A DFT kinetic study on 1,3-dipolar cycloaddition reactions in solution.
Several popular density functional theory (DFT) methods have been employed to characterize a series of 1,3-dipolar cycloaddition reactions, including the exploration of reaction mechanisms and the calculations of kinetic parameters. Both the gas- and solution-phase translational entropy models have been used to calculate the activation entropies, and the results obtained from the latter method are quite close to the experimental measurements. For some of the reactions studied, e.g., a1 + b9, a1 + b10, a5 + b9 and a12 + b5, the explicit + implicit solvation model, namely, a cluster-continuum type model, should be employed to account for the specific solvent-solute interactions. The quasi rigid-rotor-harmonic-oscillator (qRRHO) small frequency vibrational entropy correction, in conjunction with the conformational entropy correction, could further improve the calculated activation entropy data. The comparison between calculation data with experimental measurements, using 23 activation entropies and 160 reaction rate constants as test benchmark, demonstrated that our present strategy could calibrate the root-mean-square-deviation (RMSD) of activation entropies to be 1.8 cal mol-1 K-1 and that of Gibbs free energy barriers to be 1.8 kcal mol-1.


Incidence of contrast-induced nephropathy in patients with multiple myeloma undergoing contrast-enhanced CT.
The purpose of this article is to evaluate the incidence of contrast-induced nephropathy (CIN) and the effects of associated risk factors in patients with multiple myeloma undergoing contrast-enhanced CT (CECT) with IV administration of nonionic iodinated contrast agent. This retrospective review of medical records identified patients with a diagnosis of myeloma who underwent a CECT examination of the chest, abdomen, or pelvis between January 1, 2005, and December 1, 2008. Analysis for CIN, as defined by an increase in creatinine level after the CECT examination of 25% or more, or of 0.5 mg/dL, compared with the level before the CECT examination, both within 48 hours and within 7 days, was performed. Statistical correlations between the development of CIN and creatinine level before CECT examination, patient location, type and amount of contrast agent, blood urea nitrogen-creatinine ratio, history of diabetes, hypercalcemia, Bence Jones proteinuria, β(2)-microglobulin level, albumin level, International Myeloma Staging System stage, and history of myeloma provided at the time the CT examination was ordered were calculated. Forty-six patients who completed 80 unique examinations were included; their average creatinine level before CECT examination was 0.97 mg/dL. There was no significant difference in the average creatinine levels before CT examination between patients without and those with CIN. Four (5%) and 12 (15%) patients developed CIN within 48 hours and 7 days, respectively. Only serum β(2)-microglobulin level showed a statistically significant (p = 0.03) correlation with the development of CIN. The incidence of CIN in patients with multiple myeloma with a normal creatinine level is low and correlates with β(2)-microglobulin levels. The administration of contrast agent in this patient population is safe but should be based on the potential benefit of the examination and the expected low risk of developing CIN.


Isolation and function of mouse tissue resident vascular precursors marked by myelin protein zero.
Vasculogenesis describes the process of de novo vessel formation from vascular precursor cells. Although formation of the first major vessels, such as the dorsal aorta and cardinal veins, occurs during embryonic vasculogenesis, the contribution of precursor cell populations to postnatal vessel development is not well understood. Here, we identified a novel population of postnatal vascular precursor cells in mice. These cells express the Schwann cell protein myelin protein zero (Po) and exhibit a CD45(-)CD31(-)VEcad(-)c-kit(+)CXCR4(+) surface phenotype. Po(+) vascular precursors (PVPs) are recruited into the growing vasculature, and comprise a minor population of arterial endothelial cells in adult mice. Recruitment of PVPs into growing vessels is mediated by CXCL12-CXCR4 signaling, and is enhanced during vascular expansion induced by Notch inhibition. Po-specific ablation of Flk1, a receptor for VEGF, results in branching defects and insufficient arterial patterning in the retina, as well as reduced neovascularization of tumors and ischemic tissues. Thus, in postnatal mice, although growing vessels are formed primarily by angiogenesis from preexisting vessels, a minor population of arterial endothelia may be derived from tissue-resident vascular precursor cells.


MAN1B1 deficiency: an unexpected CDG-II.
Congenital disorders of glycosylation (CDG) are a group of rare metabolic diseases, due to impaired protein and lipid glycosylation. In the present study, exome sequencing was used to identify MAN1B1 as the culprit gene in an unsolved CDG-II patient. Subsequently, 6 additional cases with MAN1B1-CDG were found. All individuals presented slight facial dysmorphism, psychomotor retardation and truncal obesity. Generally, MAN1B1 is believed to be an ER resident alpha-1,2-mannosidase acting as a key factor in glycoprotein quality control by targeting misfolded proteins for ER-associated degradation (ERAD). However, recent studies indicated a Golgi localization of the endogenous MAN1B1, suggesting a more complex role for MAN1B1 in quality control. We were able to confirm that MAN1B1 is indeed localized to the Golgi complex instead of the ER. Furthermore, we observed an altered Golgi morphology in all patients' cells, with marked dilatation and fragmentation. We hypothesize that part of the phenotype is associated to this Golgi disruption. In conclusion, we linked mutations in MAN1B1 to a Golgi glycosylation disorder. Additionally, our results support the recent findings on MAN1B1 localization. However, more work is needed to pinpoint the exact function of MAN1B1 in glycoprotein quality control, and to understand the pathophysiology of its deficiency.


Benzoic acid glycine conjugation in the isolated perfused rat kidney.
The fate of varying input concentrations (0.002-372 microM) of benzoic acid was examined in the single-pass isolated perfused rat kidney preparation under constant flow rate (8 ml min-1.organ-1). With an increasing concentration of benzoate, the steady-state renal extraction ratio decreased from 0.24 to 0.1. Little unchanged drug was found in the urine; the urinary clearance of benzoate was low (0.018 ml-1 min-1.g-1) and concentration-independent, yielding a rather constant fractional excretion of approximately 0.2. Metabolic clearance, due primarily to conjugation with glycine to form hippuric acid, constituted the majority of total renal clearance, and this decreased with concentration. These divergent trends for the metabolic and urinary clearance with concentration suggest that benzoate net influx across the basolateral membrane has not been saturated. Upon fitting of the hippurate formation rates vs. the plasma unbound logarithmic average concentrations of benzoate, overall kinetic constants (KM = 5.3 microM and Vmax = 195 nmol min-1.g-1) that likely reflect glycine conjugation were obtained. The formed hippurate either returned to the venous circulation or was excreted into urine without further biotransformation; the apparent renal extraction ratio (excretion rate/formation rate of hippurate) was quite high (approximately 0.48). Avid glycine conjugation and hippurate excretion thus occurred with administration of benzoic acid to the isolated perfused rat kidney.


Selective oxidation of lignocellulosic biomass to formic acid and high-grade cellulose using tailor-made polyoxometalate catalysts.
The main goal of this project was to identify and optimize tailor-made polyoxometalate catalysts for a fractionated oxidation of lignocellulosic biomass (i.e. wood and residues from sugar or paper industries) to produce formic acid (FA) and high-grade cellulose for further processing e.g. in white biotechnology to provide bio-ethanol. Homogeneous vanadium precursors like sodium metavanadate and vanadyl sulfate as well as Keggin-type polyoxometalates (POMs) and more exotic structures like Anderson-, Wells-Dawson- and Lindqvist-type POMs were screened for the desired catalytic performance. The most promising behaviour was found using the Lindqvist-type POM K5V3W3O19, showing for the first time in the literature a selective oxidation of only hemicellulose and lignin to formic acid, while the cellulose fraction was untrapped. However, this can only be a first step towards the project goal as low product yields were obtained.


Loss of haptic feedback impairs control of hand posture: a study in chronically deafferented individuals when grasping and lifting objects.
Previous work has highlighted the role of haptic feedback for manual dexterity, in particular for the control of precision grip forces between the index finger and thumb. It is unclear how fine motor skills involving more than just two digits might be affected, especially given that loss of sensation from the hand affects many neurological patients, and impacts on everyday actions. To assess the functional consequences of haptic deficits on multi-digit grasp of objects, we studied the ability of three rare individuals with permanent large-fibre sensory loss involving the entire upper limb. All three reported difficulties in everyday manual actions (ABILHAND questionnaire). Their performance in a reach-grasp-lift task was compared to that of healthy controls. Twenty objects of varying shape, mass, opacity and compliance were used. In the reach-to-grasp phase, we found slower movement, larger grip aperture and less dynamic modulation of grip aperture in deafferented participants compared to controls. Hand posture during the lift phase also differed; deafferented participants often adopted hand postures that may have facilitated visual guidance, and/or reduced control complexity. For example, they would extend fingers that were not in contact with the object, or fold these fingers into the palm of the hand. Variability in hand postures was increased in deafferented participants, particularly for smaller objects. Our findings provide new insights into how the complex control required for whole hand actions is compromised by loss of haptic feedback, whose contribution is, thus, highlighted.


Endovascular aortic aneurysm repair by a multidisciplinary team: lessons learned and six-year clinical update.
Endovascular aneurysm repair (EVAR) (using an Federal Drug Association-approved AneuRx device) compared to conventional surgical repair of abdominal aortic aneurysm (AAA) previously rendered favourable outcomes regarding post-operative pain, avoidance of laparotomy, and rapid rehabilitation and hospital discharge in high-risk patients, including octagenarians. To assess the safety, reduction in aneurysm-related deaths, and interim survival data up to 72 months after AAA exclusion by endoluminal endografts (EVAR). We carried out an open, controlled, prospective, multidisciplinary EVAR study for the period 1998 to 2003 (six years). In the earlier part of the study, EVAR was compared with previously published results of conventional open aneurysmectomy surgery. Heart Unit, Panorama Medi-Clinic, Parow, South Africa. We recruited adult male and female patients presenting with AAA and fulfilling the inclusion criteria for endovascular repair, as recommended by the consensus 2003 meeting of the Vascular Association of South Africa (VASSA). All patients were offered open surgery as an alternative and were entered into the VASSA EVAR trial registry. Pre-operatively, AAA anatomy was assessed by spiral-computed tomography (CT), and selectively with conventional angiography and intravascular ultrasound (IVUS). Informed consent was obtained in accordance with the recommendations of the Senate of Surgery Paper 2, Ethical Guidelines, Great Britain and Ireland. Patients underwent EVAR by a multidisciplinary interventional team. Two hundred and seven adult patients with AAA were assessed. Forty-four of the 207 (21.2%) were excluded from EVAR because of irreversible comorbid factors and complex aneurysm morphology. One hundred and sixty-three patients (78%), with a mean age of 70.7 years (range 60-91 years), underwent EVAR (1998-2003). Five patients were lost to follow-up (3%). Median AAA diameter was 56.9 mm and ASA ratings were I, 1.2%; II, 15.9%; III, 57%; IV, 22.6%; and V, 2.4%. EVAR was performed in high- and low-risk categories of both sexes. Most patients were in ASA groups III and IV. DEVICES DEPLOYED: EVAR was performed using a selection of endografts over 72 months- AneuRx (Medtronic) 47; Talent (Medtronic) 49; Vanguard three; Zenith (Cook) one; Powerlink (Endologix) 62; and other, one. Thirty-day outcome: successful deployment 99%, primary stent patency 97%, surgical conversion 0.6%, procedural or intra-operative mortality 1.2%, 30-day mortality 4.3%, endoleaks 1.84%, and secondary intraprocedural endovascular interventions 24.5%. Perioperative mortality was 3.1% (one aneurysm related). One patient had suspected endograft infection. Late mortality was 21.4% (35 patients due to co-morbidities, and one was aneurysm related). Follow-up was a median of 28.3 months (range 1-69 months). In 163 patients, two persisting endoleaks (1.2%) were detected. Endotension was detected in 3/163 (1.8%) with average sac increase of 0.8 cm. Conversion to open surgery was needed in one patient (0.6%). Co-morbidities that contributed to late mortality included multi-organ failure, ischaemic heart disease (IHD), cardiomyopathy, renal failure, stroke and cancer. One procedural rupture was fatal (0.6%). Two late ruptures occurred; one was successfully endostented and the other patient died after a failed surgical intervention (0.6%). Endovascular repair of AAA is more expensive than conventional surgery. Introduction of the Endologix stent has reduced operative time from 120 to 60 minutes in un complicated patients. Newer-generation aortic stents allow better control of negative remodeling and stent migration. A multidisciplinary team can safely perform EVAR, with a low 30-day mortality rate in selected patients graded ASA II-IV and with favourable aortic aneurysm morphology. About 22% of patients with AAA are not suited for EVAR. Persisting late endoleaks occurred in 1.2% of the cohort study and were not device specific. Life-long follow-up post EVAR is a prerequisite to detect late device failure, endoleaks and aneurysm-sac enlargement, and to assure the durability of these midterm results. Short-term aneurysm rupture prevention is a predictable outcome in high-risk groups.


The massugu1 mutation of Arabidopsis identified with failure of auxin-induced growth curvature of hypocotyl confers auxin insensitivity to hypocotyl and leaf.
Unilateral application of indole-3-acetic acid (IAA) in a lanolin base to hypocotyls of partially etiolated seedlings of wild-type Arabidopsis thaliana induced growth curvature in a dose-dependent manner. The effects of IAA in concentrations from 1 to 1000 microM were studied, with maximum IAA-induced curvature at 100 microM. Three IAA-insensitive mutants were isolated and are all in the same locus, massugu1 (msg1). They did not undergo hypocotyl growth curvature at any of the IAA concentrations tested. msg1 is recessive and is located on chromosome 5. msg 1 hypocotyl growth is resistant to 2,4-dichlorophenoxyacetic acid (2,4-D), but the roots are as sensitive to 2,4-D as the wild type. Growth of the hypocotyl was inhibited to essentially the same extent as the wild type by 6-benzylaminopurine, abscisic acid, and 1-aminocyclopropane-1-carboxylate, an ethylene precursor. The msg1 leaves were also resistant to 2,4-D-induced chlorosis. The gravitropic response of the msg1 hypocotyl takes much more time to initiate and achieve the wild-type degree of curvature, whereas the msg1 roots responded normally to gravity. The mature plants and the etiolated seedlings of msg1 were generally wild type in appearance, except that their rosette leaves were either epinastic or hyponastic. msg1 is the first auxin-insensitive mutant in which it effects are mostly restricted to the hypocotyl and leaf, and msg1 also appears to be auxin specific.


Increased subchondral bone thickness in hips with cam-type femoroacetabular impingement.
Increased thickness of subchondral acetabular bone with associated articular cartilage thinning in hips with femoroacetabular (FAI) cam impingement has been observed on magnetic resonance imaging (MRI). Dynamic attrition by the cam deformity moving into the acetabulum may potentiate trans-articular shear stresses thus causing these subchondral bone changes. We aimed to quantify the hypertrophic changes of subchondral acetabular bone in patients with cam-type FAI. MRI studies were performed on an asymptomatic population of young Swiss army recruits. Subjects underwent clinical examination and completed questionnaires before undergoing an MRI of the hip. Cam deformities were graded and the dimensions of the acetabular subchondral bone quantified. Univariate linear regression was used to determine the association between the presence of cam deformities and the degree of subchondral acetabular sclerosis. There was a strong association between cam deformities and the thickness, area and shape of subchondral sclerosis. The main increase in hypertrophy was observed in the antero-superior acetabulum where impingement typically occurs. The subchondral sclerosis was 0.66 mm thicker in cam-type deformities than in hips without cam-type deformities (95% CI, 0.38-0.93, p value < 0.001). Mechanical stress in the antero-superior acetabular area is elevated in hips with a cam-type deformity. The study supports the concept that cam-type deformity induced stress leads to hypertrophy of subchondral acetabular bone in the area of impingement. This is collocated with the clinically observed cartilage damage caused by the cam mechanism.


Leonardo da Vinci's contributions to neuroscience.
Leonardo da Vinci (1452-1519) made far-reaching contributions to many areas of science, technology and art. Leonardo's pioneering research into the brain led him to discoveries in neuroanatomy (such as those of the frontal sinus and meningeal vessels) and neurophysiology (he was the first to pith a frog). His injection of hot wax into the brain of an ox provided a cast of the ventricles, and represents the first known use of a solidifying medium to define the shape and size of an internal body structure. Leonardo developed an original, mechanistic model of sensory physiology. He undertook his research with the broad goal of providing physical explanations of how the brain processes visual and other sensory input, and integrates that information via the soul.


Oral contraceptives and the risk of subarachnoid hemorrhage: a meta-analysis.
The objective of this study is to estimate the risk of subarachnoid hemorrhage produced by oral contraceptive use. Studies published since 1960 were identified using MEDLINE, Cumulated Index Medicus, Dissertation Abstracts On-line, and bibliographies of pertinent articles. Two independent reviewers screened published cohort and case-control studies that evaluated the risk of subarachnoid hemorrhage associated with oral contraceptives. Eleven of 21 pertinent studies met predefined quality criteria for inclusion in the meta-analysis. Relative risk (RR) estimations evaluating subarachnoid hemorrhage risk in oral contraceptive users compared with nonusers were extracted from each study by two independent reviewers. Study heterogeneity was assessed by design type, outcome measure (mortality versus incidence), exposure measure (current versus ever use), prevailing estrogen dose used, and control for smoking and hypertension. The overall summary RR of subarachnoid hemorrhage due to oral contraceptive use was 1.42 (95% CI, 1.12 to 1.80; p = 0.004). When the two study results failing to control for smoking were excluded from the analysis, a slightly greater effect was seen, with an RR of 1.55 (95% CI, 1.26 to 1.91; p < 0.0001). In the six studies controlling for smoking and hypertension the RR was 1.49 (95% CI, 1.20 to 1.85; p = 0.0003). High-estrogen oral contraceptives appeared to impart a greater risk than low-dose preparations in studies controlling for smoking, but the difference was not significant (high-dose RR, 1.94; 95% CI, 1.06 to 3.56; low-dose RR, 1.51; 95% CI, 1.18 to 1.92). This meta-analysis of observational studies suggests that oral contraceptive use produces a small increase in the risk of subarachnoid hemorrhage.


Hartley's fractional crystallization and Weigert's effect.
In the course of slow evaporation of an azo-dye chrysophenine-saturated gelatin-water solution, dye crystals that developed two different interference colors were observed in the gelatin; the colors were yellow and blue. The crystals that produce a blue interference color undergo disintegration on exposure to non-polarized light from a mercury lamp.


Prospective assessment of pregnancy intentions using a single- versus a multi-item measure.
Traditional measures of pregnancy intentions that are dichotomous and retrospective do not fully capture the complexity surrounding women's plans to become pregnant. During January-June 2008, 249 women aged 15-44 awaiting pregnancy test results at family planning clinics in Pittsburgh completed a survey containing both single- and multi-item measures of pregnancy intentions. Chi-square analyses were used to assess differences between subgroups of women. Few women were trying to become or planning for pregnancy (11% on the single-item measure; 20% on the multi-item measure), while approximately one-third of the sample were not trying to become or planning for pregnancy (31% on the single-item and 36% on the multi-item measure). The single-item measure categorized more women as ambivalent about pregnancy (58%) than did the multi-item measure (44%). Of women categorized as ambivalent by the single-item measure, 62% were also categorized as ambivalent by the multi-item measure. Overall, 68% of responses to the two measures were concordant. With both measures, women who were not planning or trying for pregnancy were more likely than those who were planning for pregnancy or who were ambivalent to indicate that they planned to have an abortion if their test was positive (27-29% vs. 0-2%). Prospective assessment of pregnancy intention with either a single- or a multi-item measure may allow for a more nuanced assessment of pregnancy intention than current measures. The multi-item measure may reduce the number of women categorized as ambivalent and aid the development of targeted contraceptive and preconception counseling interventions.


Citation bias and selective focus on positive findings in the literature on the serotonin transporter gene (5-HTTLPR), life stress and depression.
Caspi et al.'s 2003 report that 5-HTTLPR genotype moderates the influence of life stress on depression has been highly influential but remains contentious. We examined whether the evidence base for the 5-HTTLPR-stress interaction has been distorted by citation bias and a selective focus on positive findings. A total of 73 primary studies were coded for study outcomes and focus on positive findings in the abstract. Citation rates were compared between studies with positive and negative results, both within this network of primary studies and in Web of Science. In addition, the impact of focus on citation rates was examined. In all, 24 (33%) studies were coded as positive, but these received 48% of within-network and 68% of Web of Science citations. The 38 (52%) negative studies received 42 and 23% of citations, respectively, while the 11 (15%) unclear studies received 10 and 9%. Of the negative studies, the 16 studies without a positive focus (42%) received 47% of within-network citations and 32% of Web of Science citations, while the 13 (34%) studies with a positive focus received 39 and 51%, respectively, and the nine (24%) studies with a partially positive focus received 14 and 17%. Negative studies received fewer citations than positive studies. Furthermore, over half of the negative studies had a (partially) positive focus, and Web of Science citation rates were higher for these studies. Thus, discussion of the 5-HTTLPR-stress interaction is more positive than warranted. This study exemplifies how evidence-base-distorting mechanisms undermine the authenticity of research findings.


Profiling of 19-norandrosterone sulfate and glucuronide in human urine: implications in athlete's drug testing.
19-Norandrosterone (19-NA) as its glucuronide derivative is the target metabolite in anti-doping testing to reveal an abuse of nandrolone or nandrolone prohormone. To provide further evidence of a doping with these steroids, the sulfoconjugate form of 19-norandrosterone in human urine might be monitored as well. In the present study, the profiling of sulfate and glucuronide derivatives of 19-norandrosterone together with 19-noretiocholanolone (19-NE) were assessed in the spot urines of 8 male subjects, collected after administration of 19-nor-4-androstenedione (100mg). An LC/MS/MS assay was employed for the direct quantification of sulfoconjugates, whereas a standard GC/MS method was applied for the assessment of glucuroconjugates in urine specimens. Although the 19-NA glucuronide derivative was always the most prominent at the excretion peak, inter-individual variability of the excretion patterns was observed for both conjugate forms of 19-NA and 19-NE. The ratio between the glucuro- and sulfoconjugate derivatives of 19-NA and 19-NE could not discriminate the endogenous versus the exogenous origin of the parent compound. However, after ingestion of 100mg 19-nor-4-androstenedione, it was observed in the urine specimens that the sulfate conjugates of 19-NA was detectable over a longer period of time with respect to the other metabolites. These findings indicate that more interest shall be given to this type of conjugation to deter a potential doping with norsteroids.


Assessing mothers' attitudes about the physician's role in child health promotion.
This study assessed maternal attitudes about the physician's role in child health promotion. Home interviews were conducted with 200 Massachusetts mothers (with one child age 2 to 3 years) enrolled in a health maintenance organization. Mothers chose growth and nutrition, physical development, and illness as the most important topics and felt that providers have the ability to prevent problems and to help. Psychosocial and safety issues were less important, although mothers felt susceptible to these issues and believed they greatly affected children's health. On all issues, mothers believed physicians were more effective in helping families after, not before, problems arose. The Health Belief Model provided insight into attitudes and possible interventions.


AMPK, insulin resistance, and the metabolic syndrome.
Insulin resistance (IR) and hyperinsulinemia are hallmarks of the metabolic syndrome, as are central adiposity, dyslipidemia, and a predisposition to type 2 diabetes, atherosclerotic cardiovascular disease, hypertension, and certain cancers. Regular exercise and calorie restriction have long been known to increase insulin sensitivity and decrease the prevalence of these disorders. The subsequent identification of AMP-activated protein kinase (AMPK) and its activation by exercise and fuel deprivation have led to studies of the effects of AMPK on both IR and metabolic syndrome-related diseases. In this review, we evaluate this body of literature, with special emphasis on the hypothesis that dysregulation of AMPK is both a pathogenic factor for these disorders in humans and a target for their prevention and therapy.


Cardiac CT to assess the risk of coronary compression in patients evaluated for percutaneous pulmonary valve implantation.
Coronary compression (CC) is a life threatening complication that can occur during percutaneous pulmonary valve implantation (PPVI). We describe our experience using cardiac CT prior to PPVI to identify patients at high CC-risk due to a close relationship between the coronary arteries and pulmonary trunk (PT). A retrospective evaluation of candidates for PPVI who underwent CT prior to the procedure was done. Measurements of PT were performed using double oblique reconstructed images, with special attention to the stenotic tract of the PT. The analysis of coronary arteries included detection of anomalies of origin and course and assessment of their relationship with the PT, measuring the minimum distance between the coronary artery and the intended site of the future percutaneous valve implantation. CT analysis was performed for 52 patients. Thirty patients underwent PPVI after CT and 22 didn't. In 6/22 cases the reason not to receive a PPVI was high CC-risk detected at CT. In 6 other patients CT detected an intermediate CC-risk but the test balloon performed during angiography prior to valve placement was safe and the patients successfully underwent the procedure. None of the patients deemed as no CC-risk at CT had CC during PPVI. CT can detect patients with high and intermediate CC-risk and therefore may identify which patients are unlikely to undergo successful PPVI and those who need a careful analysis with balloon testing. CT can also rule out CC-risk identifying those patients in which balloon inflation testing could be omitted.


Consensus, Global Definitions of Whole Grain as a Food Ingredient and of Whole-Grain Foods Presented on Behalf of the Whole Grain Initiative.
Proposed global definitions of whole grain as an ingredient and whole grain food are presented by the authors on behalf of the Whole Grain Initiative. Whole grains are an important pillar of healthy and sustainable diets. Internationally accepted credible definitions of whole grains as food ingredients and whole-grain foods are necessary to ensure that all global stakeholders have shared standards, and that consumers find them clear, credible, and useful. Based on widely accepted, existing definitions and new developments, the Definitions Working Group of the global Whole Grain Initiative, with experts from academia, government agencies and industry, developed definitions for global application. The key statements of the definition documents are as follows: "Whole grains shall consist of the intact, ground, cracked, flaked or otherwise processed kernel after the removal of inedible parts such as the hull and husk; all anatomical components, including the endosperm, germ, and bran must be present in the same relative proportions as in the intact kernel" and "A whole-grain food shall contain at least 50% whole-grain ingredients based on dry weight. Foods containing 25-50% whole-grain ingredients based on dry weight, may make a front-of-pack claim on the presence of whole grain but cannot be designated 'whole grain' in the product name". The definition documents have been ratified by the leading international scientific associations in this area. We urge that these consensus Whole Grain Initiative definitions be adopted as the basis for definitions used by national regulatory authorities and for health promotion organisations worldwide to use in nutrition education and food labelling.


PrlA and PrlG suppressors reduce the requirement for signal sequence recognition.
Selection for suppressors of defects in the signal sequence of secretory proteins has led most commonly to identification of prlA alleles and less often to identification of prlG alleles. These genes, secY/prlA and secE/prlG, encode integral membrane components of the protein translocation system of Escherichia coli. We demonstrate that an outer membrane protein, LamB, that lacks a signal sequence can be exported with reasonable efficiency in both prlA and prlG suppressor strains. Although the signal sequence is not absolutely required for export of LamB, the level of export in the absence of prl suppressor alleles is exceedingly low. Such strains are phenotypically LamB-, and functional LamB can be detected only by using sensitive infectious-center assays. Suppression of the LamB signal sequence deletion is dependent on normal components of the export pathway, indicating that suppression is not occurring through a bypass mechanism. Our results indicate that the majority of the known prlA suppressors function by an identical mechanism and, further, that the prlG suppressors work in a similar fashion. We propose that both PrlA and PrlG suppressors lack a proofreading activity that normally rejects defective precursors from the export pathway.


Human gut microbiome viewed across age and geography.
Gut microbial communities represent one source of human genetic and metabolic diversity. To examine how gut microbiomes differ among human populations, here we characterize bacterial species in fecal samples from 531 individuals, plus the gene content of 110 of them. The cohort encompassed healthy children and adults from the Amazonas of Venezuela, rural Malawi and US metropolitan areas and included mono- and dizygotic twins. Shared features of the functional maturation of the gut microbiome were identified during the first three years of life in all three populations, including age-associated changes in the genes involved in vitamin biosynthesis and metabolism. Pronounced differences in bacterial assemblages and functional gene repertoires were noted between US residents and those in the other two countries. These distinctive features are evident in early infancy as well as adulthood. Our findings underscore the need to consider the microbiome when evaluating human development, nutritional needs, physiological variations and the impact of westernization.


Genetic Meningococcal Antigen Typing System (gMATS): A genotyping tool that predicts 4CMenB strain coverage worldwide.
The Meningococcal Antigen Typing System (MATS) was developed to identify meningococcus group B strains with a high likelihood of being covered by the 4CMenB vaccine, but is limited by the requirement for viable isolates from culture-confirmed cases. We examined if antigen genotyping could complement MATS in predicting strain coverage by the 4CMenB vaccine. From a panel of 3912 MATS-typed invasive meningococcal disease isolates collected in England and Wales in 2007-2008, 2014-2015 and 2015-2016, and in 16 other countries in 2000-2015, 3481 isolates were also characterized by antigen genotyping. Individual associations between antigen genotypes and MATS coverage for each 4CMenB component were used to define a genetic MATS (gMATS). gMATS estimates were compared with England and Wales human complement serum bactericidal assay (hSBA) data and vaccine effectiveness (VE) data from England. Overall, 81% of the strain panel had genetically predictable MATS coverage, with 92% accuracy and highly concordant results across national panels (Lin's accuracy coefficient, 0.98; root-mean-square deviation, 6%). England and Wales strain coverage estimates were 72-73% by genotyping (66-73% by MATS), underestimating hSBA values after four vaccine doses (88%) and VE after two doses (83%). The gMATS predicted strain coverage in other countries was 58-88%. gMATS can replace MATS in predicting 4CMenB strain coverage in four out of five cases, without requiring a cultivable isolate, and is open to further improvement. Both methods underestimated VE in England. Strain coverage predictions in other countries matched or exceeded England and Wales estimates.


The effects of inhaled budesonide on lung function in smokers and nonsmokers with mild persistent asthma.
Previous studies have suggested a reduced benefit from therapy with inhaled corticosteroids (ICSs) in asthmatic patients who smoke. The objective of this post hoc study was to study the effects of low-dose inhaled budesonide on lung function in smokers and nonsmokers with mild persistent asthma. Adult patients (age, >or= 18 years) in the inhaled Steroid Treatment As Regular Therapy in early asthma (START) study, a 3-year, randomized, placebo-controlled, double-blind study, were stratified according to their smoking habits. The effects on lung function of therapy with budesonide vs placebo were compared in 492 asthmatic patients who smoked habitually and 2,432 nonsmokers. When treated with placebo, newly diagnosed asthmatic patients who smoke had a greater 3-year decline in post-bronchodilator therapy FEV(1), the change being -263.9 mL (SE, 21.8), when compared with nonsmokers on placebo, which was -180.8 mL (SE, 10.6), the mean difference being -83.1 mL (p < 0.001). Budesonide treatment was associated with a statistically significant 3-year increase in post-bronchodilator therapy FEV(1) in both groups. The effect of budesonide vs placebo was 71.5 mL (p = 0.011) in smokers and 46.5 mL (p = 0.001) in nonsmokers. The corresponding effect in pre-bronchodilator therapy FEV(1) was 118.1 mL (p = 0.002) in smokers and 72.9 mL (p < 0.001) in nonsmokers. Asthmatic patients who smoke, and are not treated with ICSs, have a greater decline in lung function than asthmatic patients who do not smoke. The benefits of therapy with inhaled budesonide on preventing lung function decline are similar in smokers and nonsmokers with mild persistent asthma.


Bilateral assessment of functional tasks for robot-assisted therapy applications.
This article presents a novel evaluation system along with methods to evaluate bilateral coordination of arm function on activities of daily living tasks before and after robot-assisted therapy. An affordable bilateral assessment system (BiAS) consisting of two mini-passive measuring units modeled as three degree of freedom robots is described. The process for evaluating functional tasks using the BiAS is presented and we demonstrate its ability to measure wrist kinematic trajectories. Three metrics, phase difference, movement overlap, and task completion time, are used to evaluate the BiAS system on a bilateral symmetric (bi-drink) and a bilateral asymmetric (bi-pour) functional task. Wrist position and velocity trajectories are evaluated using these metrics to provide insight into temporal and spatial bilateral deficits after stroke. The BiAS system quantified movements of the wrists during functional tasks and detected differences in impaired and unimpaired arm movements. Case studies showed that stroke patients compared to healthy subjects move slower and are less likely to use their arm simultaneously even when the functional task requires simultaneous movement. After robot-assisted therapy, interlimb coordination spatial deficits moved toward normal coordination on functional tasks.


Dopamine D3 receptor selective ligands with varying intrinsic efficacies at adenylyl cyclase inhibition and mitogenic signaling pathways.
A panel of structurally related substituted 4-phenylpiperazines with nanomolar affinity and selectivity at D3 dopamine receptors has been synthesized. Compounds in which a heterocyclic (2-phenyl pyridyl, 3-phenyl pyridyl, benzothiophene, or benzofuran) moiety is adjacent to the amide was varied and/or a double bond (trans-butenyl) replaced the four-carbon aliphatic chain linking the arylamide with the 4-phenylpiperazine moiety were compared for (a) affinity at human D2 and D3 dopamine receptors, (b) intrinsic efficacy using an adenylyl cyclase inhibition assay, and (c) intrinsic efficacy using a mitogenic assay. All 16 compounds were (a) more efficacious for the D3 receptor cyclase inhibition assay than for the D3 receptor mitogenic assay and (b) exhibited the same or greater efficacy at D3 compared to D2 receptor (with the exception of one compound). Although the heterocyclic amide moiety appears to be the pivotal structural element determining the intrinsic efficacy of our D3 receptor selective compounds, the magnitude of the efficacy is modulated by the (a) substituent(s) on the phenyl piperazine and (b) the saturation of the four-carbon chain that links the arylamide and the phenylpiperazine. In addition, our ligands are functionally selective, because they can have differing intrinsic efficacies for the cyclase inhibition and the mitogenic activation signaling pathways. Compounds that are essentially full agonists at the cyclase assay appear to be only partial agonists in the mitogenic assay and compounds that are partial agonists in our cyclase assay are partial agonists or antagonists in the mitogenic assay.


18O2 labeling experiments illuminate the oxidation of ent-kaurene in bacterial gibberellin biosynthesis.
Bacteria can produce gibberellin plant hormones. While the bacterial biosynthetic pathway is similar to that of plants, the individual enzymes are very distantly related and arose via convergent evolution. The cytochromes P450 (CYPs) that catalyze the multi-step oxidation of the alkane precursor ent-kaurene (1) to ent-kauren-19-oic acid (5), are called ent-kaurene oxidases (KOs), and in plants are from the CYP701 family, and share less than 19% amino acid sequence identity with those from bacteria, which are from the phylogenetically distinct CYP117 family. Here the reaction series catalyzed by CYP117 was examined by 18O2 labeling experiments, the results indicate successive hydroxylation of 1 to ent-kauren-19-ol (2) and then ent-kauren-19,19-diol (3) and most likely an intervening dehydration to ent-kauren-19-al (4) prior to the concluding hydroxylation to 5. Accordingly, the bacterial and plant KOs converged on catalysis of the same series of reactions, despite their independent evolutionary origin.


Assessment of folate receptor expression and folate uptake in multicentric lymphomas in dogs.
To determine expression of folate receptors (FRs) and folate uptake in multicentric lymphomas in dogs. 10 dogs with histopathologically confirmed multicentric lymphoma and 20 archival lymph node biopsy specimens from dogs with multicentric lymphoma. Multicentric lymphomas in 10 dogs were prospectively evaluated for FR expression by use of immunohistochemical analysis and for in vivo folate uptake by use of nuclear scintigraphy. Dogs with FR-expressing tumors were eligible for FR-targeted chemotherapy. Twenty archival lymphoma biopsy specimens were also evaluated with immunohistochemical analysis. FRs were not detected with immunohistochemical analysis in lymph node samples obtained from the 10 dogs or in archival biopsy specimens. However, nuclear scintigraphy revealed uptake of radioactive tracer in 6 of 10 dogs. Five of these 6 dogs were treated with an FR-targeted chemotherapeutic agent; results of treatment were complete remission in 1 dog, stable disease in 2 dogs, and progressive disease in 2 dogs. Treatment-related toxicoses generally were mild. This study provided strong evidence for folate uptake in a substantial portion of multicentric lymphomas of dogs and indicated the antitumor activity of FR-targeted chemotherapeutics for these cancers. Use of FR-targeted chemotherapeutics may be promising for the treatment of FR-expressing multicentric lymphomas in dogs. Further studies are needed to determine reasons for lack of immunoreactivity to currently identified anti-FR antibodies and to develop improved methods for detecting FRs in lymphomas of dogs.


Thrombolysis in Myocardial Infarction (TIMI) Trial--phase I: hemorrhagic manifestations and changes in plasma fibrinogen and the fibrinolytic system in patients treated with recombinant tissue plasminogen activator and streptokinase.
Two hundred ninety patients with acute myocardial infarction were treated according to random assignment with an intravenous infusion of either 80 mg of recombinant tissue plasminogen activator (rt-PA) over 3 h or 1.5 million units of streptokinase over 1 h. Patients received an intravenous bolus of heparin (5,000 U [USP]) before pretreatment coronary angiography and a continuous infusion (1,000 U/h) starting 3 h later. The frequency of major and minor hemorrhagic events (33% rt-PA, 31% streptokinase) and associated transfusions (22% rt-PA, 20% streptokinase) were comparable in both groups. More than 70% of bleeding episodes in each group occurred at catheterization or vascular puncture sites. Precipitable fibrinogen levels, measured in plasma samples collected in the presence of a protease inhibitor (aprotinin), declined in rt-PA and streptokinase groups by averages of 26 and 57% at 3 h and by 33 and 58% at 5 h, respectively (rt-PA versus streptokinase, p less than 0.001). At 5 h the plasma plasminogen declined by 57% (rt-PA) and 82% (streptokinase) (p less than 0.001); plasma fibrin(ogen) degradation products were higher in streptokinase-treated patients (244 +/- 12 micrograms/ml, mean +/- SE) than in rt-PA-treated patients (97 +/- 9 micrograms/ml, p less than 0.001). At 27 h, plasma fibrinogen and plasminogen levels were lower and fibrin(ogen) degradation products higher than pretreatment levels in both groups. The frequency of hemorrhagic events was higher in patients with greater changes in plasma factors at 5 h; within treatment groups the levels of fibrin(ogen) degradation products correlated with bleeding complications (p less than 0.005). Thus, in the doses administered, rt-PA induces systemic fibrinogenolysis that is substantially less intense than that induced by streptokinase. The high frequency of bleeding encountered is related to the protocol used, including vigorous anticoagulation, arterial punctures and thrombolytic therapy. These findings emphasize the need for avoidance of invasive procedures and for meticulous care in the selection and management of patients subjected to thrombolytic therapy.


Neurologic complications of arteriovenous malformation embolization using liquid embolic agents.
Embolization of arteriovenous malformations (AVMs) is commonly used to achieve nidal volume reduction before microsurgical resection or stereotactic radiosurgery. The purpose of this study was to examine the overall neurologic complication rate in patients undergoing AVM embolization and analyze the factors that may determine increased risk. We performed a retrospective review of all patients with brain AVMs embolized at 1 center from 1995 through 2005. Demographics, including age, sex, presenting symptoms, and clinical condition, were recorded. Angiographic factors including maximal nidal size, presence of deep venous drainage, and involvement of eloquent cortex were also recorded. For each embolization session, the agent used, number of pedicles embolized, the percentage of nidal obliteration, and any complications were recorded. Complications were classified as the following: none, non-neurologic (mild), transient neurologic deficit, and permanent nondisabling and permanent disabling deficits. The permanent complications were also classified as ischemic or hemorrhagic. Modified Rankin Scale (mRS) scores were collected pre- and postembolization on all patients. Univariate regression analysis of factors associated with the development of any neurologic complication was performed. Four hundred eighty-nine embolization procedures were performed in 192 patients. There were 6 Spetzler-Martin grade I (3.1%), 26 grade II (13.5%), 71 grade III (37.0%), 57 grade IV (29.7%), and 32 grade V (16.7%) AVMs. Permanent nondisabling complications occurred in 5 patients (2.6%) and permanent disabling complications or deaths occurred in 3 (1.6%). In addition, there were non-neurologic complications in 4 patients (2.1%) and transient neurologic deficits in 22 (11.5%). Five of the 8 permanent complications (2.6% overall) were ischemic, and 3 of 8 (1.6% overall) were hemorrhagic. Of the 178 patients who were mRS 0-2 pre-embolization, 4 (2.3%) were dependent or dead (mRS >2) at follow-up. Univariate analysis of risk factors for permanent neurologic deficits following embolization showed that basal ganglia location was weakly associated with a new postembolization neurologic deficit. Embolization of brain AVMs can be performed with a high degree of technical success and a low rate of permanent neurologic complications.


Annotation of expressed sequence tags for the East African cichlid fish Astatotilapia burtoni and evolutionary analyses of cichlid ORFs.
The cichlid fishes in general, and the exceptionally diverse East African haplochromine cichlids in particular, are famous examples of adaptive radiation and explosive speciation. Here we report the collection and annotation of more than 12,000 expressed sequence tags (ESTs) generated from three different cDNA libraries obtained from the East African haplochromine cichlid species Astatotilapia burtoni and Metriaclima zebra. We first annotated more than 12,000 newly generated cichlid ESTs using the Gene Ontology classification system. For evolutionary analyses, we combined these ESTs with all available sequence data for haplochromine cichlids, which resulted in a total of more than 45,000 ESTs. The ESTs represent a broad range of molecular functions and biological processes. We compared the haplochromine ESTs to sequence data from those available for other fish model systems such as pufferfish (Takifugu rubripes and Tetraodon nigroviridis), trout, and zebrafish. We characterized genes that show a faster or slower rate of base substitutions in haplochromine cichlids compared to other fish species, as this is indicative of a relaxed or reinforced selection regime. Four of these genes showed the signature of positive selection as revealed by calculating Ka/Ks ratios. About 22% of the surveyed ESTs were found to have cichlid specific rate differences suggesting that these genes might play a role in lineage specific characteristics of cichlids. We also conclude that the four genes with a Ka/Ks ratio greater than one appear as good candidate genes for further work on the genetic basis of evolutionary success of haplochromine cichlid fishes.


(Ir)reversibility in dense granular systems driven by oscillating forces.
We use computer simulations to study highly dense systems of granular particles that are driven by oscillating forces. We implement different dissipation mechanisms that are used to extract the injected energy. In particular, the action of a simple local Stokes' drag is compared with non-linear and history-dependent frictional forces that act either between particle pairs or between particles and an external container wall. The Stokes' drag leads to particle motion that is periodic with the driving force, even at high densities around close packing where particles undergo frequent collisions. With the introduction of inter-particle frictional forces this "interacting absorbing state" is destroyed and particles start to diffuse around. By reducing the density of the material we go through another transition to a "non-interacting" absorbing state, where particles independently follow the force-induced oscillations without collisions. In the system with particle-wall frictional interactions this transition has signs of a discontinuous phase transition. It is accompanied by a diverging relaxation time, but not by a vanishing order parameter, which rather jumps to zero at the transition.


The Prognostic Value of Patient-Reported Outcome Data in Patients With Colorectal Hepatic Metastases Who Underwent Surgery.
Patient-reported outcomes (PROs) are critical to evaluate clinically effective treatments and evidence suggests that PROs might predict survival. The prognostic value of PROs in patients with isolated liver metastases from colorectal cancer (CRC) who undergo surgery is unclear. In this study we investigated whether baseline PROs are prognostic in this patient group. From April 2004 to May 2007, consecutive patients who underwent curative resection of CRC liver metastases completed the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (QLQ)-C30 and QLQ-LMC21 questionnaires before surgery. Patients were followed until death or data were censored on April 9, 2012. Cox proportional hazards models were used to assess the effect of PROs on survival controlling for predefined clinical covariates. Models were simplified using a backwards stepwise approach and model utility appraised using the Harrell C and Somers D statistics and bootstrap methods. Two hundred thirty-two patients underwent liver resection and 101 (43.5%) survived 5 years. Multivariate analysis controlling for relevant clinical covariates showed that a 10-point improvement in baseline global quality of life scores was associated with a 54% improvement in survival (hazard ratio [HR], 0.46; 95% confidence interval [CI], 0.33-0.63; P < .001), and a clinically significant weight loss was associated with 75% worse survival (HR, 1.75; 95% CI, 1.20-2.55; P = .004). Smaller effects were noted for worsening abdominal pain, taste problems, and fatigue (30%-38% poorer survival). Results of bootstrap resampling suggested that global health and weight loss most reliably predicted survival. Results of this study demonstrated that patients who reported worse baseline global quality of life and increased weight loss before liver resection for CRC liver metastases had significantly poorer survival. These findings if externally validated might be used to inform patients, and could also influence treatment planning and advise follow-up strategies and supportive care.


Effects of Deltamethrin Treatment on Small Mammal and Ectoparasite Population Dynamics and Plague Prevalence in a North American Mixed-Grass Prairie System.
Sylvatic plague affects many species in North American prairie ecosystems. Deltamethrin is commonly used to manage fleas in potential outbreak areas. Understanding the role of small mammals and their ectoparasites in sylvatic plague maintenance is pertinent to understanding the ecology of plague and its persistence in nature. This study examined the effects of plague management using deltamethrin on communities of small mammals, their flea faunas, and Yersinia pestis prevalence. We trapped small mammals from 2014 to 2016 on the Lower Brule Indian Reservation (LOBR), South Dakota, and analyzed the effects of deltamethrin treatment on small mammal populations, flea loads, and Y. pestis prevalence. We collected higher flea loads from small mammals on sites not treated with deltamethrin (1.10 fleas per animal) than from deltamethrin-treated sites (1.03 fleas per animal). We observed significant negative trends in mean flea load per animal between pre- and post-treatment collections. We detected no significant effects of deltamethrin treatment on animal captures pre- and post-treatment, but observed significant differences in animal captures by experimental unit. We detected no serological evidence for the presence of Y. pestis antibodies in small mammals and 1.2% Y. pestis prevalence across all sampled fleas. Although there is little overlap in the species of fleas infesting small mammals and prairie dogs, the occurrence of flea spillover has been documented. In our study, treatment with deltamethrin reduced flea loads on small mammals by up to 49%. Our data suggest that although the efficacy of deltamethrin on the LOBR-a mixed-grass system-may not be as high as that found in a comparable study in a short-grass system, deltamethrin is still a useful tool in the management of plague.


β-catenin tyrosine 654 phosphorylation increases Wnt signalling and intestinal tumorigenesis.
Objective Deregulation of the Wnt signalling pathway by mutations in the Apc or β-catenin genes underlies colorectal carcinogenesis. As a result, β-catenin stabilises, translocates to the nucleus, and activates gene transcription. Intestinal tumours show a heterogeneous pattern of nuclear β-catenin, with the highest levels observed at the invasion front. Activation of receptor tyrosine kinases in these tumour areas by growth factors expressed by surrounding stromal cells phosphorylate β-catenin at tyrosine residues, which is thought to increase β-catenin nuclear translocation and tumour invasiveness. This study investigates the relevance of β-catenin tyrosine phosphorylation for Wnt signalling and intestinal tumorigenesis in vivo. Design A conditional knock-in mouse model was generated into which the phospho-mimicking Y654E modification in the endogenous β-catenin gene was introduced. Results This study provided in vivo evidence that β-catenin(E654) is characterised by reduced affinity for cadherins, increased signalling and strongly increased phosphorylation at serine 675 by protein kinase A (PKA). In addition, homozygosity for the β-catenin(E654) targeted allele caused embryonic lethality, whereas heterozygosity predisposed to intestinal tumour development, and strongly enhanced Apc-driven intestinal tumour initiation associated with increased nuclear accumulation of βcatenin. Surprisingly, the expression of β-catenin(E654) did not affect histological grade or induce tumour invasiveness. Conclusions A thus far unknown mechanism was uncovered in which Y654 phosphorylation of β-catenin facilitates additional phosphorylation at serine 675 by PKA. In addition, in contrast to the current belief that β-catenin Y654 phosphorylation increases tumour progression to a more invasive phenotype, these results show that it rather increases tumour initiation by enhancing Wnt signalling.


Estimating Cost-effectiveness of a Multimodal Ovarian Cancer Screening Program in the United States: Secondary Analysis of the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS).
The United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) is the largest randomized clinical trial to evaluate screening's impact on ovarian cancer mortality, assigning women to multimodal screening (MMS) with serum cancer antigen 125 (CA-125) interpreted using a risk algorithm. If the MMS screening method is eventually shown to reduce mortality and be cost-effective, then it may be accepted by the medical community as a feasible screening tool. To estimate the cost-effectiveness of an MMS screening program in the United States. A Markov simulation model was constructed using data from UKCTOCS to compare MMS with no screening in the United States. Screening would begin at the age of 50 years for women in the general population. Published estimates of the long-term effect of MMS screening on ovarian cancer mortality and the trial's published hazard ratios were used to simulate mortality estimates up to 40 years from start of screening. Base-case costs included CA-125, ultrasound, and false-positive work-up results, in addition to a risk algorithm cost estimate of $100. The utility and costs of ovarian cancer treatment were incorporated into the model. Screening strategies varied by costs of the algorithm and treatment for advanced ovarian cancer, rates of screening compliance, ovarian cancer incidence, and extrapolation of ovarian cancer mortality. Costs, quality-adjusted life-years (QALYs), and mortality reduction of ovarian cancer screening. Multimodal screening is both more expensive and more effective in reducing ovarian cancer mortality over a lifetime than no screening. After accounting for uncertainty in the underlying parameters, screening women starting at age 50 years with MMS is cost-effective 70% of the time, when decision makers are willing to pay $150 000 per QALY. Screening reduced mortality by 15%, with an incremental cost-effectiveness ratio (ICER) ranging from $106 187 (95% CI, $97 496-$127 793) to $155 256 (95% CI, $150 369-$198 567). Ovarian cancer screening is potentially cost-effective in the United States depending on final significance of mortality reduction and cost of the CA-125 risk algorithm. These results are limited by uncertainty around the effect of screening on ovarian cancer mortality beyond the 11 years of UKCTOCS.


Unknown primary carcinoma: natural history and prognostic factors in 657 consecutive patients.
To evaluate the natural history, validate previous observations, and identify prognostic factors in patients with unknown primary carcinoma (UPC). Nine hundred twenty-seven consecutive patients referred to the M.D. Anderson Cancer Center with a preliminary diagnosis of UPC were prospectively identified. A standardized evaluation narrowed the study population to 657 patients with UPC. All data were recorded and computerized for storage, retrieval, and analysis. The primary end point for the study was survival, which was calculated from the first day of patient registration. Survival curves were estimated using the Kaplan-Meier method and compared using the Cox-Mantel log-rank test. To identify important prognostic factors, univariate and multivariate analyses were conducted. The demographics of the UPC patient population mirrored those of the general population of patients referred to our cancer center except for an excess of men among the UPC patients. Most patients had histologic or cytologic evidence of adenocarcinoma and had more than one organ site metastatically involved. Univariate and multivariate analyses identified numerous important prognostic factors with a significant influence on survival, including sex, number of organ sites involved, specific organ sites involved, and pathologic subtypes. This study validated previously identified important prognostic factors for survival in UPC. Additional variables that had an impact on survival were identified and the complex interaction of the factors was explored. As patient numbers increase, this database will be able to provide further analyses of patient subsets and potentially relate specific clinical features to the evolving molecular and biochemical understanding of these malignancies.


Presynaptic Ca2+ influx and vesicle exocytosis at the mouse endbulb of Held: a comparison of two auditory nerve terminals.
The functional properties of mammalian presynaptic nerve endings remain elusive since most terminals of the central nervous system are not accessible to direct electrophysiological recordings. In this study, direct recordings were performed for the first time at endbulb of Held terminals to characterize passive membrane properties, voltage-gated Ca(2+) channels (VGCCs) and Ca(2+)-dependent exocytosis. Endbulb of Held terminals arise from endings of auditory nerve fibres contacting spherical bushy cells (SBCs) in the anterior ventral cochlear nucleus (AVCN). These terminals had a high mean input resistance (1.1 G) and a small mean capacitance (4.3 pF). Presynaptic VGCCs were predominantly of the P/Q type (86%) and expressed at a high density with an estimated average number of 6400 channels per terminal. Presynaptic Ca(2+) currents (I(Ca(V))) activated and deactivated rapidly. Simulations of action potential (AP)-driven gating of VGCCs suggests that endbulb APs trigger brief Ca(2+) influx with a mean half-width of 240 μs and a peak amplitude of 0.45 nA which results from the opening of approximately 2600 channels. Unlike Ca(2+) currents at the calyx of Held, I(Ca(V)) of endbulb terminals showed no inactivation during trains of AP-like presynaptic depolarizations. Endbulb terminals are endowed with a large readily releasable vesicle pool (1064 vesicles) of which only a small fraction (<10%) is consumed during a single AP-like stimulus. Fast presynaptic APs together with rapidly gating VGCCs will generate brief intracellular Ca(2+) transients that favour highly synchronous transmitter release. Collectively these characteristics ensure sustained and precise transmission of timing information from auditory stimuli at the endbulbSBC synapse.


Lack of associations between betatrophin/ANGPTL8 level and C-peptide in type 2 diabetic subjects.
Betatrophin has been suggested as an inducer of β-cell proliferation in mice in addition to its function in regulating triglyceride. Recent data showed that betatrophin was increased in Type 2 Diabetes (T2D), however, its ability to induce insulin production has been questioned. We hypothesized that the increased betatrophin in T2D is not affecting insulin production from β-cells. To test this hypothesis, we investigated the association between betatrophin and C-peptide level in humans, which acts as a measure of endogenous insulin production from β-cells. This study was designed to examine the association between plasma betatrophin level and C-peptide in 749 T2D and non-diabetics. Betatrophin and C-peptide levels were higher in T2D subjects compared with non-diabetics subjects. Betatrophin showed strong correlation with C-peptide in non-diabetics subjects (r = 0.28, p = < 0.0001). No association between betatrophin and C-peptide were observed in T2D subjects (r = 0.07, p = 0.3366). Dividing obese and non-obese subjects into tertiles according to betatrophin level showed significantly higher C-peptide levels at higher tertiles of betatrophin in obese non-diabetics subjects P-trend = 0.0046. On the other hand, C-peptide level was significantly higher in subject with higher betatrophin level in non-diabetics subjects across all age groups but not in T2D subjects. Multiple logistic regression models adjusted for age, BMI, gender, ethnicity as well as C-peptide level showed that subjects in the highest tertiles of betatrophin had higher odds of having T2D [odd ratio (OR) = 7.3, 95% confidence interval (CI) 4.0-13.3]. Increased betatrophin level in obese subjects is correlated with an increase in C-peptide level; which is possibly caused by the increased insulin resistance. On the other hand, no correlation is observed between increased betatrophin level and C-peptide in T2D subjects. In conclusion, the increased betatrophin in T2D subject does not cause any increase in insulin production as indicated by C-peptide level.


Antidepressants for smoking cessation.
The pharmacological profiles and mechanisms of antidepressants are varied. However, there are common reasons why they might help people to stop smoking tobacco: nicotine withdrawal can produce short-term low mood that antidepressants may relieve; and some antidepressants may have a specific effect on neural pathways or receptors that underlie nicotine addiction. To assess the evidence for the efficacy, harms, and tolerability of medications with antidepressant properties in assisting long-term tobacco smoking cessation in people who smoke cigarettes. We searched the Cochrane Tobacco Addiction Group Specialised Register, most recently on 29 April 2022. We included randomised controlled trials (RCTs) in people who smoked, comparing antidepressant medications with placebo or no pharmacological treatment, an alternative pharmacotherapy, or the same medication used differently. We excluded trials with fewer than six months of follow-up from efficacy analyses. We included trials with any follow-up length for our analyses of harms. We extracted data and assessed risk of bias using standard Cochrane methods. Our primary outcome measure was smoking cessation after at least six months' follow-up. We used the most rigorous definition of abstinence available in each trial, and biochemically validated rates if available. Our secondary outcomes were harms and tolerance outcomes, including adverse events (AEs), serious adverse events (SAEs), psychiatric AEs, seizures, overdoses, suicide attempts, death by suicide, all-cause mortality, and trial dropouts due to treatment. We carried out meta-analyses where appropriate. We included a total of 124 studies (48,832 participants) in this review, with 10 new studies added to this update version. Most studies recruited adults from the community or from smoking cessation clinics; four studies focused on adolescents (with participants between 12 and 21 years old). We judged 34 studies to be at high risk of bias; however, restricting analyses only to studies at low or unclear risk of bias did not change clinical interpretation of the results. There was high-certainty evidence that bupropion increased smoking cessation rates when compared to placebo or no pharmacological treatment (RR 1.60, 95% CI 1.49 to 1.72; I2 = 16%; 50 studies, 18,577 participants). There was moderate-certainty evidence that a combination of bupropion and varenicline may have resulted in superior quit rates to varenicline alone (RR 1.21, 95% CI 0.95 to 1.55; I2 = 15%; 3 studies, 1057 participants). However, there was insufficient evidence to establish whether a combination of bupropion and nicotine replacement therapy (NRT) resulted in superior quit rates to NRT alone (RR 1.17, 95% CI 0.95 to 1.44; I2 = 43%; 15 studies, 4117 participants; low-certainty evidence). There was moderate-certainty evidence that participants taking bupropion were more likely to report SAEs than those taking placebo or no pharmacological treatment. However, results were imprecise and the CI also encompassed no difference (RR 1.16, 95% CI 0.90 to 1.48; I2 = 0%; 23 studies, 10,958 participants). Results were also imprecise when comparing SAEs between people randomised to a combination of bupropion and NRT versus NRT alone (RR 1.52, 95% CI 0.26 to 8.89; I2 = 0%; 4 studies, 657 participants) and randomised to bupropion plus varenicline versus varenicline alone (RR 1.23, 95% CI 0.63 to 2.42; I2 = 0%; 5 studies, 1268 participants). In both cases, we judged evidence to be of low certainty. There was high-certainty evidence that bupropion resulted in more trial dropouts due to AEs than placebo or no pharmacological treatment (RR 1.44, 95% CI 1.27 to 1.65; I2 = 2%; 25 studies, 12,346 participants). However, there was insufficient evidence that bupropion combined with NRT versus NRT alone (RR 1.67, 95% CI 0.95 to 2.92; I2 = 0%; 3 studies, 737 participants) or bupropion combined with varenicline versus varenicline alone (RR 0.80, 95% CI 0.45 to 1.45; I2 = 0%; 4 studies, 1230 participants) had an impact on the number of dropouts due to treatment. In both cases, imprecision was substantial (we judged the evidence to be of low certainty for both comparisons). Bupropion resulted in inferior smoking cessation rates to varenicline (RR 0.73, 95% CI 0.67 to 0.80; I2 = 0%; 9 studies, 7564 participants), and to combination NRT (RR 0.74, 95% CI 0.55 to 0.98; I2 = 0%; 2 studies; 720 participants). However, there was no clear evidence of a difference in efficacy between bupropion and single-form NRT (RR 1.03, 95% CI 0.93 to 1.13; I2 = 0%; 10 studies, 7613 participants). We also found evidence that nortriptyline aided smoking cessation when compared with placebo (RR 2.03, 95% CI 1.48 to 2.78; I2 = 16%; 6 studies, 975 participants), and some evidence that bupropion resulted in superior quit rates to nortriptyline (RR 1.30, 95% CI 0.93 to 1.82; I2 = 0%; 3 studies, 417 participants), although this result was subject to imprecision. Findings were sparse and inconsistent as to whether antidepressants, primarily bupropion and nortriptyline, had a particular benefit for people with current or previous depression. There is high-certainty evidence that bupropion can aid long-term smoking cessation. However, bupropion may increase SAEs (moderate-certainty evidence when compared to placebo/no pharmacological treatment). There is high-certainty evidence that people taking bupropion are more likely to discontinue treatment compared with people receiving placebo or no pharmacological treatment. Nortriptyline also appears to have a beneficial effect on smoking quit rates relative to placebo, although bupropion may be more effective. Evidence also suggests that bupropion may be as successful as single-form NRT in helping people to quit smoking, but less effective than combination NRT and varenicline. In most cases, a paucity of data made it difficult to draw conclusions regarding harms and tolerability. Further studies investigating the efficacy of bupropion versus placebo are unlikely to change our interpretation of the effect, providing no clear justification for pursuing bupropion for smoking cessation over other licensed smoking cessation treatments; namely, NRT and varenicline. However, it is important that future studies of antidepressants for smoking cessation measure and report on harms and tolerability.


[Paleoclimate of La Guajira, Colombia; by the growth rings of Capparis odoratissima (Capparidaceae)].
There is great concern about the effect of climate change in arid and subarid areas of the tropics. Climate change combined with other anthropogenic activities such as deforestation, fires and over-grazing can accelerate their degradation and, consequently, the increases in losses of biological and economic productivity. Climate models, both local and global, predict that rainfall in the arid Peninsula of La Guajira in the Colombian Caribbean would be reduced and temperature would be increased as a result of climate change. However, as there are only suitable climate records since 1972, it is not possible to verify if, indeed, this is happening. To try to verify the hypothesis of reducing rainfall and rising temperatures we developed a growth ring chronology of Capparis odoratissima in the Middle Peninsula of La Guajira with 17 trees and 45 series which attain 48 years back. We use standard dendrochronological methods that showed statistically significant linear relationship with local climatic variables such as air temperature, sea surface temperature (SST), annual precipitation and wind speed; we also reach to successful relationship of the chronology with global climatic variables as the indices SOI and MEI of the ENSO phenomenon. The transfer functions estimated with the time series (1955 and 2003) do not showed statistically significant trends, indicating that during this period of time the annual precipitation or temperatures have not changed. The annual nature of C. odoratissima growth rings, the possibility of cross-dated among the samples of this species, and the high correlation with local and global climatic variables indicate a high potential of this species for dendrochronological studies in this part of the American continent.


Locally Acquired Chronic Hepatitis E Followed by Epstein-Barr Virus Reactivation and Burkitt Lymphoma as a Suspected Extrahepatic Manifestation in a Liver Transplant Recipient.
BACKGROUND Hepatitis E virus (HEV) is a common cause of acute hepatitis in developing regions. In high-income countries, hepatitis E is an emergent zoonotic disease of increasing concern. Clinically, the infection is usually acute and self-limited in immunocompetent individuals, although rare chronic cases in immunocompromised patients have been reported. Both acute and chronic infections have been recently associated with several extrahepatic manifestations, including neurological and hematological disorders. CASE REPORT A case of autochthonous chronic HEV infection in a liver-transplanted man from a non-endemic country is presented. Phylogenetic analysis revealed a swine origin of the HEV human infection. Chronic hepatitis E was treated with a 9-week course of ribavirin, after which viral clearance was achieved. Subsequently, the patient developed a post-transplant lymphoproliferative disorder (PTLD) in the form of Burkitt lymphoma. At the time of lymphoma diagnosis, the patient had shown a strong reactivation of Epstein-Barr virus (EBV) infection. After additional antiviral ganciclovir therapy and chemotherapy, the patient had a complete recovery with no sequelae. CONCLUSIONS The differential diagnosis of persistently elevated transaminases in transplanted and/or immunocompromised patients should include testing for HEV by appropriate nucleic acid techniques (NATs). Cases of HEV infection with an atypical clinical outcome, such as the one presented herein, highlights the need for increased awareness of chronic hepatitis E and its association with a wide range of extrahepatic manifestations.


Alpha/beta-hydrolases: A unique structural motif coordinates catalytic acid residue in 40 protein fold families.
The alpha/beta-hydrolases are a family of acid-base-nucleophile catalytic triad enzymes with a common fold, but using a wide variety of substrates, having different pH optima, catalyzing unique catalytic reactions and often showing improved chemical and thermo stability. The ABH enzymes are prime targets for protein engineering. Here, we have classified active sites from 51 representative members of 40 structural ABH fold families into eight distinct conserved geometries. We demonstrate the occurrence of a common structural motif, the catalytic acid zone, at the catalytic triad acid turn. We show that binding of an external ligand does not change the structure of the catalytic acid zone and both the ligand-free and ligand-bound forms of the protein belong to the same catalytic acid zone subgroup. We also show that the catalytic acid zone coordinates the position of the catalytic histidine loop directly above its plane, and consequently, fixes the catalytic histidine in a proper position near the catalytic acid. Finally, we demonstrate that the catalytic acid zone plays a key role in multi-subunit complex formation in ABH enzymes, and is involved in interactions with other proteins. As a result, we speculate that each of the catalytic triad residues has its own supporting structural scaffold, similar to the catalytic acid zone, described above, which together form the extended catalytic triad motif. Each scaffold coordinates the function of its respective catalytic residue, and can even compensate for the loss of protein function, if the catalytic amino acid is mutated.


Distinct Responsiveness to Intravitreal Ranibizumab Therapy in Polypoidal Choroidal Vasculopathy With Single or Multiple Polyps.
To understand the prognosis of polypoidal choroidal vasculopathy (PCV) by evaluating the responsiveness to intravitreal ranibizumab (IVR) monotherapy according to the presence of a single or multiple polyps. Retrospective case series. We included 48 treatment-naïve eyes of 48 patients who received IVR monotherapy at the Medical Retina Division Clinic, Keio University Hospital between March 2009 and January 2013 and attended the clinic for at least 12 months. All patients received 3 monthly IVR injections followed by pro re nata injections and were divided into single polyp and multiple polyps groups according to indocyanine green angiography and optical coherence tomography (OCT) findings. The outcome measures included changes in best-corrected visual acuity (BCVA) and OCT findings over 2 years after initial IVR. At baseline, the multiple polyps group exhibited a poorer BCVA, larger greatest linear dimension, and higher prevalence of fibrovascular pigment epithelial detachment compared with the single polyp group. Over 2 years, the multiple polyps group showed no improvement in BCVA, although the central retinal thickness (CRT) decreased in both groups. The multiple polyps group exhibited a significantly greater CRT at 1 year and required more injections in the first year compared with the single polyp group; furthermore, it included a higher number of nonresponders judged either by BCVA or fundus findings at 1 year and fundus findings at 2 years. We propose that the stratification of PCV lesions according to the presence of single or multiple polyps may be valuable to understand the prognosis.


Prevalence of common mental disorders in a rural district of Kenya, and socio-demographic risk factors.
Association between common mental disorders (CMDs), equity, poverty and socio-economic functioning are relatively well explored in high income countries, but there have been fewer studies in low and middle income countries, despite the considerable burden posed by mental disorders, especially in Africa, and their potential impact on development. This paper reports a population-based epidemiological survey of a rural area in Kenya. A random sample of 2% of all adults living in private households in Maseno, Kisumu District of Nyanza Province, Kenya (50,000 population), were studied. The Clinical Interview Schedule-Revised (CIS-R) was used to determine the prevalence of common mental disorders (CMDs). Associations with socio-demographic and economic characteristics were explored. A CMD prevalence of 10.8% was found, with no gender difference. Higher rates of illness were found in those who were of older age and those in poor physical health. We conclude that CMDs are common in Kenya and rates are elevated among people who are older, and those in poor health.


Lack of interaction between ErbB2 and insulin receptor substrate signaling in breast cancer.
ErbB2 Receptor Tyrosine Kinase 2 (ErbB2, HER2/Neu) is amplified in breast cancer and associated with poor prognosis. Growing evidence suggests interplay between ErbB2 and insulin-like growth factor (IGF) signaling. For example, ErbB2 inhibitors can block IGF-induced signaling while, conversely, IGF1R inhibitors can inhibit ErbB2 action. ErbB receptors can bind and phosphorylate insulin receptor substrates (IRS) and this may be critical for ErbB-mediated anti-estrogen resistance in breast cancer. Herein, we examined crosstalk between ErbB2 and IRSs using cancer cell lines and transgenic mouse models. MMTV-ErbB2 and MMTV-IRS2 transgenic mice were crossed to create hemizygous MMTV-ErbB2/MMTV-IRS2 bigenic mice. Signaling crosstalk between ErbB2 and IRSs was examined in vitro by knockdown or overexpression followed by western blot analysis for downstream signaling intermediates and growth assays. A cross between MMTV-ErbB2 and MMTV-IRS2 mice demonstrated no enhancement of ErbB2 mediated mammary tumorigenesis or metastasis by elevated IRS2. Substantiating this, overexpression or knockdown of IRS1 or IRS2 in MMTV-ErbB2 mammary cancer cell lines had little effect upon ErbB2 signaling. Similar results were obtained in human mammary epithelial cells (MCF10A) and breast cancer cell lines. Despite previous evidence suggesting that ErbB receptors can bind and activate IRSs, our findings indicate that ErbB2 does not cooperate with the IRS pathway in these models to promote mammary tumorigenesis.


Simultaneous epicardial and endocardial activation sequence mapping in the isolated canine right atrium.
Since the atria are thin-walled structures, most studies that have examined the spread of activation in the atria have assumed that they behave electrophysiologically as a two-dimensional surface. It was the objective of this study to determine whether or not this assumption is true by simultaneously mapping the epicardial and endocardial activation sequences in the right atrium. Identical precisely superpositioned epicardial and endocardial electrode templates with 250 unipolar electrodes each were used to map the isolated canine right atrium (n = 8) during continuous perfusion and superfusion with Krebs-Henseleit buffer. Data were recorded during control conditions (normal sinus rhythm), continuous pacing (S1S1 = 300 msec), and premature stimulation (S1S2 = effective refractory period + 5 msec). Pacing was performed at two sites, one located on the inferior crista terminalis and one lateral to the crista terminalis on a pectinate muscle. Tachyarrhythmias were induced by a single extrastimulus during the continuous perfusion of acetylcholine (10(-3.5) mol/L). Individual electrode sites were correlated with the gross anatomy and histology. Activation time differences were calculated between each two corresponding epicardial and endocardial sites. There were differences in the activation times between the epicardium and endocardium during all experimental conditions. However, the average difference for each condition was < 1 msec, suggesting that overall activation did not spread faster on either the epicardium or the endocardium, even though in certain regions one surface could lead the other. The dispersion of time differences was smallest during normal sinus rhythm and continuous pacing (SD = 5.6-5.8 msec) and largest after premature stimulation (SD = 6.3 msec for crista pacing, p < 0.05; SD = 8.1 msec for pacing lateral to the crista, p < 0.001). Differences in the activation sequence correlated with the underlying anatomic architecture. The largest differences in activation times between the epicardium and endocardium were associated with those regions of the atrium where pectinate muscles ran below the epicardial surface. The pectinate muscles in those areas were often discontinuous with the epicardial surface and facilitated the discordant epicardial-endocardial activation. The discordant activation was also found in regions where the atrial wall thickness was < 0.5 mm and correlated with transmural differences in fiber orientation. A tachyarrhythmia induced in the presence of acetylcholine, which demonstrated a focal activation pattern, was shown to have a reentrant loop that used free-running muscle bundles connecting the epicardial and endocardial surfaces, resulting in a three-dimensional pathway. The findings of this study demonstrate that epicardial and endocardial activation can be discordant in specific regions and that discordance increases with abnormal activation sequences. Many of the differences in the epicardial and endocardial activation can be correlated with the heterogeneity of the anatomic architecture of the right atrium. The study also demonstrates that reentry can occur in a three-dimensional plane using the epicardial and endocardial surfaces connected by transmural muscle fibers.


A review of anti-hypertension therapies in diabetic patients.
The objective of this study was to review published articles on the issues surrounding tight blood pressure control in hypertensive diabetics. Relevant medical subject headings (MeSH) terms and keywords to review scientific literatures were developed. These MeSH terms were used to generate MEDLINE searches that focused on English-language, peer-reviewed scientific literature. In reviewing the exceptionally large body of research literature in anti-hypertension therapies in diabetic patients , the review focused on outcomes of importance to patients and effects of sufficient magnitude to warrant changes in medical practice ("patient oriented evidence that matters" [POEMs]). Patient-oriented outcomes include not only mortality but also other outcomes that affect patients' lives and well-being. Studies of physiological end points (diseaseoriented evidence [DOEs]) were used to address questions where POEMs were not available Treatment of hypertension in diabetic patients provides dramatic beneficial outcomes. Target diastolic BP of < 80 mmHg appears optimal; and systolic targets of 130 mmHg or less are also reasonable. Studies that compare drug classes do not suggest obviously superior agents. However, it is reasonable to conclude that ACEIs, thiazide diuretics and angiotension II receptor blockers may be the preferred first-line agents for treatment of hypertension in diabetes. ACEIs, ARBs and low dose thiazide diuretics may be the first line treatments although other agents are usually necessary and goals may not be achieved even with three or four agents. Aggressive blood pressure control may be the most important factor in preventing adverse outcomes in hypertensive patients with diabetes.


Adolescent suicide prevention: acceptability of school-based programs among secondary school principals.
High school principals' acceptability ratings of three school-based programs for the prevention of adolescent suicide were examined. From a random sample of members from the 1994-1995 membership directory of the National Association of Secondary School Principals (NASSP), a total of 185 (40%) respondents completed the Suicide Prevention Program Rating Profile (SPPRP), a measure designed to evaluate the acceptability of suicide prevention programs, after reading a description of a particular prevention program. Programs evaluated for their acceptability included (1) curriculum-based programs presented to students, (2) in-service presentations to school staff, and (3) student self-report screening measures. The results indicated that the curriculum-based and staff in-service programs were significantly more acceptable to principals than was the schoolwide student screening program. No significant differences between the acceptability of curriculum-based and inservice programs were found. Limitations of the study and implications for practice and research are discussed.


The effects of intelligence and education on the development of dementia. A test of the brain reserve hypothesis.
A number of recent epidemiological studies have shown that the prevalence and incidence of dementia are increased in population strata with low compared to high levels of education. This has been explained as a consequence of a greater 'brain reserve capacity' in people with a high level of education. Theoretically, however, brain reserve capacity is better reflected by intelligence than by level of education. Thus, the emergence of dementia will be better predicted by low pre-morbid intelligence than by low education. This prediction was tested in a population based sample of elderly subjects (N = 2063; age range 65-84; Amsterdam Study of the Elderly) who were followed over 4 years. Dementia was diagnosed using the Geriatric Mental State examination (GMS). Pre-morbid intelligence was measured using the Dutch Adult Reading Test (DART), a short reading test which gives a good estimate of verbal intelligence, and is relatively insensitive to brain dysfunction. The effects of age, gender, occupational level, number of diseases affecting the central nervous system and family history of dementia or extreme forgetfulness were also examined. Logistic regression analysis showed that low DART-IQ predicted incident dementia better than low level of education. A high occupational level (having been in charge of subordinates) had a protective effect. This result supports the brain reserve theory. It also indicates that low pre-morbid intelligence is an important risk factor for cognitive decline and dementia. Use of reading ability tests is to be preferred over years of education as estimator of pre-morbid cognitive level in (epidemiological) dementia research.


Clinical diagnosis and surgical management of diaphragmatic retroperitoneal perirenal fat and kidney herniation in a pet rabbit.
CASE DESCRIPTION A 6-year-old 2.08-kg (4.58-lb) neutered male Lionhead-mix pet rabbit (Oryctolagus cuniculus) was examined because of sneezing and increased respiratory effort. CLINICAL FINDINGS On the basis of the rabbit's radiographic findings, a diagnosis of diaphragmatic retroperitoneal perirenal fat and kidney herniation was made. Nine months later, physical examination revealed increased respiratory rate and effort and slightly decreased body weight. Thoracic radiography revealed decreased lung aeration and further craniomedial displacement of the right kidney, compared with the initial evaluation findings, suggesting progressive herniation of the retroperitoneal perirenal fat. TREATMENT AND OUTCOME During exploratory celiotomy, a tear in the right dorsal tendinous portion of the diaphragm was noted. The right kidney and perirenal fat were found to be displaced into the thorax. Diaphragmatic herniorrhaphy was performed after replacement of the right kidney and the perirenal fat in the retroperitoneal space. The rabbit recovered uneventfully from anesthesia and surgery. Clinical signs did not recur during the following 16 months. CLINICAL RELEVANCE For rabbits with increased respiratory effort, diaphragmatic retroperitoneal perirenal fat and kidney herniation should be included as a differential diagnosis. As illustrated by the case described in this report, appropriate surgical management can provide a successful outcome for affected pet rabbits.


Long-Term Impact of a Postdischarge Community Health Worker Intervention on Health Care Costs in a Safety-Net System.
Patient navigators (PNs) may represent a cost-effective strategy to improve transitional care and reduce hospital readmissions. We evaluated the impact of a PN intervention on health system costs in the 180 days after discharge for high-risk patients in a safety-net system. Primary and secondary data from an academic safety-net health system. We compared per-patient utilization and costs, overall and by age, for high-risk, medical service patients randomized to the PN intervention relative to usual care between October 2011 and April 2013. Intervention patients received hospital visits and telephone outreach from PNs for 30 days after every qualifying discharge. We used administrative and electronic encounter data, and a survey of nurses; costs were imputed from the Medicare fee schedule. Total costs per patient over the 180 days postindex discharge for those aged ≥60 years were significantly lower for PN patients compared to controls ($5,676 vs. $7,640, p = .03); differences for patients aged <60 ($9,942 vs. $9,046, p = .58) or for the entire cohort ($7,092 vs. $7,953, p = .27) were not significant. Patient navigator interventions may be useful strategies for specific groups of patients in safety-net systems to improve transitional care while containing costs.


PCR melting profile (PCR MP)--a new tool for differentiation of Candida albicans strains.
We have previously reported the use of PCR Melting Profile (PCR MP) technique based on using low denaturation temperatures during ligation mediated PCR (LM PCR) for bacterial strain differentiation. The aim of the current study was to evaluate this method for intra-species differentiation of Candida albicans strains. In total 123 Candida albicans strains (including 7 reference, 11 clinical unrelated, and 105 isolates from patients of two hospitals in Poland) were examined using three genotyping methods: PCR MP, macrorestriction analysis of the chromosomal DNA by pulsed-field gel electrophoresis (REA-PFGE) and RAPD techniques. The genotyping results of the PCR MP were compared with results from REA-PFGE and RAPD techniques giving 27, 26 and 25 unique types, respectively. The results showed that the PCR MP technique has at least the same discriminatory power as REA-PFGE and RAPD. Data presented here show for the first time the evaluation of PCR MP technique for candidial strains differentiation and we propose that this can be used as a relatively simple and cheap technique for epidemiological studies in short period of time in hospital.


Small molecule reaction networks that model the ROS dynamics of the rhizosphere.
Spontaneous reactions between plant and bacterial redox active metabolites can result in reaction-diffusion networks that regulate redox gradients and ROS concentrations. Our model system mimics known biological processes observed in plants, including the oxidative burst, travelling waves, and chemical pattern formation. Similar non-enzymatic reactions between natural products may play a role in plant-bacteria interactions, including biofilm and microbiome regulation, and be useful for the development of narrow range antibiotics.


Peak visual gamma frequency is modified across the healthy menstrual cycle.
Fluctuations in gonadal hormones over the course of the menstrual cycle are known to cause functional brain changes and are thought to modulate changes in the balance of cortical excitation and inhibition. Animal research has shown this occurs primarily via the major metabolite of progesterone, allopregnanolone, and its action as a positive allosteric modulator of the GABAA receptor. Our study used EEG to record gamma oscillations induced in the visual cortex using stationary and moving gratings. Recordings took place during twenty females' mid-luteal phase when progesterone and estradiol are highest, and early follicular phase when progesterone and estradiol are lowest. Significantly higher (∼5 Hz) gamma frequency was recorded during the luteal compared to the follicular phase for both stimuli types. Using dynamic causal modeling, these changes were linked to stronger self-inhibition of superficial pyramidal cells in the luteal compared to the follicular phase. In addition, the connection from inhibitory interneurons to deep pyramidal cells was found to be stronger in the follicular compared to the luteal phase. These findings show that complex functional changes in synaptic microcircuitry occur across the menstrual cycle and that menstrual cycle phase should be taken into consideration when including female participants in research into gamma-band oscillations.


Observing individual fish behavior in fish aggregations: tracking in dense fish aggregations using a split-beam echosounder.
Acoustic instruments are important tools for observing the behavior of aquatic organisms. This paper presents a simple but efficient method for improving the tracking of closely spaced targets using a split-beam echosounder. The traditional method has been a stepwise approach from the detection of echoes, rejection of apparently multiple targets and then tracking the remainder. This is inefficient because the split-beam angles are not included in the initial detection; rather they are only used in the rejection criteria before the subsequent tracking. A simple track-before-detection method is presented, where the phase angles, echo intensities, ranges, and times are used simultaneously, resulting in better detection and tracking of the individual fish. Two test data sets were analyzed to determine the effectiveness of this method at discriminating individual tracks from within dense fish aggregations. The first data set was collected by lowering a split-beam transducer into a herring layer. The second data set, also collected with a split-beam transducer, was from a caged aggregation of feeding herring larvae. Results indicate the potential of target tracking, using a split-beam echosounder, as a tool for understanding interindividual behavior.


E1B 55-kilodalton-associated protein: a cellular protein with RNA-binding activity implicated in nucleocytoplasmic transport of adenovirus and cellular mRNAs.
The adenovirus type 5 (Ad5) early 1B 55-kDa protein (E1B-55kDa) is a multifunctional phosphoprotein that regulates viral DNA replication and nucleocytoplasmic RNA transport in lytically infected cells. In addition, E1B-55kDa provides functions required for complete oncogenic transformation of rodent cells in cooperation with the E1A proteins. Using the far-Western technique, we have isolated human genes encoding E1B-55kDa-associated proteins (E1B-APs). The E1B-AP5 gene encodes a novel nuclear RNA-binding protein of the heterogeneous nuclear ribonucleoprotein (hnRNP) family that is highly related to hnRNP-U/SAF-A. Immunoprecipitation experiments indicate that two distinct segments in the 55-kDa polypeptide which partly overlap regions responsible for p53 binding are required for complex formation with E1B-AP5 in Ad-infected cells and that this protein interaction is modulated by the adenovirus E4orf6 protein. Expression of E1B-AP5 efficiently interferes with Ad5 E1A/E1B-mediated transformation of primary rat cells. Furthermore, stable expression of E1B-AP5 in Ad-infected cells overcomes the E1B-dependent inhibition of cytoplasmic host mRNA accumulation. These data suggest that E1B-AP5 might play a role in RNA transport and that this function is modulated by E1B-55kDa in Ad-infected cells.