment-free survival.


Expanding the Scope of Evidence-Based Cancer Care.
This article explores how oncology research can be expanded to ensure that research spending results in maximum benefit. The focus has shifted to the value and quality of care, which view cancer care with the perspective of the patient at the center and cover the spectrum of care. Because there is no agreed-upon definition for value in cancer care, we overview various contributions to defining value and quality in oncology. We outline how cancer care costs are measured in the United States and explore outcome measures that have been proposed and implemented to enable us to assess value in oncology.


Heterogeneity of tumor endothelial cells: comparison between tumor endothelial cells isolated from high- and low-metastatic tumors.
An important concept in tumor angiogenesis is that tumor endothelial cells (TECs) are genetically normal and homogeneous. However, we previously reported that TECs differ from normal ECs. Whether the characteristics of TECs derived from different tumors differ remains unknown. To elucidate this, in this study, we isolated two types of TECs from high-metastatic (HM) and low-metastatic (LM) tumors and compared their characteristics. HM tumor-derived TECs (HM-TECs) showed higher proliferative activity and invasive activity than LM tumor-derived TECs (LM-TECs). Moreover, the mRNA expression levels of pro-angiogenic genes, such as vascular endothelial growth factor (VEGF) receptors 1 and 2, VEGF, and hypoxia-inducible factor-1α, were higher in HM-TECs than in LM-TECs. The tumor blood vessels themselves and the surrounding area in HM tumors were exposed to hypoxia. Furthermore, HM-TECs showed higher mRNA expression levels of the stemness-related gene stem cell antigen and the mesenchymal marker CD90 compared with LM-TECs. HM-TECs were spheroid, with a smoother surface and higher circularity in the stem cell spheroid assay. HM-TECs differentiated into osteogenic cells, expressing activated alkaline phosphatase in an osteogenic medium at a higher rate than either LM-TECs or normal ECs. Furthermore, HM-TECs contained more aneuploid cells than LM-TECs. These results indicate that TECs from HM tumors have a more pro-angiogenic phenotype than those from LM tumors.


Association between lack of functional connectivity of the frontal brain region and poor response inhibition in children with frontal lobe epilepsy.
We investigated the relationship between electroencephalographic (EEG) functional connectivity and executive function in children with frontal lobe epilepsy (FLE). We enrolled 24 children with FLE (mean age, 11.0 years; 13 boys) and 22 sex-, age-, and intelligence-matched typically developing children (TDC) to undergo 19-channel EEG during light sleep. We estimated functional connectivity using the phase lag index (PLI) that captures the synchronization of EEG. We also performed continuous performance tests (CPTs) on the children and obtained questionnaire responses on attention deficit hyperactivity disorder and oppositional defiant disorder (ODD). The average gamma PLI was lower in the FLE group than in the TDC group, especially between long-distance frontoparietal pairs, between interhemispheric frontal pairs, and between interhemispheric parietotemporal pairs. Gamma PLIs with long-distance frontoparietal and interhemispheric frontal pairs were positively associated with inattention, ODD scores, omission error, and reaction time in the FLE group but not in the TDC group. Conversely, they were negatively associated with age, hyperactivity score, and commission error. A lack of functional connectivity of the frontal brain regions in children with FLE was associated with poor response inhibition.


Insecticidal activity and the mechanism of action of three phenylpropanoids isolated from the roots of Piper sarmentosum Roxb.
Hexane, dichloromethane and methanol extracts of the roots of Piper sarmentosum Roxb. were screened for toxicity towards Sitophilus oryzae (L.), Rhyzopertha dominica (F.), and Plodia interpunctella (Hübner) and the hexane extract exhibited the highest mortality percentage. Bioassay-guided fractionation of the hexane extract resulted in the isolation of asaricin 1, isoasarone 2, and trans-asarone 3. Asaricin 1 and isoasarone 2 were the most toxic compounds to Sitophilus oryzae, Rhyzopertha dominica, and Plodia interpunctella. Sitophilus oryzae and Rhyzopertha dominica exposed to asaricin 1 and isoasarone 2 required the lowest median lethal time. Insecticidal activity of trans-asarone 3 showed consistent toxicity throughout the 60 days towards all three insects as compared to asaricin 1 and isoasarone 2. Asaricin 1 and isoasarone 2 at different doses significantly reduced oviposition and adult emergence of the three insects in treated rice. Trans-asarone 3 had lowest toxicity with highest LC and LT values in all tested insects relative to its mild oviposition inhibition and progeny activity. Moreover, asaricin 1 and isoasarone 2 significantly inhibited acetylcholinesterase in comparison with trans-asarone 3 and the control. Acetylcholinesterase inhibition of Rhyzopertha dominica and Plodia interpunctella by asaricin 1 and isoasarone 2 were lower than that of Sitophilus oryzae, which correlated with their higher resistance.


A new method for the characterization of chemical libraries--solely by HPLC retention times.
A method has been developed for the assignment of HPLC peaks to their corresponding compounds in libraries of single compounds (parallel syntheses). The basis of the new method is the correlation of the product retention times with the different substituents in the variable positions of the molecule. The correlation is performed automatically by a new algorithm which is part of the computer program LIBFINDER. This practical, easy-to-use tool accelerates the analysis, characterization and purification of chemical libraries, without the need for expensive HPLC-MS equipment.


Fixed-dose, body weight-independent subcutaneous low molecular weight heparin Certoparin compared with adjusted-dose intravenous unfractionated heparin in patients with proximal deep venous thrombosis.
Subcutaneous body weight-adjusted low molecular weight heparin (LMWH) has been proven as effective and safe as intravenous aPTT-adjusted unfractionated heparin (UFH) for the treatment of patients with acute deep venous thrombosis (DVT). In this study we evaluate the efficacy of the initial treatment of proximal DVT with a fixed-dose, body weight-independent application of the LMWH Certoparin with a six month follow-up. In a prospective, multicentre, randomized, active-controlled study 1220 patients with objectively diagnosed proximal DVT were randomly assigned to subcutaneous 8000 U anti-factor Xa of Certoparin twice daily for 10 to 14 days or intravenous aPTT-adjusted UFH for 5 to 8 days. Both regimen were followed by oral anticoagulation for 6 months. The primary end point was the rate of symptomatic and objectively confirmed thromboembolic events within 6 months. The aim of the study was to demonstrate the non-inferiority of the Certoparin regimen as compared to UFH. The per-protocol analysis revealed 22 (3.8%) thromboembolic events in the Certoparin group and 24 (4.3%) in patients assigned to UFH within 6 months, thereby proving the non-inferiority (p<0.01), confirmed by intent-to-treat analysis (p<0.001). Major bleeding occurred in 6 and 7 patients started on Certoparin or UFH during the treatment period. Thromboembolic events were equally distributed in body weight categories with < 50, 50-80 and >80 kg as followed: 0, 3.6% and 4.1% of patients for the Certoparin group and 0, 4.6% and 4.2% of patients for the UFH group. The same was true for major bleeding complications with 0, 2.9% and 1.5% for Certoparin and 0, 3.5% and 4.2% for UFH. Overall mortality was 1.9% in the Certoparin group and 2.7% in the UFH group. Fixed-dose body weight-independent subcutaneous LMWH Certoparin is at least as efficacious and safe as intravenous aPTT-adjusted UFH for the initial treatment of acute proximal DVT. This effect is maintained during a 6-months follow-up of treatment with oral anticoagulation.


DNA transfer from Agrobacterium to Zea mays or Brassica by agroinfection is dependent on bacterial virulence functions.
DNA transfer from Agrobacterium tumefaciens, a soil bacterium, to the non-host graminaceous monocotyle-donous plant Zea mays, was analysed using the recently developed technique of agroinfection. Agroinfection of Z. mays with maize streak virus using strains of A. tumefaciens carrying mutations in the pTiC58 virulence region showed an almost absolute dependence on the products of the bacterial virC genes. In contrast, agroinfection of the control host Brassica rapa with cauliflower mosaic virus was less dependent on the virC gene products. In other respects, the basic mechanism of the plant-bacterium interaction was found to be similar. While intact virA, B, D and G functions were absolutely necessary, mutants in virE were attenuated. Agroinfection of maize was effective in the absence of an exogenously supplied vir gene inducer, and indeed wounded Z. mays tissues were found to produce substance(s) which induced the expression of A. tumefaciens vir genes. These findings are discussed in the light of current knowledge about the function of Agrobacterium vir genes.


Proposed model for the flagellar rotary motor.
Flagellated bacteria swim by rotating helical filaments driven by motors embedded in the cell wall and cytoplasmic membrane. A model is proposed to explain the mechanism of the motor. The protons passing through the channels induce a strong electric field in Mot molecules. This field originates an impulse force to cause the flagellar rotation if the following conditions are fulfilled: (a) Mot molecules have a spontaneous electric polarization. (b) The lipid bilayers are viscoelastic. (c) There is a delay of deformation in response to stress in Mot molecules. The conclusions driven from the model are in agreement with the following experimental observations, denoting the flagellar rotation velocity as omega. (1) The torque is practically constant independent of omega from 0 to a critical value omega(cr) and then decreases sharply. (2) When omega is smaller than omega(cr), the torque varies little with temperature. (3) The critical velocity omega(cr) shifts to lower speed at lower temperatures. (4) Where omega is larger than omega(cr), declining of the torque steepens at lower temperatures. (5) When omega is smaller than omega(cr), one revolution of the flagellar rotation consists of a constant number of steps. (6) When omega is smaller than omega(cr), omega is proportional to the transmembrane potential difference. (7) The stator produces constant torque even when the stator is rotated relative to the rotor by external forces. (8) How the flagellar rotation velocity changes when the direction of the proton passage is reversed. (9) The motor has a switch that reverses the sense of the flagelllar rotation with the same absolute value of torque.