Size-selective growth and stabilization of small CdSe nanoparticles in aqueous solution.
Using cysteine and its derivatives as capping molecules, we investigated the influence of the physical structure and chemical nature of capping molecules on the selective growth and stabilization of small CdSe nanoparticles (NPs) in aqueous solution at room temperature. Our investigations revealed specific roles for each functional group of cysteine, and we could correlate this structure and nature of the capping molecules with the size, size restriction, size distribution, and stability of the NPs. For selective growth and stabilization of the NPs in aqueous solution, their capping molecules should have at least one functional group with strong nucleophilicity as well as another free, charged functional group. Capping molecules acting as a monodentate ligand were more effective than those acting as a bidentate ligand for restricting the NPs to a smaller size, whereas the former was less effective than the latter for getting a narrower NP size distribution. Capping molecules with relatively bulky spatial geometry near the ligand-NP interface resulted in the formation of NPs with poor short- and long-term stabilities, whereas those having relatively compact spatial geometry near the interface led to NPs with at least moderate short-term stability. We saw that capping molecules having relatively compact outermost spatial geometry led to NPs with excellent long-term stability, whereas those having relatively bulky outermost spatial geometry produced NPs with at most only moderate long-term stability. Our results clearly showed general trends for the possibility of selective growth of stable semiconductor NPs with particular sizes in aqueous solution.


Arteether: risks of two-week administration in Macaca mulatta.
Male rhesus monkeys (Macaca mulatta) were administered daily doses of the antimalarial drug arteether. The 14-day treated group received either 24 mg/kg/day, 16 mg/kg/day, or 8 mg/kg/day. The seven-day treatment group received either 24 mg/kg/day or 8 mg/kg/day. All control cases in each group received the sesame oil vehicle alone. Neurologic signs were absent for animals in the seven and 14-day treatment groups except for one monkey which showed diffuse piloerection on day 14, and another monkey receiving 24 mg/kg/day for seven days showed mild lethargy after the fourth day. Mild, sporadic anorexia was noted in all animals by day 14, and a single animal showed diffuse piloerection on day 14. Surgical anesthesia preceded killing by exsanguination and was accompanied by perfusion fixation of the central nervous system. Brain sections were cut and then stained for study by light microscopy. Evidence of neuronal pathology, both descriptive and numerical, was collected. The neuroanatomic and neuropathologic findings demonstrated that arteether produced extensive brainstem injury when administered for 14 days. The magnitude of brainstem neurotoxicity was dose-dependent, where injury was greatest at the 24 mg/kg/day dose level, less at the 16 mg/kg/day dose level, and least at the 8 mg/kg/day dose level. Arteether induced multiple systems injury to brainstem nuclei of 1) the reticular formation (cranial and caudal pontine nuclei, and medullary gigantocellular and paragigantocellular nuclei); 2) the vestibular system (medial, descending, superior, and lateral nuclei); and 3) the auditory system (superior olivary nuclear complex and trapezoid nuclear complex). The vestibular nuclei and the reticular formation were most severely injured, with the auditory system affected less. The cranial nerve nuclei (somatic and splanchnic) appeared to escape damage, with the exception of the abducens nerve nucleus. The same brainstem nuclear groups of seven-day treated monkeys appeared normal. The statistical data are concordant with the descriptive data in demonstrating neurotoxic effects. In summary, no neurologic deficits were detected in any of the vehicle control monkeys (14-day and seven-day cases). Monkeys in the 14-day treatment group were free of clinical neurologic signs throughout the first week. At day 14, fine horizontal nystagmus was seen in one monkey, and another monkey exhibited diffuse piloerection. Monkeys in the seven-day treatment group were free of clinical neurologic signs except for one case. This monkey was treated with 24/mg/kg/day of arteether and exhibited lethargy after the fourth day. These indications of dysfunction arose too late to be practical indicators of neurotoxicity.


Social disability in schizophrenia: its development and prediction over 15 years in incidence cohorts in six European centres.
This paper focuses on the long-term course of social disability in schizophrenia assessed at first onset, and after 1, 2 and 15 years in incidence cohorts in six European centres in Bulgaria, Germany, Ireland, The Netherlands, the Czech Republic and the United Kingdom. The study population comprises 349 patients comprising 75% of the original cohorts. Social disability was assessed in a standardized way with the WHO Disability Assessment Schedule. Social disability in schizophrenia appears to be a persistent phenomenon. Its severity decreased overall in the period of follow-up, but this was not so in a small group traced to hospital or sheltered accommodation. Only 17% of subjects had no disability and 24% still suffered from severe disability. The great majority lived with their family, a partner, or alone. A deteriorating course was more frequent than late improvement. Gender, age, onset, duration of untreated psychosis or type of remission during the first 2 years did not predict the long-term outcome of disability. Severity of disability at the first three assessments of the illness contributed significantly to the explanation of its variance at 15 years. Disability generally ameliorates, but less than expected or hoped. It needs continuing attention and care in this era of de-institutionalization.


Transplantation of umbilical cord mesenchymal stem cells via different routes in rats with acute liver failure.
This study aimed to compare the therapeutic efficacy of transplantation of human umbilical cord mesenchymal stem cells (hUCMSC) in different routes in acute hepatic failure (ALF) in rats. hUCMSCs were isolated and identified by detection of surface antigens via flow cytometry. In T group and H group, ALF rats received hUCMSC transplantation through the tail vein and intrahepatic injection, respectively. In hUCMSC group, healthy rats received hUCMSCs transplantation via the tail vein. In ALF group, rats received injection of normal saline through the tail vein. The TBil and ALT in ALF rats with and without transplantation were significantly higher than in healthy rats (P<0.05). HE staining of the liver showed obvious hepatocyte regeneration and reduced infiltration of inflammatory cells, and liver pathology was improved in T group and H group as compared to ALF group. At 3 d after transplantation, CK18 expression was detectable in both H group and T group. At 1 w and 2 w, the mRNA expressions of CK8, CK18 and AFP in H group and T group were significantly different from those in ALF group (P<0.05). The liver function and differentiation of stem cells were comparable between H group and T group (P>0.05). hUCMSCs transplantation can improve the liver function and promote the liver repair following ALF. hUCMSCs transplantation via tail vein has similar therapeutic efficacy to that through intrahepatic injection.


NICU lactation consultant increases percentage of outborn versus inborn babies receiving human milk.
To determine the effect of a dedicated lactation consultant (LC) on the percentage of neonates receiving any human milk in the neonatal intensive care unit (NICU) and at discharge over time. Retrospective chart review of three time periods of 3 months each; Time period 1 (before LC hire), Time period 2 (T2; after LC arrival) and Time period 3 (subsequent period after T2). Percentage of infants receiving any HM during hospital stay and at discharge increased significantly over time after LC hire and with LC experience. Outborn (OB) infants receiving any HM in the NICU and at discharge increased over time, but there was no significant change for inborn infants, as the proportion receiving any HM remained consistently high over time. Addition of a dedicated LC to the NICU increased the percentage of neonates receiving any HM, specifically in the OB population.


A brief individualized computer-delivered sexual risk reduction intervention increases HIV/AIDS preventive behavior.
One objective of translational science is to identify elements of human immunodeficiency virus (HIV) risk-reduction interventions that have been shown to be effective and find new ways of delivering these interventions to the community to ensure that they reach the widest possible audience of at-risk individuals. The current study reports the development and evaluation of a computer-delivered, theory-based, individually tailored HIV risk-reduction intervention. This study evaluated the effectiveness of a custom computerized HIV/AIDS risk reduction intervention at increasing HIV/AIDS preventive behaviors in a randomized trial with 157 college students. The intervention content and delivery were based on the Information-Motivation-Behavioral Skills Model of Health Behavior Change and used Motivational Interviewing techniques. Participants completed a baseline assessment of HIV prevention information, motivation, behavioral skills and behavior, attended two brief computer-delivered intervention sessions, and completed a follow-up assessment. As compared to the control group (a nutrition education tutorial), participants who interacted with the computer-delivered HIV/AIDS risk reduction intervention exhibited a significant increase in risk reduction behavior. Specifically, participants reported a greater frequency of keeping condoms available and displayed greater condom-related knowledge at a four-week follow-up session; among sexually active participants, there was a significant increase in self-reported condom use. Delivery of brief individually tailored HIV/AIDS risk reduction interventions via computer may be an effective HIV/AIDS prevention approach for adolescents. More research is needed to further support the effectiveness of this type of intervention and determine the generalizability of these findings to economically and educationally disadvantaged adolescents.


Study of switching in spin transition compounds within the mechanoelastic model with realistic parameters.
Here we reproduce the static and dynamical properties of spin-crossover complexes in the framework of the mechanoelastic model applied to triangular lattices. The switching processes between the high-spin and low-spin states are studied by combining the Monte Carlo method with the elastic lattice relaxation. The transition probabilities between the two states take into account intrinsic parameters, the values of which are approximated from experimental quantities (e.g., the energy gap, and the degeneracy ratio from the thermodynamic enthalpy and the entropy difference between the states), and the elastic force or elastic energy stored in the springs connecting the spin-changing centres. The value of the corresponding spring constant is estimated from the experimentally determined variation of the ligand-field strengths in the two spin states due to the cooperativity and the bulk modulus. Both simulated hysteresis loops and relaxation curves are in agreement with experimental data. Cooperativity related phenomena such as like-spin domain formation and the evolution of the interaction distribution with the HS fraction are also analysed.


Positive schizotypy and trauma-related intrusions.
The current study extends previous investigation of schizotypy as a vulnerability factor for trauma-related intrusions through the use of a clinical sample. Fifty people seeking psychological interventions after experiencing a distressing or traumatic event completed measures of positive schizotypy, posttraumatic stress disorder symptomatology, peritraumatic dissociation, and mood. Individuals scoring high in positive schizotypy were vulnerable to experiencing more frequent trauma-related intrusions along with wider posttraumatic stress disorder symptomatology, including hypervigilance, avoidance, and low mood. Results are discussed within a theoretical context, suggesting that certain information processing styles associated with high schizotype individuals may account for a vulnerability to trauma-related intrusions.


Identification of copy number variants defining genomic differences among major human groups.
Understanding the genetic contribution to phenotype variation of human groups is necessary to elucidate differences in disease predisposition and response to pharmaceutical treatments in different human populations. We have investigated the genome-wide profile of structural variation on pooled samples from the three populations studied in the HapMap project by comparative genome hybridization (CGH) in different array platforms. We have identified and experimentally validated 33 genomic loci that show significant copy number differences from one population to the other. Interestingly, we found an enrichment of genes related to environment adaptation (immune response, lipid metabolism and extracellular space) within these regions and the study of expression data revealed that more than half of the copy number variants (CNVs) translate into gene-expression differences among populations, suggesting that they could have functional consequences. In addition, the identification of single nucleotide polymorphisms (SNPs) that are in linkage disequilibrium with the copy number alleles allowed us to detect evidences of population differentiation and recent selection at the nucleotide variation level. Overall, our results provide a comprehensive view of relevant copy number changes that might play a role in phenotypic differences among major human populations, and generate a list of interesting candidates for future studies.


Mechanics of two filaments in tight orthogonal contact.
Networks of flexible filaments often involve regions of tight contact. Predictively understanding the equilibrium configurations of these systems is challenging due to intricate couplings between topology, geometry, large nonlinear deformations, and friction. Here, we perform an in-depth study of a simple, yet canonical, problem that captures the essence of contact between filaments. In the orthogonal clasp, two filaments are brought into contact, with each centerline lying in one of a pair of orthogonal planes. Our data from X-ray tomography (μCT) and mechanical testing experiments are in excellent agreement with finite element method (FEM) simulations. Despite the apparent simplicity of the physical system, the data exhibit strikingly unintuitive behavior, even when the contact is frictionless. Specifically, we observe a curvilinear diamond-shaped ridge in the contact-pressure field between the two filaments, sometimes with an inner gap. When a relative displacement is imposed between the filaments, friction is activated, and a highly asymmetric pressure field develops. These findings contrast to the classic capstan analysis of a single filament wrapped around a rigid body. Both the μCT and FEM data indicate that the cross-sections of the filaments can deform significantly. Nonetheless, an idealized geometrical theory assuming undeformable tube cross-sections and neglecting elasticity rationalizes our observations qualitatively and highlights the central role of the small, but nonzero, tube radius of the filaments. We believe that our orthogonal clasp analysis provides a building block for future modeling efforts in frictional contact mechanics of more complex filamentary structures.


Molecular basis of inward rectification: polyamine interaction sites located by combined channel and ligand mutagenesis.
Polyamines cause inward rectification of (Kir) K+ channels, but the mechanism is controversial. We employed scanning mutagenesis of Kir6.2, and a structural series of blocking diamines, to combinatorially examine the role of both channel and blocker charges. We find that introduced glutamates at any pore-facing residue in the inner cavity, up to and including the entrance to the selectivity filter, can confer strong rectification. As these negative charges are moved higher (toward the selectivity filter), or lower (toward the cytoplasm), they preferentially enhance the potency of block by shorter, or longer, diamines, respectively. MTSEA+ modification of engineered cysteines in the inner cavity reduces rectification, but modification below the inner cavity slows spermine entry and exit, without changing steady-state rectification. The data provide a coherent explanation of classical strong rectification as the result of polyamine block in the inner cavity and selectivity filter.


Resection of recurrent pulmonary metastases in patients with soft-tissue sarcomas.
Survival benefit and prognostic factors useful for patient selection have not been previously analyzed for patients with recurrent pulmonary metastases from soft-tissue sarcomas. Twenty-nine patients in our study had two or more resections of pulmonary metastases from 1976 to 1983. There were no operative deaths and three complications for 40 operations (7.5%). Factors predictive of increased survival following the second resection of pulmonary metastases were resectability and a disease-free interval of greater than six months from the first thoracotomy to the second recurrence in the lung. The tumor doubling time of the first recurrence and the presence of three or fewer nodules on full-lung tomography before the first thoracotomy, which were predictors of survival following initial resection, also predicted survival following subsequent resections. Overall median survival following the second resection was 14.5 months (22% overall three-year survival). The postresection actuarial survival curves for patients undergoing 1, 2, or 3 or more resections were not significantly different. Our findings demonstrate that patients undergoing repeated resections of pulmonary metastases from soft-tissue sarcomas can achieve prolonged survival.


A portable microfluidic system for rapid measurement of the erythrocyte sedimentation rate.
The erythrocyte sedimentation rate (ESR) is a frequently used 30 min or 60 min clinical test for screening of several inflammatory conditions, infections, trauma, and malignant diseases, as well as non-inflammatory conditions including prostate cancer and stroke. Erythrocyte aggregation (EA) is a physiological process where erythrocytes form face-to-face linear structures, called rouleaux, at stasis or low shear rates. In this work, we proposed a method for ESR measurement from EA. We developed a microfluidic opto-electro-mechanical system, using which we experimentally showed a significant correlation (R2 = 0.86) between ESR and EA. The microfluidic system was shown to measure ESR from EA using fingerprick blood in 2 min. 40 μl of whole blood is filled in a disposable polycarbonate cartridge which is illuminated with a near infrared emitting diode. Erythrocytes were disaggregated under the effect of a mechanical shear force using a solenoid pinch valve. Following complete disaggregation, transmitted light through the cartridge was measured using a photodetector for 1.5 min. The intensity level is at its lowest at complete disaggregation and highest at complete aggregation. We calculated ESR from the transmitted signal profile. We also developed another microfluidic cartridge specifically for monitoring the EA process in real-time during ESR measurement. The presented system is suitable for ultrafast, low-cost, and low-sample volume measurement of ESR at the point-of-care.


On and off-target effects of telomere uncapping G-quadruplex selective ligands based on pentacyclic acridinium salts.
Quadruplexes DNA are present in telomeric DNA as well as in several cancer-related gene promoters and hence affect gene expression and subsequent biological processes. The conformations of G4 provide selective recognition sites for small molecules and thus these structures have become important drug-design targets for cancer treatment. The DNA G-quadruplex binding pentacyclic acridinium salt RHPS4 (1) has many pharmacological attributes of an ideal telomere-targeting agent but has undesirable off-target liabilities. Notably a cardiovascular effect was evident in a guinea pig model, manifested by a marked and sustained increase in QTcB interval. In accordance with this, significant interaction with the human recombinant ß2 adrenergic receptor, and M1, M2 and M3 muscarinic receptors was observed, together with a high inhibition of the hERG tail current tested in a patch clamp assay. Two related pentacyclic structures, the acetylamines (2) and (3), both show a modest interaction with ß2 adrenergic receptor, and do not significatively inhibit the hERG tail current while demonstrating potent telomere on-target properties comparing closely with 1. Of the two isomers, the 2-acetyl-aminopentacycle (2) more closely mimics the overall biological profile of 1 and this information will be used to guide further synthetic efforts to identify novel variants of this chemotype, to maximize on-target and minimize off-target activities. Consequently, the improvement of toxicological profile of these compounds could therefore lead to the obtainment of suitable molecules for clinical development offering new pharmacological strategies in cancer treatment.


Intraoperative interventions for preventing surgical site infection: an overview of Cochrane Reviews.
Surgical site infection (SSI) rates vary from 1% to 5% in the month following surgery. Due to the large number of surgical procedures conducted annually, the costs of these SSIs can be considerable in financial and social terms. Many interventions are used with the aim of reducing the risk of SSI in people undergoing surgery. These interventions can be broadly delivered at three stages: preoperatively, intraoperatively and postoperatively. The intraoperative interventions are largely focused on decontamination of skin using soap and antiseptics; the use of barriers to prevent movement of micro-organisms into incisions; and optimising the patient's own bodily functions to promote best recovery. Both decontamination and barrier methods can be aimed at people undergoing surgery and operating staff. Other interventions focused on SSI prevention may be aimed at the surgical environment and include methods of theatre cleansing and approaches to managing theatre traffic. To present an overview of Cochrane Reviews of the effectiveness and safety of interventions, delivered during the intraoperative period, aimed at preventing SSIs in all populations undergoing surgery in an operating theatre. Published Cochrane systematic reviews reporting the effectiveness of interventions delivered during the intraoperative period in terms of SSI prevention were eligible for inclusion in this overview. We also identified Cochrane protocols and title registrations for future inclusion into the overview. We searched the Cochrane Library on 01 July 2017. Two review authors independently screened search results and undertook data extraction and 'Risk of bias' and certainty assessment. We used the ROBIS (risk of bias in systematic reviews) tool to assess the quality of included reviews, and we used GRADE methods to assess the certainty of the evidence for each outcome. We summarised the characteristics of included reviews in the text and in additional tables. We included 32 Cochrane Reviews in this overview: we judged 30 reviews as being at low risk of bias and two at unclear risk of bias. Thirteen reviews had not been updated in the past three years. Two reviews had no relevant data to extract. We extracted data from 30 reviews with 349 included trials, totaling 73,053 participants. Interventions assessed included gloving, use of disposable face masks, patient oxygenation protocols, use of skin antiseptics for hand washing and patient skin preparation, vaginal preparation, microbial sealants, methods of surgical incision, antibiotic prophylaxis and methods of skin closure. Overall, the GRADE certainty of evidence for outcomes was low or very low. Of the 77 comparisons providing evidence for the outcome of SSI, seven provided high- or moderate-certainty evidence, 39 provided low-certainty evidence and 31 very low-certainty evidence. Of the nine comparisons that provided evidence for the outcome of mortality, five provided low-certainty evidence and four very low-certainty evidence.There is high- or moderate-certainty evidence for the following outcomes for these intraoperative interventions. (1) Prophylactic intravenous antibiotics administered before caesarean incision reduce SSI risk compared with administration after cord clamping (10 trials, 5041 participants; risk ratio (RR) 0.59, 95% confidence interval (CI) 0.44 to 0.81; high-certainty evidence - assessed by review authors). (2) Preoperative antibiotics reduce SSI risk compared with placebo after breast cancer surgery (6 trials, 1708 participants; RR 0.74, 95% CI 0.56 to 0.98; high-certainty evidence - assessed by overview authors). (3) Antibiotic prophylaxis probably reduce SSI risk in caesarean sections compared with no antibiotics (82 relevant trials, 14,407 participants; RR 0.40, 95% CI 0.35 to 0.46; moderate-certainty evidence; downgraded once for risk of bias - assessed by review authors). (4) Antibiotic prophylaxis probably reduces SSI risk for hernia repair compared with placebo or no treatment (17 trials, 7843 participants; RR 0.67, 95% CI 0.54 to 0.84; moderate-certainty evidence; downgraded once for risk of bias - assessed by overview authors); (5) There is currently no clear difference in the risk of SSI between iodine-impregnated adhesive drapes compared with no adhesive drapes (2 trials, 1113 participants; RR 1.03, 95% CI 0.66 to 1.60; moderate-certainty evidence; downgraded once for imprecision - assessed by review authors); (6) There is currently no clear difference in SSI risk between short-term compared with long-term duration antibiotics in colorectal surgery (7 trials; 1484 participants; RR 1.05 95% CI 0.78 to 1.40; moderate-certainty evidence; downgraded once for imprecision - assessed by overview authors). There was only one comparison showing negative effects associated with the intervention: adhesive drapes increase the risk of SSI compared with no drapes (5 trials; 3082 participants; RR 1.23, 95% CI 1.02 to 1.48; high-certainty evidence - rated by review authors). This overview provides the most up-to-date evidence on use of intraoperative treatments for the prevention of SSIs from all currently published Cochrane Reviews. There is evidence that some interventions are useful in reducing SSI risk for people undergoing surgery, such as antibiotic prophylaxis for caesarean section and hernia repair, and also the timing of prophylactic intravenous antibiotics administered before caesarean incision. Also, there is evidence that adhesive drapes increase SSI risk. Evidence for the many other treatment choices is largely of low or very low certainty and no quality-of-life or cost-effectiveness data were reported. Future trials should elucidate the relative effects of some treatments. These studies should focus on increasing participant numbers, using robust methodology and being of sufficient duration to adequately assess SSI. Assessment of other outcomes such as mortality might also be investigated as part of non-experimental prospective follow-up of people with SSI of different severity, so the risk of death for different subgroups can be better understood.


A 5-year course of predominantly obsessive vs. mixed subtypes of obsessive-compulsive disorder.
Obsessive-compulsive disorder (OCD) is considered a heterogeneous disorder. One of the traditional approaches to subtype OCD is based on the predominance of obsessions, compulsions or both. Some studies suggest that the "predominantly obsessive" subtype of OCD may have poor outcome, whereas few other studies suggest that "mixed" OCD is associated with poor outcome. Therefore, it is not clear if the long-term course of "predominantly obsessive" subjects is different from those with "mixed" OCD. In the establishment of diagnostic validity of psychiatric conditions, differential course is an important validating factor. This study compares the 5-6 year course of the "predominantly obsessive" subtype with that of the "mixed" subtype of OCD with the objective of determining if the course of OCD differs according to subtypes and whether course could be a validating factor for subtyping OCD based on predominance of obsessions, compulsions or both. Tertiary hospital, institutional setting. The study has a retrospective cohort design. Fifty-four subjects with "predominantly obsessions" and an equal number of the "mixed" subtype of OCD were recruited from the database of a specialty OCD clinic of a major psychiatric hospital. They were followed up after 5-6 years. The Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) checklist and severity rating scale was used for assessing OCD. The course of OCD was determined according to predefined criteria. The Chi-square/Fisher's exact test and the independent samples "t" test were used to compare categorical and continuous variables, respectively. Correlations were tested using the Pearson's correlation analysis. Thirty-eight "predominantly obsessive" (70%) and 39 "mixed" (72%) OCD subjects could be traced and evaluated. The course of illness was similar in the two subtypes. A majority of the sample (72%) did not have clinical OCD at follow-up. "Predominantly obsessive" subjects have a course similar to those with "mixed" OCD. Clinically, it is reassuring to know that obsessive subjects do not have an unfavorable course as was suggested by some previous studies. In this sample, course did not validate the subtyping method employed, but it would be premature to conclude that the subtyping method employed is incorrect based on the course alone. Prospective study of the course in larger samples and neurobiological and family-genetic data may help further validation.


Bessel-Gauss resonator with spherical output mirror: geometrical- and wave-optics analysis.
A detailed study of the axicon-based Bessel-Gauss resonator with concave output coupler is presented. We employ a technique to convert the Huygens-Fresnel integral self-consistency equation into a matrix equation and then find the eigenvalues and the eigenfields of the resonator at one time. A paraxial ray analysis is performed to find the self-consistency condition to have stable periodic ray trajectories after one or two round trips. The fast-Fourier-transform-based Fox and Li algorithm is applied to describe the three-dimensional intracavity field distribution. Special attention was directed to the dependence of the output transverse profiles, the losses, and the modal-frequency changes on the curvature of the output coupler and the cavity length. The propagation of the output beam is discussed.


Internet-based cognitive-behavior therapy for procrastination: A randomized controlled trial.
Procrastination can be a persistent behavior pattern associated with personal distress. However, research investigating different treatment interventions is scarce, and no randomized controlled trial has examined the efficacy of cognitive-behavior therapy (CBT). Meanwhile, Internet-based CBT has been found promising for several conditions, but has not yet been used for procrastination. Participants (N = 150) were randomized to guided self-help, unguided self-help, and wait-list control. Outcome measures were administered before and after treatment, or weekly throughout the treatment period. They included the Pure Procrastination Scale, the Irrational Procrastination Scale, the Susceptibility to Temptation Scale, the Montgomery Åsberg Depression Rating Scale-Self-report version, the Generalized Anxiety Disorder Assessment, and the Quality of Life Inventory. The intention-to-treat principle was used for all statistical analyses. Mixed-effects models revealed moderate between-groups effect sizes comparing guided and unguided self-help with wait-list control; the Pure Procrastination Scale, Cohen's d = 0.70, 95% confidence interval (CI) [0.29, 1.10], and d = 0.50, 95% CI [0.10, 0.90], and the Irrational Procrastination Scale, d = 0.81 95% CI [0.40, 1.22], and d = 0.69 95% CI [0.29, 1.09]. Clinically significant change was achieved among 31.3-40.0% for guided self-help, compared with 24.0-36.0% for unguided self-help. Neither of the treatment conditions was found to be superior on any of the outcome measures, Fs(98, 65.17-72.55) < 1.70, p > .19. Internet-based CBT could be useful for managing self-reported difficulties due to procrastination, both with and without the guidance of a therapist.


Iohexol vs. metrizamide: study of efficacy and morbidity in cervical myelography.
A double-blind study was conducted in 60 patients undergoing either cervical or more complete myelography via C1-C2 puncture. Patients received either iohexol or metrizamide at a 300 mg l/ml concentration. The contrast media were equally efficacious in the production of high-quality radiographs and CT scans. However, the incidence of adverse reactions differed markedly. Of patients receiving metrizamide, 68% had some type of adverse reaction, whereas only 26% receiving iohexol had symptoms. The incidence of headache (metrizamide, 34%; iohexol, 26%) was not statistically different, but the quality of the headache differed: half of the metrizamide headaches were moderate or severe, whereas all iohexol headaches were mild. Nausea (31%) and vomiting (28%) were common with metrizamide but unusual (3% nausea) with iohexol. Of the metrizamide patients, 21% had overt psychologic changes that did not occur in the iohexol group.


Clinical characteristics, functional respiratory decline and follow-up in adult patients with primary ciliary dyskinesia.
Primary ciliary dyskinesia (PCD) is a genetic disease characterised by abnormalities in ciliary function, responsible for chronic pulmonary and sinonasal diseases. Adult clinical features and outcome are poorly described. To assess the clinical characteristics and disease progression in adults with PCD. Bicentric retrospective study, focusing on adults (≥18 years) with an asserted diagnosis of PCD based on the presence of bronchiectasis with typical ultrastructural defect of cilia and/or situs inversus (SI). Clinical symptoms, respiratory function, extent of bronchiectasis, microbiology and molecular analysis were assessed. Results are expressed as median (25th; 75th centile). 78 patients were included with a median follow-up of 8.1 years. 91% of patients had respiratory symptoms and 95% had chronic rhinosinusitis. Half of ultrastructural defects concerned dynein arms. Respiratory function was significantly lower in women (FEV1=60% predicted (50; 76), vs 77% (62; 95), p=0.009) and in patients with chronic airway Pseudomonas aeruginosa (PA, n=21) infection (FEV1=60% (48; 71) vs 75% (55; 89), p=0.04). FEV1 was associated with gender (regression coefficient for men =13.8, p=0.009), chest CT score (r=-0.42, p<0.001) but not with age at diagnosis, SI or body mass index. FEV1 decline was -13.4 mL/year (-42.8; +11.9) and was greater in women (-29.3 mL/year, (-59.7; -11.9), vs -2.0 mL/year (-26.9; +25.4), p=0.002). Three patients had severe respiratory failure. Alteration of respiratory function in adults with PCD is heterogeneous and usually moderate but appears more severe in women and in patients with chronic PA infection. Only 4% of patients develop chronic respiratory failure.


Reversibly Stretchable, Optically Transparent Radio-Frequency Antennas Based on Wavy Ag Nanowire Networks.
We report a facile approach for producing reversibly stretchable, optically transparent radio-frequency antennas based on wavy Ag nanowire (NW) networks. The wavy configuration of Ag NWs is obtained by floating the NW networks on the surface of water, followed by compression. Stretchable antennas are prepared by transferring the compressed NW networks onto elastomeric substrates. The resulting antennas show excellent performance under mechanical deformation due to the wavy configuration, which allows the release of stress applied to the NWs and an increase in the contact area between NWs. The antennas formed from the wavy NW networks exhibit a smaller return loss and a higher radiation efficiency when strained than the antennas formed from the straight NW networks, as well as an improved stability in cyclic deformation tests. Moreover, the wavy NW antennas require a relatively small quantity of NWs, which leads to low production costs and provides an optical transparency. These results demonstrate the potential of these wavy Ag NW antennas in applications of wireless communications for wearable systems.


Cognitive Dysfunction in Systemic Lupus Erythematosus: A Case for Initiating Trials.
Cognitive dysfunction (CD) is an insidious and underdiagnosed manifestation of systemic lupus erythematosus (SLE) that has a considerable impact on quality of life, which can be devastating. Given the inconsistencies in the modes of assessment and the difficulties in attribution to SLE, the reported prevalence of CD ranges from 5% to 80%. Although clinical studies of SLE-related CD have been hampered by heterogeneous subject populations and a lack of sensitive and standardized cognitive tests or other validated objective biomarkers for CD, there are, nonetheless, strong data from mouse models and from the clinical arena that show CD is related to known disease mechanisms. Several cytokines, inflammatory molecules, and antibodies have been associated with CD. Proposed mechanisms for antibody- and cytokine-mediated neuronal injury include the abrogation of blood-brain barrier integrity with direct access of soluble molecules in the circulation to the brain and ensuing neurotoxicity and microglial activation. No treatments for SLE-mediated CD exist, but potential candidates include agents that inhibit microglial activation, such as angiotensin-converting enzyme inhibitors, or that protect blood-brain barrier integrity, such as C5a receptor blockers. Structural and functional neuroimaging data have shown a range of regional abnormalities in metabolism and white matter microstructural integrity in SLE patients that correlate with CD and could in the future become diagnostic tools and outcome measures in clinical trials aimed at preserving cognitive function in SLE.


The prevalence and effect of alcohol and drug abuse on cohort-matched critically injured patients.
A prospective study was undertaken at a Level I trauma center to evaluate the prevalence of substance use among victims of major trauma, along with the impact on clinical outcome. Five hundred sixteen patients had urine toxicology and blood alcohol screens performed and correlated with pattern and severity of injury, hospital course, and outcome. Three hundred seventy-one patients (71%) screened positive for alcohol or drugs, or both. Fifty-two per cent had positive alcohol screens, and 42 per cent had positive drug screens (cocaine and opiates represented 91% of positive drug screens). Univariate analysis revealed patterns of alcohol/drug use varied among subgroups according to demographics (less use among patients older than 55 years, females and Asians; more drug use in blacks; more alcohol use in Hispanics), mechanism of injury (non-use in blunt trauma patients and use of both in penetrating trauma patients) and body region injured (non-use in head-injured patients). Septic complications and mortality were more correlative with severity of injury, but not with use or non-use of alcohol or drugs. We conclude that alcohol and drug use remains a major comorbid factor in major trauma, and that injury prevention efforts should include a strong focus on counseling regarding these lifestyle choices.


Recommended configuration for personal health records by standardized data item sets for diabetes mellitus and associated chronic diseases: a report from a collaborative initiative by six Japanese associations.
It is expected that a large amount of data related to diabetes and other chronic diseases will be generated. However, databases constructed without standardized data item sets can be limited in their usefulness. To address this, the Collaborative Committee of Clinical Informatization in Diabetes Mellitus was established in 2011 by the Japan Diabetes Society and Japan Association for Medical Informatics. The committee has developed core item sets and self-management item sets for diabetes mellitus, hypertension, dyslipidemia, and chronic kidney disease in collaboration with the Japanese Society of Hypertension, Japan Atherosclerosis Society, Japanese Society of Nephrology, and Japanese Society of Laboratory Medicine, as well as a mapping table that aligns the self-management item sets with the Japanese standardized codes for laboratory testing. The committee also determined detailed specifications for implementing the four self-management item sets in personal health record applications to facilitate risk stratification, the generation of alerts using information and communications technology systems, the avoidance of data input errors, and the generation of reminders to input the self-management item set data. The approach developed by the committee may be useful for combining databases for various purposes (such as for clinical studies, patient education, and electronic medical record systems) and for facilitating collaboration between personal health record administrators.


L-dopa- and dopamine-(R)-alpha-lipoic acid conjugates as multifunctional codrugs with antioxidant properties.
A series of multifunctional codrugs (1-4), obtained by joining L-Dopa (LD) and dopamine (DA) with (R)-alpha-lipoic acid (LA), was synthesized and evaluated as potential codrugs with antioxidant and iron-chelating properties. These multifunctional molecules were synthesized to overcome the pro-oxidant effect associated with LD therapy. The physicochemical properties, together with the chemical and enzymatic stabilities of synthesized compounds, were evaluated in order to determine both their stability in aqueous medium and their sensitivity in undergoing enzymatic cleavage by rat and human plasma to regenerate the original drugs. The new compounds were tested for their radical scavenging activities, using a test involving the Fe (II)-H2O2-induced degradation of deoxyribose, and to evaluate peripheral markers of oxidative stress such as plasmatic activities of superoxide dismutase (SOD) and glutathione peroxidase (GPx) in the plasma. Furthermore, we showed the central effects of compounds 1 and 2 on spontaneous locomotor activity of rats in comparison with LD-treated animals. From the results obtained, compounds 1-4 appeared stable at a pH of 1.3 and in 7.4 buffered solution; in 80% human plasma they were turned into DA and LD. Codrugs 1-4 possess good lipophilicity (log P > 2 for all tested compounds). Compounds 1 and 2 seem to protect partially against the oxidative stress deriving from auto-oxidation and MAO-mediated metabolism of DA. This evidence, together with the "in vivo" dopaminergic activity and a sustained release of the parent drug in human plasma, allowed us to point out the potential advantages of using 1 and 2 rather than LD in treating pathologies such as Parkinson's disease, characterized by an evident decrease of DA concentration in the brain.


Bile salt-induced apoptosis of hepatocytes involves activation of protein kinase C.
Toxic bile salts induce hepatocyte apoptosis, a model relevant to liver injury during cholestasis. However, the signaling mechanisms culminating in bile salt-induced apoptosis remain unclear. Because protein kinase C (PKC) is activated by bile salts in hepatocytes and causes apoptosis in other cells, we tested the hypothesis that bile salt-induced hepatocyte apoptosis is mediated by PKC. The PKC inhibitors chelerythrine and Gö-6976 reduced, whereas a PKC agonist, phorbol 12-myristate 13-acetate (PMA), increased glycochenodeoxycholate (GCDC)-induced hepatocyte apoptosis. Membrane-associated total PKC activity was increased in GCDC-treated hepatocytes. Quantitative immunoblot analysis demonstrated membrane translocation of PKC-alpha, PKC-delta, and PKC-epsilon to hepatocyte membranes after administration of GCDC. Direct activation of PKC-alpha and PKC-delta by GCDC was also demonstrated using recombinant, baculovirus-expressed PKC isoforms in a medium of defined lipid composition. Chelerythrine and Gö-6976 reduced, whereas PMA enhanced, cathepsin B activity during treatment of hepatocytes with GCDC, demonstrating coupling of PKC activity to the protease effector mechanisms of apoptosis. In conclusion, our data suggest for the first time that PKC-dependent signaling pathways play a critical role in bile salt-induced hepatocyte apoptosis.


PEDF improves mitochondrial function in RPE cells during oxidative stress.
Oxidative stress plays an important role in health and aging. We have shown that oxidative stress impairs mitochondrial function and promotes RPE cell death in an age-dependent manner. This study investigates the role of pigment epithelium-derived factor (PEDF) in limiting oxidative stress-induced damage to RPE cells through mitochondrial pathways. Three groups of early-passaged RPE cells from donors 50 to 55, 60 to 65, and 70 to 75 years old (yo) were either preconditioned with PEDF followed by exposure to sublethal doses of hydrogen peroxide (H2O2) or post-treated with PEDF after H2O2 treatment. Effects of PEDF on mitochondrial function and cell viability were examined. Oxidative stress induced an age-dependent increase in LDH release, reactive oxygen species (ROS) levels, and cell death and a decrease in adenosine triphosphate (ATP) production and mitochondrial membrane potential (ΔΨm) in human RPE cells. Preconditioning or poststressed treatment with PEDF resulted in increased cell viability, inhibition of cytochrome c release and caspase 3 cleavage, and improved mitochondria function denoted by a decrease in ROS generation and increases in ATP production and ΔΨm. Oxidative stress also disrupted the reticular network, trafficking, and distribution of the mitochondria and blocked activation of phosphatidylinositol 3 kinase (PI3K), Akt, and Erk signaling in the cells. These effects were more pronounced in RPE cells from individuals>60 yo compared to the 50 to 55 yo age group. Pigment epithelium-derived factor mitigated negative effects of oxidative stress on mitochondrial remodeling and cellular distribution and unblocked its control of PI3K/Akt and mitogen-activated protein kinase (MAPK) signaling. Although PEDF potentiated both PI3K/Akt and MAPK signaling in the cells, stabilization of mitochondrial networks and function was dependent on its activation of PI3K/Akt. Specificity of PEDF's activity was confirmed using the pharmacological inhibitors LY294002, SH6, and U0126. We also show that in the absence of oxidative stress, pharmacological inhibition of the PI3K/Akt pathway alone was sufficient to disrupt mitochondrial structure and function. In addition, PEDF blocked effects of oxidative stress on expression of cyclophilin D and UCP2, genes controlling mitochondrial function, and the apoptotic genes caspase 3, Bax, and Bcl2. Control of ROS levels by PEDF was specifically linked to UCP2 regulation since PEDF-induced expression of this gene in UCP2-deficient cells was associated with a decrease in ROS production. We provide evidence that PEDF promotes resilience of aging RPE cells to oxidative stress by stabilizing mitochondrial networks and function and that mitochondrial dynamics in human RPE cells are controlled, in part, through the PI3K/Akt pathway.


Epidemiological aspects of rheumatoid arthritis: the sex ratio.
Many rheumatic diseases, including rheumatoid arthritis (RA) are more frequent in females than males. The objective of this article was to examine the female versus male perspective regarding prevalence/incidence, etiological factors, disease severity/outcomes, access to therapy and therapeutic responses. We also present results from some new analyses from the patient registers in Oslo to supplement existing literature in this area. We found that the prevalence of RA is higher in females than males, the incidence is 4-5 times higher below the age of 50, but above 60-70 years the female/male ratio is only about 2. Smoking is a consistent predictor of RA in males, but findings have been more inconsistent in females. We could not confirm that health status is worse in females than males when corrections were made for different disease duration and for the underlying tendency of healthy females to report worse subjective health status than males. Some studies and data presented here indicate that females have less access to health services. We also found that female sex reduces the likelihood of achieving treatment response with methotrexate and anti-tumor necrosis factor (anti-TNF) drugs by 30-50%. More research is needed to fully describe the differences between males and females regarding epidemiological data.


Different types of connective tissue alterations associated with cervical artery dissections.
This study describes the technical handling and the diagnostic evaluation of skin biopsies in order to standardize the assessment of the delicate morphologic abnormalities that are found in patients with spontaneous cervical artery dissections (sCAD). Skin biopsies from 126 patients with sCAD and from 29 healthy relatives were analyzed. The morphology of the connective tissue was normal in 54 patients with sCAD (43%) and aberrant in 72 patients with sCAD (57%). These latter patients were classified into three groups: in 43 patients, we repeatedly observed composite collagen fibrils and elastic fibers with fragmentation and minicalcifications. In 13 further patients, the dermis was significantly thinner than in healthy subjects. The collagen fibers contained fibrils with highly variable diameters. In a third group of 16 sCAD patients, the abnormalities were restricted to the elastic fibers (with fragmentation and minicalcifications) without significant alterations in the morphology of the collagen fibrils. The finding of different morphologic classes of aberrations among patients suggests that the connective tissue defects are genetically heterogeneous. The segregation of the connective tissue phenotype in three families suggested an autosomal dominant pattern of inheritance.


B7-h4 expression in human melanoma: its association with patients' survival and antitumor immune response.
Cancers have developed a number of strategies to escape immune responses including the differential expression of costimulatory molecules of the B7 family. B7-H3 and B7-H4 have recently been described in different tumor entities but the relevance for melanoma has not yet been studied so far. Using immunohistochemistry, B7-H3 and B7-H4 expression was studied on 29 melanoma lesions. Survival curves and log-rank tests were used to test the association of protein expression with survival. Cell lines were evaluated for B7-H3 and B7-H4 expression by PCR and flow cytometry. Functional T-cell-tumor coculture assays were carried out with in vitro generated tumor transfectants. B7-H3 and B7-H4 expression was detected in primary tumor lesions (29 of 29 and 28 of 29) and in metastases (28 of 29 and 26 of 29). The numbers of CD68(+) macrophages were significantly lower in patients with low B7-H4 expression, whereas CD8(+) T-cell infiltrates were independent of expression levels. Furthermore, a survival benefit for patients with B7-H4 low expressing melanoma was found, whereas B7-H3 was not associated with any clinical parameter. All 23 melanoma cell lines analyzed expressed B7-H3 and B7-H4 mRNA and protein, but B7-H4 was restricted to intracellular compartments. On silencing of B7-H3 by specific shRNA tumor-associated antigen-specific T cell responses were unaltered. Overexpression of B7-H4 on melanoma cells did not alter the cytotoxicity of different CD8(+) effector cells, but drastically inhibited cytokine production. Our study provides for the first time evidence of B7-H4 expression on melanoma cells as a mechanism controlling tumor immunity which is associated with patients' survival.


A Computer Adaptive Measure of Delay Discounting.
Delay discounting has been linked to important behavioral, health, and social outcomes, including academic achievement, social functioning and substance use, but thoroughly measuring delay discounting is tedious and time consuming. We develop and consistently validate an efficient and psychometrically sound computer adaptive measure of discounting. First, we develop a binary search-type algorithm to measure discounting using a large international data set of 4,190 participants. Using six independent samples ( N = 1,550), we then present evidence of concurrent validity with two standard measures of discounting and a measure of discounting real rewards, convergent validity with addictive behavior, impulsivity, personality, survival probability; and divergent validity with time perspective, life satisfaction, age and gender. The new measure is considerably shorter than standard questionnaires, includes a range of time delays, can be applied to multiple reward magnitudes, shows excellent concurrent, convergent, divergent, and discriminant validity-by showing more sensitivity to effects of smoking behavior on discounting.


The New Science of Practical Wisdom.
Wisdom has been discussed for centuries in religious and philosophical texts. It is often viewed as a fuzzy psychological construct analogous to consciousness, stress, and resilience. This essay provides an understanding of wisdom as a scientific construct, based on empirical research starting in the 1970s. The focus is on practical rather than theoretical wisdom. While there are different conceptualizations of wisdom, it is best defined as a complex human characteristic or trait with specific components: social decision-making, emotional regulation, prosocial behavior (such as empathy and compassion), self-reflection, acceptance of uncertainty, decisiveness, and spirituality. These psychological processes involve the fronto-limbic circuitry. Wisdom is associated with positive life outcomes including better health, well-being, happiness, life satisfaction, and resilience. Wisdom tends to increase with active aging, facilitating a contribution of wise grandparents to promoting fitness of younger kin. Despite the loss of their own fertility and physical health, older adults help enhance their children's and grandchildren's well-being, health, longevity, and fertility-the "grandmother hypothesis" of wisdom. Wisdom has important implications at individual and societal levels and is a major contributor to human thriving. We need to place a greater emphasis on promoting wisdom through our educational systems from elementary to professional schools.


Novel phosphotyrosine targets of FGFR2IIIb signaling.
In partnership exclusively with the epithelial FGFR2IIIb isotype and a structurally-specific heparan sulfate motif, stromal-derived FGF7 delivers both growth-promoting and growth-limiting differentiation signals to epithelial cells that promote cellular homeostasis between stromal and epithelial compartments. Intercompartmental homeostasis supported by FGF7/FGFR2IIIb is subverted in many solid epithelial tumors. The normally mesenchymal-derived homologue FGFR1 drives proliferation and a progressive tumor-associated phenotype when it appears ectopically in epithelial cells. In order to understand the mechanism underlying the unique biological effects of FGFR2IIIb, we developed an inducible FGFR2IIIb expression system that is specifically dependent on FGF7 for activation in an initially unresponsive cell line to avoid selection for only the growth-promoting aspects of FGFR2IIIb signaling. We then determined FGF7/FGFR2IIIb signaling-specific tyrosine phosphorylated proteins within 5 min after FGF7 stimulation by phosphopeptide immunoaffinity purification and nano-LC-MS/MS. The FGF7/FGFR2 pair caused tyrosine phosphorylation of multiple proteins that have been implicated in the growth stimulating activities of FGFR1 that included multi-substrate organizers FRS2alpha and IRS4, ERK2 and phosphatases SHP2 and SHIP2. It uniquely phosphorylated CDK2 and phosphatase PTPN18 on sites involved in the attenuation of cell proliferation, and several factors that maintain nuclear-cytosolic relationships (emerin and LAP2), protein structure and other cellular fine structures as well as some proteins of unknown functions. Several of the FGF7/FGFR2IIIb-specific targets have been associated with maintenance of function and tumor suppression and disruption in tumors. In contrast, a number of pTyr substrates associated with FGF2/FGFR1 that are generally associated with intracellular Ca(2+)-phospholipid signaling, membrane and cytoskeletal plasticity, cell adhesion, migration and the tumorigenic phenotype were not observed with FGF7/FGFR2IIIb. Our findings provide specific downstream targets for dissection of causal relationships underlying the distinct role of FGF7/FGFR2IIIb signaling in epithelial cell homeostasis.


Long-term recreational physical activity and breast cancer in the National Health and Nutrition Examination Survey I epidemiologic follow-up study.
Our purpose was to study the association between long-term recreational physical activity and breast cancer in the Epidemiological Follow-up Study (NHEFS) of the first National Health and Nutrition Examination Survey (NHANES I, 1971-1975). The analytic cohort included 6160 women who were free of breast cancer at the first NHEFS follow-up in 1982-1984 and had interview data on recreational physical activity (low, moderate, and high) in 1982-1984 and 10 years earlier, in 1971-1975. We created categories of long-term (1982-1984 + 1971-1975) recreational physical activity: (a) consistently low; (b) moderate/inconsistent; and (c) consistently high. Data were analyzed using Cox proportional hazard regression models. A total of 138 women developed breast cancer between 1982-1984 and 1992. In women > or =50 years of age in 1982-1984, consistently high (versus consistently low) recreational physical activity was associated with a 67% reduction in breast cancer risk (n = 96 cases; relative risk, 0.33; 95% confidence interval, 0.14-0.82; P for trend = 0.03); in women <50 years of age (n = 42 cases), there was no association. Associations were not modified by body mass index or by weight gain as an adult. High recreational physical activity over the long-term may reduce breast cancer risk in women > or =50 years of age; in this sample, it did so regardless of weight history.


Functional characterization of the Arabidopsis beta-ketoacyl-coenzyme A reductase candidates of the fatty acid elongase.
In plants, very-long-chain fatty acids (VLCFAs; >18 carbon) are precursors of sphingolipids, triacylglycerols, cuticular waxes, and suberin. VLCFAs are synthesized by a multiprotein membrane-bound fatty acid elongation system that catalyzes four successive enzymatic reactions: condensation, reduction, dehydration, and a second reduction. A bioinformatics survey of the Arabidopsis (Arabidopsis thaliana) genome has revealed two sequences homologous to YBR159w encoding a Saccharomyces cerevisiae beta-ketoacyl reductase (KCR), which catalyzes the first reduction during VLCFA elongation. Expression analyses showed that both AtKCR1 and AtKCR2 genes were transcribed in siliques, flowers, inflorescence stems, leaves, as well as developing embryos, but only AtKCR1 transcript was detected in roots. Fluorescent protein-tagged AtKCR1 and AtKCR2 were localized to the endoplasmic reticulum, the site of fatty acid elongation. Complementation of the yeast ybr159Delta mutant demonstrated that the two KCR proteins are divergent and that only AtKCR1 can restore heterologous elongase activity similar to the native yeast KCR gene. Analyses of insertional mutants in AtKCR1 and AtKCR2 revealed that loss of AtKCR1 function results in embryo lethality, which cannot be rescued by AtKCR2 expression using the AtKCR1 promoter. In contrast, a disruption of the AtKCR2 gene had no obvious phenotypic effect. Taken together, these results indicate that only AtKCR1 is a functional KCR isoform involved in microsomal fatty acid elongation. To investigate the roles of AtKCR1 in postembryonic development, transgenic lines expressing RNA interference and overexpression constructs targeted against AtKCR1 were generated. Morphological and biochemical characterization of these lines confirmed that suppressed KCR activity results in a reduction of cuticular wax load and affects VLCFA composition of sphingolipids, seed triacylglycerols, and root glycerolipids, demonstrating in planta that KCR is involved in elongation reactions supplying VLCFA for all these diverse classes of lipids.


Respiratory tract infections in the pathway to multiple myeloma: a population-based study in Scandinavia.
Encounter with infectious antigens has been proposed to initiate the cascade of events associated with progression from premalignancy (monoclonal gammopathy of undetermined significance, MGUS) to multiple myeloma (MM). We conducted a population-based case-control study to evaluate risk of developing MM associated with a personal history of various respiratory tracts infections occurring >1 year prior to MM. Inpatient (1977-1997) and outpatient (1994-1997) diagnoses were obtained for all MM patients (n=4,476) diagnosed in Denmark (1977-1997) and 16,727 matched controls. A personal history of pneumonia was associated with a 1.6-fold (95%CI 1.3-2.0) increased risk of MM; the elevated risk was restricted to 1-4.99 years prior to the diagnosis of MM (OR=1.7,95%CI 1.3-2.2). Individuals with two and three or more previous episodes of pneumonia had a 1.7-fold (95%CI 1.0-3.0; p=0.05) and a 1.5-fold (95%CI 0.6-3.9) elevated MM risk, respectively. Pneumonia could be a trigger to the development of MM or a manifestation of immune disturbances in late-stage MGUS.


NG2+ CNS glial progenitors remain committed to the oligodendrocyte lineage in postnatal life and following neurodegeneration.
The mammalian CNS contains a ubiquitous population of glial progenitors known as NG2+ cells that have the ability to develop into oligodendrocytes and undergo dramatic changes in response to injury and demyelination. Although it has been reported that NG2+ cells are multipotent, their fate in health and disease remains controversial. Here, we generated PDGFαR-CreER transgenic mice and followed their fate in vivo in the developing and adult CNS. These studies revealed that NG2+ cells in the postnatal CNS generate myelinating oligodendrocytes, but not astrocytes or neurons. In regions of neurodegeneration in the spinal cord of ALS mice, NG2+ cells exhibited enhanced proliferation and accelerated differentiation into oligodendrocytes but remained committed to the oligodendrocyte lineage. These results indicate that NG2+ cells in the normal CNS are oligodendrocyte precursors with restricted lineage potential and that cell loss and gliosis are not sufficient to alter the lineage potential of these progenitors.


Anterior filler displacement following injection of calcium hydroxylapatite gel (Radiesse) for anophthalmic orbital volume augmentation.
To describe the complication of anterior filler displacement following injection of calcium hydroxylapatite gel (Radiesse) for anophthalmic enophthalmos correction. Retrospective case series of patients who experienced anterior filler displacement following orbital injection of calcium hydroxylapatite. Data includes patient demographics, indication for injection, route and volume of injection, description of postinjection complications, and final outcome. Four cases of anterior filler displacement and expansion following injection of calcium hydroxylapatite were identified. The patients' ages ranged from 33 to 64 years old. All 4 patients underwent multiple prior orbital surgeries and suffered from anophthalmic enophthalmos. Injectable calcium hydroxylapatite was delivered transcutaneously, to the deep extraconal orbital space, via 27-gauge, 1.25-inch retrobulbar needles. Each patient received an initial 1.3 ml of filler, with 1 patient receiving an additional 0.8 ml. Within 1 week, all patients experienced prominent, edematous lower eyelids. A CT scan of 1 patient radiographically documented anterior migration of the filler material. Two patients required transconjunctival excision of the filler and infiltrated orbital fat. Histopathologic examination of 1 specimen revealed chronic foreign body granulomatous inflammation. Two patients were treated medically, with resolution of clinical findings over 6 to 9 months. Anterior filler displacement is a potential complication of orbital volume augmentation with injectable calcium hydroxylapatite. Patients should be counseled regarding this possibility when considering options for the treatment of anophthalmic enophthalmos. A history of multiple prior orbital surgeries, with associated tissue disruption and scarring, may be a risk factor for filler displacement.


Relationship between baseline glycemic control and cognitive function in individuals with type 2 diabetes and other cardiovascular risk factors: the action to control cardiovascular risk in diabetes-memory in diabetes (ACCORD-MIND) trial.
Diabetes is associated with cognitive decline and dementia. However, the relationship between the degree of hyperglycemia and cognitive status remains unclear. This was explored using baseline cognitive measures collected in the ongoing Memory in Diabetes (MIND) substudy of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. The relationship of A1C and fasting plasma glucose (FPG) levels to performance on four cognitive tests was assessed, adjusting for age and other determinants of cognitive status. The tests were the Digit Symbol Substitution Test (DSST), Mini Mental Status Examination (MMSE), Rey Auditory Verbal Learning Test, and Stroop Test. A statistically significant age-adjusted association was observed between the A1C level and the score on all four cognitive tests. Specifically, a 1% higher A1C value was associated with a significant 1.75-point lower DSST score (95% CI -1.22 to -2.28; P < 0.0001), a 0.20-point lower MMSE score (-0.11 to -0.28; P < 0.0001), a 0.11-point lower memory score (-0.02 to -0.19, P = 0.0142), and a worse score (i.e., 0.75 s more) on the Stroop Test (1.31-0.19, P = 0.0094). The association between the DSST score and A1C persisted in all multiple linear regression models. FPG was not associated with test performance. Higher A1C levels are associated with lower cognitive function in individuals with diabetes. The effect of glucose lowering on cognitive function will be determined by the ongoing ACCORD-MIND trial.


Sensitivity enhancement in 1D heteronuclear NMR spectroscopy via single-scan inverse experiments.
Measuring the nuclear magnetic resonance spectra of low-gamma heteronuclei such as 15N constitutes an important analytical tool for the characterization of molecular structure and dynamics. The reduced resonance frequencies and magnetic moments of these heteronuclei, however, make the sensitivity of this kind of spectroscopy inherently lower than that of comparable H NMR observations. A well-known solution to this sensitivity problem is indirect detection: a 2D NMR technique capable of enhancing the sensitivity of heteronuclear NMR by porting the actual data acquisition from the low-gamma nucleus to neighboring protons. This has become the standard method of observation in biomolecular NMR, where the resolution introduced by 2D spectroscopy is always a sought-after commodity. Indirect detection, however, has not gained a wide appeal in organic chemistry or in in vivo investigations, where one-dimensional heteronuclear NMR information usually suffices. The present study explores the possibility of retaining certain advantages derived from indirect detection while not giving up on the simple one-dimensional nature of heteronuclear NMR, by relying on the spatial-encoding scheme we have recently demonstrated for implementing single-scan multi-dimensional NMR spectroscopy. Preliminary results based on a 1D modification of this experiment confirm theoretical calculations suggesting that the sensitivity of 1D 15N NMR can be enhanced significantly in this manner; the relevance of this experiment given the advent of dedicated H-observing cryogenic probeheads with very high sensitivities is briefly discussed.


Crystallographic snapshots of a replicative DNA polymerase encountering an abasic site.
Abasic sites are common DNA lesions, which are strong blocks to replicative polymerases and are potentially mutagenic when bypassed. We report here the 2.8 A structure of the bacteriophage RB69 replicative DNA polymerase attempting to process an abasic site analog. Four different complexes were captured in the crystal asymmetric unit: two have DNA in the polymerase active site whereas the other two molecules are in the exonuclease mode. When compared to complexes with undamaged DNA, the DNA surrounding the abasic site reveals distinct changes suggesting why the lesion is so poorly bypassed: the DNA in the polymerase active site has not translocated and is therefore stalled, precluding extension. All four molecules exhibit conformations that differ from the previously published structures. The polymerase incorporates dAMP across the lesion under crystallization conditions, indicating that the different conformations observed in the crystal may be part of the active site switching reaction pathway.


Bayes factors for detection of quantitative trait loci.
A fundamental issue in quantitative trait locus (QTL) mapping is to determine the plausibility of the presence of a QTL at a given genome location. Bayesian analysis offers an attractive way of testing alternative models (here, QTL vs. no-QTL) via the Bayes factor. There have been several numerical approaches to computing the Bayes factor, mostly based on Markov Chain Monte Carlo (MCMC), but these strategies are subject to numerical or stability problems. We propose a simple and stable approach to calculating the Bayes factor between nested models. The procedure is based on a reparameterization of a variance component model in terms of intra-class correlation. The Bayes factor can then be easily calculated from the output of a MCMC scheme by averaging conditional densities at the null intra-class correlation. We studied the performance of the method using simulation. We applied this approach to QTL analysis in an outbred population. We also compared it with the Likelihood Ratio Test and we analyzed its stability. Simulation results were very similar to the simulated parameters. The posterior probability of the QTL model increases as the QTL effect does. The location of the QTL was also correctly obtained. The use of meta-analysis is suggested from the properties of the Bayes factor.


Second malignancies following treatment of chronic myeloid leukaemia in the tyrosine kinase inhibitor era.
Given that tyrosine kinase inhibitors (TKIs) have dramatically improved the survival of patients with chronic myeloid leukaemia (CML), we were interested in examining the possible risk of long-term adverse events, such as the emergence of other neoplasms. Therefore, we studied the development of second malignancies in 868 patients diagnosed with CML between 2002 and 2011 using the Swedish CML register, cross-linked to the Swedish Cancer register. With a median follow-up of 3·7 (range 0-9·9) years, 65 (7·5%) patients developed 75 second malignancies (non-haematological), 52 of which were of the invasive type. Compared to expected rates in the background population, the risk of second malignancies was higher in the CML cohort, with a standardized incidence ratio (SIR) of 1·52 (95% CI 1·13-1·99). The SIR before and after the second year following diagnosis of CML was 1·58 and 1·47, respectively. Among specific cancer types, gastrointestinal and nose and throat cancer were significantly increased. Founded on a population-based material, our results indicate that CML patients treated in the TKI era are at an increased risk of developing a second malignancy, with indications that this risk may more likely be linked to CML itself rather than to the TKI treatment.


Defective epithelial barrier in chronic rhinosinusitis: the regulation of tight junctions by IFN-γ and IL-4.
Chronic rhinosinusitis (CRS) is a common disease with still unclear pathophysiologic mechanisms. Epithelial tight junctions (TJs) have been shown to be involved in different chronic disorders, including bronchial asthma, inflammatory bowel diseases, and skin disorders. The regulation of epithelial barrier function and TJ expression has not been extensively studied in patients with CRS and in the paranasal sinus epithelium thus far. We sought to elucidate the TJ expression pattern in the epithelium of the sinonasal mucosa and its regulation in patients with CRS. Trans-tissue resistance was measured in biopsy specimens from healthy control subjects and patients with CRS with and without nasal polyps. TJ protein expression was determined by using immunofluorescence, Western blotting, and real-time PCR. Primary epithelial cell cultures from patients with CRS and control subjects were used in air-liquid interface (ALI) cultures for the measurement of transepithelial resistance (TER) and TJ expression. The effect of IFN-γ, IL-4, and IL-17 on ALI cultures was assessed. A decreased trans-tissue resistance was found in biopsy specimens from patients with CRS with nasal polyps along with an irregular, patchy, and decreased expression of the TJ molecules occludin and zonula occludens 1. TER was reduced in ALI cultures from patients with CRS with nasal polyps. The cytokines IFN-γ and IL-4 decreased TER, whereas IL-17 did not have any influence on epithelial integrity. A defective epithelial barrier was found in patients with CRS with nasal polyps along with a decreased expression of TJ proteins. The disruption of epithelial integrity by IFN-γ and IL-4 in vitro indicates a possible role for these proinflammatory cytokines in the pathogenesis of patients with CRS.


Modeling uptake of selected pharmaceuticals and personal care products into food crops from biosolids-amended soil.
Biosolids contain a variety of pharmaceuticals and personal care products (PPCPs). Studies have observed the uptake of PPCPs into plants grown in biosolids-amended soils. This study examined the ability of Dynamic Plant Uptake (DPU) model and Biosolids-amended Soil Level IV (BASL4) model to predict the concentration of eight PPCPs in the tissue of plants grown in biosolids-amended soil under a number of exposure scenarios. Concentrations in edible tissue predicted by the models were compared to concentrations reported in the literature by calculating estimated human daily intake values for both sets of data and comparing them to an acceptable daily intake value. The equilibrium partitioning (EqP) portion of BASL4 overpredicted the concentrations of triclosan, triclocarban, and miconazole in root and shoot tissue by two to three orders of magnitude, while the dynamic carrot root (DCR) portion overpredicted by a single order of magnitude. DPU predicted concentrations of triclosan, triclocarban, miconazole, carbamazepine, and diphenhydramine in plant tissues that were within an order of magnitude of concentrations reported in the literature. The study also found that more empirical data are needed on the uptake of cimetidine, fluoxetine, and gemfibrozil, and other ionizable PPCPs, to confirm the utility of both models. All hazard quotient values calculated from literature data were below 1, with 95.7% of hazard quotient values being below 0.1, indicating that consumption of the chosen PPCPs in plant tissue poses de minimus risk to human health.


Internet-Based Audiologist-Guided Cognitive Behavioral Therapy for Tinnitus: Randomized Controlled Trial.
Tinnitus is a symptom that can be very distressing owing to hearing sounds not related to any external sound source. Managing tinnitus is notoriously difficult, and access to evidence-based care is limited. Cognitive behavioral therapy (CBT) is a tinnitus management strategy with the most evidence of effectiveness but is rarely offered to those distressed by tinnitus. The provision of internet-based CBT for tinnitus overcomes accessibility barriers; however, it is not currently readily available in the United States. The aim of this study is to investigate the efficacy of internet-based CBT compared with that of weekly monitoring for the management of tinnitus in reducing tinnitus distress; reducing tinnitus-related comorbidities, including tinnitus cognitions, insomnia, anxiety, and depression; and assessing the stability of the intervention effects 2 months after the intervention. A 2-arm randomized clinical trial comparing audiologist-guided internet-based CBT (n=79) to a weekly monitoring group (n=79) with a 2-month follow-up assessed the efficacy of internet-based CBT. Eligible participants included adults seeking help for tinnitus. Recruitment was conducted on the web using an open-access website. Participants were randomized via 1:1 allocation, but blinding was not possible. The study was undertaken by English or Spanish speakers on the web. The primary outcome was a change in tinnitus distress as measured using the Tinnitus Functional Index. Secondary outcome measures included anxiety, depression, insomnia, tinnitus cognition, hearing-related difficulties, and quality of life. Internet-based CBT led to a greater reduction in tinnitus distress (mean 36.57, SD 22) compared with that in weekly monitoring (mean 46.31, SD 20.63; effect size: Cohen d=0.46, 95% CI 0.14-0.77) using an intention-to-treat analysis. For the secondary outcomes, there was a greater reduction in negative tinnitus cognition and insomnia. The results remained stable over the 2-month follow-up period. No important adverse events were observed. Further, 16% (10/158) of participants withdrew, with low overall compliance rates for questionnaire completion of 72.3% (107/148) at T1, 61% (91/148) at T2, and 42% (62/148) at T3. This study is the first to evaluate and indicate the efficacy of audiologist-delivered internet-based CBT in reducing tinnitus distress in a US population. It was also the first study to offer internet-based CBT in Spanish to accommodate the large Hispanic population in the United States. The results have been encouraging, and further work is indicated in view of making such an intervention applicable to a wider population. Further work is required to improve compliance and attract more Spanish speakers. ClinicalTrials.gov NCT04004260; https://clinicaltrials.gov/ct2/show/NCT04004260.


Serosurvey of pandemic H1N1 influenza A virus in dogs in Andalusia (southern Spain).
In April 2009, a new influenza A virus (IAV) subtype (A(H1N1)pdm09) spread worldwide and triggered the first human influenza pandemic of the 21st century. Since then, exposure to the pandemic H1N1 IAV has been confirmed in different animal species. Serological evidence and clinical infection with A(H1N1)pdm09 have been reported in canines, but the information available about the role of dogs in the epidemiology of this IAV subtype is still very limited in Europe. A cross-sectional study was carried out to determine the seroprevalence of A(H1N1)pdm09 in dogs in southern Spain, a region with endemic seasonal circulation in human. Sera from 750 companion dogs were collected during the period 2013-2016. Antibodies against pandemic H1N1 IAV were analysed using the haemagglutination inhibition test. Positive samples were also tested by single radial haemolysis assay. Seropositivity was only confirmed by both methods in one (0.13%; 95% CI: 0.00-0.38) adult animal sampled in 2013. To the best of the authors' knowledge, this is the first report of A(H1N1)pdm09 exposure in dogs in Spain. The low seroprevalence obtained indicates a limited exposure history to A(H1N1)pdm09 IAV in dogs in this country and suggests a low risk of transmission of this zoonotic IAV subtype between humans and dogs.


Novel functional profiling approach combining reverse phase protein microarrays and human 3-D ex vivo tissue cultures: expression of apoptosis-related proteins in human colon cancer.
Cancer is caused by a complex pattern of molecular perturbations. To understand the biology of cancer, it is thus important to look at the activation state of key proteins and signaling networks. The limited amount of available sample material from patients and the complexity of protein expression patterns make the use of traditional protein analysis methods particularly difficult. In addition, the only approach that is currently available for performing functional studies is the use of serial biopsies, which is limited by ethical constraints and patient acceptance. The goal of this work was to establish a 3-D ex vivo culture technique in combination with reverse-phase protein microarrays (RPPM) as a novel experimental tool for use in cancer research. The RPPM platform allows the parallel profiling of large numbers of protein analytes to determine their relative abundance and activation level. Cancer tissue and the respective corresponding normal tissue controls from patients with colorectal cancer were cultured ex vivo. At various time points, the cultured samples were processed into lysates and analyzed on RPPM to assess the expression of carcinoembryonic antigen (CEA) and 24 proteins involved in the regulation of apoptosis. The methodology displayed good robustness and low system noise. As a proof of concept, CEA expression was significantly higher in tumor compared with normal tissue (p<0.0001). The caspase 9 expression signal was lower in tumor tissue than in normal tissue (p<0.001). Cleaved Caspase 8 (p=0.014), Bad (p=0.007), Bim (p=0.007), p73 (p=0.005), PARP (p<0.001), and cleaved PARP (p=0.007) were differentially expressed in normal liver and normal colon tissue. We demonstrate here the feasibility of using RPPM technology with 3-D ex vivo cultured samples. This approach is useful for investigating complex patterns of protein expression and modification over time. It should allow functional proteomics in patient samples with various applications such as pharmacodynamic analyses in drug development.


Impact of limited solvent capacity on metabolic rate, enzyme activities, and metabolite concentrations of S. cerevisiae glycolysis.
The cell's cytoplasm is crowded by its various molecular components, resulting in a limited solvent capacity for the allocation of new proteins, thus constraining various cellular processes such as metabolism. Here we study the impact of the limited solvent capacity constraint on the metabolic rate, enzyme activities, and metabolite concentrations using a computational model of Saccharomyces cerevisiae glycolysis as a case study. We show that given the limited solvent capacity constraint, the optimal enzyme activities and the metabolite concentrations necessary to achieve a maximum rate of glycolysis are in agreement with their experimentally measured values. Furthermore, the predicted maximum glycolytic rate determined by the solvent capacity constraint is close to that measured in vivo. These results indicate that the limited solvent capacity is a relevant constraint acting on S. cerevisiae at physiological growth conditions, and that a full kinetic model together with the limited solvent capacity constraint can be used to predict both metabolite concentrations and enzyme activities in vivo.


Impact of pulsed xenon ultraviolet light on hospital-acquired infection rates in a community hospital.
The role of contaminated environments in the spread of hospital-associated infections has been well documented. This study reports the impact of a pulsed xenon ultraviolet no-touch disinfection system on infection rates in a community care facility. This study was conducted in a community hospital in Southern Florida. Beginning November 2012, a pulsed xenon ultraviolet disinfection system was implemented as an adjunct to traditional cleaning methods on discharge of select rooms. The technology uses a xenon flashlamp to generate germicidal light that damages the DNA of organisms in the hospital environment. The device was implemented in the intensive care unit (ICU), with a goal of using the pulsed xenon ultraviolet system for disinfecting all discharges and transfers after standard cleaning and prior to occupation of the room by the next patient. For all non-ICU discharges and transfers, the pulsed xenon ultraviolet system was only used for Clostridium difficile rooms. Infection data were collected for methicillin-resistant Staphylococcus aureus, C difficile, and vancomycin-resistant Enterococci (VRE). The intervention period was compared with baseline using a 2-sample Wilcoxon rank-sum test. In non-ICU areas, a significant reduction was found for C difficile. There was a nonsignificant decrease in VRE and a significant increase in methicillin-resistant S aureus. In the ICU, all infections were reduced, but only VRE was significant. This may be because of the increased role that environment plays in the transmission of this pathogen. Overall, there were 36 fewer infections in the whole facility and 16 fewer infections in the ICU during the intervention period than would have been expected based on baseline data. Implementation of pulsed xenon ultraviolet disinfection is associated with significant decreases in facility-wide and ICU infection rates. These outcomes suggest that enhanced environmental disinfection plays a role in the risk mitigation of hospital-acquired infections.


Population screening and transmission experiments indicate paramyxid-microsporidian co-infection in Echinogammarus marinus represents a non-hyperparasitic relationship between specific parasite strains.
Phylogenetically distant parasites often infect the same host. Indeed, co-infections can occur at levels greater than expected by chance and are sometimes hyperparasitic. The amphipod Echinogammarus marinus presents high levels of co-infection by two intracellular and vertically transmitted parasites, a paramyxid (Paramarteilia sp. Em) and a microsporidian strain (Dictyocoela duebenum Em). This co-infection may be hyperparasitic and result from an exploitative 'hitchhiking' or a symbiotic relationship between the parasites. However, the best-studied amphipod species are often collected from contaminated environments and may be immune-compromised. Immune-challenged animals frequently present co-infections and contaminant-exposed amphipods present significantly higher levels of microsporidian infection. This suggests the co-infections in E. marinus may result from contaminant-associated compromised immunity. Inconsistent with hyperparasitism, we find that artificial infections transmit Paramarteilia without microsporidian. Our population surveys reveal the co-infection relationship is geographically widespread but find only chance co-infection between the Paramarteilia and another species of microsporidian, Dictyocoela berillonum. Furthermore, we identify a haplotype of the Paramarteilia that presents no co-infection, even in populations with otherwise high co-infection levels. Overall, our results do not support the compromised-immunity hypothesis but rather that the co-infection of E. marinus, although non-hyperparasitic, results from a relationship between specific Paramarteilia and Dictyocoela duebenum strains.


Functional properties of human intestinal mast cells cultured in a new culture system: enhancement of IgE receptor-dependent mediator release and response to stem cell factor.
Culture of human mast cells (MC) in vitro has only been possible to date in the presence of 3T3 fibroblasts. The aim of the present study was to maintain freshly isolated human MC in culture without addition of feeder cells and to study their functional properties. We isolated cell suspensions containing 1 to 11% MC from human intestinal tissue and cultured them in standard medium. MC survived in culture for about 2 wk without cytokine supplementation and for several months with supplementation of medium with stem cell factor (SCF). SCF selectively supported MC survival, whereas the number of contaminating cells declined rapidly during culture. Most interestingly, we found that histamine and leukotriene release induced by IgE receptor cross-linking was substantially enhanced in cultured MC compared with that in MC stimulated directly after cell isolation. Cultured MC, but not freshly isolated MC, released mediators in response to SCF in a concentration-dependent fashion provided that the cells were cultured in SCF-free medium. These findings demonstrate that human MC isolated from intestinal tissue can be maintained in culture in vitro for several weeks. After culture they have different functional properties, which might resemble more closely the functional status of human intestinal MC in vivo than that of freshly isolated cells.


Confinement-Induced Giant Spin-Orbit-Coupled Magnetic Moment of Co Nanoclusters in TiO2 Films.
High magnetization materials are in great demand for the fabrication of advanced multifunctional magnetic devices. Notwithstanding this demand, the development of new materials with these attributes has been relatively slow. In this work, we propose a new strategy to achieve high magnetic moments above room temperature. Our material engineering approach invoked the embedding of magnetic nanoclusters in an oxide matrix. By precisely controlling pulsed laser deposition parameters, Co nanoclusters are formed in a 5 at % Co-TiO2 film. The presence of these nanoclusters was confirmed using transmission electron microscopy, energy-dispersive X-ray spectroscopy, and X-ray absorption fine structure. The film exhibits a very high saturation magnetization of 99 emu/cm3. Detailed studies using X-ray magnetic circular dichroism confirm that Co has an enhanced magnetic moment of 3.5 μB/atom, while the Ti and O also contribute to the magnetic moments. First-principles calculations supported our hypothesis that the metallic Co nanoclusters surrounded by a TiO2 matrix can exhibit both large spin and orbital moments. Moreover, a quantum confinement effect results in a high Curie temperature for the embedded Co nanoclusters. These findings reveal that 1-2 nm nanoclusters that are quantum confined can exhibit very large magnetic moments above room temperature, representing a promising advance for the design of new high magnetization materials.


Friends with benefits: on the positive consequences of pet ownership.
Social support is critical for psychological and physical well-being, reflecting the centrality of belongingness in our lives. Human interactions often provide people with considerable social support, but can pets also fulfill one's social needs? Although there is correlational evidence that pets may help individuals facing significant life stressors, little is known about the well-being benefits of pets for everyday people. Study 1 found in a community sample that pet owners fared better on several well-being (e.g., greater self-esteem, more exercise) and individual-difference (e.g., greater conscientiousness, less fearful attachment) measures. Study 2 assessed a different community sample and found that owners enjoyed better well-being when their pets fulfilled social needs better, and the support that pets provided complemented rather than competed with human sources. Finally, Study 3 brought pet owners into the laboratory and experimentally demonstrated the ability of pets to stave off negativity caused by social rejection. In summary, pets can serve as important sources of social support, providing many positive psychological and physical benefits for their owners.


[Pediatric neurocysticercosis].
Cysticercosis: parasitic disease which affects 3% of the population in Mexico. It is considered that there are more than 50 million infected people in the world, endemic in Mexico, Central and South America, Africa, Asia and India. It is considered the most important neurological infectious disease world-wide for its clinical manifestations. The causal agent in pigs and humans is the cysticercus of the Taenia solium, that can lodge in muscle, brain and ventricles. If pork meat contaminated with cysticercus is eaten, the tapeworm will live in the human intestine and create thousands of eggs that are excreted by the feces. When food contaminated with fecal matter is consumed by man or pig, the cisticercosis is disseminated in several parts of the organism, specially CNS. Man is the only host of the tapeworm and the pig is the only intermediary, reason why the prevalence of the teniasis-cisticercosis depends on this bond. It is diagnosed in endemic zones by the presence of convulsion crises, focal migraine, neurological symptoms, disorders of vision, endocraneal hypertension and CT scan with hypodense zones or cysts with a hyperdense ring. The antiparasitic treatment in children is controversial among pediatricians; it is suggested to use it only in the non calcified cystic phase and in cases associated with epilepsy. Few are the cases of hydrocephalic or intraventricular cysticercus that need surgical treatment.


Large introns in relation to alternative splicing and gene evolution: a case study of Drosophila bruno-3.
Alternative splicing (AS) of maturing mRNA can generate structurally and functionally distinct transcripts from the same gene. Recent bioinformatic analyses of available genome databases inferred a positive correlation between intron length and AS. To study the interplay between intron length and AS empirically and in more detail, we analyzed the diversity of alternatively spliced transcripts (ASTs) in the Drosophila RNA-binding Bruno-3 (Bru-3) gene. This gene was known to encode thirteen exons separated by introns of diverse sizes, ranging from 71 to 41,973 nucleotides in D. melanogaster. Although Bru-3's structure is expected to be conducive to AS, only two ASTs of this gene were previously described. Cloning of RT-PCR products of the entire ORF from four species representing three diverged Drosophila lineages provided an evolutionary perspective, high sensitivity, and long-range contiguity of splice choices currently unattainable by high-throughput methods. Consequently, we identified three new exons, a new exon fragment and thirty-three previously unknown ASTs of Bru-3. All exon-skipping events in the gene were mapped to the exons surrounded by introns of at least 800 nucleotides, whereas exons split by introns of less than 250 nucleotides were always spliced contiguously in mRNA. Cases of exon loss and creation during Bru-3 evolution in Drosophila were also localized within large introns. Notably, we identified a true de novo exon gain: exon 8 was created along the lineage of the obscura group from intronic sequence between cryptic splice sites conserved among all Drosophila species surveyed. Exon 8 was included in mature mRNA by the species representing all the major branches of the obscura group. To our knowledge, the origin of exon 8 is the first documented case of exonization of intronic sequence outside vertebrates. We found that large introns can promote AS via exon-skipping and exon turnover during evolution likely due to frequent errors in their removal from maturing mRNA. Large introns could be a reservoir of genetic diversity, because they have a greater number of mutable sites than short introns. Taken together, gene structure can constrain and/or promote gene evolution.


Left ventricular mechanical dyssynchrony by cardiac magnetic resonance is greater in patients with strict vs nonstrict electrocardiogram criteria for left bundle-branch block.
Left bundle-branch block (LBBB) is a marker of increased delay between septal and left ventricular (LV) lateral wall electrical activation and is a predictor of which patients will benefit from cardiac resynchronization therapy. Recent analysis has suggested that one-third of patients meeting the conventional electrocardiogram criteria for LBBB are misdiagnosed, and new strict LBBB criteria have been proposed. We tested the hypothesis that patients with strict LBBB have greater LV mechanical dyssynchrony than do patients meeting the nonstrict LBBB criteria, whereas there is no difference between patients with nonstrict LBBB and LV conduction delay with a QRS duration of 110 to 119 ms. Sixty-four patients referred for primary prevention implantable cardioverter-defibrillators underwent 12-lead electrocardiogram and cardiac magnetic resonance myocardial tagging. The patients were classified as strict LBBB, nonstrict LBBB, or non-LBBB (nonspecific LV conduction delay with a QRS duration of 110-119 ms). The time delay between septal and lateral LV wall peak circumferential strain (septal-to-lateral wall delay) was measured by cardiac magnetic resonance. Patients with strict LBBB (n = 31) had a greater septal-to-lateral wall delay compared with patients with nonstrict LBBB (n = 19) (210 ± 137 ms vs 122 ± 102 ms, P = .045). There was no significant difference between nonstrict LBBB and non-LBBB (n = 14) septal-to-lateral wall delay (122 ± 102 ms vs 100 ± 86 ms, P = .51). Strict LBBB criteria identify patients with greater mechanical dyssynchrony compared with patients only meeting the nonstrict LBBB criteria, whereas there was no significant difference between patients with nonstrict LBBB and non-LBBB. The greater observed LV dyssynchrony may explain why patients with strict LBBB have a better response to cardiac resynchronization therapy.