Adverse childhood circumstances and cognitive function in middle-aged and older Chinese adults: Lower level or faster decline?
We examine the long-term relationship between childhood circumstances and cognitive aging. In particular, we differentiate the level of cognitive deficit from the rate of cognitive decline. Applying a linear mixed-effect model to three waves of China Health and Retirement Longitudinal Surveys (CHARLS 2011, 2013, 2015) and matching cognitive outcomes to CHARLS Life History Survey (2014), we find that key domains of childhood circumstances, including family socioeconomic status (SES), neighborhood cohesion, friendship, and health conditions, are significantly associated with both the level of cognitive deficit and the rate of decline. In contrast, childhood neighborhood safety only affects the level of cognitive deficit. Childhood relationship with mother only affects the rate of cognitive decline. The effects of adverse childhood circumstances are generally larger on level of cognitive deficit than on rate of cognitive decline. Moreover, education plays a more important role in mediating the relationships compared to other later-life factors. These findings suggest that exposure to disadvantaged childhood circumstances can exacerbate cognitive deficit as well as cognitive decline over time, which may be partially ameliorated by educational attainment.


Definition of the postictal state: when does it start and end?
The postictal state is the abnormal condition occurring between the end of an epileptic seizure and return to baseline condition. Applying this definition operationally can be difficult, especially for complex partial seizures, where cognitive and sensorimotor impairments merge imperceptibly into the postictal state. Many patients are unaware of even having had a seizure. Electroencephalography sometimes helps to distinguish ictal from postictal periods, but may demonstrate focal slowing both during and after a seizure. Epileptiform electroencephalographic changes do not always correspond precisely to behavioral changes, especially with scalp recordings. The postictal state ends at the interictal state, but this too can be ambiguous. Interictal spikes and spike-waves can be associated with cognitive and behavioral impairments, suggesting that they may represent fragments of ictal episodes. Except where boundaries are clear, it is better to describe a sequence of behaviors and electroencephalographic changes, without labeling arbitrary stages as being ictal or postictal.


Early warning indicators for first-line virologic failure independent of adherence measures in a South African urban clinic.
We sought to develop individual-level Early Warning Indicators (EWI) of virologic failure (VF) for clinicians to use during routine care complementing WHO population-level EWI. A case-control study was conducted at a Durban clinic. Patients after ≥ 5 months of first-line antiretroviral therapy (ART) were defined as cases if they had VF [HIV-1 viral load (VL)>1000 copies/mL] and controls (2:1) if they had VL ≤ 1000 copies/mL. Pharmacy refills and pill counts were used as adherence measures. Participants responded to a questionnaire including validated psychosocial and symptom scales. Data were also collected from the medical record. Multivariable logistic regression models of VF included factors associated with VF (p<0.05) in univariable analyses. We enrolled 158 cases and 300 controls. In the final multivariable model, male gender, not having an active religious faith, practicing unsafe sex, having a family member with HIV, not being pleased with the clinic experience, symptoms of depression, fatigue, or rash, low CD4 counts, family recommending HIV care, and using a TV/radio as ART reminders (compared to mobile phones) were associated with VF independent of adherence measures. In this setting, we identified several key individual-level EWI associated with VF including novel psychosocial factors independent of adherence measures.


Heterocoagulation as a facile route to prepare stable serum albumin-nanoparticle conjugates for biomedical applications: synthetic protocols and mechanistic insights.
There is increasing interest in using serum albumin, the most abundant plasma protein, as a stabilizing agent in the context of nanomedicine. Using poly(vinyl amine)-stabilized polypyrrole nanoparticles as an example, we report a facile generic route to prepare serum albumin-nanoparticle conjugates via heterocoagulation. Time-resolved dynamic light scattering (DLS), disk centrifuge photosedimentometry (DCP), and circular dichroism (CD) spectroscopy studies confirm that bovine serum albumin (BSA) adsorbs rapidly onto the cationic poly(vinyl amine)-stabilized polypyrrole nanoparticles and suggest that the initial well-defined protein coronal is subsequently cross-linked via thiol-disulfide exchange. These BSA-nanoparticle conjugates were further characterized by X-ray photoelectron spectroscopy (XPS), aqueous electrophoresis, field emission scanning electron microscopy (FE SEM), and transmission electron microscopy (TEM). They exhibit excellent long-term colloidal stability under physiological conditions without further purification, suggesting strong irreversible adsorption by the BSA. Protein adsorption appears to be co-operative and both thermodynamic and mechanistic aspects were examined via aqueous electrophoresis, DCP, and DLS studies.


Effects of energy retrofits on Indoor Air Quality in multifamily buildings.
We assessed 45 multifamily buildings (240 apartments) from Finland and 20 (96 apartments) from Lithuania, out of which 37 buildings in Finland and 15 buildings in Lithuania underwent energy retrofits. Building characteristics, retrofit activities, and energy consumption data were collected, and Indoor Air Quality (IAQ) parameters, including carbon monoxide (CO), nitrogen dioxide (NO2 ), formaldehyde (CH2 O), selected volatile organic compounds (benzene, toluene, ethylbenzene, and xylenes (BTEX), radon, and microbial content in settled dust were measured before and after the retrofits. After the retrofits, heating energy consumption decreased by an average of 24% and 49% in Finnish and Lithuanian buildings, respectively. After the retrofits of Finnish buildings, there was a significant increase in BTEX concentrations (estimated mean increase of 2.5 µg/m3 ), whereas significant reductions were seen in fungal (0.6-log reduction in cells/m2 /d) and bacterial (0.6-log reduction in gram-positive and 0.9-log reduction in gram-negative bacterial cells/m2 /d) concentrations. In Lithuanian buildings, radon concentrations were significantly increased (estimated mean increase of 13.8 Bq/m3 ) after the retrofits. Mechanical ventilation was associated with significantly lower CH2 O concentrations in Finnish buildings. The results and recommendations presented in this paper can inform building retrofit studies and other programs and policies aimed to improve indoor environment and health.


Clinical trial: effect of active lactic acid bacteria on mucosal barrier function in patients with diarrhoea-predominant irritable bowel syndrome.
The intestinal permeability is increased in patients with diarrhoea-predominant irritable bowel syndrome (D-IBS). To determine the possible efficacy of lactic acid bacteria on the increased intestinal permeability in D-IBS. Treatment was employed for 4 weeks in a randomized single blind placebo controlled study with 30 D-IBS patients. Patients were given either probiotic fermented milk (Streptococcus thermophilus, Lactobacillus bulgaricus, Lactobacillus acidophilus and Bifidobacterium Longum) or milk beverage containing no bacteria. The clinical symptoms were scored and intestinal permeability was measured by a triple sugar test before and after treatment. Small bowel permeability was measured as the ratio of lactulose and mannitol recovery and colonic permeability was measured as the total mass of sucralose excretion (mg). After probiotics treatment, small bowel permeability decreased significantly from 0.038 (0.024) at baseline to 0.023 (0.020) (P = 0.004), the proportion of patients with increased small bowel permeability was lower than baseline (28.6% vs. 64.3%, P = 0.023). However, colonic permeability improved neither in the probiotics group nor in the placebo group at week 4. Treatment with probiotics significantly decreased the mean global IBS scores compared with the baseline scores (9.62 +/- 1.05 vs. 7.64 +/- 1.24, P < 0.001). Short-term active lactic acid bacteria treatment for D-IBS improved mucosal barrier function.


Optimizing production of Fc-amidated peptides by Chinese hamster ovary cells.
Amidation of the carboxyl terminal of many peptides is essential for full biological potency, often increasing receptor binding and stability. The single enzyme responsible for this reaction is peptidylglycine α-amidating monooxygenase (PAM: EC 184.108.40.206), a copper- and ascorbate-dependent Type I membrane protein. To make large amounts of high molecular weight amidated product, Chinese hamster ovary (CHO) cells were engineered to express exogenous PAM. To vary access of the enzyme to its substrate, exogenous PAM was targeted to the endoplasmic reticulum, trans-Golgi network, endosomes and lysosomes or to the lumen of the secretory pathway. PAM was equally active when targeted to each intracellular location and assayed in homogenates. Immunocytochemical analyses of CHO cells and a pituitary cell line demonstrated that targeting of exogenous PAM was partially successful. PAM substrates generated by expressing peptidylglycine substrates (glucagon-like peptide 1-Gly, peptide YY-Gly and neuromedin U-Gly) fused to the C-terminus of immunoglobulin Fc in CHO cell lines producing targeted PAM. The extent of amidation of the Fc-peptides was determined by mass spectrometry and amidation-specific enzyme immunoassays. Amidation was inhibited by copper chelation, but was not enhanced by the addition of additional copper or ascorbate. Peptide amidation was increased over endogenous levels by exogenous PAM, and targeting PAM to the endoplasmic reticulum or trans-Golgi network increased peptide amidation compared to endogenous CHO PAM.


Blood glucose area under the curve. Methodological aspects.
To specify the influence of methods used in estimating area under the curve (AUC) and the meaning of total and incremental AUC, 75 glycemic responses to a mixed meal were studied in 75 diabetic patients, 39 with insulin-dependent diabetes mellitus and 36 with non-insulin-dependent diabetes mellitus. AUC was integrated with five computerized methods: polynomial interpolation of third and fourth degree, trapezoidal rule, Simpson's integration, and cubic interpolatory splines. Although these methods gave significantly different results (P less than 0.001), a strong correlation was found between estimations of AUC with different methods (r greater than 0.99, P less than 0.001). In addition, variation between methods was less than or equal to 2%, whereas the coefficient of variation between subjects was 38%. Total AUC was strongly correlated with basal blood glucose value (r = 0.90, P less than 0.001), whereas incremental and positive AUC were not (r = 0.12 and 0.07, respectively, NS). Incremental and positive AUC were strongly correlated with glycemic rise (r = 0.89 and 0.93, respectively, P less than 0.001), whereas total AUC was only slightly so (r = 0.31, P less than 0.01). Incremental and positive AUC gave slightly but significantly different information on glucose response. These results suggest that variations related to the method used in estimating AUC are not clinically relevant and that a simple method such as trapezoidal rule can be used. Total AUC is a descriptive factor related to basal blood glucose value, whereas incremental and positive AUC more accurately describe glycemic response to foods.


Further evidence that the KIAA0319 gene confers susceptibility to developmental dyslexia.
The DYX2 locus on chromosome 6p22.2 is the most replicated region of linkage to developmental dyslexia (DD). Two candidate genes within this region have recently been implicated in the disorder: KIAA0319 and DCDC2. Variants within DCDC2 have shown association with DD in a US and a German sample. However, when we genotyped these specific variants in two large, independent UK samples, we obtained only weak, inconsistent evidence for their involvement in DD. Having previously found evidence that variation in the KIAA0319 gene confers susceptibility to DD, we sought to refine this genetic association by genotyping 36 additional SNPs in the gene. Nine SNPs, predominantly clustered around the first exon, showed the most significant association with DD in one or both UK samples, including rs3212236 in the 5' flanking region (P = 0.00003) and rs761100 in intron 1 (P = 0.0004). We have thus refined the region of association with developmental dyslexia to putative regulatory sequences around the first exon of the KIAA0319 gene, supporting the presence of functional mutations that could affect gene expression. Our data also suggests a possible interaction between KIAA0319 and DCDC2, which requires further testing.


Meckel's diverticulum.
Although Meckel's diverticulum is the most prevalent congenital abnormality of the gastrointestinal tract, it is often difficult to diagnose. It may remain completely asymptomatic, or it may mimic such disorders as Crohn's disease, appendicitis and peptic ulcer disease. Ectopic tissue, found in approximately 50 percent of cases, consists of gastric tissue in 60 to 85 percent of cases and pancreatic tissue in 5 to 16 percent. The diagnosis of Meckel's diverticulum should be considered in patients with unexplained abdominal pain, nausea and vomiting, or intestinal bleeding. Major complications include bleeding, obstruction, intussusception, diverticulitis and perforation. The most useful method of diagnosis is with a technetium-99m pertechnetate scan, which is dependent on uptake of the isotope in heterotopic tissue. Management is by surgical resection.


Influences of sensory attribute intensity, emotional responses, and non-sensory factors on purchase intent toward mixed-vegetable juice products under informed tasting condition.
Product-related sensory and non-sensory cues have been studied in the past to understand purchase behavior among consumers. However, there has been little research related to integrating emotional responses with such cues to achieve better prediction of consumer purchase behavior. This study aimed to determine the impacts of sensory attribute intensities (SAI), non-sensory factors (NSF), and emotions on purchase intent and consumer choice. Emotional responses were measured using a self-reported emotion questionnaire (EQ), facial expression analysis (FE), and autonomic nervous system responses (ANS). Sixty-nine adults were asked to view product labels, and look at, smell, and drink five commercially-available vegetable juice samples. For each sample, SAI, NSF, EQ, FE, ANS, and purchase intent ratings were measured. Participants were also asked to select the one they would be most likely to buy. Results showed that the five samples differed significantly with respect to SAI, NSF, and emotional responses measured by EQ and FEs. SAI (bitterness intensity) and NSF (brand liking) played an extremely important role in purchase-related behavior of vegetable juice products. Correlation analysis and a PLSR prediction model further revealed that products with higher ratings of purchase intent elicited lower levels of negative emotions and higher levels of positive emotions, as measured by EQ as well as FE. In conclusion, this study shows that NSF in combination with SAI and emotions measured using EQ and FE can modulate consumer purchase intent toward vegetable juice products under informed tasting conditions.


Which instruments to support diagnosis of depression have sufficient accuracy? A systematic review.
Instruments are frequently used in case finding, diagnosis and severity grading of major depression, but the evidence supporting their utility is weak. To systematically review the specificity and sensitivity of instruments used to diagnose and grade the severity of depression. MEDLINE, PsycInfo, Embase and the Cochrane Library databases were searched until April 2014. Fifty studies fulfilled the inclusion criteria. Risk of bias was assessed with QUADAS. The average sensitivity and specificity of each instrument was estimated with hierarchical summary receiver operating characteristics analyses and the confidence in the estimates was evaluated using GRADE. Minimum acceptable sensitivity/specificity, with structured interview as the reference, was 80%/80% for structured interviews and 80%/70% for case-finding instruments. The minimum acceptable standard for severity measures was a correlation of 0.7 with DSM-IV classification. Twenty instruments were investigated. The average sensitivity/specificity was 85%/92% for the Structured Clinical Interview for DSM-IV-Axis-I Disorders (SCID-I), 95%/84% for the Mini International Neuropsychiatric Interview (MINI), < 70%/85% for the Primary Care Evaluation of Mental Disorders (PRIME-MD), 88%/78% for the Patient Health Questionnaire-9 (PHQ-9) with a cut-off score of 10, 69%/95% for PHQ-9 as a diagnostic algorithm and 70%/83% for the Hospital Anxiety and Depression Scale (HADS) with a cut-off score of 7. The confidence in the estimates for the other instruments was very low. Only the SCID-I, MINI and PHQ-9 with a cut-off score of 10 fulfilled the minimum criteria for sensitivity and specificity. The use of the PRIME-MD and HADS is not supported by current evidence.


Genes that regulate both development and longevity in Caenorhabditis elegans.
The nematode Caenorhabditis elegans responds to conditions of overcrowding and limited food by arresting development as a dauer larva. Genetic analysis of mutations that alter dauer larva formation (daf mutations) is presented along with an updated genetic pathway for dauer vs. nondauer development. Mutations in the daf-2 and daf-23 genes double adult life span, whereas mutations in four other dauer-constitutive genes positioned in a separate branch of this pathway (daf-1, daf-4, daf-7 and daf-8) do not. The increased life spans are suppressed completely by a daf-16 mutation and partially in a daf-2; daf-18 double mutant. A genetic pathway for determination of adult life span is presented based on the same strains and growth conditions used to characterize Daf phenotypes. Both dauer larva formation and adult life span are affected in daf-2; daf-12 double mutants in an allele-specific manner. Mutations in daf-12 do not extend adult life span, but certain combinations of daf-2 and daf-12 mutant alleles nearly quadruple it. This synergistic effect, which does not equivalently extend the fertile period, is the largest genetic extension of life span yet observed in a metazoan.


The anticancer immune response: indispensable for therapeutic success?
Although the impact of tumor immunology on the clinical management of most cancers is still negligible, there is increasing evidence that anticancer immune responses may contribute to the control of cancer after conventional chemotherapy. Thus, radiotherapy and some chemotherapeutic agents, in particular anthracyclines, can induce specific immune responses that result either in immunogenic cancer cell death or in immunostimulatory side effects. This anticancer immune response then helps to eliminate residual cancer cells (those that fail to be killed by chemotherapy) or maintains micrometastases in a stage of dormancy. Based on these premises, in this Review we address the question, How may it be possible to ameliorate conventional therapies by stimulating the anticancer immune response? Moreover, we discuss the rationale of clinical trials to evaluate and eventually increase the contribution of antitumor immune responses to the therapeutic management of neoplasia.


Health Status and Lifestyle Habits of US Medical Students: A Longitudinal Study.
Evidence shows that physicians and medical students who engage in healthy lifestyle habits are more likely to counsel patients about such behaviors. Yet medical school is a challenging time that may bring about undesired changes to health and lifestyle habits. This study assessed changes in students' health and lifestyle behaviors during medical school. In a longitudinal study, students were assessed at both the beginning and end of medical school. Anthropometric, metabolic, and lifestyle variables were measured at a clinical research center. Data were collected from 2006 to 2011, and analyzed in 2013-2014 with SAS version 9.3. Pearson's correlations were used to assess associations between variables and a generalized linear model was used to measure change over time. Seventy-eight percent (97/125) of participants completed both visits. At baseline, mean anthropometric and clinical measures were at or near healthy values and did not change over time, with the exception of increased diastolic blood pressure (P = 0.01), high-density lipoprotein-cholesterol (P < 0.001), and insulin (P < 0.001). Self-reported diet and physical activity habits were congruent with national goals, except for Vitamin D and sodium. Dietary intake did not change over time, with the exceptions of decreased carbohydrate (percent of total energy) (P < 0.001) and sodium (P = 0.04) and increased fat (percent of total energy) and Vitamin D (both P < 0.01). Cardiovascular fitness showed a trend toward declining, while self-reported physical activity increased (P < 0.001). Students' clinical measures and lifestyle behaviors remain generally healthy throughout medical school; yet some students exhibit cardiometabolic risk and diet and activity habits not aligned with national recommendations. Curricula that include personal health and lifestyle assessment may motivate students to adopt healthier practices and serve as role models for patients.


Mosaic evolution and the pattern of transitions in the hominin lineage.
Humans are uniquely unique, in terms of the extreme differences between them and other living organisms, and the impact they are having on the biosphere. The evolution of humans can be seen, as has been proposed, as one of the major transitions in evolution, on a par with the origins of multicellular organisms or the eukaryotic cell (Maynard Smith & Szathmáry 1997 Major transitions in evolution). Major transitions require the evolution of greater complexity and the emergence of new evolutionary levels or processes. Does human evolution meet these conditions? I explore the diversity of evidence on the nature of transitions in human evolution. Four levels of transition are proposed-baseline, novel taxa, novel adaptive zones and major transitions-and the pattern of human evolution considered in the light of these. The primary conclusions are that changes in human evolution occur continuously and cumulatively; that novel taxa and the appearance of new adaptations are not clustered very tightly in particular periods, although there are three broad transitional phases (Pliocene, Plio-Pleistocene and later Quaternary). Each phase is distinctive, with the first based on ranging and energetics, the second on technology and niche expansion, and the third on cognition and cultural processes. I discuss whether this constitutes a 'major transition' in the context of the evolutionary processes more broadly; the role of behaviour in evolution; and the opportunity provided by the rich genetic, phenotypic (fossil morphology) and behavioural (archaeological) record to examine in detail major transitions and the microevolutionary patterns underlying macroevolutionary change. It is suggested that the evolution of the hominin lineage is consistent with a mosaic pattern of change.This article is part of the themed issue 'Major transitions in human evolution'.


ML277 specifically enhances the fully activated open state of KCNQ1 by modulating VSD-pore coupling.
Upon membrane depolarization, the KCNQ1 potassium channel opens at the intermediate (IO) and activated (AO) states of the stepwise voltage-sensing domain (VSD) activation. In the heart, KCNQ1 associates with KCNE1 subunits to form IKs channels that regulate heart rhythm. KCNE1 suppresses the IO state so that the IKs channel opens only to the AO state. Here, we tested modulations of human KCNQ1 channels by an activator ML277 in Xenopus oocytes. It exclusively changes the pore opening properties of the AO state without altering the IO state, but does not affect VSD activation. These observations support a distinctive mechanism responsible for the VSD-pore coupling at the AO state that is sensitive to ML277 modulation. ML277 provides insights and a tool to investigate the gating mechanism of KCNQ1 channels, and our study reveals a new strategy for treating long QT syndrome by specifically enhancing the AO state of native IKs currents.


Identification of NIPSNAP1 as a nocistatin-interacting protein involving pain transmission.
4-Nitrophenylphosphatase domain and non-neuronal SNAP25-like protein homolog 1 (NIPSNAP1) is a molecule of physiologically unknown function, although it is predominantly expressed in the brain, spinal cord, liver, and kidney. We identified NIPSNAP1 as a protein that interacts with the neuropeptide nocistatin (NST) from synaptosomal membranes of mouse spinal cord using high-performance affinity latex beads. NST, which is produced from the same precursor protein as an opioid-like neuropeptide nociceptin/orphanin FQ (N/OFQ), has opposite effects on pain transmission evoked by N/OFQ. The calculated full-length pre-protein of NIPSNAP1 was 33 kDa, whereas the N-terminal truncated form of NIPSNAP1 (29 kDa) was ubiquitously expressed in the neuronal tissues, especially in synaptic membrane and mitochondria of brain. The 29-kDa NIPSNAP1 was distributed on the cell surface, and NST interacted with the 29-kDa but not the 33-kDa NIPSNAP1. Although intrathecal injection of N/OFQ induced tactile allodynia in both wild-type and NIPSNAP1-deficient mice, the inhibition of N/OFQ-evoked tactile allodynia by NST seen in wild-type mice was completely lacking in the deficient mice. These results suggest that NIPSNAP1 is an interacting molecule of NST and plays a crucial role in pain transmission.


Maternal depressive symptoms and child social preference during the early school years: mediation by maternal warmth and child emotion regulation.
This longitudinal study examined processes that mediate the association between maternal depressive symptoms and peer social preference during the early school years. Three hundred and fifty six kindergarten children (182 boys) and their mothers participated in the study. During kindergarten, mothers reported their level of depressive symptomatology. In first grade, teachers rated children's emotion regulation at school and observers rated the affective quality of mother-child interactions. During second grade, children's social preference was assessed by peer nomination. Results indicated that mothers' level of depressive symptomatology negatively predicted their child's social preference 2 years later, controlling for the family SES and teacher-rated social preference during kindergarten. Among European American families, the association between maternal depressive symptoms and social preference was partially mediated by maternal warmth and the child's emotion regulation. Although the relation between maternal depressive symptoms and children peer preference was stronger among African American families than Europrean American families, its mediation by the maternal warmth and child's emotion regulation was not found in African American families.


Extensive adenocarcinoma and large cell undifferentiated carcinoma of the lung treated with 5-FU, vincristine, and mitomycin C (FOMi).
Fifty-six patients with extensive (52 with TNM stage III M1 disease and four with TNM stage III M0 disease) adenocarcinoma (46 patients) and large cell undifferentiated carcinoma (ten patients) of the lung were treated with combination chemotherapy consisting of 5-FU, vincristine, and mitomycin C (FOMi). The patients had not received prior chemotherapy. The overall response rate was 41% (23 of 56 patients). Four patients achieved a complete response and 19 achieved a partial response. In 12 patients the disease was stable. Response did not vary by cell type: adenocarcinoma, 18 of 43 patients (42%); large cell carcinoma, four of ten (40%); and alveolar cell carcinoma, one of three (33%). The response varied by initial performance status. For a Karnofsky score of greater than or equal to 70%, 20 of 41 patients (49%) responded, while for a Karnofsky score of less than 70%, three of 15 patients (20%) responded (P = 0.22). Survival was improved for responding patients regardless of initial performance status. The median survival duration was 24 weeks for the entire group of patients treated with FOMi. Survival of the responders (complete response plus partial response) was significantly improved over that of patients with progressive disease (28 weeks versus 13 weeks, respectively; P = 0.002). The FOMi combination was very well-tolerated. Nausea was common, but vomiting occurred in only four of 56 patients. Thrombocytopenia, requiring a reduction in the mitomycin C dose, developed after the third treatment course in 14 patients.


Resolution of allergic inflammation and airway hyperreactivity is dependent upon disruption of the T1/ST2-IL-33 pathway.
Although there have been numerous studies on the development of allergen-induced inflammation, the mechanisms leading to resolution of inflammation remain poorly understood. This represents an important consideration because failure to resolve allergen driven inflammation potentially leads to irreversible airway remodeling, characteristic of chronic asthma. We investigated the resolution of allergic inflammation and identified the factors responsible. BALB/c and C57BL/6 mice were sensitized to ovalbumin and challenged through the airways to induce allergic inflammation. Mice were analyzed at 24 hours and 7 days after the final challenge. Airway hyperreactivity (AHR) and increased mucus production were present 7 days after the cessation of allergen challenge in BALB/c mice. Persisting AHR correlated with the continued presence of Th2 cells but not eosinophils in the lungs. The role of Th2 cells in maintaining AHR was confirmed using blocking antibodies against T1/ST2, IL-4, and IL-13 during the resolution period. Moreover, AHR in the "Th1 type" C57BL/6 mouse strain was resolved 1 week after allergen challenge, concomitant with clearance of Th2 cells from the lung. Expression of the T1/ST2 ligand, IL-33, also correlated with maintenance of AHR. We have used blockade of Th2 function and strain differences to show for the first time that resolution of allergic inflammation and AHR may be dependent on the T1/ST2-IL-33 pathway and the presence of Th2 cells, suggesting they are necessary not only for the development of an allergic response but also for its maintenance.


Solution conformation of a deoxynucleotide containing tandem G.A mismatched base pairs and 3'-overhanging ends in d(GTGAACTT)2.
We have used 31P and 1H NMR spectroscopy and circular dichroism to define the solution conformation of d(GTGAACTT)2 which contains tandem G.A mismatched base pairs and 3'-overhanging TT ends. Measurements of coupling constants and NOE intensities show that the sugar puckers of the nucleotides are predominantly in the south domain (i.e., near C2'-endo) and that the glycosidic torsion angles are anti. The sequential NOE intensities indicate the presence of a right-handed helix. Analysis of the 31P and 1H NMR spectra of the duplex shows that the tandem mismatch forms a block in which there are unusual backbone torsion angles (i.e., in the BII state), within an otherwise B-like structure. The chemical shift of the N1H of the mismatched guanosine and NOEs between the mismatched base pairs and their nearest neighbors are inconsistent with the imino pairing present in single A.G mismatches or in the X-ray structure of a tandem mismatch [Privé, G. G., et al. (1987) Science 238, 498-503] but the data are consistent with the amino pairing found by Li et al. (1991) [Li, Y., et al. (1991) Proc. Natl. Acad. Sci. U.S.A. 88, 26-30]. The strong base-base stacking both within the tandem G.A block and between the G.A mismatches and their other nearest neighbors offsets the intrinsic destabilizing effects of the mismatch. Further, the 3'-TT overhangs stack onto the ends of the helix and stabilize the duplex against fraying, which accounts for the observed increase in the melting temperature compared with the flush-ended duplex.


Hemophagocytic lymphohistiocytosis onset during induction therapy for precursor B-cell acute lymphoblastic leukemia.
We report the clinical course of a child with precursor B-cell acute lymphoblastic leukemia who developed fever, hepatosplenomegaly, and refractory thrombocytopenia after initiation of chemotherapy. Bone marrow aspiration on Day 8 of induction showed new onset of hemophagocytosis and he met clinical, laboratory, and histopathologic criteria for hemophagocytic lymphohistiocytosis. His symptoms improved significantly after an increased dosage of steroids.


Cytoplasmic heat shock granules are formed from precursor particles and are associated with a specific set of mRNAs.
In heat-shocked tomato cell cultures, cytoplasmic heat shock granules (HSGs) are tightly associated with a specific subset of mRNAs coding mainly for the untranslated control proteins. This messenger ribonucleoprotein complex was banded in a CsCl gradient after fixation with formaldehyde (approximately 1.30 g/cm3). It contains all the heat shock proteins and most of the RNA applied to the gradient. During heat shock, a reversible aggregation of HSGs from 15S precursor particles can be shown. These pre-HSGs are not identical to the 19S plant prosomes. Ultrastructural analysis supports the ribonucleoprotein nature of HSGs and their composition of approximately 10-nm precursor particles. A model summarizes our results. It gives a reasonable explanation for the striking conservation of untranslated mRNAs during heat shock and may apply also to animal cells.


Two-dimensional culture of human pancreatic adenocarcinoma cells results in an irreversible transition from epithelial to mesenchymal phenotype.
Many commercially available cell lines have been in culture for ages, acquiring phenotypes that differ from the original cancers from which these cell lines were derived. Therefore, research on new cell lines could improve the success rates of translational research in cancer. We have developed methods for the isolation and culture of human pancreatic ductal adenocarcinoma (PDAC) cells from murine xenografts of human PDAC. We hypothesize that phenotypes of PDAC cells are modified by in vitro culture conditions over time and by in vivo implantation. Patient-derived xenografts were created in immunodeficient mice using surgically resected tumor specimens. These murine xenografts were then used to establish human PDAC cell lines in culture. Earlier (<5) passage and later (>20) passage cell lines were evaluated separately regarding proliferation, cell cycle, genetic mutations, invasiveness, chemosensitivity, tumorigenesis, epithelial-mesenchymal transition (EMT) status, and proteomics. Later passage cells accelerated their doubling time and colony formation, and were more concentrated in the G0/G1 phase and less in the G2/M checkpoint phase. Later passage cells were more sensitive to gemcitabine and 5-fluorouracil than earlier passage cells, but all four new cell lines were more chemo-resistant compared with commercial ATCC cell lines. EMT induction was observed when establishing and passaging cell lines in vitro and furthermore by growing them as subcutaneous tumors in vivo. This study demonstrates a novel approach to the establishment of PDAC cell lines and observes a process by which newly established cell lines undergo phenotypic changes during in vitro culture and in vivo tumorigenesis. This may help explain differences of treatment effects often observed between experiments conducted in vitro, in vivo, and in human clinical trials.


Can we predict "problem residents"?
This study investigates whether data available at the time of residency application can be used to predict more accurately future problems of performance, both during and after residency. The authors identified all residents with reported problematic behavior across 20 years (1987-2007) at a single residency program and created a set of matched controls. Problems were further divided into "major" (leading to significant disruptions of performance and disciplinary action) and "minor" (remediable and resolved). Application materials were then reviewed for United States Medical Licensing Examination (USMLE) scores, evidence of academic failures, interviewer ratings, negative interviewer comments, negative comments in the dean's letter, and negative comments in letters of recommendation. The presence of any negative comments in the dean's letter yielded significant correlations with future problems. Further, those applicants with future major problems had significantly more negative comments in the dean's letter than did those with future minor problems. Other factors such as USMLE scores, failed courses, letters of recommendation, and interviewer ratings and comments did not predict future problems. Most of the factors the authors assessed in prospective applicants did not predict future problems, with the exception of negative (even mildly so) comments in the dean's letter. The authors suggest that more attention should be paid to the use of the dean's letter to assess risk among applicants, and prospective study of this assessment should be performed.


A rapid and sensitive assay for quantification of siRNA efficiency and specificity.
RNA Interference has rapidly emerged as an efficient procedure for knocking down gene expression in model systems. However, cross-reactivity, whereby multiple genes may be simultaneously targeted by a single short interfering RNA (siRNA), can potentially jeopardize correct interpretation of gene function. As such, it is essential to test the specificity of a siRNA prior to a full phenotypic analysis. To this end, we have adapted a reporter-based assay harnessing the sensitivity of luciferase activity to provide a quantitative readout of relative RNAi efficacy and specificity. We have tested different siRNAs directed against Thymosin beta4 (Tbeta4); determined their effectiveness at silencing Tbeta4 and have both excluded off-target silencing of the Tbeta4 homologue Thymosin beta10 (Tbeta10) and demonstrated partial knockdown of Tbeta10 despite significant (12/23; 52%) sequence mismatch. This assay system is applicable to any RNAi study where there is a risk of targeting homologous genes and to the monitoring of off-target effects at the genome level following microarray expression profiling.


Spontaneous Metacognition in Rhesus Monkeys.
Metacognition is the ability to think about thinking. Although monitoring and controlling one's knowledge is a key feature of human cognition, its evolutionary origins are debated. In the current study, we examined whether rhesus monkeys (Macaca mulatta; N = 120) could make metacognitive inferences in a one-shot decision. Each monkey experienced one of four conditions, observing a human appearing to hide a food reward in an apparatus consisting of either one or two tubes. The monkeys tended to search the correct location when they observed this baiting event, but engaged in information seeking-by peering into a center location where they could check both potential hiding spots-if their view had been occluded and information seeking was possible. The monkeys only occasionally approached the center when information seeking was not possible. These results show that monkeys spontaneously use information about their own knowledge states to solve naturalistic foraging problems, and thus provide the first evidence that nonhumans exhibit information-seeking responses in situations with which they have no prior experience.


Temper tantrums in young children: 1. Behavioral composition.
Although tantrums are among the most common behavioral problems of young children and may predict future antisocial behavior, little is known about them. To develop a model of this important phenomenon of early childhood, behaviors reported in parental narratives of the tantrums of 335 children aged 18 to 60 months were encoded as present or absent in consecutive 30-second periods. Principal Component (PC) analysis identified Anger and Distress as major, independent emotional and behavioral tantrum constituents. Anger-related behaviors formed PCs at three levels of intensity. High-intensity anger decreased with age, and low-intensity anger increased. Distress, the fourth PC, consisted of whining, crying, and comfort-seeking. Coping Style, the fifth PC, had high but opposite loadings on dropping down and running away, possibly reflecting the tendency to either "submit" or "escape." Model validity was indicated by significant correlations of the PCs with tantrum variables that were, by design, not included in the PC analysis.


Current and Future Treatments of Rhinitis and Sinusitis.
Advances in understanding the pathogenic mechanisms of both rhinitis and chronic rhinosinusitis have resulted in new treatment options, especially for chronic rhinosinusitis. A review of relevant medical and surgical clinical studies shows that intranasal corticosteroids, antihistamines, and allergen immunotherapy continue to be the best treatments for chronic rhinitis. Dupilumab is the first biologic approved for chronic rhinosinusitis with polyps. Omalizumab, mepolizumab, and benralizumab may have a future role in the treatment of chronic rhinosinusitis. Novel corticosteroid delivery devices such as an exhalation delivery system for fluticasone and bioabsorbable sinus implants provide enhanced and localized distribution of corticosteroids. Surgical management tailored to the underlying disease process improves clinical outcomes in chronic rhinosinusitis with or without nasal polyposis. Advances in the understanding of the heterogeneous nature of rhinitis and rhinosinusitis have resulted in more precise treatments. Improving the understanding of different endotypes should provide better knowledge to determine appropriate current and new therapies to treat these diseases.


The Gut Microbiota of Laying Hens and Its Manipulation with Prebiotics and Probiotics To Enhance Gut Health and Food Safety.
The microbiota plays a vital role in maintaining gut health and influences the overall performance of chickens. Most gut microbiota-related studies have been performed in broilers, which have different microbial communities compared to those of layers. The normal gut microbiota of laying chickens is dominated by Proteobacteria, Firmicutes, Bacteroidetes, Fusobacteria, and Actinobacteria at the phylum level. The composition of the gut microbiota changes with chicken age, genotype, and production system. The metabolites of gut microbiota, such as short-chain fatty acids, indole, tryptamine, vitamins, and bacteriocins, are involved in host-microbiota cross talk, maintenance of barrier function, and immune homeostasis. Resident gut microbiota members also limit and control the colonization of foodborne pathogens. In-feed supplementations of prebiotics and probiotics strengthen the gut microbiota for improved host performance and colonization resistance to gut pathogens, such as Salmonella and Campylobacter The mechanisms of action of prebiotics and probiotics come through the production of organic acids, activation of the host immune system, and production of antimicrobial agents. Probiotic candidates, including Lactobacillus, Bifidobacterium, Bacillus, Saccharomyces, and Faecalibacterium isolates, have shown promising results toward enhancing food safety and gut health. Additionally, a range of complex carbohydrates, including mannose oligosaccharides, fructo-oligosaccharides, and galacto-oligosaccharides, and inulin are promising candidates for improving gut health. Here, we review the potential roles of prebiotics and probiotics in the reshaping of the gut microbiota of layer chickens to enhance gut health and food safety.


Meleagrin, a new FabI inhibitor from Penicillium chryosogenum with at least one additional mode of action.
Bacterial enoyl-acyl carrier protein reductase (FabI) is a promising novel antibacterial target. We isolated a new class of FabI inhibitor from Penicillium chrysogenum, which produces various antibiotics, the mechanisms of some of them are unknown. The isolated FabI inhibitor was determined to be meleagrin by mass spectroscopy and nuclear magnetic resonance spectral analyses, and its more active and inactive derivatives were chemically prepared. Consistent with their selective inhibition of Staphylococcus aureus FabI, meleagrin and its more active derivatives directly bound to S. aureus FabI in a fluorescence quenching assay, inhibited intracellular fatty acid biosynthesis and growth of S. aureus, and increased the minimum inhibitory concentration for fabI-overexpressing S. aureus. The compounds that were not effective against the FabK isoform, however, inhibited the growth of Streptococcus pneumoniae that contained only the FabK isoform. Additionally no resistant mutant to the compounds was obtained. Importantly, fabK-overexpressing Escherichia coli was not resistant to these compounds, but was resistant to triclosan. These results demonstrate that the compounds inhibited another target in addition to FabI. Thus, meleagrin is a new class of FabI inhibitor with at least one additional mode of action that could have potential for treating multidrug-resistant bacteria.


[Modern ultrasound technologies and their application in pediatric urinary tract imaging].
In children ultrasound plays a central role in the diagnostic imaging of the urinary tract. It is used most frequently and as a primary diagnostic option. Consequently, innovations in ultrasound technology and ultrasound contrast media have major impact on pediatric urosonography. Harmonic imaging is a modality that produces artifact-free images with high resolution. It has been shown that harmonic imaging is superior to fundamental mode in many urosonographic indications. Color Doppler is an established imaging modality, but its application for diagnosis of stones in the urinary tract, especially in children, is relatively new. The so-called twinkling sign, a color Doppler artifact at the site where one normally expects the acoustic shadow to be, enhances the conspicuity of the stone. A further development is three-dimensional (3D) ultrasound. It offers better volume measurement of the bladder and kidneys than 2D ultrasound. Contrast-enhanced voiding urosonography has already proven to be a valuable alternative in the diagnosis of vesicoureteral reflux. Thus, a significant decrease of radiation exposure has become possible as it replaces the radiological methods. With the introduction of contrast-specific ultrasound imaging modalities, further improvements in voiding urosonography are emerging.


Inhibition of platelet-derived growth factor-BB-induced fibroblast proliferation by plasmin-activated alpha 2-macroglobulin is mediated via an alpha 2-macroglobulin receptor/low density lipoprotein receptor-related protein-dependent mechanism.
alpha 2-Macroglobulin (alpha 2M) is a potentially important regulator of platelet-derived growth factor-BB (PDGF-BB)-stimulated cell growth due to our previous observation that PDGF-BB binds to alpha 2M noncovalently (Bonner, J. C., Goodell, A. L., Lasky, J. A., and Hoffman, M. R. (1992) J. Biol. Chem. 267, 12837-12844). We examined the in vitro effect of native and plasmin-activated (receptor-recognized) alpha 2M on the PDGF-BB-induced proliferation of mouse Swiss 3T3 and rat lung fibroblasts. Nondenaturing polyacrylamide gel electrophoresis showed that plasmin converted alpha 2M to its electrophoretically "fast" form at a 2:1 molar ratio and that 125I-PDGF-BB bound both alpha 2M and alpha 2M-plasmin. PDGF-BB-induced growth was not affected by native alpha 2M (0.3 microM) or plasmin (0.6 microM). The combination of plasmin and alpha 2M (2:1 molar ratio) inhibited PDGF-BB-induced cell proliferation 80-90%. Complexes of PDGF-BB.alpha 2M purified by gel filtration chromatography retained growth promoting activity, but the PDGF-BB.alpha 2M-plasmin complex did not. Preincubation of fibroblasts (37 degrees C for 24 h) with alpha 2M-plasmin did not change 125I-PDGF-BB binding or affect gene expression of the 6.5-kilobase PDGF-alpha receptor or 5.2-kilobase PDGF-beta receptor mRNA. However, preincubation with alpha 2M-plasmin (0-4 degrees C for 4 h) increased 125I-PDGF-BB binding 2-fold, and this increase was blocked by a receptor-associated protein antagonist of the alpha 2M-receptor/low density lipoprotein receptor-related protein. The receptor-associated protein antagonist blocked 125I-alpha 2M-methylamine binding, inhibited PDGF-BB-alpha 2M-plasmin uptake from fibroblast-cultured supernatants, and abolished the inhibitory effect of alpha 2M-plasmin on PDGF-stimulated growth. These data suggest that inhibition of PDGF-stimulated proliferation by alpha 2M-plasmin is mediated in part by clearance of PDGF-BB-alpha 2M-plasmin through the lipoprotein receptor-related protein.


Suppression of thyroid function during ingestion of seaweed "Kombu" (Laminaria japonoca) in normal Japanese adults.
The effect of ingesting seaweed "Kombu" (Laminaria japonica) on thyroid function was studied in normal Japanese adults. Ingesting 15 and 30 g of Kombu (iodine contents: 35 and 70 mg) daily for a short term (7-10 days) significantly increased serum thyrotropin (TSH) concentrations, exceeding the normal limits in some subjects. The serum free thyroxine (FT(4)) and/or free 3,5,3'-triiodothyronine (FT(3)) concentrations were slightly decreased within the normal limits. During long term daily ingestion of 15 g of Kombu (55-87 days), the TSH levels were elevated and sustained while the FT(4) and FT(3) levels were almost unchanged. Urinary excretion of iodine significantly increased during ingestion of Kombu. These abnormal values returned to the initial levels 7 to 40 days after discontinuing the ingestion of Kombu. Based on these findings that thyroid function was suppressed during ingestion of Kombu, though the effect was reversible, we recommend Japanese people avoid ingesting excessive amounts of seaweed.


FALDO: a semantic standard for describing the location of nucleotide and protein feature annotation.
Nucleotide and protein sequence feature annotations are essential to understand biology on the genomic, transcriptomic, and proteomic level. Using Semantic Web technologies to query biological annotations, there was no standard that described this potentially complex location information as subject-predicate-object triples. We have developed an ontology, the Feature Annotation Location Description Ontology (FALDO), to describe the positions of annotated features on linear and circular sequences. FALDO can be used to describe nucleotide features in sequence records, protein annotations, and glycan binding sites, among other features in coordinate systems of the aforementioned "omics" areas. Using the same data format to represent sequence positions that are independent of file formats allows us to integrate sequence data from multiple sources and data types. The genome browser JBrowse is used to demonstrate accessing multiple SPARQL endpoints to display genomic feature annotations, as well as protein annotations from UniProt mapped to genomic locations. Our ontology allows users to uniformly describe - and potentially merge - sequence annotations from multiple sources. Data sources using FALDO can prospectively be retrieved using federalised SPARQL queries against public SPARQL endpoints and/or local private triple stores.


Monitoring primary breast cancer throughout chemotherapy using FDG-PET.
We have compared 2-deoxy-2-[(18)F]-fluoro-D-glucose positron emission tomography (FDG-PET) images of large or locally advanced breast cancers (LABC) acquired during Anthracycline-based chemotherapy. The purpose was to determine whether there is an optimal method for defining tumour volume and an optimal imaging time for predicting pathologic chemotherapy response. PET data were acquired before the first and second cycles, at the midpoint and at the endpoint of neoadjuvant chemotherapy. FDG uptake was quantified using the mean and maximum standardized uptake values (SUV) and the coefficient of variation within a region of interest. Receiver-operator characteristic (ROC) analysis was used to determine the discrimination between tumours demonstrating a high pathological response (i.e. those with greater than 90% reduction in viable tumour cells) and low pathological response. Only tumours with an initial tumour to background ratio (TBR) of greater than five showed a difference between response categories. In terms of response discrimination, there was no statistically significant advantage of any of the methods used for image quantification or any of the time points. The best discrimination was measured for mean SUV at the midpoint of therapy, which identified 77% of low responding tumours whilst correctly identifying 100% of high responding tumours and had an ROC area of 0.93. FDG-PET is efficacious for predicting the pathologic response of most primary breast tumours throughout the duration of a neoadjuvant chemotherapy regimen. However, this technique is ineffective for tumours with low image contrast on pre-therapy PET scans.


First Report of Leaf Blight and Stem Canker of Pachysandra terminalis Caused by Pseudonectria pachysandricola in Korea.
Pachysandra terminalis Siebold & Zucc., known as Japanese pachysandra, is a creeping evergreen perennial belonging to the family Buxaceae. In April 2011, hundreds of plants showing symptoms of leaf blight and stem canker with nearly 100% incidence were found in a private garden in Suwon, Korea. Plants with the same symptoms were found in Seoul in May and Hongcheon in August. Affected leaves contained tan-to-yellow brown blotches. Stem and stolon cankers first appeared as water soaked and developed into necrotic lesions. Sporodochia were solitary, erumpent, circular, 50 to 150 μm in diameter, salmon-colored, pink-orange when wet, and with or without setae. Setae were hyaline, acicular, 60 to 100 μm long, and had a base that was 4 to 6 μm wide. Conidiophores were in a dense fascicle, not branched, hyaline, aseptate or uniseptate, and 8 to 20 × 2 to 3.5 μm. Conidia were long, ellipsoid to cylindric, fusiform, rounded at the apex, subtruncate at the base, straight to slightly bent, guttulate, hyaline, aseptate, 11 to 26 × 2.5 to 4.0 μm. A single-conidial isolate formed cream-colored colonies that turned into salmon-colored colonies on potato dextrose agar (PDA). Morphological and cultural characteristics of the fungus were consistent with previous reports of Pseudonectria pachysandricola B.O. Dodge (1,3,4). Voucher specimens were housed at Korea University (KUS). Two isolates, KACC46110 (ex KUS-F25663) and KACC46111 (ex KUS-F25683), were accessioned in the Korean Agricultural Culture Collection. Fungal DNA was extracted with DNeasy Plant Mini DNA Extraction Kits (Qiagen Inc., Valencia, CA). The complete internal transcribed spacer (ITS) region of rDNA was amplified with the primers ITS1/ITS4 and sequenced using ABI Prism 337 automatic DNA sequencer (Applied Biosystems, Foster, CA). The resulting sequence of 487 bp was deposited in GenBank (Accession No. JN797821). This showed 100% similarity with a sequence of P. pachysandricola from the United States (HQ897807). Isolate KACC46110 was used in pathogenicity tests. Inoculum was prepared by harvesting conidia from 2-week-old cultures on PDA. Ten young leaves wounded with needles were sprayed with conidial suspensions (~1 × 106 conidia/ml). Ten young leaves that served as the control were treated with sterile distilled water. Plants were covered with plastic bags to maintain a relative humidity of 100% at 25 ± 2°C for 24 h. Typical symptoms of brown spots appeared on the inoculated leaves 4 days after inoculation and were identical to the ones observed in the field. P. pachysandricola was reisolated from 10 symptomatic leaf tissues, confirming Koch's postulates. No symptoms were observed on control plants. Previously, the disease was reported in the United States, Britain, Japan, and the Czech Republic (2,3), but not in Korea. To our knowledge, this is the first report of P. pachysandricola on Pachysandra terminalis in Korea. Since this plant is popular and widely planted in Korea, this disease could cause significant damage to nurseries and the landscape. References: (1) B. O. Dodge. Mycologia 36:532, 1944. (2) D. F. Farr and A. Y. Rossman. Fungal Databases. Systematic Mycology and Microbiology Laboratory, ARS, USDA. Retrieved from http://nt.ars-grin.gov/fungaldatabases/ , September 24, 2011. (3) I. Safrankova. Plant Prot. Sci. 43:10, 2007. (4) W. A. Sinclair and H. H. Lyon. Disease of Trees and Shrubs. 2nd ed. Cornell University Press, Ithaca, NY, 2005.


Efficacy of Adalimumab in Korean Patients with Crohn's Disease.
Adalimumab is effective for both remission induction and the maintenance of Crohn's disease (CD) in Western countries. We evaluated the efficacy of adalimumab in the conventional step-up treatment approach for CD in Korea. We retrospectively reviewed 62 patients with CD who were treated with adalimumab. Their Crohn's disease activity index (CDAI) was measured at weeks 4, 8, and 52. Clinical remission was defined as a CDAI score <150. Induction and maintenance outcomes were analyzed. Forty-one patients (66.1%) achieved a reduction of 70 CDAI points at week 8. Among them, 28 (45.2%) achieved clinical remission at week 8, 20 (32.3%) maintained remission at week 52. The absence of prior anti-tumor necrosis factor (TNF) therapy and Montreal classification L1 at baseline predicted clinical remission at week 8 in the multivariate logistic regression analysis. In the Cox proportional hazards model, the hazard ratio for the secondary loss of response during maintenance therapy after clinical remission induction was significantly higher in patients who showed initial mild CDAI severity or Montreal classification A3. In our study, anti-TNF therapy-naive and Montreal classification L1 were associated with adalimumab efficacy as induction therapy in CD. Further studies are warranted to determine the prognostic factors for the long-term response after adalimumab therapy.


Fixed-bearing versus mobile-bearing total knee arthroplasty: a prospective randomised, clinical and radiological study with mid-term results at 7 years.
Mobile-bearing (MB) total knee arthroplasty (TKA) was developed as an alternative to the established fixed-bearing (FB) design because of theoretical advantages. Short-term studies comparing these designs have not shown any differences in clinical and radiographic results. We compared the results at 7 years of a randomised study of patients undergoing TKA using either a FB or a MB variant of the same prosthesis. Fifty-two patients (52 knees) with an average age of 70 years received a FB posterior-stabilized prosthesis, and 50 patients (52 knees) with an average age of 72 years, a MB prosthesis. All implants were cemented and the patella was routinely resurfaced. Preoperatively, there were no differences between the two groups, and surgical procedure and postoperative protocol were the same for both. At an average follow-up of 7.1 years, no significant differences of FB over MB design could be demonstrated with respect to the American Knee Society score (AKSS), pain score, a questionnaire of general health (SF-12 score), range of motion (ROM), or complication rates. Radiographs showed no significant difference in prosthetic alignment or evidence of loosening. Two knees with a MB design required reoperation, one for persistent joint stiffness and another to treat septic loosening. One patient with a MB prosthesis with signs of tibial component loosening was asymptomatic. We conclude that at mid-term follow-up there is no evidence to prove the superiority of MB over FB TKA with regard to the clinical and radiographic results.


Increased l1 retrotransposition in the neuronal genome in schizophrenia.
Recent studies indicate that long interspersed nuclear element-1 (L1) are mobilized in the genome of human neural progenitor cells and enhanced in Rett syndrome and ataxia telangiectasia. However, whether aberrant L1 retrotransposition occurs in mental disorders is unknown. Here, we report high L1 copy number in schizophrenia. Increased L1 was demonstrated in neurons from prefrontal cortex of patients and in induced pluripotent stem (iPS) cell-derived neurons containing 22q11 deletions. Whole-genome sequencing revealed brain-specific L1 insertion in patients localized preferentially to synapse- and schizophrenia-related genes. To study the mechanism of L1 transposition, we examined perinatal environmental risk factors for schizophrenia in animal models and observed an increased L1 copy number after immune activation by poly-I:C or epidermal growth factor. These findings suggest that hyperactive retrotransposition of L1 in neurons triggered by environmental and/or genetic risk factors may contribute to the susceptibility and pathophysiology of schizophrenia.


Early Pragmatics in Deaf and Hard of Hearing Infants.
A set of important pragmatic skills emerge during infancy and pave the way for later language learning. It is thought these early social communication skills develop through infant-caregiver interaction. In a microanalysis, we tested whether deaf and hard of hearing (DHH) infants (typically at high risk of reduced access to rich communicative interaction in infancy) are less likely to engage in gestural and vocal pragmatic behaviors. We coded the naturalistic communication of 8 DHH infants who had no additional needs, who were not preterm or low birth weight, whose parents were hearing, monolingual English speakers, and who had spoken English as their primary target language. The frequency of use of 5 types of infant communication known to positively predict later language development (show gestures, give gestures, index-finger pointing, communicative vocalizations, and early word use) was compared with that of 8 typically hearing infants matched for age, sex, and socioeconomic status. Hearing loss had a significant negative effect on the frequency with which infants engaged in all types of early communication that predict later language development. DHH infants are at high risk of delay in the gestural and vocal communicative skills that lay the foundations for later language. Delay in the gestural domain suggests this is not simply a consequence of difficulties in imitating auditory stimuli. There is significant potential to lift DHH infants onto a positive developmental trajectory by supporting caregivers to nurture interaction from the first year.


Reduced structural flexibility for an exonuclease deficient DNA polymerase III mutant.
DNA synthesis, carried out by DNA polymerases, requires balancing speed and accuracy for faithful replication of the genome. High fidelity DNA polymerases contain a 3'-5' exonuclease domain that can remove misincorporated nucleotides on the 3' end of the primer strand, a process called proofreading. The E. coli replicative polymerase, DNA polymerase III, has spatially separated (∼55 Å apart) polymerase and exonuclease subunits. Here, we report on the dynamics of E. coli DNA polymerase III proofreading in the presence of its processivity factor, the β2-sliding clamp, at varying base pair termini using single-molecule FRET. We find that the binding kinetics do not depend on the base identity at the termini, indicating a tolerance for DNA mismatches. Further, our single-molecule data and MD simulations show two previously unobserved features: (1) DNA Polymerase III is a highly dynamic protein that adopts multiple conformational states while bound to DNA with matched or mismatched ends, and (2) an exonuclease-deficient DNA polymerase III has reduced conformational flexibility. Overall, our single-molecule experiments provide high time-resolution insight into a mechanism that ensures high fidelity DNA replication to maintain genome integrity.


Preoperative Dehydration Predicts Adverse Events Following Anterior Cervical Discectomy and Fusion.
Anterior cervical discectomy and fusion (ACDF) is a common procedure for neck arthritis, typically alleviating pain and improving function. Preoperative dehydration has been correlated with postoperative infection, acute renal failure, deep vein thrombosis, and increased hospital length of stay. However, some studies have suggested that preoperative dehydration has a minimal relationship with postoperative outcomes, specifically in arthroplasty and lumbar surgery candidates. Patients who underwent ACDF from 2015 to 2020 as part of the American College of Surgeons National Surgical Quality Improvement Program database were identified. We excluded patients who presented with acute trauma. Dehydration was determined using the accepted definition of preoperative blood urea nitrogen to creatinine ratio greater than 20. Lengths of stay and 30-day postoperative adverse events were compared between dehydrated and nondehydrated cohorts, adjusting for baseline features using standard multivariate regression. We identified 14,932 patients, and 4206 (28.1%) of whom were preoperatively dehydrated. Dehydrated patients had significantly higher odds of wound, hematological, and pulmonary complications; Clavien-Dindo grade IV, delayed length of stay (>5 days); and a lower likelihood of being discharged home (P < 0.005), even after controlling for demographic features (eg, sex, age, body mass index, race, and ethnicity). Furthermore, linear regression suggested an overall half-day increased length of hospital stay for dehydrated patients (95% CI [0.36, 0.60], P < 0.001). Preoperative dehydration is common among ACDF surgery patients and appears to correlate with an increased risk of postoperative complications and prolonged length of hospital stay. Evaluation of a patient's hydration status from standard preoperative laboratory metrics can be employed for risk stratification, patient counseling, and timing of ACDF surgeries.


Sulfur and metal fertilization of the lower continental crust.
Mantle-derived melts and metasomatic fluids are considered to be important in the transport and distribution of trace elements in the subcontinental lithospheric mantle. However, the mechanisms that facilitate sulfur and metal transfer from the upper mantle into the lower continental crust are poorly constrained. This study addresses this knowledge gap by examining a series of sulfide- and hydrous mineral-rich alkaline mafic-ultramafic pipes that intruded the lower continental crust of the Ivrea-Verbano Zone in the Italian Western Alps. The pipes are relatively small (< 300 m diameter) and primarily composed of a matrix of subhedral to anhedral amphibole (pargasite), phlogopite and orthopyroxene that enclose sub-centimeter-sized grains of olivine. The 1 to 5 m wide rim portions of the pipes locally contain significant blebby and disseminated Fe-Ni-Cu-PGE sulfide mineralization. Stratigraphic relationships, mineral chemistry, geochemical modelling and phase equilibria suggest that the pipes represent open-ended conduits within a large magmatic plumbing system. The earliest formed pipe rocks were olivine-rich cumulates that reacted with hydrous melts to produce orthopyroxene, amphibole and phlogopite. Sulfides precipitated as immiscible liquid droplets that were retained within a matrix of silicate crystals and scavenged metals from the percolating hydrous melt, associated with partial melting of a metasomatized continental lithospheric mantle. New high-precision chemical abrasion TIMS U-Pb dating of zircons from one of the pipes indicates that these pipes were emplaced at 249.1 ± 0.2 Ma, following partial melting of lithospheric mantle pods that were metasomatized during the Eo-Variscan oceanic to continental subduction (~420-310 Ma). The thermal energy required to generate partial melting of the metasomatized mantle was most likely derived from crustal extension, lithospheric decompression and subsequent asthenospheric rise during the orogenic collapse of the Variscan belt (< 300 Ma). Unlike previous models, outcomes from this study suggest a significant temporal gap between the occurrence of mantle metasomatism, subsequent partial melting and emplacement of the pipes. We argue that this multi-stage process is a very effective mechanism to fertilize the commonly dry and refractory lower continental crust in metals and volatiles. During the four-dimensional evolution of the thermo-tectonic architecture of any given terrain, metals and volatiles stored in the lower continental crust may become available as sources for subsequent ore-forming processes, thus enhancing the prospectivity of continental block margins for a wide range of mineral systems.


Oridonin Enhances Radiation-Induced Cell Death by Promoting DNA Damage in Non-Small Cell Lung Cancer Cells.
Although many attempts have been made to improve the efficacy of radiotherapy to treat cancer, radiation resistance is still an obstacle in lung cancer treatment. Oridonin is a natural compound with promising antitumor efficacy that can trigger cancer cell death; however, its direct cellular targets, efficacy as a radiosensitizer, and underlying mechanisms of activity remain unclear. Herein, we report that oridonin exhibits additive cytotoxic and antitumor activity with radiation using the H460 non-small cell lung cancer cell lines. We assessed the effect of oridonin by proliferation, clonogenic, reactive oxygen species (ROS) production, DNA damage, and apoptosis assays. In vitro, oridonin enhanced the radiation-induced inhibition of cell growth and clonogenic survival. Oridonin also facilitated radiation-induced ROS production and DNA damage and enhanced apoptotic cell death. In vivo, the combination of oridonin and radiation effectively inhibited H460 xenograft tumor growth, with higher caspase-3 activation and H2A histone family member X (H2AX) phosphorylation compared with that of radiation alone. Our findings suggest that oridonin possesses a novel mechanism to enhance radiation therapeutic responses by increasing DNA damage and apoptosis. In conclusion, oridonin may be a novel small molecule to improve radiotherapy in non-small cell lung cancer.


Hidden Markov Models Predict the Future Choice Better Than a PSTH-Based Method.
Beyond average firing rate, other measurable signals of neuronal activity are fundamental to an understanding of behavior. Recently, hidden Markov models (HMMs) have been applied to neural recordings and have described how neuronal ensembles process information by going through sequences of different states. Such collective dynamics are impossible to capture by just looking at the average firing rate. To estimate how well HMMs can decode information contained in single trials, we compared HMMs with a recently developed classification method based on the peristimulus time histogram (PSTH). The accuracy of the two methods was tested by using the activity of prefrontal neurons recorded while two monkeys were engaged in a strategy task. In this task, the monkeys had to select one of three spatial targets based on an instruction cue and on their previous choice. We show that by using the single trial's neural activity in a period preceding action execution, both models were able to classify the monkeys' choice with an accuracy higher than by chance. Moreover, the HMM was significantly more accurate than the PSTH-based method, even in cases in which the HMM performance was low, although always above chance. Furthermore, the accuracy of both methods was related to the number of neurons exhibiting spatial selectivity within an experimental session. Overall, our study shows that neural activity is better described when not only the mean activity of individual neurons is considered and that therefore, the study of other signals rather than only the average firing rate is fundamental to an understanding of the dynamics of neuronal ensembles.


The clinical efficacy of low-power laser therapy on pain and function in cervical osteoarthritis.
Pain is a major symptom in cervical osteoarthritis (COA). Low-power laser (LPL) therapy has been claimed to reduce pain in musculoskeletal pathologies, but there have been concerns about this point. The aim of this study was to evaluate the analgesic efficacy of LPL therapy and related functional changes in COA. Sixty patients between 20 and 65 years of age with clinically and radiologically diagnosed COA were included in the study. They were randomised into two equal groups according to the therapies applied, either with LPL or placebo laser. Patients in each group were investigated blindly in terms of pain and pain-related physical findings, such as increased paravertebral muscle spasm, loss of lordosis and range of neck motion restriction before and after therapy. Functional improvements were also evaluated. Pain, paravertebral muscle spasm, lordosis angle, the range of neck motion and function were observed to improve significantly in the LPL group, but no improvement was found in the placebo group. LPL seems to be successful in relieving pain and improving function in osteoarthritic diseases.


Prostatomembranous urethral disruptions: management by suprapubic cystostomy and delayed urethroplasty.
Management of prostatomembranous urethral disruptions associated with pelvic fractures remains a major controversy in urology. A group of 64 patients who suffered a prostatomembranous urethral disruption in association with a pelvic fracture and who were managed initially by suprapubic cystostomy with delayed urethroplasty was compared to 17 patients managed initially by primary realignment. No statistically significant difference in the incidence of impotence or urinary incontinence was found between the 2 groups (p greater than 0.5) Secondary reconstructions for impassable strictures developed in 95% of the patients treated by a suprapubic tube alone compared to 53% of those treated by primary realignment. Indeed, only 1 patient in the latter group achieved urethral continuity that did not require further intervention. We conclude that while primary realignment is associated with no increase in the instance of impotence and urinary incontinence, it subjects the patient to a major operation at a critical time and provides little in the way of long-term positive gains for the effort expended. In the final analysis the outcome is more dependent upon the nature of the injury and the quality of the repair than upon the order in which the repair is effected.


Fates of visual cortical neurons in the ferret after isochronic and heterochronic transplantation.
In the mammalian cerebral cortex, neurons in a given layer are generated at about the same time in development. These cells also tend to share similar sets of morphological and physiological properties and have projection patterns characteristic of that layer. This correspondence between the birthday and eventual fate of a cortical neuron suggests the possibility that the commitment of a cell to a particular laminar position and set of connections may occur very early on in cortical development. The experiments described here constitute an attempt to manipulate the fates of newly generated cortical neurons upon transplantation. The first set of experiments addressed the normal development of neurons in the primary visual cortex (area 17) of the ferret. Injections of 3H-thymidine into newborn ferrets showed that neurons generated after birth are destined to sit in layer 2/3 of the cortex, whereas neurons born on embryonic day (E) 32 populate primarily layers 5 and 6. Many layer 2/3 neurons in adult ferrets could be retrogradely labeled with HRP from visual cortical areas 18 and 19, while about half of the neurons in layer 6 were found to project to the lateral geniculate nucleus (LGN). In the second set of experiments, presumptive layer 2/3 cells were labeled in vivo by injecting ferrets with 3H-thymidine on P1 and P2. Before the cells had a chance to migrate, they were removed from the donor brain, incubated in a fluorescent dye (DAPI or fast blue), and dissociated into a single-cell suspension. The labeled cells were then transplanted into the proliferative zone of a littermate host ferret ("isochronic" transplants). Over the next few weeks, many of these dye-labeled cells underwent changes in their position and morphology that were consistent with a radially directed migration and subsequent differentiation into cortical neurons. The final positions of isochronically transplanted neurons in the host brain were mapped out by using the 3H-thymidine marker after long survival periods. About 97% of radioactively labeled cells had migrated out into the visual cortex, where they attained a compact laminar distribution: 99% were found in layer 2/3, their normal destination. The labeled cells had normal, mostly pyramidal neuronal morphologies and appeared to be well integrated with host neurons when viewed in Nissl-stained sections. Ten isochronically transplanted neurons were successfully labeled after HRP injection into 2 normal target regions, areas 18 and 19.(ABSTRACT TRUNCATED AT 400 WORDS)


Repeated glucoprivation delayed hyperphagic responses while activating neuropeptide Y neurons in rats.
It is well known that glucoprivation induces the release of counterregulatory hormones such as glucagon, and that the response is attenuated when the stimuli are repeated. Glucoprivation also activates orexigenic neurons and induces hyperphagic responses, although it remains unclear whether these responses are attenuated in repeated glucoprivation. In this study, we examined time course changes in feeding as well as activities of orexigenic neuropeptide Y (NPY) neurons in repeated glucoprivation in rats. Either 2-deoxy-d-glucose (2DG), which blocks glucose utilization, or isotonic saline (control) was injected subcutaneously to rats for 14 days, and food consumption for 1 and 2h after injection was monitored throughout the experiment. While 2DG injection induced robust feeding responses during the first 1h after injection, the response was gradually attenuated and the food consumption was significantly less on days 12-14 compared to that on day 1. On the other hand, food consumption during 2h after 2DG injection was not changed significantly for 14 days. The transcriptional activities of NPY neurons in the arcuate nucleus and C1/A1 region of the hindbrain, measured by intronic in situ hybridization, were significantly enhanced after repeated 2DG injection for 14 days, while the feeding responses to intracerebroventricular injection of NPY were significantly less in the 2DG-repeated group compared to the saline-repeated group. It is thus demonstrated that repeated glucoprivation delayed hyperphagic responses while activating NPY neurons in rats. Our data also suggest that decreased feeding responses to NPY might be at least partially responsible for the delayed response.


Carers: The navigators of the maze of care for people with dementia-A qualitative study.
Dementia is a challenge in our society, with individuals accessing services across multiple settings. Carers are navigating and delivering care services in the home. This research sought to investigate the experiences of people with dementia and their carers when transitioning home from hospital. This study used a qualitative descriptive design, employing in-depth interviews with 30 carers recruited through networks known to one state branch of Alzheimer's Australia. Emerging themes were validated in one focus group. During the hospital stay carers experienced a paradox: being required to deliver care yet perceiving that they were being ignored in regard to decisions about care. The time in hospital was considered by some carers to be stressful, as they were concerned about the safety of the person with dementia. Many reported that discharge home was rarely planned and coordinated. Returning home carers found re-establishing and/or accessing new services challenging, with available services often inappropriate to need. The paradox of the care experience in the acute setting, whereby the carer was either invited, or sought, to deliver care, yet was excluded in staff decisions about that care, challenges the current communication and coordination of care. For people with dementia and their carers, there is a need for a coordinated seamless service that enables continued unbroken care and support from acute care to home. Carers also need support navigating the wide range of services available and importantly both carers and care providers may need to understand service boundaries. This study highlights the need to acknowledge the expertise of the carer, and their need for support. Enabling a smooth discharge from hospital and support to navigate care access in the community is paramount. These experiences provide insight into gaps in service provision and modifying existing services may lead to improved experiences.


Practice on an augmented reality/haptic simulator and library of virtual brains improves residents' ability to perform a ventriculostomy.
Ventriculostomy is a neurosurgical procedure for providing therapeutic cerebrospinal fluid drainage. Complications may arise during repeated attempts at placing the catheter in the ventricle. We studied the impact of simulation-based practice with a library of virtual brains on neurosurgery residents' performance in simulated and live surgical ventriculostomies. Using computed tomographic scans of actual patients, we developed a library of 15 virtual brains for the ImmersiveTouch system, a head- and hand-tracked augmented reality and haptic simulator. The virtual brains represent a range of anatomies including normal, shifted, and compressed ventricles. Neurosurgery residents participated in individual simulator practice on the library of brains including visualizing the 3-dimensional location of the catheter within the brain immediately after each insertion. Performance of participants on novel brains in the simulator and during actual surgery before and after intervention was analyzed using generalized linear mixed models. Simulator cannulation success rates increased after intervention, and live procedure outcomes showed improvement in the rate of successful cannulation on the first pass. However, the incidence of deeper, contralateral (simulator) and third-ventricle (live) placements increased after intervention. Residents reported that simulations were realistic and helpful in improving procedural skills such as aiming the probe, sensing the pressure change when entering the ventricle, and estimating how far the catheter should be advanced within the ventricle. Simulator practice with a library of virtual brains representing a range of anatomies and difficulty levels may improve performance, potentially decreasing complications due to inexpert technique.


Crucial role of endogenous interleukin-10 production in myocardial ischemia/reperfusion injury.
The anti-inflammatory cytokine interleukin-10 (IL-10) has been detected in the plasma of patients with myocardial ischemia/reperfusion. The aim of our study was to investigate the role of endogenously produced IL-10 in myocardial ischemia/reperfusion. In the present study, we used wild-type and IL-10-deficient mice subjected to myocardial ischemia/reperfusion. Significant levels of IL-10 were produced in wild-type mice at 2 to 6 hours after myocardial reperfusion. The genetic deletion of IL-10 enhanced neutrophil infiltration into the reperfused tissues at 6 hours after reperfusion and increased infarct size and myocardial necrosis. Furthermore, in the absence of IL-10, an enhancement of the inflammatory response was seen, as demonstrated by increased plasma levels of tumor necrosis factor-alpha, nitrite/nitrate (breakdown products of NO), and increased tissue expression of intercellular adhesion molecule-1. Reperfusion for 24 hours was associated with a 75% mortality rate in IL-10-deficient mice, whereas no deaths occurred in the wild-type animals. The present findings provide the first direct evidence that endogenous IL-10 inhibits the production of tumor necrosis factor-alpha and NO and serves to protect the ischemic and reperfused myocardium through the suppression of neutrophil recruitment.


Who Cares about Forests and Why? Individual Values Attributed to Forests in a Post-Frontier Region in Amazonia.
Understanding the multiple ways people value forests is important, as individual values regarding nature have been shown to partly determine willingness to participate in conservation initiatives. As individual values are influenced by past experiences, the way people value forests may be related to the ecosystem services they use and receive. We here aim to investigate if people value forests because of material and non-material benefits forest provide (material and non-material values), and if these values are defined by previous experiences associated with using forest resources and having frequent contact with forests. By interviewing 363 residents across 20 landscapes varying in forest cover in a post-frontier region in Amazonia, we evaluated: (1) if the use of forest resources-especially bushmeat, important for sustenance and cash income in virtually all tropical forests-is associated with attributing higher material value to forests; (2) whether the contact with forest (estimated by local forest cover and visits to forests) is associated with attributing higher non-material value to forests. As expected, respondents from households where hunting occurs and bushmeat consumption is more frequent attributed higher material value to forests, and those living in more deforested landscapes and that visited forests less often attributed lower non-material value to forests. The importance of bushmeat in shaping the way people value forests suggests that encouraging the sustainable use of this product will encourage forest conservation. Results also point to a potential dangerous reinforcing cycle: low forest cover and the loss of contact with forests may erode forest values and facilitate further deforestation. Engaging rural communities in forest conservation initiatives is challenging yet urgent in degraded landscapes, although harnessing appreciation for bushmeat could offer a starting point.


QuIN: A Web Server for Querying and Visualizing Chromatin Interaction Networks.
Recent studies of the human genome have indicated that regulatory elements (e.g. promoters and enhancers) at distal genomic locations can interact with each other via chromatin folding and affect gene expression levels. Genomic technologies for mapping interactions between DNA regions, e.g., ChIA-PET and HiC, can generate genome-wide maps of interactions between regulatory elements. These interaction datasets are important resources to infer distal gene targets of non-coding regulatory elements and to facilitate prioritization of critical loci for important cellular functions. With the increasing diversity and complexity of genomic information and public ontologies, making sense of these datasets demands integrative and easy-to-use software tools. Moreover, network representation of chromatin interaction maps enables effective data visualization, integration, and mining. Currently, there is no software that can take full advantage of network theory approaches for the analysis of chromatin interaction datasets. To fill this gap, we developed a web-based application, QuIN, which enables: 1) building and visualizing chromatin interaction networks, 2) annotating networks with user-provided private and publicly available functional genomics and interaction datasets, 3) querying network components based on gene name or chromosome location, and 4) utilizing network based measures to identify and prioritize critical regulatory targets and their direct and indirect interactions. QuIN's web server is available at http://quin.jax.org QuIN is developed in Java and JavaScript, utilizing an Apache Tomcat web server and MySQL database and the source code is available under the GPLV3 license available on GitHub: https://github.com/UcarLab/QuIN/.


Physical properties of emulsion-based hydroxypropyl methylcellulose films: effect of their microstructure.
The initial characteristics of emulsions and the rearrangement of the oil droplets in the film matrix during film drying, which defines its microstructure, has an important role in the physical properties of the emulsion-based films. The objective of this work was to study the effect of the microstructure (two droplet size distributions) and stability (with or without surfactant) of HPMC oil-in-water emulsions over physical properties of HPMC emulsion-based edible films. HPMC was used to prepare sunflower oil-in-water emulsions containing 0.3 or 1.0% (w/w) of oil with or without SDS, as surfactant, using an ultrasonic homogenizer. Microstructure, rheological properties and stability of emulsions (creaming) were measured. In addition, microstructure, coalescence of oil droplets, surface free energy, optical and mechanical properties and water vapor transfer of HPMC films were evaluated. Image analysis did not show differences among droplet size distributions of emulsions prepared at different oil contents; however, by using SDS the droplet size distributions were shifted to lower values. Volume mean diameters were 3.79 and 3.77 μm for emulsions containing 0.3 and 1.0% without surfactant, respectively, and 2.72 and 2.71 μm for emulsions with SDS. Emulsions formulated with 1.0% of oil presented higher stability, with almost no change during 5 and 3 days of storage, for emulsions with and without SDS, respectively. Internal and surface microstructure of emulsion-based films was influenced by the degree of coalescence and creaming of the oil droplets. No effect of microstructure over the surface free energy of films was found. The incorporation of oil impaired the optical properties of films due to light scattering of light. Addition of oil and SDS decreased the stress at break of the emulsion-based films. The replace of HPMC by oil and SDS produce a lower "amount" of network structure in the films, leading to a weakening of their structure. The oil content and SDS addition had an effect over the microstructure and physical properties of HPMC-based emulsions which lead to different microstructures during film formation. The way that oil droplets were structured into the film had an enormous influence over the physical properties of HPMC films.


The Influence of Pain-Related Expectations on Intensity Perception of Nonpainful Somatosensory Stimuli.
The extent to which pain-related expectations, known to affect pain perception, also affect perception of nonpainful sensations remains unclear, as well as the potential role of unpredictability in this context. In a proprioceptive fear conditioning paradigm, various arm extension movements were associated with predictable and unpredictable electrocutaneous pain or its absence. During a subsequent test phase, nonpainful electrocutaneous stimuli with a high or low intensity were presented during movement execution. We used hierarchical drift diffusion modeling to examine the influence of expecting pain on the perceptual decision-making process underlying intensity perception of nonpainful sensations. In the first experiment (n = 36), the pain stimulus was never presented during the test phase after conditioning. In the second experiment (n = 39), partial reinforcement was adopted to prevent extinction of pain expectations. In both experiments, movements that were associated with (un)predictable pain led to higher pain expectancy, self-reported fear, unpleasantness, and arousal as compared with movements that were never paired with pain (effect sizes η2 ranging from 0.119 to 0.557; all p values < .05). Only in the second experiment-when the threat of pain remained present-we found that the expectation of pain affected decision making. Compared with the no pain condition, an a priori decision-making bias toward the high-intensity decision threshold was found with the strongest bias during unpredictable pain (effect sizes η2 ranging from 0.469 to 0.504; all p-values < .001). Thus, the expectation of pain affects inferential processes not only for subsequent painful but also for nonpainful bodily stimuli, with unpredictability moderating these effects, and only when the threat of pain remains present due to partial reinforcement.


Venous surgery for impotence.
Venous surgery for impotence is in a dynamic state. The drainage of the corpora cavernosa normally occurs through the crural veins or the cavernous veins and the deep dorsal penile vein. Patients with drainage seen on cavernosography only into a superficial system that persists after injection of intracavernous vasoactive agents are likely to have good results if this drainage is eliminated. This type of patient is not common. A surgical approach that attempts to eliminate the deep dorsal penile system or the crural veins is not as successful. Perhaps subtle arterial disease, concurrent presence of neurologic disease, and collateralization all add to the significant failure rate. Many failures of spontaneous erection will, however, respond to intracavernous injection of vasoactive agents postoperatively. Deep dorsal vein arterialization probably should be reserved for those patients who have an arterial component to their impotence as well as a venogenic cause.


Newer uses of glucose-insulin-potassium regimen.
Diabetic ketoacidosis and moderate degree of hyperglycemia can be managed by glucose-insulin-potassium (GIK) regimen. The GIK regimen is also useful in the treatment of acute myocardial infarction (AMI). But, the exact mechanism(s) of the beneficial action of GIK regimen is not known. I suggest that glucose-insulin can suppress the secretion and antagonize the harmful effects of tumor necrosis factor alpha (TNF alpha) and macrophage migration inhibitory factor (MIF). If this is true, it suggests that GIK regimen may be useful in septicemia and septic shock, and other inflammatory conditions such as ulcerative colitis, Crohn's disease, rheumatoid arthritis, systemic lupus erythematosus and cancer, conditions in which TNF alpha and MIF appear to play a major role.


Density functional models of the interfacial tensions near the critical endpoints and tricritical point of three-phase equilibria.
We treat two different density-functional models of the structures and tensions of the interfaces between phases on approach to the tricritical point of three-phase equilibrium. The major objective is to account for some of the results of earlier experimental measurements of these tensions. The thermodynamic background is first reviewed, including representations of the properties near the critical endpoints and tricritical point and of the wetting transitions that may occur on approach to those critical points. The first of the models treated is analytically soluble. Its properties are illuminating but at the price of some artificiality paid for its analytical solubility. The second model, called model T, is in a class of those treated in the past and analyzed numerically. Some of its properties are obtained with sufficient precision to allow one to conclude with near certainty what the analytically exact results would be. This model, too, illuminates the experimental measurements. It is noted where its properties are in accord with those of the analytically soluble model and where the two differ.


Exploring the relationship between sequence similarity and accurate phylogenetic trees.
We have characterized the relationship between accurate phylogenetic reconstruction and sequence similarity, testing whether high levels of sequence similarity can consistently produce accurate evolutionary trees. We generated protein families with known phylogenies using a modified version of the PAML/EVOLVER program that produces insertions and deletions as well as substitutions. Protein families were evolved over a range of 100-400 point accepted mutations; at these distances 63% of the families shared significant sequence similarity. Protein families were evolved using balanced and unbalanced trees, with ancient or recent radiations. In families sharing statistically significant similarity, about 60% of multiple sequence alignments were 95% identical to true alignments. To compare recovered topologies with true topologies, we used a score that reflects the fraction of clades that were correctly clustered. As expected, the accuracy of the phylogenies was greatest in the least divergent families. About 88% of phylogenies clustered over 80% of clades in families that shared significant sequence similarity, using Bayesian, parsimony, distance, and maximum likelihood methods. However, for protein families with short ancient branches (ancient radiation), only 30% of the most divergent (but statistically significant) families produced accurate phylogenies, and only about 70% of the second most highly conserved families, with median expectation values better than 10(-60), produced accurate trees. These values represent upper bounds on expected tree accuracy for sequences with a simple divergence history; proteins from 700 Giardia families, with a similar range of sequence similarities but considerably more gaps, produced much less accurate trees. For our simulated insertions and deletions, correct multiple sequence alignments did not perform much better than those produced by T-COFFEE, and including sequences with expressed sequence tag-like sequencing errors did not significantly decrease phylogenetic accuracy. In general, although less-divergent sequence families produce more accurate trees, the likelihood of estimating an accurate tree is most dependent on whether radiation in the family was ancient or recent. Accuracy can be improved by combining genes from the same organism when creating species trees or by selecting protein families with the best bootstrap values in comprehensive studies.