Terahertz transmission properties of thin, subwavelength metallic hole arrays.
We present experimental results of the transmission magnitude and phase change of terahertz pulses through thin metallic films patterned with subwavelength hole arrays on silicon wafers. Terahertz time-domain spectroscopy measurements reveal a sharp phase peak centered on the surface plasmon resonance. Correspondingly, and consistent with the Kramers-Kronig relations, the measured transmission magnitude has the shape of the derivative of this peak. In addition, we determine that the aperture shape has a notable effect on the transmission properties of two-dimensional hole arrays.


Immunogenicity and immunologic memory of meningococcal C conjugate vaccine in premature infants.
Protein-polysaccharide conjugate vaccines against Neisseria meningitidis serogroup C were introduced into the U.K. routine immunization schedule in 1999. This study is the first to describe both persistence of antibody and evidence for induction of immune memory using meningococcal C conjugate (MCC) vaccine in preterm infants. Immunogenicity and induction of immunologic memory by as MCC vaccine was assessed in premature infants; 62 preterm and 60 term controls received MCC at the accelerated schedule (2, 3 and 4 months of age). A meningococcal C polysaccharide challenge was administered at 12 months of age. Both groups achieved similar protective titers after primary immunization that then waned significantly by 1 year of age. Postchallenge serum bactericidal activity was significantly lower in preterm infants (P = 0.03); 73% of preterm versus 88% of term controls achieved a 4-fold rise in serum bactericidal activity (P = 0.07). MCC vaccine is immunogenic and primes for immunologic memory in preterm infants. The decreased memory responses in these preterm infants in conjunction with waning clinical efficacy data for all U.K. infants suggest a role for a routine booster dose of vaccine in all infants receiving MCC, especially those born preterm.


Evaluation of five different antigens in enzyme-linked immunosorbent assay for the detection of avian pneumovirus antibodies.
Five different antigens were evaluated in enzyme-linked immunosorbent assay (ELISA) tests for the detection of avian pneumovirus (APV) antibodies. Two of the 5 antigens were prepared from recent APV isolates from Minnesota. The 2 older isolates were passage 63 of a strain currently used as a live, attenuated vaccine and a Colorado strain isolated for the first time in the United States and currently used in an ELISA test. The fifth antigen is based on an APV recombinant N-protein. Basic parameters and positive-negative threshold of the assays were established for all 5 antigens on the basis of data obtained by testing 46 known negative and 46 known positive serum samples. Subsequently, 449 field samples were tested by all 5 ELISAs. The optical density difference (ODD) was calculated by subtracting optical density of the sample in the negative antigen well from that in the positive antigen well. In the current ELISA test based on the Colorado strain, an ODD of 0.2 is considered to be the cutoff value to classify samples as negative or positive. In this study, however, use of different cutoffs, based on ODD of negative control plus 3 SD or values estimated from Receiver operating characteristic analysis, was considered to be more appropriate for the various antigens used. Overall person-to-person and day-to-day variability was found to be large for all tests using either ODD or sample to positive ratio to report results. In addition, results suggest that antigenicity of the APV isolates in the United States has not changed between 1997 and 2000.


Is cytomegalovirus reactivation increasing the mortality of patients with severe sepsis?
Cytomegalovirus (CMV) is a ubiquitous virus present in approximately two-thirds of the healthy population. This virus rarely causes an active disease in healthy individuals, but it is among the most common opportunistic infections in immunocompromised patients such as solid organ transplant recipients, patients receiving chemotherapy for cancer or patients with human immunodeficiency virus. Critically ill patients who are immunocompetent before intensive care unit admission may also become more prone to develop active CMV infection if they have prolonged hospitalizations, high disease severity, and severe sepsis. The development of active CMV infection in these critically ill patients has been associated with a significantly higher risk of death in several previous studies. The present issue of Critical Care brings a new study by Heininger and colleagues in which the authors found that patients with severe sepsis who developed active CMV infection had significantly longer intensive care unit and hospital stays, prolonged mechanical ventilation, but no changes in mortality compared to patients without CMV infection. We discuss the possible reasons for their findings (for example, selection bias and low (20%) statistical power to detect mortality endpoints), and also perform an update of our previous meta-analysis with the addition of Heininger and colleagues' study to verify whether the higher mortality rate with CMV holds. Our updated meta-analysis with approximately 1,000 patients shows that active CMV infection continues to be associated with a significant 81% higher mortality rate than that in critically ill patients without active CMV infection.


A new tyrosyl radical on Phe208 as ligand to the diiron center in Escherichia coli ribonucleotide reductase, mutant R2-Y122H. Combined x-ray diffraction and EPR/ENDOR studies.
The R2 protein subunit of class I ribonucleotide reductase (RNR) belongs to a structurally related family of oxygen bridged diiron proteins. In wild-type R2 of Escherichia coli, reductive cleavage of molecular oxygen by the diferrous iron center generates a radical on a nearby tyrosine residue (Tyr122), which is essential for the enzymatic activity of RNR, converting ribonucleotides into deoxyribonucleotides. In this work, we characterize the mutant E. coli protein R2-Y122H, where the radical site is substituted with a histidine residue. The x-ray structure verifies the mutation. R2-Y122H contains a novel stable paramagnetic center which we name H, and which we have previously proposed to be a diferric iron center with a strongly coupled radical, Fe(III)Fe(III)R.. Here we report a detailed characterization of center H, using 1H/2H -14N/15N- and 57Fe-ENDOR in comparison with the Fe(III)Fe(IV) intermediate X observed in the iron reconstitution reaction of R2. Specific deuterium labeling of phenylalanine residues reveals that the radical results from a phenylalanine. As Phe208 is the only phenylalanine in the ligand sphere of the iron site, and generation of a phenyl radical requires a very high oxidation potential, we propose that in Y122H residue Phe208 is hydroxylated, as observed earlier in another mutant (R2-Y122F/E238A), and further oxidized to a phenoxyl radical, which is coordinated to Fe1. This work demonstrates that small structural changes can redirect the reactivity of the diiron site, leading to oxygenation of a hydrocarbon, as observed in the structurally similar methane monoxygenase, and beyond, to formation of a stable iron-coordinated radical.


Body Mass Index and the Spontaneous Onset of Parturition.
To investigate the relationship between body mass index (BMI) and the onset of parturition throughout gestation. This was a secondary analysis of the Maternal-Fetal Medicine Units Network Preterm Prediction Study. Time-to-spontaneous-birth-event (ie, "survival") methods were used to study the association of BMI with the timing of spontaneous onset of labor throughout gestation with indicated births censored at delivery. A Kaplan-Meier estimate of the probability of spontaneous labor was compared with a log rank test across five categories of BMI (kg/m): underweight (less than 18.5), normal weight (18.5-24.99), preobese (25-29.99), obese I (30-34.99), and obese II+ (35 or greater). A proportional hazards model was estimated to compare time to spontaneous onset of labor adjusted for multiple variables known to be associated with the onset of labor. Normal-weight women (n=1,054) had a median delivery gestational age of 39 3/7 weeks. Obese II+ women (n=178) had a median delivery gestational age 5 days later than normal-weight women (P<.001). Delivery gestational age of preobese (n=866) and obese I (n=548) women was not significantly different from normal-weight women. Underweight women (n=41) had a median delivery gestational age 5 days earlier than normal-weight women (P<.001). Compared with women with normal BMIs, obese II+ women were significantly less likely and underweight women significantly more likely to enter spontaneous labor at all gestational ages. In the multivariable model, BMI was significantly associated with spontaneous onset of labor throughout pregnancy (BMI [five-unit] adjusted hazard ratio 0.874, 0.829-0.921). Body mass index is significantly associated with the likelihood of the spontaneous onset of labor at all gestational ages with gestational age at the time of delivery and BMI being inversely related. This novel observation unifies previous reports focusing on the association of overweight and underweight BMIs and preterm and postterm birth and may inform discussions surrounding elective induction of labor at term.


Striatal activity underlies novelty-based choice in humans.
The desire to seek new and unfamiliar experiences is a fundamental behavioral tendency in humans and other species. In economic decision making, novelty seeking is often rational, insofar as uncertain options may prove valuable and advantageous in the long run. Here, we show that, even when the degree of perceptual familiarity of an option is unrelated to choice outcome, novelty nevertheless drives choice behavior. Using functional magnetic resonance imaging (fMRI), we show that this behavior is specifically associated with striatal activity, in a manner consistent with computational accounts of decision making under uncertainty. Furthermore, this activity predicts interindividual differences in susceptibility to novelty. These data indicate that the brain uses perceptual novelty to approximate choice uncertainty in decision making, which in certain contexts gives rise to a newly identified and quantifiable source of human irrationality.


Thrombomodulin Ala455Val Polymorphism and the risk of cerebral infarction in a biracial population: the Stroke Prevention in Young Women Study.
The genes encoding proteins in the thrombomodulin-protein C pathway are promising candidate genes for stroke susceptibility because of their importance in thrombosis regulation and inflammatory response. Several published studies have shown that the Ala455Val thrombomodulin polymorphism is associated with ischemic heart disease, but none has examined the association with stroke. Using data from the Stroke Prevention in Young Women Study, we sought to determine the association between the Ala455Val thrombomodulin polymorphism and the occurrence of ischemic stroke in young women. All 59 hospitals in the greater Baltimore-Washington area participated in a population-based case-control study of stroke in young women. We compared 141 cases of first ischemic stroke (44% black) among women 15 to 44 years of age with 210 control subjects (35% black) who were identified by random digit dialing and frequency matched to the cases by age and geographical region of residence. Data on historical risk factors were collected by standardized interview. Genotyping of the thrombomodulin Ala455Val polymorphism was performed by pyrosequencing. The A allele (frequency = 0.85) was associated with stroke under the recessive model. After adjustment for age, race, cigarette smoking, hypertension, and diabetes, the AA genotype, compared with the AV and VV genotypes combined, was significantly associated with stroke (odds ratio 1.9, 95% CI 1.1-3.3). The AA genotype was more common among black than white control subjects (81% versus 68%) but there was no significant interaction between the risk genotype and race (adjusted odds ratio 2.7 for blacks and 1.6 for whites). A secondary analysis removing all probable (n = 16) and possible (n = 15) cardioembolic strokes demonstrated an increased association (odds ratio 2.2, 95% CI 1.2-4.2). Among women aged 15 to 44 years, the AA genotype is more prevalent among blacks than whites and is associated with increased risk of early onset ischemic stroke. Removing strokes potentially related to cardioembolic phenomena increased this association. Further studies are needed to determine whether this polymorphism is functionally related to thrombomodulin expression or whether the association is due to population stratification or linkage to a nearby functional polymorphism.


Na+/H+ exchanger blockade inhibits enterocyte inflammatory response and protects against colitis.
Na+/H+ exchangers (NHEs) are integral transmembrane proteins found in all mammalian cells. There is substantial evidence indicating that NHEs regulate inflammatory processes. Because intestinal epithelial cells express a variety of NHEs, we tested the possibility that NHEs are also involved in regulation of the epithelial cell inflammatory response. In addition, since the epithelial inflammatory response is an important contributor to mucosal inflammation in inflammatory bowel disease (IBD), we examined the role of NHEs in the modulation of disease activity in a mouse model of IBD. In human gut epithelial cells, NHE inhibition using a variety of agents, including amiloride, 5-(N-methyl-N-isobutyl)amiloride, 5-(N-ethyl-N-isopropyl)- amiloride, harmaline, clonidine, and cimetidine, suppressed interleukin-8 (IL-8) production. The inhibitory effect of NHE inhibition on IL-8 was associated with a decrease in IL-8 mRNA accumulation. NHE inhibition suppressed both activation of the p42/p44 mitogen-activated protein kinase and nuclear factor-kappaB. Finally, NHE inhibition ameliorated the course of IBD in dextran sulfate-treated mice. Our data demonstrate that inhibition of NHEs may be an approach worthy of pursuing for the treatment of IBD.


Phosphoglucomutase-1 deficiency: Early presentation, metabolic management and detection in neonatal blood spots.
Phosphoglucomutase 1 deficiency is a congenital disorder of glycosylation (CDG) with multiorgan involvement affecting carbohydrate metabolism, N-glycosylation and energy production. The metabolic management consists of dietary D-galactose supplementation that ameliorates hypoglycemia, hepatic dysfunction, endocrine anomalies and growth delay. Previous studies suggest that D-galactose administration in juvenile patients leads to more significant and long-lasting effects, stressing the urge of neonatal diagnosis (0-6 months of age). Here, we detail the early clinical presentation of PGM1-CDG in eleven infantile patients, and applied the modified Beutler test for screening of PGM1-CDG in neonatal dried blood spots (DBSs). All eleven infants presented episodic hypoglycemia and elevated transaminases, along with cleft palate and growth delay (10/11), muscle involvement (8/11), neurologic involvement (5/11), cardiac defects (2/11). Standard dietary measures for suspected lactose intolerance in four patients prior to diagnosis led to worsening of hypoglycemia, hepatic failure and recurrent diarrhea, which resolved upon D-galactose supplementation. To investigate possible differences in early vs. late clinical presentation, we performed the first systematic literature review for PGM1-CDG, which highlighted respiratory and gastrointestinal symptoms as significantly more diagnosed in neonatal age. The modified Butler-test successfully identified PGM1-CDG in DBSs from seven patients, including for the first time Guthrie cards from newborn screening, confirming the possibility of future inclusion of PGM1-CDG in neonatal screening programs. In conclusion, severe infantile morbidity of PGM1-CDG due to delayed diagnosis could be prevented by raising awareness on its early presentation and by inclusion in newborn screening programs, enabling early treatments and galactose-based metabolic management.


Ergonomics and musculoskeletal pain among postgraduate students and faculty members of the School of Dentistry of the University of Barcelona (Spain). A cross-sectional study.
To evaluate the intensity and location of musculoskeletal pain suffered by students and professors from different postgraduate programs of the School of Dentistry of the University of Barcelona (Spain), to identify the variables related to the occurrence of musculoskeletal symptoms and signs, and to establish possible preventive measures for such disorders. A cross-sectional study was made among students and faculty members from different postgraduate courses of the School of Dentistry at the University of Barcelona between May and June 2007. A total of 74 dentists (54 postgraduate students and 20 faculty members) completed an anonymous questionnaire containing 19 questions. The variables were divided into three main groups: sociodemographic information, ergonomic features and musculoskeletal pain arising from professional practice. Most of the dentists (79.8%) had experienced some kind of musculoskeletal pain in the last 6 months. On comparing the different locations of pain (lumbar, cervical, dorsal, wrist, shoulder and others), the neck was found to be the most commonly affected location (58% of all subjects), and only 34% of the respondents took some preventive measures against musculoskeletal disorders. Women showed a higher frequency of intense pain involving the cervical, lumbar, dorsal and wrist areas (p<0.05). A higher incidence of wrist pain was recorded in professionals exclusively dedicated to oral surgery (p<0.05). No statistically significant correlation was found between the workload (hours) and pain in the different anatomical locations (p>0.05). An important incidence of pain symptoms secondary to musculoskeletal disorders was observed, particularly in the cervical region. Females and younger dentists showed a higher frequency of such symptoms. The implementation of preventive measures is necessary, in view of the high incidence of these disorders.


[Infection of a hip prosthesis after dry needling].
A 57-year-old patient presented to the orthopaedic department with hip pain 7 months after hip replacement and two weeks after dry needling by a physiotherapist. Dry needling is used by physiotherapists to treat pain and stiffness. In the Netherlands, there are no clear guidelines or contra-indications described for this treatment. The surgical scar of our patient showed signs of inflammation for which debridement and irrigation were performed. Tissue samples showed positive bacterial cultures and the patient was treated with antibiotics. One week after completing this treatment, the infection returned. Debridement and irrigation were repeated and antibiotic treatment was recommenced. Three months later, the patient showed no signs of infection with the prosthesis still in situ. Although there is no strong evidence for a causal relationship between dry needling and the infection, dry needling should be used carefully in patients with a joint replacement, due to the increased risk of infection.


Mapping QTLs for improving grain yield using the USDA rice mini-core collection.
Yield is the most important and complex trait for genetic improvement in crops, and marker-assisted selection enhances the improvement efficiency. The USDA rice mini-core collection derived from over 18,000 accessions of global origins is an ideal panel for association mapping. We phenotyped 203 O. sativa accessions for 14 agronomic traits and identified 5 that were highly and significantly correlated with grain yield per plant: plant height, plant weight, tillers, panicle length, and kernels/branch. Genotyping with 155 genome-wide molecular markers demonstrated 5 main cluster groups. Linkage disequilibrium (LD) decayed at least 20 cM and marker pairs with significant LD ranged from 4.64 to 6.06% in four main groups. Model comparisons revealed that different dimensions of principal component analysis affected yield and its correlated traits for mapping accuracy, and kinship did not improve the mapping in this collection. Thirty marker-trait associations were highly significant, 4 for yield, 3 for plant height, 6 for plant weight, 9 for tillers, 5 for panicle length and 3 for kernels/branch. Twenty-one markers contributed to the 30 associations, because 8 markers were co-associated with 2 or more traits. Allelic analysis of OSR13, RM471 and RM7003 for their co-associations with yield traits demonstrated that allele 126 bp of RM471 and 108 bp of RM7003 should receive greater attention, because they had the greatest positive effect on yield traits. Tagging the QTLs responsible for multiple yield traits may simultaneously help dissect the complex yield traits and elevate the efficiency to improve grain yield using marker-assisted selection in rice.


Preferential expression of the gene for a putative inositol 1,4,5-trisphosphate receptor homologue in the mushroom bodies of the brain of the worker honeybee Apis mellifera L.
A gene expressed preferentially in the mushroom bodies of the brain of the worker honeybee Apis mellifera L. was identified by the differential display method and its cDNA was isolated. The cDNA fragment of 534 bp (clone A1) contained an open reading frame encoding 177 amino acid residues having 78, 72, 70, 59 and 55% sequence identities with the inositol 1,4,5-trisphosphate (IP3) receptors of Drosophila melanogaster, Xenopus laevis and humans (types 1, 2 and 3), respectively, suggesting that it encodes a putative IP3 receptor homologue of the honeybee. In situ hybridization revealed that the gene encoding clone A1 was expressed preferentially in the mushroom bodies and not in the optic lobes, antennal lobes and central bodies; in the mushroom body, it was expressed strongly in the large type Kenyon cells and weakly in the small type Kenyon cells. Reverse transcription polymerase chain reaction analysis showed that the gene was expressed strongly in the head and weakly in the antennae, legs, thorax, and abdomen. These results suggest that the A1 gene product plays a crucial role in neural transmission in the mushroom bodies of the worker bee brain.


Conformation of bis-nitroxide polarizing agents by multi-frequency EPR spectroscopy.
The chemical structure of polarizing agents critically determines the efficiency of dynamic nuclear polarization (DNP). For cross-effect DNP, biradicals are the polarizing agents of choice and the interaction and relative orientation of the two unpaired electrons should be optimal. Both parameters are affected by the molecular structure of the biradical in the frozen glassy matrix that is typically used for DNP/MAS NMR and likely differs from the structure observed with X-ray crystallography. We have determined the conformations of six bis-nitroxide polarizing agents, including the highly efficient AMUPol, in their DNP matrix with EPR spectroscopy at 9.7 GHz, 140 GHz, and 275 GHz. The multi-frequency approach in combination with an advanced fitting routine allows us to reliably extract the interaction and relative orientation of the nitroxide moieties. We compare the structures of six bis-nitroxides to their DNP performance at 500 MHz/330 GHz.


Managing cancer-related fatigue in men with prostate cancer: a systematic review of non-pharmacological interventions.
The aim of this systematic review was to synthesize the best available evidence informing the effectiveness of non-pharmacological interventions for managing cancer-related fatigue in men treated for prostate cancer. This review considered experimental studies that included men with prostate cancer (regardless of staging, previous treatment or comorbidities), aged 18 years and over who were undergoing any treatment, or had completed any treatment for prostate cancer within the previous 12 months. Three interventions were identified for the management of cancer-related fatigue in men with prostate cancer. Evidence from five studies including 447 participants demonstrates the effectiveness of physical activity, both aerobic and resistance exercise, and from three studies including 153 participants suggesting the benefits of psychosocial interventions including education and cognitive behavioural therapy. Health professionals require knowledge of a range of effective interventions aimed at reducing cancer-related fatigue in men with prostate cancer and should incorporate those interventions into their patient management. Although physical activity appears to show the greatest benefit, other non-pharmacological interventions such as education and cognitive behavioural therapy have demonstrated benefit and should also be considered as a strategy in treating this debilitating side effect of cancer and its treatment.


Standardization of the prone extension postural test on children ages 4 through 8.
The prone extension postural test is a measurement of vestibular functioning that has been used by occupational therapists in assessing children suspected of having vestibular system deficits. The purpose of this study was to standardize the prone extension postural test because no standardized procedures or normative data were previously available for its administration. Reliability and validity were estimated and normative data gathered on 242 normal children ranging in age from 4 through 8 years. Performance involving duration and score on a qualitative scale was recorded. Four and 5 year olds performed similarly and statistically, and significantly differently from 6, 7, and 8 year olds. When a small group of learning-disabled children was compared to a nondisabled group, the prone extension postural test differentiated between the two groups with the exception of the 4 year olds.


The clinical impact of bacterial biofilms.
Bacteria survive in nature by forming biofilms on surfaces and probably most, if not all, bacteria (and fungi) are capable of forming biofilms. A biofilm is a structured consortium of bacteria embedded in a self-produced polymer matrix consisting of polysaccharide, protein and extracellular DNA. Bacterial biofilms are resistant to antibiotics, disinfectant chemicals and to phagocytosis and other components of the innate and adaptive inflammatory defense system of the body. It is known, for example, that persistence of staphylococcal infections related to foreign bodies is due to biofilm formation. Likewise, chronic Pseudomonas aeruginosa lung infections in cystic fibrosis patients are caused by biofilm growing mucoid strains. Gradients of nutrients and oxygen exist from the top to the bottom of biofilms and the bacterial cells located in nutrient poor areas have decreased metabolic activity and increased doubling times. These more or less dormant cells are therefore responsible for some of the tolerance to antibiotics. Biofilm growth is associated with an increased level of mutations. Bacteria in biofilms communicate by means of molecules, which activates certain genes responsible for production of virulence factors and, to some extent, biofilm structure. This phenomenon is called quorum sensing and depends upon the concentration of the quorum sensing molecules in a certain niche, which depends on the number of the bacteria. Biofilms can be prevented by antibiotic prophylaxis or early aggressive antibiotic therapy and they can be treated by chronic suppressive antibiotic therapy. Promising strategies may include the use of compounds which can dissolve the biofilm matrix and quorum sensing inhibitors, which increases biofilm susceptibility to antibiotics and phagocytosis.


Spatiotemporal and gender-specific parasitism in two species of gobiid fish.
Parasitism is considered a major selective force in natural host populations. Infections can decrease host condition and vigour, and potentially influence, for example, host population dynamics and behavior such as mate choice. We studied parasite infections of two common marine fish species, the sand goby (Pomatoschistus minutus) and the common goby (Pomatoschistus microps), in the brackish water Northern Baltic Sea. We were particularly interested in the occurrence of parasite taxa located in central sensory organs, such as eyes, potentially affecting fish behavior and mate choice. We found that both fish species harbored parasite communities dominated by taxa transmitted to fish through aquatic invertebrates. Infections also showed significant spatiotemporal variation. Trematodes in the eyes were very few in some locations, but infection levels were higher among females than males, suggesting differences in exposure or resistance between the sexes. To test between these hypotheses, we experimentally exposed male and female sand gobies to infection with the eye fluke Diplostomum pseudospathaceum. These trials showed that the fish became readily infected and females had higher parasite numbers, supporting higher susceptibility of females. Eye fluke infections also caused high cataract intensities among the fish in the wild. Our results demonstrate the potential of these parasites to influence host condition and visual abilities, which may have significant implications for survival and mate choice in goby populations.


The Drosophila gene Medea demonstrates the requirement for different classes of Smads in dpp signaling.
Signals from transforming growth factor-beta (TGF-beta) ligands are transmitted within the cell by members of the Smad family, which can be grouped into three classes based on sequence similarities. Our previous identification of both class I and II Smads functioning in a single pathway in C. elegans, raised the issue of whether the requirement for Smads derived from different classes is a general feature of TGF-beta signaling. We report here the identification of a new Drosophila class II Smad, Medea, a close homolog of the human tumor-suppressor gene DPC4. Embryos from germline clones of both Medea and Mad (a class I Smad) are ventralized, as are embryos null for the TGF-beta-like ligand decapentaplegic (dpp). Loss of Medea also blocks dpp signaling during later development, suggesting that Medea, like Mad, is universally required for dpp signaling. Furthermore, we show that the necessity for these two closely related, non-redundant Smads, is due to their different signaling properties - upon activation of the Dpp pathway, Mad is required to actively translocate Medea into the nucleus. These results provide a paradigm for, and distinguish between, the requirement for class I and II Smads in Dpp/BMP signaling.


Field performance of a genetically engineered strain of pink bollworm.
Pest insects harm crops, livestock and human health, either directly or by acting as vectors of disease. The Sterile Insect Technique (SIT)--mass-release of sterile insects to mate with, and thereby control, their wild counterparts--has been used successfully for decades to control several pest species, including pink bollworm, a lepidopteran pest of cotton. Although it has been suggested that genetic engineering of pest insects provides potential improvements, there is uncertainty regarding its impact on their field performance. Discrimination between released and wild moths caught in monitoring traps is essential for estimating wild population levels. To address concerns about the reliability of current marking methods, we developed a genetically engineered strain of pink bollworm with a heritable fluorescent marker, to improve discrimination of sterile from wild moths. Here, we report the results of field trials showing that this engineered strain performed well under field conditions. Our data show that attributes critical to SIT in the field--ability to find a mate and to initiate copulation, as well as dispersal and persistence in the release area--were comparable between the genetically engineered strain and a standard strain. To our knowledge, these represent the first open-field experiments with a genetically engineered insect. The results described here provide encouragement for the genetic control of insect pests.


Self-perceived health status of women three to five years after the diagnosis of gestational diabetes: a survey of cases and matched controls.
Our purpose was to determine the long-term effect on self-perceived health status and maternal perceptions of the offspring's health status after women had been labeled with a diagnosis of gestational diabetes. We designed a mail survey of women who had participated in a large cohort study 3 to 5 years earlier. A tentative address list was developed for 139 women diagnosed with gestational diabetes and 406 matched controls; 33 and 89 questionnaires, respectively, were returned as "wrong address," but 106 case and 317 control addresses were potentially valid. The primary analysis compared cases and controls on the general health scale of the SF-36. Secondary outcomes included comparisons of the groups' mean results on a worry scale, ratings of the health of the child born in the index pregnancy, disability days, physician visits, diabetes preventive behaviors, and diabetes risk appraisal. The usable response rates were 65 of 106 (61.3%) and 197 of 317 (62.1%), with no meaningful demographic differences found between respondents and nonrespondents. For general health, the mean score for cases was 68.9 (SD 22.34) vs 73.8 (SD 19.86) for controls, p = 0.05 (prespecified, one-tailed). After factors found to be independently related to health perception (age, race, birth place, and comorbidity) were controlled, the differences narrowed, with a mean score for cases of 70.09 versus 73.38 for controls, p = 0.11, two-tailed. Compared with controls, cases were more worried about their own health (p = 0.02, two-tailed), rated their children as less healthy (p = 0.005, two-tailed), and perceived themselves as more likely to have diabetes (p < 0.0001, two-tailed). The diagnosis of gestational diabetes may lead to long-term changes in how women view their own health status and that of the child born during the affected pregnancy.


Long-term clinical outcomes after bilateral laminotomy or total laminectomy for lumbar spinal stenosis: a single-institution experience.
OBJECTIVELumbar spinal stenosis (LSS) is the most common spinal disease in the geriatric population, and is characterized by a compression of the lumbosacral neural roots from a narrowing of the lumbar spinal canal. LSS can result in symptomatic compression of the neural elements, requiring surgical treatment if conservative management fails. Different surgical techniques with or without fusion are currently treatment options. The purpose of this study was to provide a description of the long-term clinical outcomes of patients who underwent bilateral laminotomy compared with total laminectomy for LSS.METHODSThe authors retrospectively reviewed all the patients treated surgically by the senior author for LSS with total laminectomy and bilateral laminotomy with a minimum of 10 years of follow-up. Patients were divided into 2 treatment groups (total laminectomy, group 1; and bilateral laminotomy, group 2) according to the type of surgical decompression. Clinical outcomes measures included the visual analog scale (VAS), the 36-Item Short-Form Health Survey (SF-36) scores, and the Oswestry Disability Index (ODI). In addition, surgical parameters, reoperation rate, and complications were evaluated in both groups.RESULTSTwo hundred fourteen patients met the inclusion and exclusion criteria (105 and 109 patients in groups 1 and 2, respectively). The mean age at surgery was 69.5 years (range 58-77 years). Comparing pre- and postoperative values, both groups showed improvement in ODI and SF-36 scores; at final follow-up, a slightly better improvement was noted in the laminotomy group (mean ODI value 22.8, mean SF-36 value 70.2), considering the worse preoperative scores in this group (mean ODI value 70, mean SF-36 value 38.4) with respect to the laminectomy group (mean ODI 68.7 vs mean SF-36 value 36.3), but there were no statistically significant differences between the 2 groups. Significantly, in group 2 there was a lower incidence of reoperations (15.2% vs 3.7%, p = 0.0075).CONCLUSIONSBilateral laminotomy allows adequate and safe decompression of the spinal canal in patients with LSS; this technique ensures a significant improvement in patients' symptoms, disability, and quality of life. Clinical outcomes are similar in both groups, but a lower incidence of complications and iatrogenic instability has been shown in the long term in the bilateral laminotomy group.


An old model with new insights: endogenous retroviruses drive the evolvement toward ASD susceptibility and hijack transcription machinery during development.
The BTBR T+Itpr3tf/J (BTBR/J) strain is one of the most valid models of idiopathic autism, serving as a potent forward genetics tool to dissect the complexity of autism. We found that a sister strain with an intact corpus callosum, BTBR TF/ArtRbrc (BTBR/R), showed more prominent autism core symptoms but moderate ultrasonic communication/normal hippocampus-dependent memory, which may mimic autism in the high functioning spectrum. Intriguingly, disturbed epigenetic silencing mechanism leads to hyperactive endogenous retrovirus (ERV), a mobile genetic element of ancient retroviral infection, which increases de novo copy number variation (CNV) formation in the two BTBR strains. This feature makes the BTBR strain a still evolving multiple-loci model toward higher ASD susceptibility. Furthermore, active ERV, analogous to virus infection, evades the integrated stress response (ISR) of host defense and hijacks the transcriptional machinery during embryonic development in the BTBR strains. These results suggest dual roles of ERV in the pathogenesis of ASD, driving host genome evolution at a long-term scale and managing cellular pathways in response to viral infection, which has immediate effects on embryonic development. The wild-type Draxin expression in BTBR/R also makes this substrain a more precise model to investigate the core etiology of autism without the interference of impaired forebrain bundles as in BTBR/J.


A Retrospective Case Series of a Novel Spinal Cord Stimulator Trial Technique with Less Displacement and Migration of the Trial Leads.
Spinal cord stimulation is an established treatment option for certain chronic pain conditions which have been previously unresponsive to conservative therapies or potentially for a subset of patients who have not improved following spine surgery. Prior to permanent lead implantation, stimulator lead trials are performed to ensure adequate patient benefit. During these trials, one of the most common complications and reasons for failure is the displacement and migration of the trial leads, resulting in lost therapeutic coverage. Other complications include infection and dislodged bulky dressings. There is a paucity of literature describing an adequate procedural method to prevent these common complications. This study utilizes a series of 19 patients to evaluate a new technique for securing percutaneous spinal cord simulator trial leads, which may minimize dislodgement and migration complications and improve the rate of trial success. Retrospective case series. New Jersey Medical School, Department of Anesthesiology, Pain Management Division. A retrospective chart review was conducted on 19 consecutive patients undergoing placement of the percutaneous thoracic spinal cord stimulator trial leads for pain associated with lumbar spine pathology over a two-year period (2010-2012). Of the 19 patients in our cohort, there was one trial lead displacement, no lead migrations, and no site infections. Thirteen patients went on to permanent lead implantation. This improved trial lead placement technique had a high success rate with a low number of complications. Small sample size, retrospective case series, and no control group for comparison. This case series was able to demonstrate that our described novel spinal cord stimulator trial lead placement and dressing technique can decrease the incidence of lead displacement and migration, thus improving trial success.


An adaptive Bayesian pruning for neural networks in a non-stationary environment.
Pruning a neural network to a reasonable smaller size, and if possible to give a better generalization, has long been investigated. Conventionally the common technique of pruning is based on considering error sensitivity measure, and the nature of the problem being solved is usually stationary. In this article, we present an adaptive pruning algorithm for use in a nonstationary environment. The idea relies on the use of the extended Kalman filter (EKF) training method. Since EKF is a recursive Bayesian algorithm, we define a weight-importance measure in term of the sensitivity of a posteriori probability. Making use of this new measure and the adaptive nature of EKF, we devise an adaptive pruning algorithm called adaptive Bayesian pruning. Simulation results indicate that in a noisy nonstationary environment, the proposed pruning algorithm is able to remove network redundancy adaptively and yet preserve the same generalization ability.


Controversies in reproductive immunology.
Nine areas of current controversy in the field of immunology of reproduction have been selected for discussion: (1) do antisperm antibodies cause infertility; (2) does cell mediated immunity cause infertility; (3) do antibodies cause spontaneous abortion; (4) is abortion due to rejection of the "fetal allograft"; (5) is altered antigen expression crucial for survival of the "fetal allograft"; (6) is abortion mediated by graft rejection mechanisms; (7) does locoregional suppression prevent abortion; (8) does immunization to prevent abortion and promote pregnancy act via immunotropism and cytokine cross-talk; (9) do immune responses prevent spontaneous abortion in humans? The reasons for debate and uncertainty are reviewed and current data considered in an attempt to arrive at the most likely answer to each question. Directions for future research are proposed where appropriate.


Diagnostic utility of perilesional muscle edema in myositis ossificans.
To investigate the value of extensive perilesional muscle edema for the differentiation between myositis ossificans (MO) and malignant intramuscular soft tissue tumors on MRI. Two blinded readers analyzed MR examinations of 90 consecutive patients with intramuscular soft tissue masses (group 1: MO, n = 20; group 2: malignant tumors, n = 70). Extent of edema around lesions was graded (0, none; 1, minimal edema; 2, moderate edema; 3, extensive edema). Edema-lesion ratio (ELR = ratio of the maximal diameter of the edema and the maximal diameter of the central lesion) was calculated. ROC analysis, Mann-Whitney U test, and Kappa test were used. A total of 70% and 60% of patients with MO had edema grade 3 (reader 1/reader 2), 30%/40% edema grade 2. For the patients with malignant tumors, it was 2.9%/1.4% (edema grade 3) and 16%/23% (edema grade 2). Interrater reliability was substantial (kappa = 0.66). Extent of edema was significantly higher for patients of group 1 (p < 0.0001, both readers). Mean ELR was 3.60 (group 1) and 1.35 (group 2), with statistically significant differences (p < 0.0001). Grade 3 edema showed a sensitivity/specificity of 70%/97.1% (reader 1) and 60%/99% (reader 2) for diagnosing MO. For ELR > 2.0, sensitivity was 90% and specificity 91% for diagnosing MO. Extensive perilesional muscle edema on MRI of more than double the size of the central lesion is highly specific, but not pathognomonic for myositis ossificans in the early/intermediate stage in the differentiation to malignant intramuscular soft tissue lesions.


Polysomnography in patients with obstructive sleep apnea: an evidence-based analysis.
The objective of this health technology policy assessment was to evaluate the clinical utility and cost-effectiveness of sleep studies in Ontario. TARGET POPULATION AND CONDITION Sleep disorders are common and obstructive sleep apnea (OSA) is the predominant type. Obstructive sleep apnea is the repetitive complete obstruction (apnea) or partial obstruction (hypopnea) of the collapsible part of the upper airway during sleep. The syndrome is associated with excessive daytime sleepiness or chronic fatigue. Several studies have shown that OSA is associated with hypertension, stroke, and other cardiovascular disorders; many researchers believe that these cardiovascular disorders are consequences of OSA. This has generated increasing interest in recent years in sleep studies. There is no 'gold standard' for the diagnosis of OSA, which makes it difficult to calibrate any test for diagnosis. Traditionally, polysomnography (PSG) in an attended setting (sleep laboratory) has been used as a reference standard for the diagnosis of OSA. Polysomnography measures several sleep variables, one of which is the apnea-hypopnea index (AHI) or respiratory disturbance index (RDI). The AHI is defined as the sum of apneas and hypopneas per hour of sleep; apnea is defined as the absence of airflow for ≥ 10 seconds; and hypopnea is defined as reduction in respiratory effort with ≥ 4% oxygen desaturation. The RDI is defined as the sum of apneas, hypopneas, and abnormal respiratory events per hour of sleep. Often the two terms are used interchangeably. The AHI has been widely used to diagnose OSA, although with different cut-off levels, the basis for which are often unclear or arbitrarily determined. Generally, an AHI of more than five events per hour of sleep is considered abnormal and the patient is considered to have a sleep disorder. An abnormal AHI accompanied by excessive daytime sleepiness is the hallmark for OSA diagnosis. For patients diagnosed with OSA, continuous positive airway pressure (CPAP) therapy is the treatment of choice. Polysomnography may also used for titrating CPAP to individual needs. In January 2005, the College of Physicians and Surgeons of Ontario published the second edition of Independent Health Facilities: Clinical Practice Parameters and Facility Standards: Sleep Medicine, commonly known as "The Sleep Book." The Sleep Book states that OSA is the most common primary respiratory sleep disorder and a full overnight sleep study is considered the current standard test for individuals in whom OSA is suspected (based on clinical signs and symptoms), particularly if CPAP or surgical therapy is being considered. Polysomnography in a sleep laboratory is time-consuming and expensive. With the evolution of technology, portable devices have emerged that measure more or less the same sleep variables in sleep laboratories as in the home. Newer CPAP devices also have auto-titration features and can record sleep variables including AHI. These devices, if equally accurate, may reduce the dependency on sleep laboratories for the diagnosis of OSA and the titration of CPAP, and thus may be more cost-effective. Difficulties arise, however, when trying to assess and compare the diagnostic efficacy of in-home PSG versus in-lab. The AHI measured from portable devices in-home is the sum of apneas and hypopneas per hour of time in bed, rather than of sleep, and the absolute diagnostic efficacy of in-lab PSG is unknown. To compare in-home PSG with in-lab PSG, several researchers have used correlation coefficients or sensitivity and specificity, while others have used Bland-Altman plots or receiver operating characteristics (ROC) curves. All these approaches, however, have potential pitfalls. Correlation coefficients do not measure agreement; sensitivity and specificity are not helpful when the true disease status is unknown; and Bland-Altman plots measure agreement (but are helpful when the range of clinical equivalence is known). Lastly, receiver operating characteristics curves are generated using logistic regression with the true disease status as the dependent variable and test values as the independent variable. Thus, each value of the test is used as a cut-point to measure sensitivity and specificity, which are then plotted on an x-y plane. The cut-point that maximizes both sensitivity and specificity is chosen as the cut-off level to discriminate between disease and no-disease states. In the absence of a gold standard to determine the true disease status, ROC curves are of minimal value. At the request of the Ontario Health Technology Advisory Committee (OHTAC), MAS has thus reviewed the literature on PSG published over the last two years to examine new developments. There is a large body of literature on sleep studies and several reviews have been conducted. Two large cohort studies, the Sleep Heart Health Study and the Wisconsin Sleep Cohort Study, are the main sources of evidence on sleep literature. To examine new developments on PSG published in the past two years, MEDLINE, EMBASE, MEDLINE In-Process & Other Non-Indexed Citations, the Cochrane Database of Systematic Reviews and Cochrane CENTRAL, INAHTA, and websites of other health technology assessment agencies were searched. Any study that reported results of in-home or in-lab PSG was included. All articles that reported findings from the Sleep Heart Health Study and the Wisconsin Sleep Cohort Study were also reviewed. DIFFUSION OF SLEEP LABORATORIES: To estimate the diffusion of sleep laboratories, a list of sleep laboratories licensed under the Independent Health Facility Act was obtained. The annual number of sleep studies per 100,000 individuals in Ontario from 2000 to 2004 was also estimated using administrative databases. A total of 315 articles were identified that were published in the past two years; 227 were excluded after reviewing titles and abstracts. A total of 59 articles were identified that reported findings of the Sleep Heart Health Study and the Wisconsin Sleep Cohort Study. Based on cross-sectional data from the Wisconsin Sleep Cohort Study of 602 men and women aged 30 to 60 years, it is estimated that the prevalence of sleep-disordered breathing is 9% in women and 24% in men, on the basis of more than five AHI events per hour of sleep. Among the women with sleep disorder breathing, 22.6% had daytime sleepiness and among the men, 15.5% had daytime sleepiness. Based on this, the prevalence of OSA in the middle-aged adult population is estimated to be 2% in women and 4% in men. Snoring is present in 94% of OSA patients, but not all snorers have OSA. Women report daytime sleepiness less often compared with their male counterparts (of similar age, body mass index [BMI], and AHI). Prevalence of OSA tends to be higher in older age groups compared with younger age groups. DIAGNOSTIC VALUE OF POLYSOMNOGRAPHY: It is believed that PSG in the sleep laboratory is more accurate than in-home PSG. In the absence of a gold standard, however, claims of accuracy cannot be substantiated. In general, there is poor correlation between PSG variables and clinical variables. A variety of cut-off points of AHI (> 5, > 10, and > 15) are arbitrarily used to diagnose and categorize severity of OSA, though the clinical importance of these cut-off points has not been determined. Recently, a study of the use of a therapeutic trial of CPAP to diagnose OSA was reported. The authors studied habitual snorers with daytime sleepiness in the absence of other medical or psychiatric disorders. Using PSG as the reference standard, the authors calculated the sensitivity of this test to be 80% and its specificity to be 97%. Further, they concluded that PSG could be avoided in 46% of this population. OBSTRUCTIVE SLEEP APNEA AND OBESITY: Obstructive sleep apnea is strongly associated with obesity. Obese individuals (BMI >30 kg/m(2)) are at higher risk for OSA compared with non-obese individuals and up to 75% of OSA patients are obese. It is hypothesized that obese individuals have large deposits of fat in the neck that cause the upper airway to collapse in the supine position during sleep. The observations reported from several studies support the hypothesis that AHIs (or RDIs) are significantly reduced with weight loss in obese individuals. OBSTRUCTIVE SLEEP APNEA AND CARDIOVASCULAR DISEASES: Associations have been shown between OSA and comorbidities such as diabetes mellitus and hypertension, which are known risk factors for myocardial infarction and stroke. Patients with more severe forms of OSA (based on AHI) report poorer quality of life and increased health care utilization compared with patients with milder forms of OSA. From animal models, it is hypothesized that sleep fragmentation results in glucose intolerance and hypertension. There is, however, no evidence from prospective studies in humans to establish a causal link between OSA and hypertension or diabetes mellitus. It is also not clear that the associations between OSA and other diseases are independent of obesity; in most of these studies, patients with higher values of AHI had higher values of BMI compared with patients with lower AHI values. A recent meta-analysis of bariatric surgery has shown that weight loss in obese individuals (mean BMI = 46.8 kg/m(2); range = 32.30-68.80) significantly improved their health profile. Diabetes was resolved in 76.8% of patients, hypertension was resolved in 61.7% of patients, hyperlipidemia improved in 70% of patients, and OSA resolved in 85.7% of patients. This suggests that obesity leads to OSA, diabetes, and hypertension, rather than OSA independently causing diabetes and hypertension. (ABSTRACT TRUNCATED)


Health effects of green tea catechins in overweight and obese men: a randomised controlled cross-over trial.
Regular consumption of green tea may be cardioprotective. In the present study we investigated the health effects of dietary supplementation with green tea catechins and the potential modifying effect of the catechol-O-methyltransferase (COMT) Val/Met genotype. Subjects (sedentary males, aged 40-69 years, with BMI ≥ 28 and ≤ 38 kg/m(2)) were randomly assigned to consume decaffeinated green tea extract (DGT; 530 mg containing about 400 mg total catechins/capsule, twice daily) and placebo in a complete cross-over design. Ambulatory blood pressure and biomarkers of metabolic function (cholesterol, TAG, glucose and insulin) were measured at weeks 0 and 6. Although a marked increase in the concentration of plasma epigallocatechin gallate (EGCG), urinary epigallocatechin (EGC) and urinary 4'-O-methyl EGC was found after DGT treatment, no effect on blood pressure or biomarkers of metabolic function was observed. However, a period × treatment interaction (P < 0·05) was detected for body-weight change. Despite a similar increase in estimated energy intake during intervention period 1, body weight decreased by 0·64 (sd 2·2) kg and increased by 0·53 (sd 1·9) kg in the DGT and placebo groups, respectively (P = 0·025), suggesting a protective effect of green tea catechins on weight gain. Additionally, the COMT Val/Met genotype influenced urinary accumulation of EGC and 4'-O-methyl EGC (P < 0·01). Mean concentrations were lower in individuals homozygous for the high-activity G-allele, possibly reflecting increased metabolic flux and a more rapid conversion to downstream metabolic species, compared with individuals carrying at least one copy of the low-activity A-allele. Additional studies are needed to confirm these findings and further explore the modifying effect of genotype.


Novel Genetic Variants for Cartilage Thickness and Hip Osteoarthritis.
Osteoarthritis is one of the most frequent and disabling diseases of the elderly. Only few genetic variants have been identified for osteoarthritis, which is partly due to large phenotype heterogeneity. To reduce heterogeneity, we here examined cartilage thickness, one of the structural components of joint health. We conducted a genome-wide association study of minimal joint space width (mJSW), a proxy for cartilage thickness, in a discovery set of 13,013 participants from five different cohorts and replication in 8,227 individuals from seven independent cohorts. We identified five genome-wide significant (GWS, P≤5·0×10-8) SNPs annotated to four distinct loci. In addition, we found two additional loci that were significantly replicated, but results of combined meta-analysis fell just below the genome wide significance threshold. The four novel associated genetic loci were located in/near TGFA (rs2862851), PIK3R1 (rs10471753), SLBP/FGFR3 (rs2236995), and TREH/DDX6 (rs496547), while the other two (DOT1L and SUPT3H/RUNX2) were previously identified. A systematic prioritization for underlying causal genes was performed using diverse lines of evidence. Exome sequencing data (n = 2,050 individuals) indicated that there were no rare exonic variants that could explain the identified associations. In addition, TGFA, FGFR3 and PIK3R1 were differentially expressed in OA cartilage lesions versus non-lesioned cartilage in the same individuals. In conclusion, we identified four novel loci (TGFA, PIK3R1, FGFR3 and TREH) and confirmed two loci known to be associated with cartilage thickness.The identified associations were not caused by rare exonic variants. This is the first report linking TGFA to human OA, which may serve as a new target for future therapies.


Effect of nitrergic system on colonic motility in a rat model of irritable bowel syndrome.
The aim of this study is to investigate whether nitric oxide (NO)-mediated colonic motility was altered in rat irritable bowel syndrome (IBS) model, using different isoforms of NO-synthase (NOS) inhibitors. The animal model of IBS-like visceral hypersensitivity was induced by intra-colonic infusion of 0.5% acetic acid (AA) in saline once daily from postnatal days 8 to 21. Control animals received saline instead of AA. Experiments were performed at the end of 8 weeks. Distal colon tissues were resected and direct effects of different NOS inhibitors; N-omega-nitro-L-arginine methyl ester hydrochloride, (L-NAME), ARL-17477 dihydrochloride hydrate (ARL 17477), N-[3-(Aminomethyl) phenyl] methyl]-ethanimidamidedihydrochloride (1400 W), and N5-(1-Iminoethyl)-L-ornithine dihydrochloride (L-NIO) were evaluated concentration-dependently in vitro tissue bath. Besides, morphology of both groups was assessed with hematoxylin and eosin (H and E) staining and the impact of NO antibodies was determined using the immunohistochemical method. The mean pressure values of spontaneous contractions and KCL (80 mmol/L) responses of distal colonic segments were similar in normal and IBS rats. L-NAME and ARL-17477 significantly increased the mean pressure of spontaneous colonic contractions in normal rats versus own base values (P < 0.05), but this increase did not significantly different when compared to IBS rats. In H and E staining, there was no difference with regard to morphology between two groups. Neuronal NOS (nNOS) immunoreactivity was found to be significantly decreased in IBS when compared to control groups (P < 0.05). L-NAME and ARL-17477 mediated mean pressure values were found to be slightly decreased in IBS rats. These findings may be related to a decrease in nNOS level in IBS.


Negative isotope effect for charge transport in acenes and derivatives--a theoretical conclusion.
The isotope effect (IE) on charge transport in polyacenes was proposed in 1970 to judge the transport mechanism. However, there had not been a definitive answer for more than 40 years as to whether such an IE is positive or negative, both theoretically and experimentally, because either theory was too approximate or the experimental estimate was too rough to make a judgment. Employing the quantum nuclear tunneling model for organic semiconductors, we investigate the IE on both hole and electron transport for acenes and their derivatives. We show that both (13)C-substitution and deuteration lead to a negative IE. By introducing phenyl, chlorine, or alkyl side-chains into acenes, the IE becomes more remarkable, especially for hole transport. The vibrational relaxation processes involving in-plane bending of ring or alkyl side-chain motions are found to be responsible for the IE.


Incorporating edoxaban into the choice of anticoagulants for atrial fibrillation.
The non-vitamin K antagonist oral anticoagulants (NOACs) are replacing warfarin for stroke prevention in many patients with nonvalvular atrial fibrillation. Edoxaban, an oral factor Xa inhibitor, is the newest entrant in this class. Results of the Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation (ENGAGE AF) study demonstrate that edoxaban is noninferior to warfarin for prevention of stroke and systemic embolic events, and is associated with significantly less major bleeding, including intracranial bleeding, and reduced cardiovascular mortality. With a net clinical benefit over warfarin, edoxaban is well positioned as a choice among the NOACs, which include dabigatran, rivaroxaban, and apixaban. But how will clinicians choose amongst them? The purpose of this paper is to (a) place the ENGAGE AF trial results into context with results of the studies with the other NOACs, and (b) aid clinicians in selection of the right anticoagulant for the right atrial fibrillation patient.


"One for All": Functional Transfer of OMV-Mediated Polymyxin B Resistance From Salmonella enterica sv. Typhi ΔtolR and ΔdegS to Susceptible Bacteria.
The appearance of multi-resistant strains has contributed to reintroducing polymyxin as the last-line therapy. Although polymyxin resistance is based on bacterial envelope changes, other resistance mechanisms are being reported. Outer membrane vesicles (OMVs) are nanosized proteoliposomes secreted from the outer membrane of Gram-negative bacteria. In some bacteria, OMVs have shown to provide resistance to diverse antimicrobial agents either by sequestering and/or expelling the harmful agent from the bacterial envelope. Nevertheless, the participation of OMVs in polymyxin resistance has not yet been explored in S. Typhi, and neither OMVs derived from hypervesiculating mutants. In this work, we explored whether OMVs produced by the hypervesiculating strains Salmonella Typhi ΔrfaE (LPS synthesis), ΔtolR (bacterial envelope) and ΔdegS (misfolded proteins and σ E activation) exhibit protective properties against polymyxin B. We found that the OMVs extracted from S. Typhi ΔtolR and ΔdegS protect S. Typhi WT from polymyxin B in a concentration-depending manner. By contrast, the protective effect exerted by OMVs from S. Typhi WT and S. Typhi ΔrfaE is much lower. This effect is achieved by the sequestration of polymyxin B, as assessed by the more positive Zeta potential of OMVs with polymyxin B and the diminished antibiotic's availability when coincubated with OMVs. We also found that S. Typhi ΔtolR exhibited an increased MIC of polymyxin B. Finally, we determined that S. Typhi ΔtolR and S. Typhi ΔdegS, at a lesser level, can functionally and transiently transfer the OMV-mediated polymyxin B resistance to susceptible bacteria in cocultures. This work shows that mutants in genes related to OMVs biogenesis can release vesicles with improved abilities to protect bacteria against membrane-active agents. Since mutations affecting OMV biogenesis can involve the bacterial envelope, mutants with increased resistance to membrane-acting agents that, in turn, produce protective OMVs with a high vesiculation rate (e.g., S. Typhi ΔtolR) can arise. Such mutants can functionally transfer the resistance to surrounding bacteria via OMVs, diminishing the effective concentration of the antimicrobial agent and potentially favoring the selection of spontaneous resistant strains in the environment. This phenomenon might be considered the source for the emergence of polymyxin resistance in an entire bacterial community.


c-Type cytochromes in Pelobacter carbinolicus.
Previous studies failed to detect c-type cytochromes in Pelobacter species despite the fact that other close relatives in the Geobacteraceae, such as Geobacter and Desulfuromonas species, have abundant c-type cytochromes. Analysis of the recently completed genome sequence of Pelobacter carbinolicus revealed 14 open reading frames that could encode c-type cytochromes. Transcripts for all but one of these open reading frames were detected in acetoin-fermenting and/or Fe(III)-reducing cells. Three putative c-type cytochrome genes were expressed specifically during Fe(III) reduction, suggesting that the encoded proteins may participate in electron transfer to Fe(III). One of these proteins was a periplasmic triheme cytochrome with a high level of similarity to PpcA, which has a role in Fe(III) reduction in Geobacter sulfurreducens. Genes for heme biosynthesis and system II cytochrome c biogenesis were identified in the genome and shown to be expressed. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis gels of protein extracted from acetoin-fermenting P. carbinolicus cells contained three heme-staining bands which were confirmed by mass spectrometry to be among the 14 predicted c-type cytochromes. The number of cytochrome genes, the predicted amount of heme c per protein, and the ratio of heme-stained protein to total protein were much smaller in P. carbinolicus than in G. sulfurreducens. Furthermore, many of the c-type cytochromes that genetic studies have indicated are required for optimal Fe(III) reduction in G. sulfurreducens were not present in the P. carbinolicus genome. These results suggest that further evaluation of the functions of c-type cytochromes in the Geobacteraceae is warranted.


Effect of passive immunotherapy on murine gut-derived sepsis caused by Pseudomonas aeruginosa.
The effect of passive immunotherapy with antisera against heat-killed Pseudomonas aeruginosa and three of its exo-enzymes (elastase, alkaline protease and exotoxin A) in gut-derived P. aeruginosa sepsis was evaluated. Mice were given a suspension of P. aeruginosa strain D4 in their drinking water, together with ampicillin (200 mg/kg) to disrupt the normal bacterial flora. Cyclophosphamide was then administered to induce translocation of P. aeruginosa that had colonised the gastrointestinal tract so that gut-derived septicaemia was produced. In this model, intraperitoneal administration of antiserum against heat-killed bacteria, 100 microl/mouse, twice a day for 3 consecutive days significantly increased the survival rate over that of mice treated with normal rabbit serum. Antiserum against elastase, alkaline protease, or a combination of these two antisera, failed to provide significant protection. In contrast, antiserum against exotoxin A significantly increased the survival rate over that of mice treated with normal rabbit serum. These results indicate that passive immunisation with antiserum against heat-killed bacteria and exotoxin A, but not with antiserum against either elastase or alkaline protease, protects mice against gut-derived sepsis caused by P. aeruginosa.


Multifocal and multicentric glioblastoma: Improved characterisation with FLAIR imaging and prognostic implications.
Glioblastoma usually presents on imaging as a single peripherally enhancing lesion, but multiple enhancing lesions can occur, termed multifocal if there is a connection between enhancing lesions, or multicentric when no communication is demonstrated. We aim to determine the incidence and prognostic implications of multifocal and multicentric glioblastoma in the era of modern MRI, focusing on the added benefit of T2-weighted fluid-attenuated inversion recovery (FLAIR) imaging. Patients with a new diagnosis of glioblastoma were identified. Preoperative MRI were reviewed to determine whether more than one distinct enhancing lesion was present, and whether there was communication between lesions. The findings were compared against survival data. More than one discrete contrast-enhancing lesion was present in 51 of the 151 patients (34%). Communication between lesions was identified in 47 of these, most commonly direct parenchymal spread (41 patients). The patients with multiple lesions had worse survival (median 176days, compared to 346days), but this difference was not statistically significant (p=0.253). These tumours more frequently involved deep structures (p<0.001) and the posterior fossa (p=0.045), both of which were associated with worse survival. The presence of multiple enhancing foci in glioblastoma is common, occurring in about one-third of patients, and the majority have multifocal disease. The FLAIR sequence is the crucial sequence for demonstrating a communication between lesions. The worse survival of these patients is, at least in large part related to more extensive tumour dissemination and more frequent involvement of key structures, rather than multiplicity per se.


Human Neocortical Neurosolver (HNN), a new software tool for interpreting the cellular and network origin of human MEG/EEG data.
Magneto- and electro-encephalography (MEG/EEG) non-invasively record human brain activity with millisecond resolution providing reliable markers of healthy and disease states. Relating these macroscopic signals to underlying cellular- and circuit-level generators is a limitation that constrains using MEG/EEG to reveal novel principles of information processing or to translate findings into new therapies for neuropathology. To address this problem, we built Human Neocortical Neurosolver (HNN, https://hnn.brown.edu) software. HNN has a graphical user interface designed to help researchers and clinicians interpret the neural origins of MEG/EEG. HNN's core is a neocortical circuit model that accounts for biophysical origins of electrical currents generating MEG/EEG. Data can be directly compared to simulated signals and parameters easily manipulated to develop/test hypotheses on a signal's origin. Tutorials teach users to simulate commonly measured signals, including event related potentials and brain rhythms. HNN's ability to associate signals across scales makes it a unique tool for translational neuroscience research.


Microglial CD206 Gene Has Potential as a State Marker of Bipolar Disorder.
The pathophysiology of bipolar disorder, especially the underlying mechanisms of the bipolarity between manic and depressive states, has yet to be clarified. Microglia, immune cells in the brain, play important roles in the process of brain inflammation, and recent positron emission tomography studies have indicated microglial overactivation in the brain of patients with bipolar disorder. We have recently developed a technique to induced microglia-like (iMG) cells from peripheral blood (monocytes). We introduce a novel translational approach focusing on bipolar disorder using this iMG technique. We hypothesize that immunological conditional changes in microglia may contribute to the shift between manic and depressive states, and thus we herein analyzed gene profiling patterns of iMG cells from three patients with rapid cycling bipolar disorder during both manic and depressive states, respectively. We revealed that the gene profiling patterns are different between manic and depressive states. The profiling pattern of case 1 showed that M1 microglia is dominant in the manic state compared to the depressive state. However, the patterns of cases 2 and 3 were not consistent with the pattern of case 1. CD206, a mannose receptor known as a typical M2 marker, was significantly downregulated in the manic state among all three patients. This is the first report to indicate the importance of shifting microglial M1/M2 characteristics, especially the CD206 gene expression pattern between depressive and manic states. Further translational studies are needed to dig up the microglial roles in the underlying biological mechanisms of bipolar disorder.


Preclinical evaluation and intraoperative human retinal imaging with a high-resolution microscope-integrated spectral domain optical coherence tomography device.
The authors have recently developed a high-resolution microscope-integrated spectral domain optical coherence tomography (MIOCT) device designed to enable OCT acquisition simultaneous with surgical maneuvers. The purpose of this report is to describe translation of this device from preclinical testing into human intraoperative imaging. Before human imaging, surgical conditions were fully simulated for extensive preclinical MIOCT evaluation in a custom model eye system. Microscope-integrated spectral domain OCT images were then acquired in normal human volunteers and during vitreoretinal surgery in patients who consented to participate in a prospective institutional review board-approved study. Microscope-integrated spectral domain OCT images were obtained before and at pauses in surgical maneuvers and were compared based on predetermined diagnostic criteria to images obtained with a high-resolution spectral domain research handheld OCT system (HHOCT; Bioptigen, Inc) at the same time point. Cohorts of five consecutive patients were imaged. Successful end points were predefined, including ≥80% correlation in identification of pathology between MIOCT and HHOCT in ≥80% of the patients. Microscope-integrated spectral domain OCT was favorably evaluated by study surgeons and scrub nurses, all of whom responded that they would consider participating in human intraoperative imaging trials. The preclinical evaluation identified significant improvements that were made before MIOCT use during human surgery. The MIOCT transition into clinical human research was smooth. Microscope-integrated spectral domain OCT imaging in normal human volunteers demonstrated high resolution comparable to tabletop scanners. In the operating room, after an initial learning curve, surgeons successfully acquired human macular MIOCT images before and after surgical maneuvers. Microscope-integrated spectral domain OCT imaging confirmed preoperative diagnoses, such as full-thickness macular hole and vitreomacular traction, and demonstrated postsurgical changes in retinal morphology. Two cohorts of five patients were imaged. In the second cohort, the predefined end points were exceeded with ≥80% correlation between microscope-mounted OCT and HHOCT imaging in 100% of the patients. This report describes high-resolution MIOCT imaging using the prototype device in human eyes during vitreoretinal surgery, with successful achievement of predefined end points for imaging. Further refinements and investigations will be directed toward fully integrating MIOCT with vitreoretinal and other ocular surgery to image surgical maneuvers in real time.


Effect of maternal use of labetalol on the cerebral autoregulation in premature infants.
Hypertensive disorders of pregnancy (HDP) are normally treated to avoid maternal complications. In this study we aimed to investigate if there was an effect of maternal HDP treatment on the cerebral autoregulation of the neonates by analysing measurements of mean arterial blood pressure (MABP) and rScO2 by means of correlation, coherence, and transfer function analysis. We found that these infants presented higher values of transfer function gain, which indicates impaired cerebral autoregulation, with a decreasing trend towards normality. We hypothesised that this trend was due to a vasodilation effect of the maternal use of labetalol due to accumulation, which disappeared by the third day after birth. Therefore, we investigated the values of pulse pressure in order to find evidence for a vasodilatory effect. We found that lower values of pulse pressure were present in these infants when compared with a control population, which, together with increased transfer function gain values, suggests an effect of the drug on the cerebral autoregulation.


Perspectives: Using Results from HRSA's Health Workforce Simulation Model to Examine the Geography of Primary Care.
Inform health planning and policy discussions by describing Health Resources and Services Administration's (HRSA's) Health Workforce Simulation Model (HWSM) and examining the HWSM's 2025 supply and demand projections for primary care physicians, nurse practitioners (NPs), and physician assistants (PAs). HRSA's recently published projections for primary care providers derive from an integrated microsimulation model that estimates health workforce supply and demand at national, regional, and state levels. Thirty-seven states are projected to have shortages of primary care physicians in 2025, and nine states are projected to have shortages of both primary care physicians and PAs. While no state is projected to have a 2025 shortage of primary care NPs, many states are expected to have only a small surplus. Primary care physician shortages are projected for all parts of the United States, while primary care PA shortages are generally confined to Midwestern and Southern states. No state is projected to have shortages of all three provider types. Projected shortages must be considered in the context of baseline assumptions regarding current supply, demand, provider-service ratios, and other factors. Still, these findings suggest geographies with possible primary care workforce shortages in 2025 and offer opportunities for targeting efforts to enhance workforce flexibility.


Modelling Oscillatory Patterns in the Bovine Estrous Cycle with Boolean Delay Equations.
Boolean delay equations (BDEs), with their relatively simple and intuitive mode of modelling, have been used in many research areas including, for example, climate dynamics and earthquake propagation. Their application to biological systems has been scarce and limited to the molecular level. Here, we derive and present two BDE models. One is directly derived from a previously published ordinary differential equation (ODE) model for the bovine estrous cycle, whereas the second model includes a modification of a particular biological mechanism. We not only compare the simulation results from the BDE models with the trajectories of the ODE model, but also validate the BDE models with two additional numerical experiments. One experiment induces a switch in the oscillatory pattern upon changes in the model parameters, and the other simulates the administration of a hormone that is known to shift the estrous cycle in time. The models presented here are the first BDE models for hormonal oscillators, and the first BDE models for drug administration. Even though automatic parameter estimation still remains challenging, our results support the role of BDEs as a framework for the systematic modelling of complex biological oscillators.


Two novel missense mutations in HAIRY-AND-ENHANCER-OF-SPLIT-7 in a family with spondylocostal dysostosis.
Spondylocostal dysostosis (SCD) is an inherited disorder with abnormal vertebral segmentation that results in extensive hemivertebrae, truncal shortening and abnormally aligned ribs. It arises during embryonic development by a disruption of formation of somites (the precursor tissue of the vertebrae, ribs and associated tendons and muscles). Four genes causing a subset of autosomal recessive forms of this disease have been identified: DLL3 (SCDO1: MIM 277300), MESP2 (SCDO2: MIM 608681), LFNG (SCDO3: MIM609813) and HES7 (SCDO4). These genes are all essential components of the Notch signalling pathway, which has multiple roles in development and disease. Previously, only a single SCD-causative missense mutation was described in HES7. In this study, we have identified two new missense mutations in the HES7 gene in a single family, with only individuals carrying both mutant alleles being affected by SCD. In vitro functional analysis revealed that one of the mutant HES7 proteins was unable to repress gene expression by DNA binding or protein heterodimerization.


Quest for the holy grail: Assessment of echo-derived dynamic parameters as predictors of fluid responsiveness in patients with acute aneurysmal subarachnoid hemorrhage.
Acute aneurysmal subarachnoid hemorrhage (aSAH) is a potentially devastating event often presenting with a plethora of hemodynamic fluctuations requiring meticulous fluid management. The aim of this study was to assess the utility of newer dynamic predictors of fluid responsiveness such as Delta down (DD), superior vena cava collapsibility index (SVCCI), and aortic velocity time integral variability (VTIAoV) in patients with SAH undergoing neurosurgery. Fifteen individuals with SAH undergoing surgery for intracranial aneurysmal clipping were enrolled in this prospective study. Postinduction, vitals, anesthetic parameters, and the study variables were recorded as the baseline. Following this, patients received a fluid bolus of 10 ml/kg of colloid over 20 min, and measurements were repeated postfluid loading. Continuous variables were expressed as mean ± standard deviation and compared using Student's t-test, with a P < 0.05 considered statistically significant. The predictive ability of variables for fluid responsiveness was determined using Pearson's coefficient analysis (r). There were 12 volume responders and 3 nonresponders (NR). DD >5 mm Hg was efficient in differentiating the responders from NR (P < 0.05) with a sensitivity and specificity of 90% and 85%, respectively, with a good predictive ability to identify fluid responders and NR; r = 0.716. SVCCI of >38% was 100% sensitive and 95% specific in detecting the volume status and in differentiating the responders from NR (P < 0.05) and is an excellent predictor of fluid responsive status; r = 0.906. VTIAoV >20% too proved to be a good predictor of fluid responsiveness, with a sensitivity and specificity of 100% and 90%, respectively, with a predictive power; r = 0.732. Our study showed that 80% of patients presenting with aSAH for intracranial aneurysm clipping were fluid responders with normal hemodynamic parameters such as heart rate and blood pressure. Among the variables, SVCCI >38% appears to be an excellent predictor followed by VTIAoV >20% and DD >5 mmHg in assessing the fluid status in this population.


Male-specific lethal mutations of Drosophila melanogaster.
A total of 7,416 ethyl methanesulfonate (EMS)-treated second chromosomes and 6,212 EMS-treated third chromosomes were screened for sex-specific lethals. Four new recessive male-specific lethal mutations were recovered. When in homozygous condition, each of these mutations kills males during the late larval or early pupal stages, but has no detectable effect in females. One mutant, mlets, is a temperature sensitive allele of maleless, mle (Fukunaga, Tanaka and Oishi 1975), while the other three mutants identify two new loci: male-specific lethal-1 (msl-1) (two alleles) at map position 2-53.3 and male-specific lethal-2 (msl-2) at 2-9.0----The male-specific lethality associated with these mutants is not related to the sex per se of the mutant flies, since sex-transforming genes fail to interact with these mutations. Moreover, the presence or absence of a Y chromosome in males or females has no influence on the male-specific lethal action of these mutations. Finally, no single region of the X chromosome, when present as a duplication, is sufficient to rescue males from the lethal effects of msl-1 or msl-2. These results suggest that the number of complete X chromosomes determines whether a fly homozygous for a male-specific lethal mutation lives or dies.


Changes in microbial ecology after fecal microbiota transplantation for recurrent C. difficile infection affected by underlying inflammatory bowel disease.
Gut microbiota play a key role in maintaining homeostasis in the human gut. Alterations in the gut microbial ecosystem predispose to Clostridium difficile infection (CDI) and gut inflammatory disorders such as inflammatory bowel disease (IBD). Fecal microbiota transplantation (FMT) from a healthy donor can restore gut microbial diversity and pathogen colonization resistance; consequently, it is now being investigated for its ability to improve inflammatory gut conditions such as IBD. In this study, we investigated changes in gut microbiota following FMT in 38 patients with CDI with or without underlying IBD. There was a significant change in gut microbial composition towards the donor microbiota and an overall increase in microbial diversity consistent with previous studies after FMT. FMT was successful in treating CDI using a diverse set of donors, and varying degrees of donor stool engraftment suggesting that donor type and degree of engraftment are not drivers of a successful FMT treatment of CDI. However, patients with underlying IBD experienced an increased number of CDI relapses (during a 24-month follow-up) and a decreased growth of new taxa, as compared to the subjects without IBD. Moreover, the need for IBD therapy did not change following FMT. These results underscore the importance of the existing gut microbial landscape as a decisive factor to successfully treat CDI and potentially for improvement of the underlying pathophysiology in IBD. FMT leads to a significant change in microbial diversity in patients with recurrent CDI and complete resolution of symptoms. Stool donor type (related or unrelated) and degree of engraftment are not the key for successful treatment of CDI by FMT. However, CDI patients with IBD have higher proportion of the original community after FMT and lack of improvement of their IBD symptoms and increased episodes of CDI on long-term follow-up.


Mutational analysis of the HIV-1 auxiliary protein Vif identifies independent domains important for the physical and functional interaction with HIV-1 reverse transcriptase.
The HIV-1 accessory protein Vif plays a dual role: it counteracts the natural restriction factors APOBEC3G and 3F and ensures efficient retrotranscription of the HIV-1 RNA genome. We have previously shown that Vif can act as an auxiliary factor for HIV-1 reverse transcriptase (RT), increasing its rate of association to RNA or DNA templates. Here, by using seven different Vif mutants, we provide in vitro evidences that Vif stimulates HIV-1 RT through direct protein-protein interaction, which is mediated by its C-terminal domain. Physical interaction appears to require the proline-rich region comprised between amino acid (aa) 161 and 164 of Vif, whereas the RT stimulatory activity requires, in addition, the extreme C-terminal region (aa 169-192) of the Vif protein. Neither the RNA interaction domain, nor the Zn(++)-binding domain of Vif are required for its interaction with the viral RT. Pseudotyped HIV-1 lentiviral vectors bearing Vif mutants deleted in the RNA- or RT-binding domains show defects in retrotranscription/integration processes in both permissive and nonpermissive cells. Our results broaden our knowledge on how three important functions of Vif (RNA binding, RT binding and stimulation and Zn(++) binding), are coordinated by different domains.


Co-translational involvement of the chaperonin GroEL in the folding of newly translated polypeptides.
A large fraction of the newly translated polypeptides emerging from the ribosome require certain proteins, the so-called molecular chaperones, to assist in their folding. In Escherichia coli, three major chaperone systems are considered to contribute to the folding of newly synthesized cytosolic polypeptides. Trigger factor (TF), a ribosome-tethered chaperone, and DnaK are known to exhibit overlapping co-translational roles, whereas the cage-shaped GroEL, with the aid of the co-chaperonin, GroES, and ATP, is believed to be implicated in folding only after the polypeptides are released from the ribosome. However, the recent finding that GroEL-GroES overproduction permits the growth of E. coli cells lacking both TF and DnaK raised questions regarding the separate roles of these chaperones. Here, we report the puromycin-sensitive association of GroEL-GroES with translating ribosomes in vivo. Further experiments in vitro, using a reconstituted cell-free translation system, clearly demonstrate that GroEL associates with the translation complex and accomplishes proper folding by encapsulating the newly translated polypeptides in the central cavity formed by GroES. Therefore, we propose that GroEL is a versatile chaperone, which participates in the folding pathway co-translationally and also achieves correct folding post-translationally.


Association between cardiorespiratory fitness and accelerometer-derived physical activity and sedentary time in the general population.
To determine the association between cardiorespiratory fitness and sedentary behavior, independent of exercise activity. We included 2223 participants (aged 12-49 years; 1053 females [47%]) without known heart disease who had both cardiovascular fitness testing and at least 1 day of accelerometer data from the National Health and Nutrition Examination Survey 2003-2004. From accelerometer data, we quantified bouts of exercise as mean minutes per day for each participant. Sedentary time was defined as less than 100 counts per minute in mean minutes per day. Cardiorespiratory fitness was derived from a submaximal exercise treadmill test. Multivariable-adjusted linear regression analyses were performed with fitness as the dependent variable. Models were stratified by sex, adjusted for age, body mass index, and wear time, and included sedentary and exercise time. An additional hour of daily exercise activity time was associated with a 0.88 (0.37-1.39; P<.001) metabolic equivalent of task (MET) higher fitness for men and a 1.37 (0.43-2.31; P=.004) MET higher fitness for women. An additional hour of sedentary time was associated with a -0.12 (-0.02 to -0.22; P=.03) and a -0.24 (-0.10 to -0.38; P<.001) MET difference in fitness for men and women, respectively. After adjustment for exercise activity, sedentary behavior appears to have an inverse association with fitness. These findings suggest that the risk related to sedentary behavior might be mediated, in part, through lower fitness levels.


Longitudinal assessment of physical activity in women undergoing Roux-en-Y gastric bypass.
Patients undergoing bariatric surgery do not seem to increase objectively measured physical activity (PA) after surgery, despite substantial weight loss. The aims of the present study were (i) to objectively characterize 3 months pre-surgery to 9 months postsurgery PA and sedentary behavior changes in women undergoing Roux-en-Y gastric bypass (RYGB) using tri-axial accelerometers and (ii) to examine associations between pre-surgery versus postsurgery PA and sedentary behavior with anthropometric measures taken in home environment. Fifty-six women, with an average pre-surgery body mass index (BMI) of 37.6 (SD 2.6) and of age 39.5 years (SD 5.7), were recruited at five Swedish hospitals. PA was measured for 1 week by the Actigraph GT3X+ accelerometer, and anthropometric measures were taken at home visits 3 months pre-surgery and 9 months postsurgery, thus limiting seasonal effects. Average BMI loss, 9 months postsurgery, was 11.7 (SD 2.7) BMI units. There were no significant pre- to postsurgery differences in PA or sedentary behavior. However, pre-surgery PA showed negative association with PA change and positive association with postsurgery PA. Adjustments for pre-surgery BMI had no impact on these associations. No significant differences were observed in objectively measured changes in PA or time spent sedentary from 3 months pre-surgery to 9 months postsurgery among women undergoing RYGB. However, women with higher pre-surgery PA decreased their PA postsurgery while women with lower pre-surgery PA increased their PA.


The Effects of a 6-Month High Dose Omega-3 and Omega-6 Polyunsaturated Fatty Acids and Antioxidant Vitamins Supplementation on Cognitive Function and Functional Capacity in Older Adults with Mild Cognitive Impairment.
The aim of the present study was to examine the effects of a high-dose omega-3 and omega-6 fatty acids supplementation, in combination with antioxidant vitamins, on cognitive function and functional capacity of older adults with mild cognitive impairment (MCI), over a 6-month period in a randomized, double-blind, placebo-controlled trial. Forty-six older adults with MCI (age: 78.8 ± 7.3 years) were randomized 1:1 to receive either a 20 mL dose of a formula containing a mixture of omega-3 (810 mg Eicosapentaenoic acid and 4140 mg Docosahexaenoic acid) and omega-6 fatty acids (1800 mg gamma-Linolenic acid and 3150 mg Linoleic acid) (1:1 w/w), with 0.6 mg vitamin A, vitamin E (22 mg) plus pure γ-tocopherol (760 mg), or 20mL placebo containing olive oil. Participants completed assessments of cognitive function, functional capacity, body composition and various aspects of quality of life at baseline and following three and six months of supplementation. Thirty-six participants completed the study (eighteen from each group). A significant interaction between supplementation and time was found on cognitive function (Addenbrooke's Cognitive Examination -Revised (ACE-R), Mini-Mental State Examination (MMSE) and Stroop Color and Word Test (STROOP) color test; p < 0.001, p = 0.011 and p = 0.037, respectively), functional capacity (6-min walk test and sit-to-stand-60; p = 0.028 and p = 0.032, respectively), fatigue (p < 0.001), physical health (p = 0.007), and daily sleepiness (p = 0.007)-showing a favorable improvement for the participants receiving the supplement. The results indicate that this nutritional modality could be promising for reducing cognitive and functional decline in the elderly with MCI.


Fine needle aspiration biopsy of the adrenal gland: Cytological features and clinical applications.
The ability to visualize the adrenal glands with modern imaging techniques has improved our detection of small adrenal masses. In cancer patients, metastatic tumors to the adrenal glands are common, but not all adrenal masses are metastases. Percutaneous fine needle aspiration biopsy can be used in distinguishing metastatic malignancies to the adrenal glands from primary adrenal lesions. In our series we achieved a success rate of 86% in obtaining cellular material for diagnosis. A diagnosis of metastatic malignancy obviates the need for surgical intervention and is essential for staging and therapeutic planning. Primary adrenal cortical masses with benign cytology and under 5 cm in size can be managed conservatively with follow-up scans; those with atypical cytology or greater than 5 cm in size warrant surgical exploration. Adrenalectomy is the treatment of choice for any adrenal tumor associated with endocrine abnormality, irrespective of tumor size and cytology.


Generation of twisted nanowires with achiral organic amphiphilic copper complexes.
Drying under solvent atmosphere (DUSA) was investigated as an experimental technique to generate self-assembled nanowires and needles from solutions of organic molecules under controlled conditions. Experimental observations of twisted nanowires are reported. These twisted nanowires were obtained by drying of solutions of achiral molecules under solvent controlled atmospheres: achiral, amphiphilic copper complexes were dissolved in an achiral solvent and these solutions were dried under controlled conditions. Two structurally related copper complexes were investigated. Microscopic investigations of the resulting nanowires revealed, and scanning electron microscopy confirmed: self-assembled twisted ribbons could be selectively obtained from one of these compounds. This behavior could be explained by comparing the ratio of the size of the head group and the overall length of the molecules. The occurrence of chiral filaments and chiral phases of nanosegregated filaments are rare in achiral compounds. The occurance of such twisted filaments is thought to be related to symmetry-breaking during a phase transition from liquid crystalline or lyotropic liquid crystalline phases to a nanosegregated phase. In the reported experiments, the concentration of a solution was gradually increased until crystallization occurred. The results clearly show how DUSA can be applied to investigate the capability of achiral substances to yield twisted filaments. Moreover, the investigated compounds had high-enough charge carrier mobilities, such that the twisted filaments obtained are candidates for self-assembled, intrinsically coiled nano-inductivities.


Judgment analysis: a method for quantitative evaluation of trainee surgeons' judgments of surgical risk.
Surgical judgment and decision making require valid methods of assessment. The aim of this study was to evaluate the use of judgment analysis as a technique for quantitative evaluation of surgeons' risk estimates. Thirty trainee surgeons' estimates of conversion risk in laparoscopic cholecystectomy were investigated using judgment analysis. Hypothetical cases were created, differing in relevant risk factors. Twenty repeat cases were incorporated to test for reliability. Surgeons' estimates were compared with an outcome-derived gold standard from the published literature. The mean reliability was .77 (range, .47-.98), and regression models indicating the weighting of variables had a mean adjusted R(2) value of .53 (range, .12-.76). Variables were subject to wide variation in weighting. The mean correlation to the gold standard model was .48 (range, .08-.72). Judgment analysis allows detailed quantitative evaluation of the consistency of surgeons' risk estimates and the influence of different variables on them. Comparison with a gold standard model enables accuracy to be measured.


Self-Directedness Predicts Quality of Life in Individuals with Psychotic Experiences: A 1-Year Follow-Up Study.
There is a high prevalence of psychotic-like experiences in nonclinical patient cohorts from Brazil. This study aimed to test whether personality dimensions, as well as schizotypy, are important predictors of quality of life (QoL) in individuals with psychotic experiences (PE). 115 participants were recruited from Spiritist Centers in Brazil. At the 1-year follow up, 90 participants (78%) were reassessed. Instruments were the SCID-I (Structured Clinical Interview for DSM-IV), TCI-R 140 (Revised Temperament and Character Inventory), OLIFE-R (Oxford-Liverpool Inventory of Feelings and Experiences), and WHOQOL-BREF (World Health Organization QoL Instrument). Mean age (±SD) was 36.8 (±12.5) years; 70% were female. Participants reported 74.4% of PE at time 1 and 72.3% at time 2. At time 1, temperament and character explained 47% of the psychological QoL variance; self-directedness was the strongest predictor of higher QoL, while harm avoidance and introverted anhedonia predicted worse QoL. At the 1-year follow-up, self-directedness remained the most important predictor of psychological QoL. Individuals reporting PE can show psychological QoL when they are high on self-directedness. Those with high levels of introverted anhedonia and cognitive disorganization can have a lower QoL and may be at risk for mental health problems.