Kinetic analysis of regeneration by dilution of a covalently modified protein.
An analysis of regeneration by dilution of a covalently modified protein is presented. It is shown that, when protein regeneration is realized through the intermediacy of a protein-modifying agent adsorptive complex, the reaction is described by a summation of two exponential functions of reaction time plus a constant-term equation. The conditions whereby this equation reduces to a single-exponential equation are delineated. It is shown that, when protein regeneration is described by a single-exponential function of reaction time, the first-order protein-regeneration rate constant is a function of modifying-agent concentration and also of the microscopic reaction rate constants. Accordingly, the protein-modifying agent dissociation constant (Ki), as well as the protein-covalent-modification and -regeneration, rate constants (k+2 and K-2), may be determined by an analysis of dilution-induced protein-regeneration (or enzyme-reactivation) data obtained at different dilutions of the covalently modified protein-modifying agent preparation.


Spontaneous Intraventricular Hemorrhage: When Should Intraventricular tPA Be Considered?
Spontaneous intracerebral hemorrhage (ICH) is the most common cause of intraventricular hemorrhage (IVH) in adults. Complicating approximately 40% of ICH cases, IVH adds to the morbidity and mortality of this often fatal form of stroke. It is also a severity factor that complicates subarachnoid hemorrhage and traumatic brain injury, along with other less common causes of intracranial bleeding. Medical and surgical interventions to date have focused on limiting ICH and IVH expansion, controlling intracranial pressure, and relieving obstructive hydrocephalus. The placement of an external ventricular drain (EVD) can achieve the latter two goals but has not demonstrated improvement in clinical outcomes beyond mortality reduction. More recently, intraventricular fibrinolysis, utilizing the EVD, has gained interest as a safe and potentially effective method to maintain catheter patency and facilitate hematoma removal. A recent phase III clinical trial evaluating the efficacy of intraventricular alteplase versus intraventricular saline showed a mortality benefit, but failed to meet the primary endpoint of significant functional improvement. However, planned subgroup analysis focusing on patients with IVH volume > 20 mL, and those with IVH removal > 85% suggest that significant functional benefits may be attainable with this therapy. The practice of intraventricular fibrinolysis for spontaneous IVH is not the standard of care; however, based on 20 years of experience, it meets thresholds as a safe intervention, and in those patients with a high burden of intraventricular blood, aggressive clearance may lead to improved quality of life in survivors of this morbid syndrome.


Deletion of phd2 in myeloid lineage attenuates hypertensive cardiovascular remodeling.
Hypertension induces cardiovascular hypertrophy and fibrosis. Infiltrated macrophages are critically involved in this process. We recently reported that inhibition of prolyl hydroxylase domain protein 2 (PHD2), which hydroxylates the proline residues of hypoxia-inducible factor-α (HIF-α) and thereby induces HIF-α degradation, suppressed inflammatory responses in macrophages. We examined whether myeloid-specific Phd2 deletion affects hypertension-induced cardiovascular remodeling. Myeloid-specific PHD2-deficient mice (MyPHD2KO) were generated by crossing Phd2-floxed mice with LysM-Cre transgenic mice, resulting in the accumulation of HIF-1α and HIF-2α in macrophage. Eight- to ten-week-old mice were given N(G)-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor, and Angiotensin II (Ang II) infusion. L-NAME/Ang II comparably increased systolic blood pressure in control and MyPHD2KO mice. However, MyPHD2KO mice showed less aortic medial and adventitial thickening, and macrophage infiltration. Cardiac interstitial fibrosis and myocyte hypertrophy were also significantly ameliorated in MyPHD2KO mice. Transforming growth factor-β and collagen expression were decreased in the aorta and heart from MyPHD2KO mice. Echocardiographic analysis showed that left ventricular hypertrophy and reduced ejection fraction induced by L-NAME/Ang II treatment in control mice were not observed in MyPHD2KO mice. Administration of digoxin that inhibits HIF-α synthesis to L-NAME/Ang II-treated MyPHD2KO mice reversed these beneficial features. Phd2 deletion in myeloid lineage attenuates hypertensive cardiovascular hypertrophy and fibrosis, which may be mediated by decreased inflammation- and fibrosis-associated gene expression in macrophages. PHD2 in myeloid lineage plays a critical role in hypertensive cardiovascular remodeling.


Pulmonary Endogenous Fluorescence Allows the Distinction of Primary Lung Cancer from the Perilesional Lung Parenchyma.
Pre-therapeutic pathological diagnosis is a crucial step of the management of pulmonary nodules suspected of being non small cell lung cancer (NSCLC), especially in the frame of currently implemented lung cancer screening programs in high-risk patients. Based on a human ex vivo model, we hypothesized that an embedded device measuring endogenous fluorescence would be able to distinguish pulmonary malignant lesions from the perilesional lung tissue. Consecutive patients who underwent surgical resection of pulmonary lesions were included in this prospective and observational study over an 8-month period. Measurements were performed back table on surgical specimens in the operative room, both on suspicious lesions and the perilesional healthy parenchyma. Endogenous fluorescence signal was characterized according to three criteria: maximal intensity (Imax), wavelength, and shape of the signal (missing, stable, instable, photobleaching). Ninety-six patients with 111 suspicious lesions were included. Final pathological diagnoses were: primary lung cancers (n = 60), lung metastases of extra-thoracic malignancies (n = 27) and non-tumoral lesions (n = 24). Mean Imax was significantly higher in NSCLC targeted lesions when compared to the perilesional lung parenchyma (p<0,0001) or non-tumoral lesions (p<0,0001). Similarly, photobleaching was more frequently found in NSCLC than in perilesional lung (p<0,0001), or in non-tumoral lesions (p<0,001). Respective associated wavelengths were not statistically different between perilesional lung and either primary lung cancers or non-tumoral lesions. Considering lung metastases, both mean Imax and wavelength of the targeted lesions were not different from those of the perilesional lung tissue. In contrast, photobleaching was significantly more frequently observed in the targeted lesions than in the perilesional lung (p≤0,01). Our results demonstrate that endogenous fluorescence applied to the diagnosis of lung nodules allows distinguishing NSCLC from the surrounding healthy parenchyma and from non-tumoral lesions. Inconclusive results were found for lung metastases due to the heterogeneity of this population.


Tea extracts protect normal lymphocytes but not leukemia cells from UV radiation-induced ROS production: An EPR spin trap study.
An ex vivo method for detection of free radicals and their neutralization by aqueous tea in human normal lymphocytes and MEC-1 leukemia cells under ultraviolet (UV) irradiation was investigated. This method is based on the electron paramagnetic resonance (EPR) spectroscopy spin-trapping technique. 5-tert-butoxycarbonyl 5-methyl-1-pyrroline N-oxide (BMPO) was used as the spin trap. Normal human lymphocytes and leukemia cells were exposed to UVB radiation (290-315 nm) at 47.7 and 159 mJ/cm(2) and to UVA radiation (315-400 nm) at 53.7 J/cm(2). No significant radical production at 47.7 mJ/cm(2) UVB dose in both cell lines was observed. In normal cells, free radical production was observed at 159 mJ/cm(2) UVB and 53.7 J/cm(2) UVA doses. However, both UV sources did not significantly produce free radicals in leukemia cells. A radical scavenging property of tea extracts (black, green, sage, rosehip) was observed in normal lymphocytes after both UVB and UVA exposure. In leukemia cells, the intensities of EPR signals produced in BMPO with tea extracts were found to be increased substantially after UVA exposure. These results showed that UV radiation induced free radical formation in normal human lymphocytes and indicated that tea extracts may be useful as photoprotective agents for them. On the other hand, tea extracts facilitated free radical production in leukemia cells.


Correlations in weighted networks.
We develop a statistical theory to characterize correlations in weighted networks. We define the appropriate metrics quantifying correlations and show that strictly uncorrelated weighted networks do not exist due to the presence of structural constraints. We also introduce an algorithm for generating maximally random weighted networks with arbitrary P(k,s) to be used as null models. The application of our measures to real networks reveals the importance of weights in a correct understanding and modeling of these heterogeneous systems.


Preparation, In Vivo Administration, Dose-Limiting Toxicities, and Antineoplastic Activity of Cytochalasin B.
An effective and inexpensive protocol for producing cytochalasins A and B is being disclosed to propose a viable method by which to examine the in vivo antineoplastic activity of these congeners in preclinical tumor-bearing mammalian models. In addition, we determine the maximum tolerated doses of cytochalasin B using multiple routes and formulations, characterize the tissue distribution of intravenous bolus cytochalasin B, and assess the in vivo antineoplastic activity of cytochalasin B in comparison in doxorubicin in Balb/c mice challenged intradermally with M109 murine lung carcinoma. We also examine the effects of cytochalasin B against several other murine neoplastic cell lines (Lewis lung, LA4, B16F10, and M5076). Finally, we examine a potential mechanism of the antimetastatic activity of cytochalasin B by observing the effects of the agent on the secretion of N-acetylglucosaminidase (GlcNACase) by B16BL6 and B16F10 murine melanomas in vitro. The results of the study can be summarized as follows: 1) Cytochalasin B can be safely administered intravenously, intraperitoneally, and subcutaneously in murine models, with the maximum tolerated dose of all routes of administration being increased by liposome encapsulation. 2) Cytochalasin B can significantly inhibit the growth of tumors in mice challenged with M109, Lewis lung, LA4, B16F10, or M5076, producing long-term survival against lung carcinomas and adenocarcinomas (M109, Lewis lung, and LA4) and B16F10 melanoma, but not M5076 sarcoma. These effects were comparable to intraperitoneally administered doxorubicin. 4) Low concentrations of cytochalasin B inhibit the secretion of GlcNACase, indicating that cytochalasin B may inhibit metastatic progression by mechanisms not directly associated with its influence on cell adhesion and motility.


Health-related fitness in children and adolescents.
The American Physical Therapy Association Section on Pediatrics developed a task force to summarize fitness guidelines for children and adolescents. The purposes of this article were to review components, measurement methods, and consequences of physical fitness, and to summarize evidence-based activity recommendations for youth. Health-related fitness is comprised of body composition, flexibility, cardiorespiratory endurance, and muscular strength and endurance. Each of these components is reviewed in terms of definition, assessment, normative values, and recommendations. The task force supports the guidelines of the US Department of Health and Human Services, which state that to promote overall health and wellness, youth should participate in 60 minutes or more of physical activity every day. Physical therapists should apply research relevant to health-related fitness when treating youth. Promoting fitness, health, and wellness in our communities is a responsibility all therapists should assume.


Gender and social geography: impact on Lady Health Workers mobility in Pakistan.
In Pakistan, where gendered norms restrict women's mobility, female community health workers (CHWs) provide doorstep primary health services to home-bound women. The program has not achieved optimal functioning. One reason, I argue, may be that the CHWs are unable to make home visits because they have to operate within the same gender system that necessitated their appointment in the first place. Ethnographic research shows that women's mobility in Pakistan is determined not so much by physical geography as by social geography (the analysis of social phenomena in space). Irrespective of physical location, the presence of biradaria members (extended family) creates a socially acceptable 'inside space' to which women are limited. The presence of a non-biradari person, especially a man, transforms any space into an 'outside space', forbidden space. This study aims to understand how these cultural norms affect CHWs' home-visit rates and the quality of services delivered. Data will be collected in district Attock, Punjab. Twenty randomly selected CHWs will first be interviewed to explore their experiences of delivering doorstep services in the context of gendered norms that promote women's seclusion. Each CHW will be requested to draw a map of her catchment area using social mapping techniques. These maps will be used to survey women of reproductive age to assess variations in the CHW's home visitation rates and quality of family planning services provided. A sample size of 760 households (38 per CHW) is estimated to have the power to detect, with 95% confidence, households the CHWs do not visit. To explore the role of the larger community in shaping the CHWs mobility experiences, 25 community members will be interviewed and five CHWs observed as they conduct their home visits. The survey data will be merged with the maps to demonstrate if any disjunctures exist between CHWs' social geography and physical geography. Furthermore, the impacts these geographies have on home visitation rates and quality of services delivered will be explored. The study will provide generic and theoretical insights into how the CHW program policies and operations can improve working conditions to facilitate the work of female staff in order to ultimately provide high-quality services.


Development and integration of xerogel polymeric absorbance micro-filters into lab-on-chip systems.
This work reports on the implementation of different absorption micro-filters based on a dye-doped hybrid organic-inorganic xerogel polymeric material synthesized by the sol-gel process. Microstructures containing eight different filter widths were fabricated in polydimethylsiloxane (PDMS), bonded to glass substrates and filled with the corresponding dye doped polymeric material by a soft lithography approach. The filtering capacity as a function of dye concentration and filter width was studied and revealed a linear dependence with both parameters, as expected according to the Beer-Lambert law. Zero passband transmittance values and relatively sharp stopband regions were achieved with all the filters, also showing rejection levels between -6 dB and -55 dB. Finally, such filters were monolithically integrated into a disposable fluorescence-based photonic lab-on-a-chip (PhLoC) approach. Calibration curves carried out with a model fluorophore target analyte showed an over two-fold increase in sensitivity and a thirty-fold decrease of the limit of detection (LOD) compared with the values recorded using the same PhLoC system but without the polymeric filter structure. The results presented herein clearly indicate the feasibility of these xerogel-based absorbance filtering structures for being applied as low-cost optical components that can be easily incorporated into disposable fluorescence-based photonic lab on a chip systems.


High-dose immunoglobulin preparations improve survival in a CLP-induced rat model of sepsis.
The efficacy of intravenous immunoglobulin G in the treatment of patients with severe sepsis or septic shock is still being debated. We investigated the impact of high-dose immunoglobulin administration on the survival rate and serum high-mobility group box chromosomal protein 1 (HMGB1) level in a rat model of sepsis created by cecal ligation and puncture (CLP). Rats received either CLP-induced sepsis or had additional immunoglobulin treatment in 1,500 or 300 mg/kg. After induction of sepsis and respective treatment conditions, pulmonary and renal tissues were examined histologically for pathological changes at postoperative hour (POH) 4, and serum cytokine and HMGB1 levels were measured at POH 4, 8, 20, and 44. Using other rats, we also observed the survival rate after CLP for 7 days. Treatment with immunoglobulin significantly improved survival rate at postoperative day 7 (73% in the high-dose group vs. 33% in the control group; p = 0.037). The serum lactate dehydrogenase, endotoxin, creatinine, and blood urea nitrogen levels were significantly lower in the high-dose group than in the other groups. The serum HMGB1 level had increased at 4 h postoperatively in the control group (10.2 ± 3.3 ng/mL) and low-dose group (10.3 ± 4.0 ng/mL), but it was significantly reduced in the high-dose group (4.2 ± 0.8 ng/mL) compared with the control group (p = 0.03). Our results suggest that high-dose immunoglobulin therapy may improve the serum endotoxin and HMGB1 levels and overall survival rate in sepsis by inhibiting the inflammation.


Analysis of photometric factors based on photometric linearization.
We propose a method for analyzing photometric factors, such as diffuse reflection, specular reflection, attached shadow, and cast shadow. For analyzing real images, we utilize the photometric linearization method, which was originally proposed for image synthesis. First, we show that each pixel can be photometrically classified by a simple comparison of the pixel intensity. Our classification algorithm requires neither 3D shape information nor color information of the scene. Then, we show that the accuracy of the photometric linearization can be improved by introducing a new classification-based criterion to the linearization process. Experimental results show that photometric factors can be correctly classified without any special devices. A further experiment shows that the proposed method is effective for photometric stereo.


Decitabine rescues cisplatin resistance in head and neck squamous cell carcinoma.
Cisplatin resistance in head and neck squamous cell carcinoma (HNSCC) reduces survival. In this study we hypothesized that methylation of key genes mediates cisplatin resistance. We determined whether a demethylating drug, decitabine, could augment the anti-proliferative and apoptotic effects of cisplatin on SCC-25/CP, a cisplatin-resistant tongue SCC cell line. We showed that decitabine treatment restored cisplatin sensitivity in SCC-25/CP and significantly reduced the cisplatin dose required to induce apoptosis. We then created a xenograft model with SCC-25/CP and determined that decitabine and cisplatin combination treatment resulted in significantly reduced tumor growth and mechanical allodynia compared to control. To establish a gene classifier we quantified methylation in cancer tissue of cisplatin-sensitive and cisplatin-resistant HNSCC patients. Cisplatin-sensitive and cisplatin-resistant patient tumors had distinct methylation profiles. When we quantified methylation and expression of genes in the classifier in HNSCC cells in vitro, we showed that decitabine treatment of cisplatin-resistant HNSCC cells reversed methylation and gene expression toward a cisplatin-sensitive profile. The study provides direct evidence that decitabine restores cisplatin sensitivity in in vitro and in vivo models of HNSCC. Combination treatment of cisplatin and decitabine significantly reduces HNSCC growth and HNSCC pain. Furthermore, gene methylation could be used as a biomarker of cisplatin-resistance.


Automatic analysis, theme generation, and summarization of machine-readable texts.
Vast amounts of text material are now available in machine-readable form for automatic processing. Here, approaches are outlined for manipulating and accessing texts in arbitrary subject areas in accordance with user needs. In particular, methods are given for determining text themes, traversing texts selectively, and extracting summary statements that reflect text content.


Grade-Dependent Metabolic Reprogramming in Kidney Cancer Revealed by Combined Proteomics and Metabolomics Analysis.
Kidney cancer [or renal cell carcinoma (RCC)] is known as "the internist's tumor" because it has protean systemic manifestations, suggesting that it utilizes complex, nonphysiologic metabolic pathways. Given the increasing incidence of this cancer and its lack of effective therapeutic targets, we undertook an extensive analysis of human RCC tissue employing combined grade-dependent proteomics and metabolomics analysis to determine how metabolic reprogramming occurring in this disease allows it to escape available therapeutic approaches. After validation experiments in RCC cell lines that were wild-type or mutant for the Von Hippel-Lindau tumor suppressor, in characterizing higher-grade tumors, we found that the Warburg effect is relatively more prominent at the expense of the tricarboxylic acid cycle and oxidative metabolism in general. Further, we found that the glutamine metabolism pathway acts to inhibit reactive oxygen species, as evidenced by an upregulated glutathione pathway, whereas the β-oxidation pathway is inhibited, leading to increased fatty acylcarnitines. In support of findings from previous urine metabolomics analyses, we also documented tryptophan catabolism associated with immune suppression, which was highly represented in RCC compared with other metabolic pathways. Together, our results offer a rationale to evaluate novel antimetabolic treatment strategies being developed in other disease settings as therapeutic strategies in RCC.


Positive and negative effects of widespread badger culling on tuberculosis in cattle.
Human and livestock diseases can be difficult to control where infection persists in wildlife populations. For three decades, European badgers (Meles meles) have been culled by the British government in a series of attempts to limit the spread of Mycobacterium bovis, the causative agent of bovine tuberculosis (TB), to cattle. Despite these efforts, the incidence of TB in cattle has risen consistently, re-emerging as a primary concern for Britain's cattle industry. Recently, badger culling has attracted controversy because experimental studies have reached contrasting conclusions (albeit using different protocols), with culled areas showing either markedly reduced or increased incidence of TB in cattle. This has confused attempts to develop a science-based management policy. Here we use data from a large-scale, randomized field experiment to help resolve these apparent differences. We show that, as carried out in this experiment, culling reduces cattle TB incidence in the areas that are culled, but increases incidence in adjoining areas. These findings are biologically consistent with previous studies but will present challenges for policy development.


Misoprostol in addition to routine treatment of postpartum hemorrhage: a hospital-based randomized-controlled trial in Karachi, Pakistan.
Postpartum hemorrhage (PPH) remains a major killer of women worldwide. Standard uterotonic treatments used to control postpartum bleeding do not always work and are not always available. Misoprostol's potential as a treatment option for PPH is increasingly known, but its use remains ad hoc and available evidence does not support the safety or efficacy of one particular regimen. This study aimed to determine the adjunct benefit of misoprostol when combined with standard oxytocics for PPH treatment. A randomized controlled trial was conducted in four Karachi hospitals from December 2005 - April 2007 to assess the benefit of a 600 mcg dose of misoprostol given sublingually in addition to standard oxytocics for postpartum hemorrhage treatment. Consenting women had their blood loss measured after normal vaginal delivery and were enrolled in the study after losing more than 500 ml of blood. Women were randomly assigned to receive either 600 mcg sublingual misoprostol or matching placebo in addition to standard PPH treatment with injectable oxytocics. Both women and providers were blinded to the treatment assignment. Blood loss was collected until active bleeding stopped and for a minimum of one hour after PPH diagnosis. Total blood loss, hemoglobin measures, and treatment outcomes were recorded for all participants. Due to a much lower rate of PPH than expected (1.2%), only sixty-one patients were diagnosed and treated for their PPH in this study, and we were therefore unable to measure statistical significance in any of the primary endpoints. The addition of 600 mcg sublingual misoprostol to standard PPH treatments does, however, suggest a trend in reduced postpartum blood loss, a smaller drop in postpartum hemoglobin, and need for fewer additional interventions. Women who bled less overall had a significantly smaller drop in hemoglobin and received fewer additional interventions. There were no hysterectomies or maternal deaths among study participants. The rate of transient shivering and fever was significantly higher among women receiving misoprostol A 600 mcg dose of misoprostol given sublingually shows promise as an adjunct treatment for PPH and its use should continue to be explored for its life-saving potential in the care of women experiencing PPH. Clinical trials.gov, Registry No. NCT00116480.


Using self-reported callous-unemotional traits to cross-nationally assess the DSM-5 'With Limited Prosocial Emotions' specifier.
The presence of callous-unemotional (CU) traits designates an important subgroup of antisocial youth at risk for severe, persistent, and impairing conduct problems. As a result, the fifth revision of the Diagnostic and Statistical Manual includes a specifier for youth meeting diagnostic criteria for Conduct Disorder who show elevated CU traits. The current study evaluated the DSM-5 criteria using Item Response Theory (IRT) analyses and evaluated two methods for using a self-report measure of CU traits to make this diagnosis. The sample included 2257 adolescent (M age = 15.64, SD = 1.69 years) boys (53%) and girls (47%) from community and incarcerated settings in the United States and the European countries of Belgium, Germany, and Cyprus. IRT analyses suggested that four- or eight-item sets from the self-report measure (comparable to the symptoms used by the DSM-5 specifier) provided good model fit, suggesting that they assess a single underlying CU construct. Further, the most stringent method of scoring the self-report scale (i.e. taking only the most extreme responses) to approximate symptom presence provided the best discrimination in IRT analyses, showed reasonable prevalence rates of the specifier, and designated community adolescents who were highly antisocial, whereas the less stringent method best discriminated detained youth. Refined self-report scales developed on the basis of IRT findings provided good assessments of most of the symptoms used in the DSM-5 criteria. These scales may be used as one component of a multimethod assessment of the 'With Limited Prosocial Emotions' specifier for Conduct Disorder.


Clinical assessment of the scapula: a review of the literature.
Scientific evidence supporting a role for faulty scapular positioning in patients with various shoulder disorders is cumulating. Clinicians who manage patients with shoulder pain and athletes at risk of developing shoulder pain need to have the skills to assess static and dynamic scapular positioning and dynamic control. Several methods for the assessment of scapular positioning are described in scientific literature. However, the majority uses expensive and specialised equipment (laboratory methods), making their use in clinical practice nearly impossible. On the basis of biometric and kinematic studies, guidelines for interpreting the observation of static and dynamic scapular positioning pattern in patients with shoulder pain are provided. At this point, clinicians can use reliable clinical tests for the assessment of both static and dynamic scapular positioning in patients with shoulder pain. However, this review also provides clinicians several possible pitfalls when performing clinical scapular evaluation. On the basis of its clinical relevance, its proven reliability, its relation to body length and its applicability in a clinical setting, this review recommends to assess the scapula both static (visual observation and acromial distance or Baylor/double square method for shoulder protraction) and semidynamic (visual observation and inclinometry for scapular upward rotation). In addition, when the patient demonstrates with shoulder impingement symptoms, the scapular repositioning test and scapular assistant test are recommended for relating the patients' symptoms to the position or movement of the scapula.


Hepatic Autophagy Deficiency Compromises Farnesoid X Receptor Functionality and Causes Cholestatic Injury.
Autophagy is important for hepatic homeostasis, nutrient regeneration, and organelle quality control. We investigated the mechanisms by which liver injury occurred in the absence of autophagy function. We found that mice deficient in autophagy because of the lack of autophagy-related gene 7 or autophagy-related gene 5, key autophagy-related genes, manifested intracellular cholestasis with increased levels of serum bile acids, a higher ratio of tauromuricholic acid/taurocholic acid in the bile, increased hepatic bile acid load, abnormal bile canaliculi, and altered expression of hepatic transporters. In determining the underlying mechanism, we found that autophagy sustained and promoted the basal and up-regulated expression of farnesoid X receptor (Fxr) in the fed and starved conditions, respectively. Consequently, expression of Fxr and its downstream genes, particularly bile salt export pump, and the binding of FXR to the promoter regions of these genes, were suppressed in autophagy-deficient livers. In addition, codeletion of nuclear factor erythroid 2-related factor 2 (Nrf2) in autophagy deficiency status reversed the FXR suppression. Furthermore, the cholestatic injury of autophagy-deficient livers was reversed by enhancement of FXR activity or expression, or by Nrf2 deletion. Conclusion: Together with earlier reports that FXR can suppress autophagy, our findings indicate that autophagy and FXR form a regulatory loop and deficiency of autophagy causes abnormal FXR functionality, leading to the development of intracellular cholestasis and liver injury.


Extremes in vitamin K status of bone are related to bone ultrasound properties in children with juvenile idiopathic arthritis.
Osteopenia is a common complication of juvenile idiopathic arthritis (JIA). In adults, low bone density and increased fracture risk are associated with low vitamin K status of bone. The vitamin K-dependent protein osteocalcin plays an important role in bone metabolism. Its activity depends upon post-translational carboxylation in which vitamin K is an essential co-factor. Hence, vitamin K deficiency leads to under-carboxylated (i.e., inactive) osteocalcin (ucOC). Little is known about the vitamin K status and bone health in children with juvenile idiopathic arthritis (JIA). We studied the vitamin K status of bone and its association with bone mass properties in children with JIA compared to healthy children. We performed a cross sectional study in 55 children with JIA and 54 healthy controls between 6-18 years of age. Bone markers, ultrasound bone mass properties and vitamin K status of bone were determined. Overall, no differences in vitamin K status of bone were found between the study groups. Among children with JIA, a high ratio of ucOC/cOC indicating low vitamin K status was associated with low bone ultrasound parameters, whereas children with a high vitamin K status had markedly higher bone properties. This association was independent of physical activity, age, gender and BMI. These results suggest that vitamin K may be one of multiple risk factors for low bone mass in children with JIA, in addition to other recognized determinants of bone mass. The question remains whether JIA patients would benefit from increased dietary vitamin K intake.


Increased glycation and oxidative damage to apolipoprotein B100 of LDL cholesterol in patients with type 2 diabetes and effect of metformin.
The aim of this study was to investigate whether apolipoprotein B100 of LDL suffers increased damage by glycation, oxidation, and nitration in patients with type 2 diabetes, including patients receiving metformin therapy. For this study, 32 type 2 diabetic patients and 21 healthy control subjects were recruited; 13 diabetic patients were receiving metformin therapy (median dose: 1.50 g/day). LDL was isolated from venous plasma by ultracentrifugation, delipidated, digested, and analyzed for protein glycation, oxidation, and nitration adducts by stable isotopic dilution analysis tandem mass spectrometry. Advanced glycation end product (AGE) content of apolipoprotein B100 of LDL from type 2 diabetic patients was higher than from healthy subjects: arginine-derived AGE, 15.8 vs. 5.3 mol% (P < 0.001); and lysine-derived AGE, 2.5 vs. 1.5 mol% (P < 0.05). Oxidative damage, mainly methionine sulfoxide residues, was also increased: 2.5 vs. 1.1 molar equivalents (P < 0.001). 3-Nitrotyrosine content was decreased: 0.04 vs. 0.12 mol% (P < 0.05). In diabetic patients receiving metformin therapy, arginine-derived AGE and methionine sulfoxide were lower than in patients not receiving metformin: 19.3 vs. 8.9 mol% (P < 0.01) and 2.9 vs. 1.9 mol% (P < 0.05), respectively; 3-nitrotyrosine content was higher: 0.10 vs. 0.03 mol% (P < 0.05). Fructosyl-lysine residue content correlated positively with fasting plasma glucose. Arginine-derived AGE residue contents were intercorrelated and also correlated positively with methionine sulfoxide. Patients with type 2 diabetes had increased arginine-derived AGEs and oxidative damage in apolipoprotein B100 of LDL. This was lower in patients receiving metformin therapy, which may contribute to decreased oxidative damage, atherogenicity, and cardiovascular disease.


Demographic, lifestyle, and other factors in relation to antimüllerian hormone levels in mostly late premenopausal women.
To identify reproductive, lifestyle, hormonal, and other correlates of circulating antimüllerian hormone (AMH) concentrations in mostly late premenopausal women. Cross-sectional study. Not applicable. A total of 671 premenopausal women not known to have cancer. None. Concentrations of AMH were measured in a single laboratory using the picoAMH ELISA. Multivariable-adjusted median (and interquartile range) AMH concentrations were calculated using quantile regression for several potential correlates. Older women had significantly lower AMH concentrations (≥40 [n = 444] vs. <35 years [n = 64], multivariable-adjusted median 0.73 ng/mL vs. 2.52 ng/mL). Concentrations of AMH were also significantly lower among women with earlier age at menarche (<12 [n = 96] vs. ≥14 years [n = 200]: 0.90 ng/mL vs. 1.12 ng/mL) and among current users of oral contraceptives (n = 27) compared with never or former users (n = 468) (0.36 ng/mL vs. 1.15 ng/mL). Race, body mass index, education, height, smoking status, parity, and menstrual cycle phase were not significantly associated with AMH concentrations. There were no significant associations between AMH concentrations and androgen or sex hormone-binding globulin concentrations or with factors related to blood collection (e.g., sample type, time, season, and year of blood collection). Among premenopausal women, lower AMH concentrations are associated with older age, a younger age at menarche, and currently using oral contraceptives, suggesting these factors are related to a lower number or decreased secretory activity of ovarian follicles.


Analysis of correlation-based biomolecular networks from different omics data by fitting stochastic block models.
Background: Biological entities such as genes, promoters, mRNA, metabolites or proteins do not act alone, but in concert in their network context. Modules, i.e., groups of nodes with similar topological properties in these networks characterize important biological functions of the underlying biomolecular system. Edges in such molecular networks represent regulatory and physical interactions, and comparing them between conditions provides valuable information on differential molecular mechanisms. However, biological data is inherently noisy and network reduction techniques can propagate errors particularly to the level of edges. We aim to improve the analysis of networks of biological molecules by deriving modules together with edge relevance estimations that are based on global network characteristics. Methods: The key challenge we address here is investigating the capability of stochastic block models (SBMs) for representing and analyzing different types of biomolecular networks. Fitting them to SBMs both delivers modules of the networks and enables the derivation of edge confidence scores, and it has not yet been investigated for analyzing biomolecular networks. We apply SBM-based analysis independently to three correlation-based networks of breast cancer data originating from high-throughput measurements of different molecular layers: either transcriptomics, proteomics, or metabolomics. The networks were reduced by thresholding for correlation significance or by requirements on scale-freeness. Results and discussion: We find that the networks are best represented by the hierarchical version of the SBM, and many of the predicted blocks have a biologically and phenotypically relevant functional annotation. The edge confidence scores are overall in concordance with the biological evidence given by the measurements. We conclude that biomolecular networks can be appropriately represented and analyzed by fitting SBMs. As the SBM-derived edge confidence scores are based on global network connectivity characteristics and potential hierarchies within the biomolecular networks are considered, they could be used as additional, integrated features in network-based data comparisons.


Surgical outcome of lumbar fusion surgery in patients with Parkinson disease.
Retrospective study. To investigate the overall surgical outcome of lumbar fusion surgery in patients with Parkinson disease (PD). SUMMARY OF BACK GROUND DATA: Poor bone quality and muscular dysfunction are important clinical manifestations connected with musculoskeletal diseases in PD patients. These secondary changes caused by PD often result in spinal pathology, indicating spine operations for some patients with scoliosis, kyphosis, osteoporotic fracture, or degenerative spondylosis. However, little is known about the surgical outcome or prognosis of spine surgery in PD patients. Lumbar fusion surgery was performed on 20 patients who had PD and degenerative spinal diseases. At the time of lumbar fusion surgery, the mean duration of PD, age, sex, the preoperative visual analog pain scale (VAS, 0 to 100 mm) for low back pain, Hoehn and Yahr staging, and other comorbidities were evaluated. Patients' postoperative clinical outcome was measured using the criteria of Kim and Kim and VAS for back pain. Radiographic assessment was made using plain films and a dynamogram. At the time of the spine surgery, Hoehn and Yahr staging of PD was from 1 to 2 in all patients. Only 1 patient had a satisfactory outcome; a good result according to Kim and Kim's criteria. The average postoperative VAS (mm) was 55.2, whereas the mean preoperative VAS (mm) was 53.9. Radiological assessment showed fusion status in 15 patients and probably no solid fusion mass in 5 patients. A poor surgical outcome would be inevitable because of the worsening of symptoms owing to the natural history of PD. Therefore, our current study suggested surgical indication should be exercised cautiously in the patients with PD and spinal stenosis.


Neural mechanisms for learning self and other ownership.
Sense of ownership is a ubiquitous and fundamental aspect of human cognition. Here we used model-based functional magnetic resonance imaging and a novel minimal ownership paradigm to probe the behavioural and neural mechanisms underpinning ownership acquisition for ourselves, friends and strangers. We find a self-ownership bias at multiple levels of behaviour from initial preferences to reaction times and computational learning rates. Ventromedial prefrontal cortex (vmPFC) and anterior cingulate sulcus (ACCs) responded more to self vs. stranger associations, but despite a pervasive neural bias to track self-ownership, no brain area tracked self-ownership exclusively. However, ACC gyrus (ACCg) specifically coded ownership prediction errors for strangers and ownership associative strength for friends and strangers but not for self. Core neural mechanisms for associative learning are biased to learn in reference to self but also engaged when learning in reference to others. In contrast, ACC gyrus exhibits specialization for learning about others.


The epilepsy treatment gap in developing countries: a systematic review of the magnitude, causes, and intervention strategies.
In many developing countries, people with epilepsy do not receive appropriate treatment for their condition, a phenomenon called the treatment gap (TG). We carried out a systematic review to investigate the magnitude, causes, and intervention strategies to improve outcomes in developing countries. We systematically searched MEDLINE, EMBASE, and PsycINFO databases, supplemented by a hand search of references in the key papers. The degree of heterogeneity and a pooled TG estimate were determined using metaanalysis techniques. The estimates were further stratified by continent and location of study (urban, rural). Twenty-seven studies met the inclusion criteria: twelve from Africa, nine from Asia and six from Latin America. We observed a high degree of heterogeneity and inconsistency between studies. The overall estimate of the TG was 56/100 [95% confidence interval (CI) 31.1-100.0]. The variation in estimates could possibly be explained by nonuniform TG estimation methods and the diverse study populations, among other factors. The TG was mainly attributed to inadequate skilled manpower, cost of treatment, cultural beliefs, and unavailability of antiepileptic drugs (AEDs). These factors have been addressed using different intervention strategies, such as education and supply of AEDs. Future research should estimate the TG coherently and develop sustainable interventions that will address the causes.


Performance of microbial fuel cell in response to change in sludge loading rate at different anodic feed pH.
Performance of two dual chambered mediator-less microbial fuel cells (MFCs) was evaluated at different sludge loading rate (SLR) and feed pH. Optimum performance in terms of organic matter removal and power production was obtained at the SLR of 0.75 kg COD kg VSS(-1) d(-1). Maximum power density of 158 mW/m(2) and 600 mW/m(2) was obtained in MFC-1 (feed pH 6.0) and MFC-2 (feed pH 8.0), respectively. Internal resistance of the cell decreased with increase in SLR. When operated only with biofilm on anode, the maximum power density was 109.5 mW/m(2) in MFC-1 and 459 mW/m(2) in MFC-2, which was, respectively, 30% and 23.5% less than the value obtained in MFC-1 and MFC-2 at SLR of 0.75 kg COD kg VSS(-1) d(-1). Maximum volumetric power of 15.51 W/m(3) and 36.72 W/m(3) was obtained in MFC-1 and MFC-2, respectively, when permanganate was added as catholyte. Higher feed pH (8.0) favoured higher power production.


The New Destination Disadvantage: Disparities in Hispanic Health Insurance Coverage Rates in Metropolitan and Nonmetropolitan New and Established Destinations.
Hispanics have the lowest health insurance rates of any racial/ethnic group, but rates vary significantly across the U.S. The unprecedented growth of the Hispanic population since 1990 in rural areas with previously small or non-existent Hispanic populations raises questions about disparities in access to health insurance coverage. Identifying spatial disparities in Hispanic health insurance rates can illuminate the specific contexts within which Hispanics are least likely to have health care access and inform policy approaches for increasing coverage in different spatial contexts. Using county-level data from the 2009/2013 American Community Survey, I find that early new destinations (i.e., those that experienced rapid Hispanic population growth during the 1990s) have the lowest Hispanic adult health insurance coverage rates, with little variation by metropolitan status. Conversely, among the most recent new destinations that experienced significant Hispanic population growth during the 2000s, metropolitan counties have Hispanic health insurance rates that are similar to established destinations, but rural counties have Hispanic health insurance rates that are significantly lower than those in established destinations. Findings demonstrate that the new destination disadvantage is driven entirely by higher concentrations of immigrant non-citizen Hispanics in these counties, but labor market conditions were salient drivers of the spatially uneven distribution of foreign-born non-citizen Hispanics to new destinations, particularly in rural areas.


Skin pigmentation, self-perceived color, and arterial blood pressure in Puerto Rico.
Darker skin color has been associated with higher average blood pressure in several African-derived populations in the Americas. This pattern has been interpreted as evidence of genetic, physiologic, or sociocultural mechanisms, but existing evidence does not provide an adequate means of evaluating these alternatives. This paper introduces a measurement strategy to isolate the cultural and biological dimensions of skin color, and it develops a specific hypothesis regarding the cultural significance of skin color in Puerto Rico and its relationship to arterial blood pressure. Data come from a face-to-face survey in southeastern Puerto Rico (N = 100). There is no association between blood pressure and skin pigmentation, as measured by reflectance spectrophotometry. However, the discrepancy between self-perceived color and skin pigmentation, a measure we call "color incongruity," is associated with systolic blood pressure (SBP) through an interaction with socioeconomic status (SES) (P = 0.009). For low-SES respondents, darker self-ratings of color relative to skin pigmentation are associated with higher mean SBP. For high-SES respondents, however, darker self-ratings of color relative to pigmentation are associated with lower mean SBP. We interpret this pattern as evidence that the relationship between skin color and blood pressure is mediated by sociocultural processes, and we highlight the need for testable hypotheses and appropriate measurement operations in research on racial inequalities in health.


Deep insights into Dictyocaulus viviparus transcriptomes provides unique prospects for new drug targets and disease intervention.
The lungworm, Dictyocaulus viviparus, causes parasitic bronchitis in cattle, and is responsible for substantial economic losses in temperate regions of the world. Here, we undertake the first large-scale exploration of available transcriptomic data for this lungworm, examine differences in transcription between different stages/both genders and identify and prioritize essential molecules linked to fundamental metabolic pathways, which could represent novel drug targets. Approximately 3 million expressed sequence tags (ESTs), generated by 454 sequencing from third-stage larvae (L3s) as well as adult females and males of D. viviparus, were assembled and annotated. The assembly of these sequences yielded ~61,000 contigs, of which relatively large proportions encoded collagens (4.3%), ubiquitins (2.1%) and serine/threonine protein kinases (1.9%). Subtractive analysis in silico identified 6928 nucleotide sequences as being uniquely transcribed in L3, and 5203 and 7889 transcripts as being exclusive to the adult female and male, respectively. Most peptides predicted from the conceptual translations were nucleoplasmins (L3), serine/threonine protein kinases (female) and major sperm proteins (male). Additional analyses allowed the prediction of three drug target candidates, whose Caenorhabditis elegans homologues were linked to a lethal RNA interference phenotype. This detailed exploration, combined with future transcriptomic sequencing of all developmental stages of D. viviparus, will facilitate future investigations of the molecular biology of this parasitic nematode as well as genomic sequencing. These advances will underpin the discovery of new drug and/or vaccine targets, focused on biotechnological outcomes.


Epstein-Barr virus-specific T cell therapy for progressive multiple sclerosis.
Increasing evidence indicates a role for EBV in the pathogenesis of multiple sclerosis (MS). EBV-infected autoreactive B cells might accumulate in the CNS because of defective cytotoxic CD8+ T cell immunity. We sought to determine the feasibility and safety of treating progressive MS patients with autologous EBV-specific T cell therapy. An open-label phase I trial was designed to treat 5 patients with secondary progressive MS and 5 patients with primary progressive MS with 4 escalating doses of in vitro-expanded autologous EBV-specific T cells targeting EBV nuclear antigen 1, latent membrane protein 1 (LMP1), and LMP2A. Following adoptive immunotherapy, we monitored the patients for safety and clinical responses. Of the 13 recruited participants, 10 received the full course of T cell therapy. There were no serious adverse events. Seven patients showed improvement, with 6 experiencing both symptomatic and objective neurological improvement, together with a reduction in fatigue, improved quality of life, and, in 3 patients, reduced intrathecal IgG production. All 6 patients receiving T cells with strong EBV reactivity showed clinical improvement, whereas only 1 of the 4 patients receiving T cells with weak EBV reactivity showed improvement (P = 0.033, Fisher's exact test). EBV-specific adoptive T cell therapy was well tolerated. Clinical improvement following treatment was associated with the potency of EBV-specific reactivity of the administered T cells. Further clinical trials are warranted to determine the efficacy of EBV-specific T cell therapy in MS. Australian New Zealand Clinical Trials Registry, ACTRN12615000422527. MS Queensland, MS Research Australia, Perpetual Trustee Company Ltd., and donations from private individuals who wish to remain anonymous.


Cannabinoids and gastrointestinal motility: animal and human studies.
The plant Cannabis has been known for centuries to be beneficial in a variety of gastrointestinal diseases, including emesis, diarrhea, inflammatory bowel disease and intestinal pain. delta9-tetrahydrocannabinol, the main psychotropic component of Cannabis, acts via at least two types of cannabinoid receptors, named CB1 and CB2 receptors. CB1 receptors are located primarily on central and peripheral neurons (including the enteric nervous system) where they modulate neurotransmitter release, whereas CB2 receptors are concerned with immune function, inflammation and pain. The discovery of endogenous ligands [i.e. anandamide and 2-arachidonoyl glycerol (2-AG)] for these receptors indicates the presence of a functional endogenous cannabinoid system in the gastrointestinal tract. Anatomical and functional evidence suggests the presence of CB1 receptors in the myenteric plexus, which are associated with cholinergic neurons in a variety of species, including in humans. Activation of prejunctional CB1 receptors reduces excitatory enteric transmission (mainly cholinergic transmission) in different regions of the gastrointestinal tract. Consistently, in vivo studies have shown that cannabinoids reduce gastrointestinal transit in rodents through activation of CB1, but not CB2, receptors. However, in pathophysiological states, both CB1 and CB2 receptors could reduce the increase of intestinal motility induced by inflammatory stimuli. Cannabinoids also reduce gastrointestinal motility in randomized clinical trials. Overall, modulation of the gut endogenous cannabinoid system may provide a useful therapeutic target for disorders of gastrointestinal motility.


Social barriers to listing for adult liver transplantation: their prevalence and association with program characteristics.
Social barriers to effective medical care are mandated to be routinely assessed as part of an evaluation for liver transplantation. This study explores how frequently liver transplant programs encounter these barriers in patients undergoing an evaluation and whether programs with higher proportions of Medicaid patients, historically disadvantaged minority patients, and rural patients encounter social barriers more frequently. A survey for assessing patient demographics and social barriers was electronically completed by representatives of 61 of 104 eligible US adult liver transplant programs (59%). Fifty-eight of the 61 programs identified themselves, and their characteristics were similar to those of all 104 US programs according to publicly available data from the Organ Procurement and Transplantation Network. Social barriers were reported to be encountered sometimes (10%-30%) or frequently (>30%) by the 61 programs as follows: inadequate or unstable health insurance (68.9% of the programs), a chaotic social environment (63.9%), a lack of a care partner (60.7%), an inability to obtain transportation (49.2%), a low educational level (36.1%), inadequate housing (23.0%), a language barrier (19.7%), no reliable way of contacting the patient (16.4%), difficulty in obtaining child care (11.5%), and food insecurity (8.2%). The frequencies of perceived social barriers did not differ significantly between programs reporting higher or lower proportions of Medicaid, minority, or rural patients. Our analysis suggests that program-level operational planning for addressing social barriers to transplant listing should be considered regardless of the proportions of Medicaid-insured, racial or ethnic minority, and rural patients in the population.


Effects of functional endoscopic sinus surgery on the acoustics of the sinonasal tract.
Nasal and paranasal cavities are supposed to contribute substantially to the vocal tract resonator properties. However, their acoustical effects as well as the effects of sinus surgery on the voice remain unclear. In this work we investigate resonance phenomena of paranasal sinuses prior to and after various rhinosurgical procedures in cadaveric human sinonasal tracts and corresponding 3D casts. Nasal and paranasal cavities of formalin-preserved cadavers and corresponding 3D replicas were excited by sine-tone sweeps from an earphone placed in the epipharynx. The response was picked up by a microphone at the nostrils. Different FESS procedures were performed and the acoustical responses following excitation were recorded. The measured acoustical changes in the obtained transfer functions were then evaluated. Marked low frequency dips were detected in the transfer functions when sinus cavities were included in the nasal resonator system. These dips showed a significant correlation with sinus volumes. Following FESS procedures they moved upwards in frequency depending on the extent of the surgical intervention. The transfer functions obtained in cadaveric situs and 3D replicas showed dips at the resonance frequencies of the paranasal cavities. Marked acoustic effects in terms of increase in dip frequency following FESS procedures were reproducibly documented.


Composition of human islet cell preparations for transplantation.
To study the cellular composition of human islet cell isolates for transplantation, formalin-fixed and paraffin-embedded cell pellets were stained by the immunoperoxidase method with a panel of antibodies characterising endocrine, epithelial, soft tissue and haematolymphoid components. Immediately after separation, the isolates contained 30-80% islet cells, differing mainly in the content of islet and acinar cells, whereas the soft tissue, ductal/ductular and haematolymphoid elements comprised a relatively constant 10-20%. After 1 week in culture the islet cell content of less highly purified isolates (30-40% islets) dropped dramatically to 5%. The highly purified isolates (70-80% islets) showed only a minimal change in cellular composition; however, approximately two-thirds of islet cells were degranulated and did not stain for insulin. Haematolymphoid components were still present in all cultured isolates. We conclude that primarily mechanical purification methods and short-term culture are not sufficient to eliminate highly immunogenic cells. In addition, short-term culture is deleterious to the isolate if a significant number of acinar cells is still present after enrichment.


The efficacy of Kiko exercises on the prevention of migraine headaches: a pilot study.
Migraine headaches, a common chronic medical problem, require prophylactic treatment when they are frequent and severe. This is the first study to investigate the efficacy of Kiko, a Japanese practice of Qigong that uses repetitive coordinated breathing and movement as a prophylactic treatment of migraine headaches. This pilot study, a single arm, non-randomized 4-month trial, investigated whether 3 months of Kiko training would reduce the severity and/or frequency of migraine and/or MIDAS scores. The baseline migraine data were collected from participants in the first month and then participants were taught Kiko exercises in 3 monthly sessions. Participants practiced at home and had the opportunity to utilize a Kiko DVD. The participants were instructed by Washin-Ryu style martial arts Master, Hidy Ochiai. Subjects completed monthly diaries that recorded the frequency and severity of their migraines, as well as the frequency and duration of their home Kiko practice. Six of the original 13 subjects completed the trial. All the individuals who completed the study had measurable improvement in their migraines. All participants reported a positive experience in learning the technique, and there were no reported adverse effects. Although the results of this study need to be confirmed in a larger clinical trial with adequate controls for placebo effects, these preliminary results are consistent with other trials that have documented the potential benefits of mind-body practices in controlling symptoms and improving the quality of life of patients suffering from chronic medical illness.


A Dbf4p BRCA1 C-terminal-like domain required for the response to replication fork arrest in budding yeast.
Dbf4p is an essential regulatory subunit of the Cdc7p kinase required for the initiation of DNA replication. Cdc7p and Dbf4p orthologs have also been shown to function in the response to DNA damage. A previous Dbf4p multiple sequence alignment identified a conserved approximately 40-residue N-terminal region with similarity to the BRCA1 C-terminal (BRCT) motif called "motif N." BRCT motifs encode approximately 100-amino-acid domains involved in the DNA damage response. We have identified an expanded and conserved approximately 100-residue N-terminal region of Dbf4p that includes motif N but is capable of encoding a single BRCT-like domain. Dbf4p orthologs diverge from the BRCT motif at the C terminus but may encode a similar secondary structure in this region. We have therefore called this the BRCT and DBF4 similarity (BRDF) motif. The principal role of this Dbf4p motif was in the response to replication fork (RF) arrest; however, it was not required for cell cycle progression, activation of Cdc7p kinase activity, or interaction with the origin recognition complex (ORC) postulated to recruit Cdc7p-Dbf4p to origins. Rad53p likely directly phosphorylated Dbf4p in response to RF arrest and Dbf4p was required for Rad53p abundance. Rad53p and Dbf4p therefore cooperated to coordinate a robust cellular response to RF arrest.


Isometric or dynamic training: differential effects on mechanical properties of a human muscle.
This work compares the specific effects of 3 mo of moderate, isometric, or dynamic voluntary exercises on the contractile properties of human adductor pollicis muscle. Isometric training consisted of 10 daily contractions of 5-s duration at the frequency of one contraction per minute. Dynamic training consisted of 10 daily series of 10 fast contractions (less than 0.5-s duration) moving a load of one-third of the maximal muscle strength at a frequency of one series per minute. Both training programs produced a concomitant increase in maximal tetanic tension and in peak rate of tension development (Ro). A larger increase (P less than 0.05) was found after isometric training (20 vs. 11% after dynamic exercises), whereas Ro augmented more (P less than 0.05) after dynamic contractions (31 vs. 18% after isometric training). Enhancements of twitch force (Pt), rates of twitch tension development (Rt), and of relaxation (St) were, respectively, 20, 20, and 12% after isometric training. There was no modification of contraction time and time of half relaxation (T 1/2R). Conversely, dynamic training produced increases of Rt (25%) and St (16%), associated with an apparently paradoxical decrease of Pt (10%) and reductions of contraction time (11%) and T 1/2R (9%). Maximal shortening velocity was only increased after dynamic training (21%), whereas the maximal muscle power presented a large increase (P less than 0.05) after isometric exercises (51 vs. 19% after dynamic exercises) and a shift of its optimal peak toward heavier loads. This study suggests that human muscle adapts differently to isometric or to dynamic training programs and provides evidence that its contractile kinetics can be altered by exercises performed in physiological conditions.


The Energy Density and Treatment Times Are the Main Factors That Affect the Efficacy of Long-Pulsed 1,064-nm Nd:YAG Laser Treatment for Onychomycosis Caused by Trichophyton rubrum.
No optimal regimen exists for the LPNYL (long-pulsed 1,064-nm neodymium:yttrium-aluminum-garnet laser) for treating onychomycosis. To establish an optimal LPNYL treatment regimen for onychomycosis caused by Trichophyton rubrum (OCTr). First, 511 infected nails of 177 patients were treated using LPNYL with orthogonally designed regimens according to various energy densities, spot sizes, pulse widths, and treatment times. The optimal treatment regimen was established by multivariate analysis. Next, 69 patients with 221 infected nails were randomized to receive oral itraconazole (drug group) and the optimal regimen of LPNYL treatment (laser group). The clinical efficacy (CE) and mycological efficacy (ME) were evaluated at 6 and 12 months following the start of treatment, and adverse reactions were recorded in both groups. Both CE and ME were significantly correlated with the energy density (p < 0.05) and treatment times (p < 0.05), but not with the spot size (0.071 < p < 0.083) or pulse width (0.051 < p < 0.060), at 6 or 12 months. There were no significant differences at 6 or 12 months (p > 0.05), and no significant difference was observed in CE at 12 months between the two groups (p > 0.05). At 6 months, the CE in the laser group was significantly higher than that in the drug group (p < 0.001). LPNYL is effective and safe for treating OCTr. The energy density and treatment times are the main factors that affect the efficacy. The optimal regimen for LPNYL is an energy density of 45 J/cm2, pulse width of 35 ms, spot size of 4 mm, frequency of 1 Hz, and 6 treatments with 1-week intervals. Laser treatment has rapid clinical recovery.


Transient visually evoked potential.
A light delivered to the human eye will instigate changes in electrical potentials recorded over the visual cortex that last for some finite time, at least several hundred milliseconds. If the rate of stimulation is sufficiently low, the response is completed before the next visual stimulus arrives; the cortical potential is then called a transient evoked response. This review of the transient evoked potential describes the techniques by which the response is obtained, the problems inherent in its use, and procedures by which these difficulties can be overcome or minimized. A summary of the research results from the field enumerates those findings which have been well established and replicated by many investigators, those that are more controversial or as yet inconclusive, and the many practical applications of the technique for science and medicine. Finally, the needs for an underlying physiological theory and for future research are discussed.


Action of methotrexate and tofacitinib on directly stimulated and bystander-activated lymphocytes.
Chronic inflammation associated with autoimmune activation is characteristic of rheumatic diseases from childhood to adulthood. In recent decades, significant improvements in the treatment of these types of disease have been achieved using disease modifying anti-rheumatic drugs (DMARDs), such as methotrexate (MTX) and, more recently, using biologic inhibitors. The recent introduction of kinase inhibitors (for example, tofacitinib; Tofa) further increases the available ARDs. However, there are patients that do not respond to any treatment strategies, for whom combination therapies are proposed. The data regarding the combined action of different drugs is lacking and the knowledge of the mechanisms of ARDs and their actions upon pathogenic lymphocytes, which are hypothesized to sustain disease, is poor. An in vitro model of inflammation was developed in the current study, in which stimulated and unstimulated lymphocytes were cultured together, but tracked separately, to investigate the action of MTX and Tofa on the two populations. By analysing lymphocyte proliferation and activation, and cytokine secretion in the culture supernatants, it was established that, due to the presence of activated cells, unstimulated cells underwent a bystander activation that was modulated by the ARDs. Additionally, varying administration schedules were demonstrated to affect lymphocytes differently in vitro, either directly or via bystander activation. Furthermore, MTX and Tofa exerted different effects; while MTX showed an antiproliferative effect, Tofa marginally effected activation, although only a slight antiproliferative action, which could be potentiated by sequential treatment with MTX. Thus, it was hypothesized that these differences may be exploited in sequential therapeutic strategies, to maximize the anti‑rheumatic effect. These findings are notable and must be accounted for, as bystander‑activated cells in vivo could contribute to the spread of autoimmune activation and disease progression.


Continuous nasogastric milk feeding versus intermittent bolus milk feeding for premature infants less than 1500 grams.
Milk feedings can be given via nasogastric tube either intermittently, typically over 10 to 20 minutes every two or three hours, or continuously, using an infusion pump. Although theoretical benefits and risks of each method have been proposed, effects on clinically important outcomes remain uncertain. To examine the evidence regarding the effectiveness of continuous versus intermittent bolus nasogastric milk feeding in premature infants less than 1500 grams. Searches were performed of the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 3, 2011), MEDLINE, CINAHL and HealthSTAR up to July 2011. Randomised and quasi-randomised clinical trials comparing continuous versus intermittent bolus nasogastric milk feeding in premature infants less than 1500 grams. Two review authors independently assessed all trials for relevance and methodologic quality. The standard methods of the Cochrane Neonatal Review Group were used to extract data. Overall, the seven included trials, involving 511 infants, found no differences in time to achieve full enteral feeds between feeding methods (weighted mean difference (WMD) 2 days; 95% CI -0.3 to 3.9) . In the subgroup analysis of those studies comparing continuous nasogastric versus intermittent bolus nasogastric milk feedings the findings remained unchanged (WMD 2 days, 95% CI -0.4 to 4.1). There was no significant difference in somatic growth and incidence of NEC between feeding methods irrespective of tube placement. One study noted a trend toward more apneas during the study period in infants fed by the continuous tube feeding method compared to those fed by intermittent feedings delivered predominantly by orogastric tube placements [mean difference (MD) 14.0 apneas during study period; 95% CI -0.2 to 28.2]. In subgroup analysis based on weight groups, one study suggested that infants less than 1000 grams and 1000 to 1250 grams birth weight gained weight faster when fed by the continuous nasogastric tube feeding method compared to intermittent nasogastric tube feeding method (MD 2.0 g/day; 95% CI 0.5 to 3.5; MD 2.0 g/day; 95% CI 0.2 to 3.8, respectively). A trend toward earlier discharge for infants less than 1000 grams birth weight fed by the continuous tube feeding method compared to intermittent nasogastric tube feeding method (MD -11 days; 95% CI -21.8 to -0.2). Small sample sizes, methodologic limitations, inconsistencies in controlling variables that may affect outcomes, and conflicting results of the studies to date make it difficult to make universal recommendations regarding the best tube feeding method for premature infants less than 1500 grams. The clinical benefits and risks of continuous versus intermittent nasogastric tube milk feeding cannot be reliably discerned from the limited information available from randomised trials to date.


Complex pattern of interaction between in utero hypoxia-ischemia and intra-amniotic inflammation disrupts brain development and motor function.
Infants born preterm commonly suffer from a combination of hypoxia-ischemia (HI) and infectious perinatal inflammatory insults that lead to cerebral palsy, cognitive delay, behavioral issues and epilepsy. Using a novel rat model of combined late gestation HI and lipopolysaccharide (LPS)-induced inflammation, we tested our hypothesis that inflammation from HI and LPS differentially affects gliosis, white matter development and motor impairment during the first postnatal month. Pregnant rats underwent laparotomy on embryonic day 18 and transient systemic HI (TSHI) and/or intra-amniotic LPS injection. Shams received laparotomy and anesthesia only. Pups were born at term. Immunohistochemistry with stereological estimates was performed to assess regional glial loads, and western blots were performed for protein expression. Erythropoietin ligand and receptor levels were quantified using quantitative PCR. Digigait analysis detected gait deficits. Statistical analysis was performed with one-way analysis of variance and post-hoc Bonferonni correction. Microglial and astroglial immunolabeling are elevated in TSHI + LPS fimbria at postnatal day 2 compared to sham (both P < 0.03). At postnatal day 15, myelin basic protein expression is reduced by 31% in TSHI + LPS pups compared to shams (P < 0.05). By postnatal day 28, white matter injury shifts from the acute injury pattern to a chronic injury pattern in TSHI pups only. Both myelin basic protein expression (P < 0.01) and the phosphoneurofilament/neurofilament ratio, a marker of axonal dysfunction, are reduced in postnatal day 28 TSHI pups (P < 0.001). Erythropoietin ligand to receptor ratios differ between brains exposed to TSHI and LPS. Gait analyses reveal that all groups (TSHI, LPS and TSHI + LPS) are ataxic with deficits in stride, paw placement, gait consistency and coordination (all P < 0.001). Prenatal TSHI and TSHI + LPS lead to different patterns of injury with respect to myelination, axon integrity and gait deficits. Dual injury leads to acute alterations in glial response and cellular inflammation, while TSHI alone causes more prominent chronic white matter and axonal injury. Both injuries cause significant gait deficits. Further study will contribute to stratification of injury mechanisms in preterm infants, and guide the use of promising therapeutic interventions.


Abdominal infections in the intensive care unit: characteristics, treatment and determinants of outcome.
Abdominal infections are frequent causes of sepsis and septic shock in the intensive care unit (ICU) and are associated with adverse outcomes. We analyzed the characteristics, treatments and outcome of ICU patients with abdominal infections using data extracted from a one-day point prevalence study, the Extended Prevalence of Infection in the ICU (EPIC) II. EPIC II included 13,796 adult patients from 1,265 ICUs in 75 countries. Infection was defined using the International Sepsis Forum criteria. Microbiological analyses were performed locally. Participating ICUs provided patient follow-up until hospital discharge or for 60 days. Of the 7,087 infected patients, 1,392 (19.6%) had an abdominal infection on the study day (60% male, mean age 62 ± 16 years, SAPS II score 39 ± 16, SOFA score 7.6 ± 4.6). Microbiological cultures were positive in 931 (67%) patients, most commonly Gram-negative bacteria (48.0%). Antibiotics were administered to 1366 (98.1%) patients. Patients who had been in the ICU for ≤ 2 days prior to the study day had more Escherichia coli, methicillin-sensitive Staphylococcus aureus and anaerobic isolates, and fewer enterococci than patients who had been in the ICU longer. ICU and hospital mortality rates were 29.4% and 36.3%, respectively. ICU mortality was higher in patients with abdominal infections than in those with other infections (29.4% vs. 24.4%, p < 0.001). In multivariable analysis, hematological malignancy, mechanical ventilation, cirrhosis, need for renal replacement therapy and SAPS II score were independently associated with increased mortality. The characteristics, microbiology and antibiotic treatment of abdominal infections in critically ill patients are diverse. Mortality in patients with isolated abdominal infections was higher than in those who had other infections.


A Bond Charge Model Ansatz for Intrinsic Bond Energies: Application to C-C Bonds.
A simple bond charge model is proposed to predict intrinsic bond energies. Model parameters can be derived from the topology of the electron localization function and equilibrium geometries through classic considerations. Results for carbon-carbon covalent bonds are shown to be very accurate in different chemical environments. Insight can be extracted from the application of the model due to its elementary construction and simple mathematical formulation. The remarkable robustness of the fitted model highlights how different density functional approximations relate geometries, densities, and energies.


Lower Interferon Regulatory Factor-8 Expression in Peripheral Myeloid Cells Tracks With Adverse Central Nervous System Outcomes in Treated HIV Infection.
Cognitive dysfunction persists in 30-50% of chronically HIV-infected individuals despite combination antiretroviral therapy (ART). Although monocytes are implicated in poor cognitive performance, distinct biological mechanisms associated with cognitive dysfunction in HIV infection are unclear. We previously showed that a regulatory region of the interferon regulatory factor-8 (IRF8) gene is hyper-methylated in HIV-infected individuals with cognitive impairment compared to those with normal cognition. Here, we investigated IRF-8 protein expression and assessed relationships with multiple parameters associated with brain health. Intracellular IRF-8 expression was measured in cryopreserved peripheral blood mononuclear cells from chronically HIV-infected individuals on ART using flow cytometry. Neuropsychological performance was assessed by generating domain-specific standardized (NPZ) scores, with a global score defined by aggregating individual domain scores. Regional brain volumes were obtained by magnetic resonance imaging and soluble inflammatory factors were assessed by immunosorbent assays. Non-parametric analyses were conducted and statistical significance was defined as p < 0.05. Twenty aviremic (HIV RNA<50 copies/ml) participants, 84% male, median age 51 [interquartile range (IQR) 46, 55], median CD4 count 548 [439, 700] were evaluated. IRF-8 expression was highest in plasmacytoid dendritic cells (pDCs). Assessing cognitive function, lower IRF-8 density in classical monocytes significantly correlated with worse NPZ_learning memory (LM; rho = 0.556) and NPZ_working memory (WM; rho = 0.612) scores, in intermediate monocytes with worse NPZ_LM (rho = 0.532) scores, and in non-classical monocytes, lower IRF-8 correlated with worse global NPZ (rho = 0.646), NPZ_LM (rho = 0.536), NPZ_WM (rho = 0.647), and NPZ_executive function (rho = 0.605) scores. In myeloid DCs (mDCs) lower IRF-8 correlated with worse NPZ_WM (rho = 0.48) scores and in pDCs with worse NPZ_WM (rho = 0.561) scores. Declines in IRF-8 in classical monocytes significantly correlated with smaller hippocampal volume (rho = 0.573) and in intermediate and non-classical monocytes with smaller cerebral white matter volume (rho = 0.509 and rho = 0.473, respectively). IRF-8 density in DCs did not significantly correlate with brain volumes. Among biomarkers tested, higher soluble ICAM-1 levels significantly correlated with higher IRF-8 in all monocyte and DC subsets. These data may implicate IRF-8 as a novel transcription factor in the neuropathophysiology of brain abnormalities in treated HIV and serve as a potential therapeutic target to decrease the burden of cognitive dysfunction in this population.


Estimation of serum sialic acid in oral submucous fibrosis and oral squamous cell carcinoma.
Sialic acid (SA) N-acetyl neuraminic acid is a negatively charged 9-carbon monosaccharide, commonly attached to the nonreducing residues of carbohydrate chains of glycoconjugates by glycosidic linkage. SA is widely distributed in glycoproteins (GPs) of cell membrane. The alterations in GPs start at an early stage of tumorigenesis. Hence, the aim of the present study is to evaluate the levels of serum SA in normal individuals, in patients with oral submucous fibrosis (OSMF), oral squamous cell carcinoma (OSCC), and compare the levels with respect to the clinical staging and histological grading. A total of 90 individuals were selected for the purpose of the study. Thirty cases of clinically diagnosed and histopathologically confirmed cases of OSMF and OSCC each were included. A control group of 30 age and gender-matched individuals with no systemic diseases were selected. Serum levels of SA were measured based on the reaction between SA and ninhydrin. The absorbance was read using a spectrophotometer. Serum SA levels were significantly increased in OSMF, OSCC patients as compared with controls. When multiple comparison was done using post hoc Tukey test, there is a statistically significant difference between clinical staging and histopathological grading of OSMF and OSCC (P < 0.05). The serum SA levels in OSMF and OSCC patients were increased as compared with controls suggesting that, it can be used as a reliable biomarker for prognostic evaluation, and also give a clue about the amount of tumor burden in the individual.


Photoluminescent and biodegradable porous silicon nanoparticles for biomedical imaging.
Porous silicon nanoparticles (PSiNPs) have attracted increasing interest as biomedical probes for drug delivery and imaging. In particular, a set of unique properties including biodegradability, intrinsic photoluminescence, and favorable mesoporous structure providing high drug loading allow PSiNPs to address current challenges of translational nanomedicine. In this review, the important features of PSiNPs considered as a biomedical imaging probe will be concisely discussed along with recent advances in fabrication and theranostic applications. Firstly, an overview of PSiNP fabrication with controllable geometry through top-down or bottom-up strategies is provided. Next, intrinsic photoluminescence, the key element allowing application of PSiNPs as an imaging agent, is highlighted with near-infrared emission and micro-second scale lifetime. Emerging technologies for biodegradable nanomedicine based on PSiNPs are then presented. Advances of PSiNPs for disease treaments including photodynamic and photothermal therapeutics are also discussed to open up potential translational medical strategies. In addition, the versatile surface chemistry and modification of PSiNPs in the context of biomedical applications are extensively discussed. Overall, the promising characteristics of PSiNPs encourage further exploration for biomedical research and translational medical platforms, particularly in biomedical imaging.


Bioplasmonic paper-based assay for perilipin-2 non-invasively detects renal cancer.
Renal cell carcinoma (RCC) has poor survival prognosis because it is asymptomatic at an early, more curative stage. Recently, urine perilipin-2 (PLIN-2) was demonstrated to be a sensitive and specific biomarker for the noninvasive, early detection of RCC and an indispensable indicator to distinguish cancer from a benign renal mass. However, current Western blot or ELISA PLIN-2 assays are complicated, expensive, time-consuming or insensitive, making them unsuitable for routine analysis in clinical settings. Here we developed a plasmonic biosensor based on the high refractive index sensitivity of gold nanorattles for the rapid detection of PLIN-2 in patient urine. The paper-based plasmonic assay is highly sensitive and has a dynamic range of 50 pg/ml to 5 μg/ml PLIN-2. The assay is not compromised by variations in urine pH or high concentrations of interfering proteins such as albumin and hemoglobin, making it an excellent candidate for routine clinical applications. The urine PLIN-2 assay readily distinguished patients with pathologically proven clear cell carcinomas of various size, stage and grade (55.9 [39.5, 75.8] ng/ml, median [1st and 3rd quartile]) from age-matched controls (0.3 [0.3, 0.5] ng/ml), patients with bladder cancer (0.5 [0.4, 0.6] ng/ml) and patients with diabetic nephropathy (0.6 [0.4, 0.7] ng/ml). Urine PLIN-2 concentrations were roughly proportional to tumor size (Pearson coefficient 0.59). Thus, this cost-effective and label-free method represents a novel approach to conduct a non-invasive population screen or rapid differential diagnosis of imaged renal masses, significantly facilitating the early detection and diagnosis of RCC.


Children's Oncology Group Phase III Trial of Reduced-Dose and Reduced-Volume Radiotherapy With Chemotherapy for Newly Diagnosed Average-Risk Medulloblastoma.
Children with average-risk medulloblastoma (MB) experience survival rates of ≥ 80% at the expense of adverse consequences of treatment. Efforts to mitigate these effects include deintensification of craniospinal irradiation (CSI) dose and volume. ACNS0331 (ClinicalTrials.gov identifier: NCT00085735) randomly assigned patients age 3-21 years with average-risk MB to receive posterior fossa radiation therapy (PFRT) or involved field radiation therapy (IFRT) following CSI. Young children (3-7 years) were also randomly assigned to receive standard-dose CSI (SDCSI; 23.4 Gy) or low-dose CSI (LDCSI; 18 Gy). Post hoc molecular classification and mutational analysis contextualized outcomes according to known biologic subgroups (Wingless, Sonic Hedgehog, group 3, and group 4) and genetic biomarkers. Neurocognitive changes and ototoxicity were monitored over time. Five hundred forty-nine patients were enrolled on study, of which 464 were eligible and evaluable to compare PFRT versus IFRT and 226 for SDCSI versus LDCSI. The five-year event-free survival (EFS) was 82.5% (95% CI, 77.2 to 87.8) and 80.5% (95% CI, 75.2 to 85.8) for the IFRT and PFRT regimens, respectively, and 71.4% (95% CI, 62.8 to 80) and 82.9% (95% CI, 75.6 to 90.2) for the LDCSI and SDCSI regimens, respectively. IFRT was not inferior to PFRT (hazard ratio, 0.97; 94% upper CI, 1.32). LDCSI was inferior to SDCSI (hazard ratio, 1.67%; 80% upper CI, 2.10). Improved EFS was observed in patients with Sonic Hedgehog MB who were randomly assigned to the IFRT arm (P = .018). Patients with group 4 MB receiving LDCSI exhibited inferior EFS (P = .047). Children receiving SDCSI exhibited greater late declines in IQ (estimate = 5.87; P = .021). Reducing the radiation boost volume in average-risk MB is safe and does not compromise survival. Reducing CSI dose in young children with average-risk MB results in inferior outcomes, possibly in a subgroup-dependent manner, but is associated with better neurocognitive outcome. Molecularly informed patient selection warrants further exploration for children with MB to be considered for late-effect sparing approaches.


Lateral intermolecular forces between biomembrane lipids in two dimensions: 1,2-dipalmitin at the heptane/water interface compared with phospholipids.
The lateral interaction forces between phospholipids in two-dimensional arrays are fundamental to understanding membrane biophysics. In previous studies the related thermodynamic functions have been measured for spread phospholipid monolayers at the oil/water interface over a range of temperatures and densities, and the two-dimensional virial coefficients obtained. These coefficients have been computed from a model that emphasizes the head group zwitterion interactions. In this study we examine the contribution of the diglyceride portion of phospholipid molecules to the lateral intermolecular forces. Measurements of the heptane/water interfacial tension as a function of the concentration of 1,2-dipalmitoyl glycerol (DP) in the heptane were made over a range of low surface pressures at 25 degrees C. Infrared measurements on the DP solutions show that the solutions are ideal. The results are interpreted to give two-dimensional virial coefficients for the adsorbed monolayer. The second virial coefficient B2(T) for DP is +0.31 nm2/molecule, in marked contrast to the much larger positive values found for the corresponding phospholipids at the same interface and temperature, and clearly indicating an attractive component to the lateral potentials of mean force between pairs of DP molecules. The contribution of the diglyceride moiety to the pair potentials of the phospholipids thus appears to be minor but not negligible. The differences in the second virial coefficients for DP and the phospholipids are interpreted primarily in terms of the orientation of the ester carbonyl dipoles, also drawing on spectroscopic and diffraction evidence from related structures.


Development of the empowerment scale for family caregivers of community-dwelling people with dementia in Japan.
This study aimed to develop the empowerment scale for family caregivers of community-dwelling people with dementia (PWD) in Japan (EFCD) and to validate the scale. The questionnaires were mailed to 820 family caregivers of PWD. The first version of the EFCD based on interviews with family caregivers and elderly care specialists and content validity results was tested. Participants also completed the Revised Scale for Caregiving Self-Efficacy and the General Health Questionnaire. For the EFCD development procedure, construct validity was evaluated by item analysis and exploratory factor analysis. Criterion validity was tested using Spearman's correlations between scores of the three scales. Reliability was evaluated using Cronbach's alpha, intraclass correlation coefficients (ICC), and Bland and Altman analysis. The final model was verified by confirmatory factor analysis. Data from 304 family caregivers were analyzed. Exploratory factor analysis identified a 16-item, four-factor structure for the final version of the EFCD, as follows: (a) Excellent Practice in Dementia Care; (b) Understanding the Essence of Dementia Care; (c) Caring for Oneself as well as for the Person with Dementia; and (d) Having Peers with Shared Support Activities. Reliability and validity of the scale was established using the methods described. The developed EFCD is a reliable and valid measure that provides a simple assessment of empowerment among family caregivers of PWD.


Using ecphoric confidence ratings to discriminate seen from unseen faces: the effects of retention interval and distinctiveness.
Theories of confidence processing for recognition judgments suggest that confidence indexes the degree of match between a presented stimulus and an image in memory (ecphoric similarity). Recent research has demonstrated that having participants rate their confidence that a face had been previously seen provides an equivalent or a better index of the stimulus's status than does eliciting a simple binary response (Sauer, Brewer, & Weber, Journal of Experimental Psychology: General 137: 528-547, 2008). Using a face recognition paradigm, we manipulated retention interval and stimulus distinctiveness to directly test the suggestion that confidence indexes ecphoric similarity and to probe the boundary conditions for using confidence ratings to discriminate seen from unseen faces. Consistent with the proposed ecphoric basis for confidence ratings, mean confidence was higher for previously seen than for unseen faces, and conditions conducive to the formation of strong memories improved confidence-based discrimination. In all conditions, after the application of a classification algorithm, confidence ratings provided a more sensitive index of face status (i.e., seen or unseen) than did binary responses.


Effects of information framing on the intentions of family physicians to prescribe long-term hormone replacement therapy.
To determine whether the way in which information on benefits and harms of long-term hormone replacement therapy (HRT) is presented influences family physicians' intentions to prescribe this treatment. Family physicians were randomized to receive information on treatment outcomes expressed in relative terms, or as the number needing to be treated (NNT) with HRT to prevent or cause an event. A control group received no information. Primary care. Family physicians practicing in the Hunter Valley, New South Wales, Australia. Estimates of the impact of long-term HRT on risk of coronary events, hip fractures, and breast cancer were summarized as relative (proportional) decreases or increases in risk, or as NNT. Intention to prescribe HRT for seven hypothetical patients was measured on Likert scales. Of 389 family physicians working in the Hunter Valley, 243 completed the baseline survey and 215 participated in the randomized trial. Baseline intention to prescribe varied across patients-it was highest in the presence of risk factors for hip fracture, but coexisting risk factors for breast cancer had a strong negative influence. Overall, a larger proportion of subjects receiving information expressed as NNT had reduced intentions, and a smaller proportion had increased intentions to prescribe HRT than those receiving the information expressed in relative terms, or the control group. However, the differences were small and only reached statistical significance for three hypothetical patients. Framing effects were minimal when the hypothetical patient had coexisting risk factors for breast cancer. Information framing had some effect on family physicians' intentions to prescribe HRT, but the effects were smaller than those previously reported, and they were modified by the presence of serious potential adverse treatment effects.


Reducing children's behavior problems through social capital: A causal assessment.
Behavior problems among young children have serious detrimental effects on short and long-term educational outcomes. An especially promising prevention strategy may be one that focuses on strengthening the relationships among families in schools, or social capital. However, empirical research on social capital has been constrained by conceptual and causal ambiguity. This study attempts to construct a more focused conceptualization of social capital and aims to determine the causal effects of social capital on children's behavior. Using data from a cluster randomized trial of 52 elementary schools, we apply several multilevel models to assess the causal relationship, including intent to treat and treatment on the treated analyses. Taken together, these analyses provide stronger evidence than previous studies that social capital improves children's behavioral outcomes and that these improvements are not simply a result of selection into social relations but result from the social relations themselves.


An augmented echo state network for nonlinear adaptive filtering of complex noncircular signals.
A novel complex echo state network (ESN), utilizing full second-order statistical information in the complex domain, is introduced. This is achieved through the use of the so-called augmented complex statistics, thus making complex ESNs suitable for processing the generality of complex-valued signals, both second-order circular (proper) and noncircular (improper). Next, in order to deal with nonstationary processes with large nonlinear dynamics, a nonlinear readout layer is introduced and is further equipped with an adaptive amplitude of the nonlinearity. This combination of augmented complex statistics and enhanced adaptivity within ESNs also facilitates the processing of bivariate signals with strong component correlations. Simulations in the prediction setting on both circular and noncircular synthetic benchmark processes and real-world noncircular and nonstationary wind signals support the analysis.


Pathogenesis of arteritis of SL/Ni mice. Possible lytic effect of anti-gp70 antibodies on vascular smooth muscle cells.
The SL/Ni strain of mice spontaneously develops a necrotizing polyarteritis (NPA) that is histologically quite similar to human polyarteritis nodosa. This NPA most frequently affected parametrial tissues and/or ovaries of females and small arterioles of the major salivary glands. Electron microscopic studies of early arterial lesions revealed massive budding of C-type particles from arterial smooth muscle cells just before or at the onset of arteritis. In addition, binding of mouse IgG and C3 to the plasma membrane of virus-producing smooth muscle cells was shown by immunoelectron microscopy. Antibody-bound muscle cells showed disintegration of their plasma membrane, but degeneration and necrosis of muscle cells were not associated with dense infiltration of neutrophils. SL/Ni mice had natural antibodies that bound specifically to a fibroblast cell line infected with an endogenous ecotropic murine leukemia virus (MuLV) recovered from a SL/Ni mouse. Most of the natural antibodies were cytotoxic in the presence of murine complement. Western blot immunoassays revealed that among 14 SL/Ni female mice tested, all of the 9 mice that were affected by arteritis had anti-gp70 antibodies, while the 3 anti-gp70- mice were not affected. The presence of anti-p30 or anti-p15 (anti-p12) antibodies, which were also detected in some SL/Ni mice, did not correlate with the development of arteritis. These results strongly support the hypothesis that NPA in SL/Ni mice is mediated by the lysis of arterial smooth muscle cells due to the deposition of cytotoxic natural antibodies directed to cell membrane-bound gp70 molecules of an endogenous ecotropic MuLV.


The pediatrician's role in the diagnosis and treatment of substance abuse.
Abuse of drugs and alcohol is pervasive in our society. The role of the pediatrician as a health-care provider from birth through young adulthood includes recognizing the stigmata in newborns of prenatally ingested drugs as well as being able to treat neonatal drug withdrawal syndromes. Questioning about drug use and other closely related topics should be incorporated into all health-care maintenance visits, starting at the age of 10 y, with parental participation and anticipatory guidance being offered. Physical examination and laboratory testing are not as helpful in confirming an impression of substance abuse as a comprehensive interview and a full appreciation of the warning signs of substance abuse. Treatment of the problematic user with a multidisciplinary team that understands adolescent development and behavior as well as the problem of substance abuse is crucial. The decision to treat the teen in an ambulatory or inpatient setting is determined by the extent of abuse, underlying medical problems and psychopathology, and the degree of family dysfunction. The pediatrician must not avoid addressing these issues with patients. If, however, upon identifying an adolescent or a newborn with a drug problem, the pediatrician feels uncomfortable or ill-prepared to manage the patient, appropriate professional referrals are warranted. Despite exercising the referral option for treatment, as advocate for child and family, the pediatrician remains professionally bound to track all drug abuse-related referrals while continuing to participate in the general ongoing care of the patient and family. Finally, the pediatrician should retain a public advocacy role in the community by offering educational, preventive, and supportive efforts in the continuing struggle against drug abuse.


Molecular Pathways Controlling Autophagy in Pancreatic Cancer.
Pancreatic ductal adenocarcinoma (PDAC) is one of the few cancer types where the 5-year survival rate shows no improvement. Despite conflicting evidence, the majority of data points to an essential role for autophagy in PDAC growth and survival, in particular constitutively activated autophagy, can provide crucial fuel to PDAC tumor cells in their nutrient-deprived environment. Autophagy, which is required for cell homeostasis, can both suppress and promote tumorigenesis and tumor survival in a context-dependent manner. Protein by protein, the mystery of how PDAC abuses the cell's homeostasis system for its malignant growth has recently begun to be unraveled. In this review, we focus on how autophagy is responsible for growth and development of PDAC tumors and where autophagy and the mechanisms controlling it fit into PDAC metabolism. Understanding the range of pathways controlling autophagy and their interplay in PDAC could open the way for new therapeutic avenues.