Integration of Social Information by Human Groups.
We consider a situation in which individuals search for accurate decisions without direct feedback on their accuracy, but with information about the decisions made by peers in their group. The "wisdom of crowds" hypothesis states that the average judgment of many individuals can give a good estimate of, for example, the outcomes of sporting events and the answers to trivia questions. Two conditions for the application of wisdom of crowds are that estimates should be independent and unbiased. Here, we study how individuals integrate social information when answering trivia questions with answers that range between 0% and 100% (e.g., "What percentage of Americans are left-handed?"). We find that, consistent with the wisdom of crowds hypothesis, average performance improves with group size. However, individuals show a consistent bias to produce estimates that are insufficiently extreme. We find that social information provides significant, albeit small, improvement to group performance. Outliers with answers far from the correct answer move toward the position of the group mean. Given that these outliers also tend to be nearer to 50% than do the answers of other group members, this move creates group polarization away from 50%. By looking at individual performance over different questions we find that some people are more likely to be affected by social influence than others. There is also evidence that people differ in their competence in answering questions, but lack of competence is not significantly correlated with willingness to change guesses. We develop a mathematical model based on these results that postulates a cognitive process in which people first decide whether to take into account peer guesses, and if so, to move in the direction of these guesses. The size of the move is proportional to the distance between their own guess and the average guess of the group. This model closely approximates the distribution of guess movements and shows how outlying incorrect opinions can be systematically removed from a group resulting, in some situations, in improved group performance. However, improvement is only predicted for cases in which the initial guesses of individuals in the group are biased.


Mono-BHT heteroleptic magnesium complexes: synthesis, molecular structure and catalytic behavior in the ring-opening polymerization of cyclic esters.
Numerous heteroleptic 2,6-di-tert-butyl-4-methylphenolate (BHT) magnesium complexes have been synthesized by treatment of (BHT)MgBu(THF)2 with various alcohols. Molecular structures of the complexes have been determined by X-ray diffraction. The magnesium coordination number in [(BHT)Mg(μ-OBn)(THF)]2 (3) and [(BHT)Mg(μ-O-tert-BuC6H4)(THF)]2 (4) is equal to 4. Complexes formed from esters of glycolic and lactic acids, [(BHT)Mg(μ-OCH2COOEt)(THF)]2 (5) and [(BHT)Mg(μ-OCH(CH3)COOCH2COOtBu)(THF)]2 (6) contain chelate fragments with pentacoordinated magnesium. Compounds 3-6 contain THF molecules coordinated to magnesium atoms. Complex {(BHT)Mg[μ-O(CH2)3CON(CH3)2]}2 (7) does not demonstrate any tendency to form an adduct with THF. It has been experimentally determined that complexes 3 and 5 are highly active catalysts of lactide polymerization. The activity of 4 is rather low, and complex 7 demonstrates moderate productivity. According to DOSY NMR experiments, compounds 3 and 5 retain their dimeric structures even in THF. The free energies of model dimeric [(DBP)Mg(μ-OMe)(Sub)]2 and monomeric (DBP)Mg(OMe)(Sub)2 products on treatment of [(DBP)Mg(μ-OMe)(THF)]2 with a series of σ-electron donors (Sub) have been estimated by DFT calculations. These results demonstrate that the substitution of THF by Sub in a dimeric molecule is an energetically allowed process, whereas the dissociation of dimers is energetically unfavorable. DFT modeling of ε-CL and (dl)-lactide ROP catalyzed by dimeric and monomeric complexes showed that a cooperative effect of two magnesium atoms occurs within the ROP for binuclear catalytic species. A comparison of the reaction profiles for ROP catalyzed by binuclear and mononuclear species allowed us to conclude that the binuclear mechanism is favorable in early stages of ROP initiated by dimers 3 and 5.


Oligodendrocytes as regulators of neuronal networks during early postnatal development.
Oligodendrocytes are the glial cells responsible for myelin formation. Myelination occurs during the first postnatal weeks and, in rodents, is completed during the third week after birth. Myelin ensures the fast conduction of the nerve impulse; in the adult, myelin proteins have an inhibitory role on axon growth and regeneration after injury. During brain development, oligodendrocytes precursors originating in multiple locations along the antero-posterior axis actively proliferate and migrate to colonize the whole brain. Whether the initial interactions between oligodendrocytes and neurons might play a functional role before the onset of myelination is still not completely elucidated. In this article, we addressed this question by transgenically targeted ablation of proliferating oligodendrocytes during cerebellum development. Interestingly, we show that depletion of oligodendrocytes at postnatal day 1 (P1) profoundly affects the establishment of cerebellar circuitries. We observed an impressive deregulation in the expression of molecules involved in axon growth, guidance and synaptic plasticity. These effects were accompanied by an outstanding increase of neurofilament staining observed 4 hours after the beginning of the ablation protocol, likely dependent from sprouting of cerebellar fibers. Oligodendrocyte ablation modifies localization and function of ionotropic glutamate receptors in Purkinje neurons. These results show a novel oligodendrocyte function expressed during early postnatal brain development, where these cells participate in the formation of cerebellar circuitries, and influence its development.


A genomic approach to inferring kinship reveals limited intergenerational dispersal in the yellow fever mosquito.
Understanding past dispersal and breeding events can provide insight into ecology and evolution and can help inform strategies for conservation and the control of pest species. However, parent-offspring dispersal can be difficult to investigate in rare species and in small pest species such as mosquitoes. Here, we develop a methodology for estimating parent-offspring dispersal from the spatial distribution of close kin, using pairwise kinship estimates derived from genome-wide single nucleotide polymorphisms (SNPs). SNPs were scored in 162 Aedes aegypti (yellow fever mosquito) collected from eight close-set, high-rise apartment buildings in an area of Malaysia with high dengue incidence. We used the SNPs to reconstruct kinship groups across three orders of kinship. We transformed the geographical distances between all kin pairs within each kinship category into axial standard deviations of these distances, then decomposed these into components representing past dispersal events. From these components, we isolated the axial standard deviation of parent-offspring dispersal and estimated neighbourhood area (129 m), median parent-offspring dispersal distance (75 m) and oviposition dispersal radius within a gonotrophic cycle (36 m). We also analysed genetic structure using distance-based redundancy analysis and linear regression, finding isolation by distance both within and between buildings and estimating neighbourhood size at 268 individuals. These findings indicate the scale required to suppress local outbreaks of arboviral disease and to target releases of modified mosquitoes for mosquito and disease control. Our methodology is readily implementable for studies of other species, including pests and species of conservation significance.


A One-Year Prospective Study of Work-Related Mental Health in the Intensivists of a COVID-19 Hub Hospital.
The COVID-19 pandemic has severely tested the physical and mental health of health care workers (HCWs). The various stages of the epidemic have posed different problems; consequently, only a prospective study can effectively describe the changes in the workers' health. This repeated cross-sectional study is based on a one-year investigation (spring 2020 to spring 2021) of intensive care physicians in one of the two COVID-19 hub hospitals in Central Italy and aims to study the evolution of the mental health status of intensivists during the pandemic. Changes in their work activity due to the pandemic were studied anonymously together with their perception of organisational justice, occupational stress, sleep quality, anxiety, depression, burnout, job satisfaction, happiness, and intention to quit. In May-June 2021, one year after the baseline, doctors reported an increased workload, isolation at work and in their social life, a lack of time for physical activity and meditation, and compassion fatigue. Stress was inversely associated with the perception of justice in safety procedures and directly correlated with work isolation. Occupational stress was significantly associated with anxiety, depression, burnout, dissatisfaction, and their intention to quit. Procedural justice was significantly associated with happiness. Doctors believed vaccinations would help control the problem; however, this positive attitude had not yet resulted in improved mental health. Doctors reported high levels of distress (73%), sleep problems (28%), anxiety (25%), and depression (64%). Interventions to correct the situation are urgently needed.


Peripheral Nerve Sheath Tumors of the Eyelid Dermis: A Clinicopathologic and Immunohistochemical Analysis.
To determine the incidences, clinical features, and detailed histopathologic and immunohistochemical findings of 10 peripheral nerve tumors (isolated neurofibromas, solitary circumscribed neuromas [SCNs], and schwannomas) localized to the eyelid dermis. In this retrospective clinicopathologic study, clinical records and paraffin sections subjected to hematoxylin and eosin, Masson trichrome, periodic acid-Schiff, reticulin, and Alcian blue staining were critically reviewed from each case. Additional paraffin sections were immunoreacted for S100, neurofilament, CD34, epithelial membrane antigen (EMA), glucose transporter-1 (glut-1), and calretinin. Ten patients with a median age of 57 years had solitary, small, flesh-colored papules, 70% at the eyelid margin. Microscopically, they were diagnosed either as a SCN or an isolated neurofibroma. SCN was diffusely S100-positive (and sometimes diffusely calretinin-positive) with myriad neurofilaments. Fascicles of cells were separated by CD34-positive septa, and the lesions were surrounded by a glut-1/EMA-positive capsule. Neurofibromas were calretinin-negative and had a moderate number of S100-positive cells, with widely scattered neurofilaments, many CD34-postive intermixed cells, and no capsule. No schwannomas were diagnosed. Peripheral nerve tumors of the eyelid have a distinct clinical presentation at the eyelid margin. Careful histopathologic and immunohistochemical studies can reliably separate the entities in the categories of isolated neurofibroma, SCN, and schwannoma when the last occurs. These distinctions can have important systemic implications.


Update on ventricular assist device technology.
Ventricular assist devices are an important component in the arsenal of therapies to support the failing heart. This article provides an update on the variety of pulsatile, centrifugal, and axial-flow devices available in the United States. Common indications such as Bridge to Recovery and Bridge to Transplant are explored, as are the emerging indications Destination Therapy, Bridge to Decision, and Bridge to Bridge. Ventricular assist devices as support during high-risk percutaneous coronary intervention and the devices that can be rapidly deployed for this support are included. Clinical aspects of patient care including common complications, psychosocial concerns, and ethical considerations are reviewed.


Comparative clinical pharmacology of short-acting mu opioids in drug abusers.
The clinical pharmacology of fentanyl and alfentanil was examined in opioid-experienced volunteers with agonist and antagonist sensitivity measures. Two studies used within-subject, placebo-controlled, crossover designs. In study 1, fentanyl (0.125, 0.25 mg/70 kg i.v.) was followed at 0, 20, 60 and 180 min by naloxone (10 mg/70 kg i.m.). Agonist effects during 180-min and 0-min (control; simultaneous fentanyl-naloxone i.v. infusion) challenge sessions were compared. Fentanyl rapidly constricted pupils, depressed respiration and produced subjective "high" and opiate symptoms lasting 60 to 120 min, depending on the measure. Naloxone precipitated withdrawal symptoms of comparable intensity at each challenge point. In study 2, fentanyl (0.125, 0.25 mg/70 kg i.v.), alfentanil (1, 2 mg/70 kg i.v.) and saline were followed at 1 and 6 hr by naloxone (10 mg/70 kg i.m.). Agonist effects were examined during 6-hr challenge sessions. The two drugs produced a comparable range of effects with similar peak magnitude for 0.125 mg/70 kg fentanyl and 1 mg/70 kg alfentanil and for 0.25 mg/70 kg fentanyl and 2 mg/70 kg alfentanil. Alfentanil's duration of action was brief ( < 60 min). Withdrawal was precipitated at 6 hr only after 0.25 mg/70 kg fentanyl. These findings support typical mu opioid characteristics (pleasurable subjective effects, physical dependence) for both drugs, differential duration of action (fentanyl > alfentanil) and peak effects consistent with a 1:8 (fentanyl/alfentanil) potency ratio.


Arabidopsis tubulin folding cofactor B interacts with alpha-tubulin in vivo.
Microtubule biogenesis requires alphabeta tubulin dimers that are generated from alpha and beta tubulin following post-translational modification by several tubulin folding cofactors (TFCs). Here we report the isolation and characterization of Arabidopsis TFCB (AtTFCB). AtTFCB is expressed in all organs of Arabidopsis. The subcellular localization of AtTFCB is mainly cytosolic. AtTFCB-overexpressing cells have fewer microtubules compared with the controls. Multimode fluorescence resonance energy transfer (FRET) microscopy reveals a direct physical interaction of AtTFCB with alpha tubulin in living plant cells. We conclude that AtTFCB interacts with alpha tubulin in vivo and its overexpression reduces the number of microtubules.


Secondary electrospray ionization-mass spectrometry and a novel statistical bioinformatic approach identifies a cancer-related profile in exhaled breath of breast cancer patients: a pilot study.
Breath analysis represents a new frontier in medical diagnosis and a powerful tool for cancer biomarker discovery due to the recent development of analytical platforms for the detection and identification of human exhaled volatile compounds. Statistical and bioinformatic tools may represent an effective complement to the technical and instrumental enhancements needed to fully exploit clinical applications of breath analysis. Our exploratory study in a cohort of 14 breast cancer patients and 11 healthy volunteers used secondary electrospray ionization-mass spectrometry (SESI-MS) to detect a cancer-related volatile profile. SESI-MS full-scan spectra were acquired in a range of 40-350 mass-to-charge ratio (m/z), converted to matrix data and analyzed using a procedure integrating data pre-processing for quality control, and a two-step class prediction based on machine-learning techniques, including a robust feature selection, and a classifier development with internal validation. MS spectra from exhaled breath showed an individual-specific breath profile and high reciprocal homogeneity among samples, with strong agreement among technical replicates, suggesting a robust responsiveness of SESI-MS. Supervised analysis of breath data identified a support vector machine (SVM) model including 8 features corresponding to m/z 106, 126, 147, 78, 148, 52, 128, 315 and able to discriminate exhaled breath from breast cancer patients from that of healthy individuals, with sensitivity and specificity above 0.9.Our data highlight the significance of SESI-MS as an analytical technique for clinical studies of breath analysis and provide evidence that our noninvasive strategy detects volatile signatures that may support existing technologies to diagnose breast cancer.


Application of magnetohydrodynamic actuation to continuous flow chemistry.
Continuous flow microreactors with an annular microchannel for cyclical chemical reactions were fabricated by either bulk micromachining in silicon or by rapid prototyping using EPON SU-8. Fluid propulsion in these unusual microchannels was achieved using AC magnetohydrodynamic (MHD) actuation. This integrated micropumping mechanism obviates the use of moving parts by acting locally on the electrolyte, exploiting its inherent conductive nature. Both silicon and SU-8 microreactors were capable of MHD actuation, attaining fluid velocities of the order of 300 microm s(-1) when using a 500 mM KCl electrolyte. The polymerase chain reaction (PCR), a thermocycling process, was chosen as an illustrative example of a cyclical chemistry. Accordingly, temperature zones were provided to enable a thermal cycle during each revolution. With this approach, fluid velocity determines cycle duration. Here, we report device fabrication and performance, a model to accurately describe fluid circulation by MHD actuation, and compatibility issues relating to this approach to chemistry.


Magnetic resonance microscopy of flows and compressions of the circulatory, respiratory, and digestive systems in pupae of the tobacco hornworm, Manduca sexta.
Circulatory, respiratory, and digestive motions in Manduca sexta pupae were observed using proton-density weighted and fast-imaging with steady-state free procession magnetic resonance microscopy. Proton-density weighted images clearly differentiated pupal air sacs from the hemolymph and organs because, as expected, the air sacs appeared dark in these images. Steady-state free procession imaging allowed real-time monitoring of respiration and circulation, creating movies of hemolymph circulation. Some of the movies show compression and inflation of the air sacs as well as abdominal movements consistent with previously reported ceolopulses. To our knowledge, this is the first magnetic resonance microscopy study of insect circulation and respiration and these preliminary results demonstrate the potential of magnetic resonance microscopy for studying in vivo dynamic processes in insects.


Robustness of Synchrony in Complex Networks and Generalized Kirchhoff Indices.
In network theory, a question of prime importance is how to assess network vulnerability in a fast and reliable manner. With this issue in mind, we investigate the response to external perturbations of coupled dynamical systems on complex networks. We find that for specific, nonaveraged perturbations, the response of synchronous states depends on the eigenvalues of the stability matrix of the unperturbed dynamics, as well as on its eigenmodes via their overlap with the perturbation vector. Once averaged over properly defined ensembles of perturbations, the response is given by new graph topological indices, which we introduce as generalized Kirchhoff indices. These findings allow for a fast and reliable method for assessing the specific or average vulnerability of a network against changing operational conditions, faults, or external attacks.


Severe anasarca due to beriberi heart disease and diabetic nephropathy.
A 40-year-old man was transferred to our hospital because of severe anasarca. He was a heavy drinker for more than 20 years, and diagnosed with diabetes mellitus 8 years earlier and treated with retinal photocoagulation 8 months earlier. He reported loss of appetite after divorce 10 months prior to admission. On admission, he presented with systemic edema and dyspnea. Chest radiography showed massive pleural effusion and cardiomegaly. Serum total protein was 5.6 g/dl, albumin 2.6 g/dl, and urinary protein excretion was 5.3 g/day. Glucose tolerance test showed normal pattern. Ultrafiltration and continuous hemofiltration resulted in loss of 40 kg body weight in 5 days. Echocardiography revealed high-output heart failure and blood tests showed low serum thiamine level of 12 ng/ml (normal, >28 ng/ml). Accordingly, the diagnosis was established as beriberi heart disease complicated with nephrotic syndrome. Treatment with 50 mg/day thiamine intravenously and 80 mg/day furosemide resulted in increase in urine output, decrease in cardiac output, resolution of pulmonary effusion, and about 70 kg body weight loss. Percutaneous renal biopsy showed nodular glomerulosclerosis, mesangial matrix expansion, and thickening of glomerular basement membrane (GBM). Immunofluorescence study showed no glomerular deposition of immunoglobulin or complement. Electron microscopy showed GBM thickening and mesangial matrix deposition without electron-dense deposits or fibrils. These findings were compatible with diabetic glomerulosclerosis. In this patient, extreme malnutrition altered glucose tolerance but, on the other hand, nephrotic syndrome associated with diabetic nephropathy made the diagnosis of beriberi heart disease difficult.


Rare loss of function variants in candidate genes and risk of colorectal cancer.
Although ~ 25% of colorectal cancer or polyp (CRC/P) cases show familial aggregation, current germline genetic testing identifies a causal genotype in the 16 major genes associated with high penetrance CRC/P in only 20% of these cases. As there are likely other genes underlying heritable CRC/P, we evaluated the association of variation at novel loci with CRC/P. We evaluated 158 a priori selected candidate genes by comparing the number of rare potentially disruptive variants (PDVs) found in 84 CRC/P cases without an identified CRC/P risk-associated variant and 2440 controls. We repeated this analysis using an additional 73 CRC/P cases. We also compared the frequency of PDVs in select genes among CRC/P cases with two publicly available data sets. We found a significant enrichment of PDVs in cases vs. controls: 20% of cases vs. 11.5% of controls with ≥ 1 PDV (OR = 1.9, p = 0.01) in the original set of cases. Among the second cohort of CRC/P cases, 18% had a PDV, significantly different from 11.5% (p = 0.02). Logistic regression, adjusting for ancestry and multiple testing, indicated association between CRC/P and PDVs in NTHL1 (p = 0.0001), BRCA2 (p = 0.01) and BRIP1 (p = 0.04). However, there was no significant difference in the frequency of PDVs at each of these genes between all 157 CRC/P cases and two publicly available data sets. These results suggest an increased presence of PDVs in CRC/P cases and support further investigation of the association of NTHL1, BRCA2 and BRIP1 variation with CRC/P.


No physiological or biomechanical sex-by-load interactions during treadmill-based load carriage.
This study investigated whether physiological demand or gait mechanics differ between sexes during treadmill load carriage. Female (n = 15) and male (n = 15) military recruit-type participants with no load carriage experience completed three 10-minute walking trials at a self-selected speed with increasing relative body-borne loads (0%, 20%, and 40% body weight). A range of cardiorespiratory, perceptual and biomechanical variables were measured. Self-selected walking speed was similar between sexes (4.6-4.8 km·h-1, p > .05) and there were no significant sex-by-load interactions for any variables. Absolute VO2 and VCO2 were greater in males (difference 175-178 mL·min-1, p < .001), however, when relative to body mass, VO2 was similar between sexes (p > .05). Across all loads, cadence was 7 ± 2 steps·min-1 faster (p = .004) and stance time was 0.06 ± 0.02 s shorter (p = .013) in females. Increasing load resulted in greater physiological demand, cadence, % stance time, and step length (p < .05). Practitioner summary: Literature comparing physiological and biomechanical variables between sexes during load carriage is scarce. Physiological and biomechanical sex differences were limited to relative measures associated with physical size (height and mass). Future research may pool male and female participants when conducting trials up to ten minutes in length. Abbreviations: BW: body weight; COM: centre of mass; HR: heart rate; HRmax: maximum heart rate; RER: respiratory exchange ratio; RPE: rating of perceived exertion; VCO2: volume of carbon dioxide; VE: ventilation; VO2: volume of oxygen; VO2max: maximum volume of oxygen.


Development and validation of a model to predict cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke in patients with type 2 diabetes mellitus and established atherosclerotic cardiovascular disease.
Among individuals with atherosclerotic cardiovascular disease (ASCVD), type 2 diabetes mellitus (T2DM) is common and confers increased risk for morbidity and mortality. Differentiating risk is key to optimize efficiency of treatment selection. Our objective was to develop and validate a model to predict risk of major adverse cardiovascular events (MACE) comprising the first event of cardiovascular death, myocardial infarction (MI), or stroke for individuals with both T2DM and ASCVD. Using data from the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS), we used Cox proportional hazards models to predict MACE among participants with T2DM and ASCVD. All baseline covariates collected in the trial were considered for inclusion, although some were excluded immediately because of large missingness or collinearity. A full model was developed using stepwise selection in each of 25 imputed datasets, and comprised candidate variables selected in 20 of the 25 datasets. A parsimonious model with a maximum of 10 degrees of freedom was created using Cox models with least absolute shrinkage and selection operator (LASSO), where the adjusted R-square was used as criterion for selection. The model was then externally validated among a cohort of participants with similar criteria in the ACCORD (Action to Control Cardiovascular Risk in Diabetes) trial. Discrimination of both models was assessed using Harrell's C-index and model calibration by the Greenwood-Nam-D'Agostino statistic based on 4-year event rates. Overall, 1491 (10.2%) of 14,671 participants in TECOS and 130 (9.3%) in the ACCORD validation cohort (n = 1404) had MACE over 3 years' median follow-up. The final model included 9 characteristics (prior stroke, age, chronic kidney disease, prior MI, sex, heart failure, insulin use, atrial fibrillation, and microvascular complications). The model had moderate discrimination in both the internal and external validation samples (C-index = 0.65 and 0.61, respectively). The model was well calibrated across the risk spectrum-from a cumulative MACE rate of 6% at 4 years in the lowest risk quintile to 26% in the highest risk quintile. Among patients with T2DM and prevalent ASCVD, this 9-factor risk model can quantify the risk of future ASCVD complications and inform decision making for treatments and intensity.


The role of microsurgical varicocelectomy in treating male infertility.
Varicoceles are the most common cause of male infertility. They afflict 15-20% of the general male population and 40% of males with primary infertility. Although multiple treatment modalities exist, including radiographic embolization and laparoscopy, open subinguinal microsurgical varicocelectomy is currently the gold standard of treatment for this condition. In this article, we discuss the role of varicocelectomy in the treatment of the modern infertile male and present a practical, safe, and reproducible technique for the microsurgical approach.


Temporal and spatial alterations in GPi neuronal encoding might contribute to slow down movement in Parkinsonian monkeys.
Although widely investigated, the exact relationship between changes in basal ganglia neuronal activity and parkinsonian symptoms has not yet been deciphered. It has been proposed that bradykinesia (motor slowness) is related either to a modification of the activity of the globus pallidus internalis (GPi), the main output structure, or to a loss of spatial selectivity of the extrapyramidal motor system. Here we investigate the relationship between movement initiation and GPi activity in parkinsonian non-human primates. We compare neuronal encoding of movement in the normal and pathological conditions. After dopamine depletion, we observe an increased number of neurons responding to movement, with a less specific somato-sensory receptive field and a disruption of the selection mechanism. Moreover, the temporal order of the response of GPi neurons in parkinsonian animals is reversed. Indeed, whereas muscle activity and movement are delayed in parkinsonian animals, GPi neuronal responses to movement occur earlier and are prolonged, compared with normal conditions. Parkinsonian bradykinesia could thus result from an impairment of both temporal and spatial specificity of the GPi response to movement.


Individual attachment style modulates human amygdala and striatum activation during social appraisal.
Adult attachment style refers to individual personality traits that strongly influence emotional bonds and reactions to social partners. Behavioral research has shown that adult attachment style reflects profound differences in sensitivity to social signals of support or conflict, but the neural substrates underlying such differences remain unsettled. Using functional magnetic resonance imaging (fMRI), we examined how the three classic prototypes of attachment style (secure, avoidant, anxious) modulate brain responses to facial expressions conveying either positive or negative feedback about task performance (either supportive or hostile) in a social game context. Activation of striatum and ventral tegmental area was enhanced to positive feedback signaled by a smiling face, but this was reduced in participants with avoidant attachment, indicating relative impassiveness to social reward. Conversely, a left amygdala response was evoked by angry faces associated with negative feedback, and correlated positively with anxious attachment, suggesting an increased sensitivity to social punishment. Secure attachment showed mirror effects in striatum and amygdala, but no other specific correlate. These results reveal a critical role for brain systems implicated in reward and threat processing in the biological underpinnings of adult attachment style, and provide new support to psychological models that have postulated two separate affective dimensions to explain these individual differences, centered on the ventral striatum and amygdala circuits, respectively. These findings also demonstrate that brain responses to face expressions are not driven by facial features alone but determined by the personal significance of expressions in current social context. By linking fundamental psychosocial dimensions of adult attachment with brain function, our results do not only corroborate their biological bases but also help understand their impact on behavior.


The use of mechanistic evidence in drug approval.
The role of mechanistic evidence tends to be under-appreciated in current evidence-based medicine (EBM), which focusses on clinical studies, tending to restrict attention to randomized controlled studies (RCTs) when they are available. The EBM+ programme seeks to redress this imbalance, by suggesting methods for evaluating mechanistic studies alongside clinical studies. Drug approval is a problematic case for the view that mechanistic evidence should be taken into account, because RCTs are almost always available. Nevertheless, we argue that mechanistic evidence is central to all the key tasks in the drug approval process: in drug discovery and development; assessing pharmaceutical quality; devising dosage regimens; assessing efficacy, harms, external validity, and cost-effectiveness; evaluating adherence; and extending product licences. We recommend that, when preparing for meetings in which any aspect of drug approval is to be discussed, mechanistic evidence should be systematically analysed and presented to the committee members alongside analyses of clinical studies.


Toxicological risk assessment and prioritization of drinking water relevant contaminants of emerging concern.
Toxicological risk assessment of contaminants of emerging concern (CEC) in (sources of) drinking water is required to identify potential health risks and prioritize chemicals for abatement or monitoring. In such assessments, concentrations of chemicals in drinking water or sources are compared to either (i) health-based (statutory) drinking water guideline values, (ii) provisional guideline values based on recent toxicity data in absence of drinking water guidelines, or (iii) generic drinking water target values in absence of toxicity data. Here, we performed a toxicological risk assessment for 163 CEC that were selected as relevant for drinking water. This relevance was based on their presence in drinking water and/or groundwater and surface water sources in downstream parts of the Rhine and Meuse, in combination with concentration levels and physicochemical properties. Statutory and provisional drinking water guideline values could be derived from publically available toxicological information for 142 of the CEC. Based on measured concentrations it was concluded that the majority of substances do not occur in concentrations which individually pose an appreciable human health risk. A health concern could however not be excluded for vinylchloride, trichloroethene, bromodichloromethane, aniline, phenol, 2-chlorobenzenamine, mevinphos, 1,4-dioxane, and nitrolotriacetic acid. For part of the selected substances, toxicological risk assessment for drinking water could not be performed since either toxicity data (hazard) or drinking water concentrations (exposure) were lacking. In absence of toxicity data, the Threshold of Toxicological Concern (TTC) approach can be applied for screening level risk assessment. The toxicological information on the selected substances was used to evaluate whether drinking water target values based on existing TTC levels are sufficiently protective for drinking water relevant CEC. Generic drinking water target levels of 37 μg/L for Cramer class I substances and 4 μg/L for Cramer class III substances in drinking water were derived based on these CEC. These levels are in line with previously reported generic drinking water target levels based on original TTC values and are shown to be protective for health effects of the majority of contaminants of emerging concern evaluated in the present study. Since the human health impact of many chemicals appearing in the water cycle has been studied insufficiently, generic drinking water target levels are useful for early warning and prioritization of CEC with unknown toxicity in drinking water and its sources for future monitoring.


Validity and reliability of Polar® RS800CX heart rate monitor, measuring heart rate in dogs during standing position and at trot on a treadmill.
The aim of the present study was to assess criterion validity, and relative and absolute reliability of Polar® RS800CX heart rate monitor, compared to simultaneously recorded electrocardiogram (ECG) data, in measuring heart rate of dogs during standing position and at trot on a treadmill. Heart beats from Polar® RS800CX and Cardiostore ECG were recorded simultaneously during seven continuous minutes in standing position and at trot, in 10 adult healthy dogs. Polar® data was statistically compared to ECG data for a variety of mean beats per minute (BPM), standard deviation and confidence interval. Criterion validity was calculated by Pearson product moment correlation method and intraclass correlation coefficient (ICC2.1). Relative and absolute reliability were calculated by ICC2.1, the Bland and Altman analysis and standard error of measurement (SEM and SEM%). The correlation, criterion validity, between Polar® and ECG data in standing position was r=0.99 (p<0.0005) and at trot r=0.97 (p<0.0005). Polar® data was not significantly different from ECG data. Mean difference between ECG and uncorrected Polar® data was -0.6 BPM in standing position and -0.6 BPM at trot. Polar® was over- and underestimating ECG data. SEM and SEM% in standing were ±2.6 BPM and 3.0%, at trot ±3.8 BPM and 3.1%, indicating that measurement errors were low. This study showed that the criterion validity and the instrument reliability were excellent in Polar® RS800CX heart rate measuring system. The equipment seemed to be valid and reliable in measuring BPM in the dogs studied during submaximal cardiovascular conditions such as in standing position and at trot on a treadmill.


The need for a National Service Framework for leg ulcers.
Leg ulcers are common and costly to treat, and the quality of care provided to patients with this condition varies widely across the UK. The introduction of specialized community-based leg ulcer clinics in Gloucestershire has been associated with increased ulcer healing rates and decreased rates of ulcer recurrence, but this model of care has not been widely replicated. One way of ending this 'postcode lottery' is to produce a National Service Framework for leg ulcers, with the aim of delivering high-quality evidence-based care via such clinics under the supervision of local consultant vascular surgeons. Existing National Service Frameworks cover a range of common conditions that are, like leg ulceration, associated with significant morbidity, disability and resource use. These documents aim to raise quality and decrease regional variations in health care across the National Health Service, and leg ulceration fulfils all the necessary criteria for inclusion in a National Service Framework. Centrally defined standards of care for patients with leg ulceration, and the reorganization and restructuring of local services to allow the accurate assessment and treatment of such patients are required. Without a National Service Framework to drive up the quality of care across the country, the treatment of patients with leg ulcers will remain suboptimal for the majority of those who suffer from this common and debilitating condition.


Cellular aging of skeletal muscle: telomeric and free radical evidence that physical inactivity is responsible and not age.
Telomeres play an essential role in maintaining chromosomal integrity in the face of physiological stressors. Although the age-related shortening of TL (telomere length) in highly proliferative tissue is predominantly due to the replication process, the mechanism for telomere shortening in skeletal muscle, which is minimally proliferative, is unclear. By studying TL in both the upper and lower limbs of the young, old-mobile and old-immobile subjects and by virtue of the bipedal nature of human locomotion, which declines with age, it may be possible to elucidate the mechanism(s) responsible for cellular aging of skeletal muscle. With this approach, we revealed that TL (~15 kb) in arm skeletal muscle is unaffected by age. In contrast TL fell progressively in the legs across the young (~15 kb), the old mobile (~13 kb) and old immobile (~11 kb) subjects. Interestingly, there was a reciprocal increase in leg muscle free radicals across these groups that was correlated with TL (r=0.7), with no such relationship in the arm (r=0.09). Our results document that chronological age does not affect the cellular aging of skeletal muscle, but reveals that physical inactivity, probably mediated by free radicals, has a profound effect upon this process.


BLT2 up-regulates interleukin-8 production and promotes the invasiveness of breast cancer cells.
The elevated production of interleukin (IL)-8 is critically associated with invasiveness and metastatic potential in breast cancer cells. However, the intracellular signaling pathway responsible for up-regulation of IL-8 production in breast cancer cells has remained unclear. In this study, we report that the expression of BLT2 is markedly up-regulated in the highly aggressive human breast cancer cell lines MDA-MB-231 and MDA-MB-435 compared with MCF-10A immortalized human mammary epithelial cells, as determined by RT-PCR, real-time PCR and FACS analysis. Blockade of BLT2 with BLT2 siRNA knockdown or BLT2 inhibitor treatment downregulated IL-8 production and thereby diminished the invasiveness of aggressive breast cancer cells, analyzed by Matrigel invasion chamber assays. We further characterized the downstream signaling mechanism by which BLT2 stimulates IL-8 production and identified critical mediatory roles for the generation of reactive oxygen species (ROS) and the consequent activation of the transcription factor NF-κB. Moreover, blockade of BLT2 suppressed the formation of metastatic lung nodules by MDA-MB-231 cells in both experimental and orthotopic metastasis models. Taken together, our study demonstrates that a BLT2-ROS-NF-κB pathway up-regulates IL-8 production in MDA-MB-231 and MDA-MB-435 cells, thereby contributing to the invasiveness of these aggressive breast cancer cells. Our findings provide insight into the molecular mechanism of invasiveness in breast cancer.


Protection against tuberculosis in Eurasian wild boar vaccinated with heat-inactivated Mycobacterium bovis.
Tuberculosis (TB) caused by Mycobacterium bovis and closely related members of the Mycobacterium tuberculosis complex continues to affect humans and animals worldwide and its control requires vaccination of wildlife reservoir species such as Eurasian wild boar (Sus scrofa). Vaccination efforts for TB control in wildlife have been based primarily on oral live BCG formulations. However, this is the first report of the use of oral inactivated vaccines for controlling TB in wildlife. In this study, four groups of 5 wild boar each were vaccinated with inactivated M. bovis by the oral and intramuscular routes, vaccinated with oral BCG or left unvaccinated as controls. All groups were later challenged with a field strain of M. bovis. The results of the IFN-gamma response, serum antibody levels, M. bovis culture, TB lesion scores, and the expression of C3 and MUT genes were compared between these four groups. The results suggested that vaccination with heat-inactivated M. bovis or BCG protect wild boar from TB. These results also encouraged testing combinations of BCG and inactivated M. bovis to vaccinate wild boar against TB. Vaccine formulations using heat-inactivated M. bovis for TB control in wildlife would have the advantage of being environmentally safe and more stable under field conditions when compared to live BCG vaccines. The antibody response and MUT expression levels can help differentiating between vaccinated and infected wild boar and as correlates of protective response in vaccinated animals. These results suggest that vaccine studies in free-living wild boar are now possible to reveal the full potential of protecting against TB using oral M. bovis inactivated and BCG vaccines.


A Multiplex PCR for the Detection of Phytophthora nicotianae and P. cactorum, and a Survey of Their Occurrence in Strawberry Production Areas of Japan.
We aimed to simultaneously detect two pathogens causing strawberry diseases, Phytophthora nicotianae and P. cactorum, by multiplex polymerase chain reaction (PCR), and to survey their occurrence in the main strawberry production areas of Japan. Due to the need to combine different primer pairs for multiplex PCR and the low specificity of published specific primers for P. nicotianae and P. cactorum, new species-specific primers for P. nicotianae and P. cactorum were designed based on the internal transcribed spacer regions of ribosomal DNA and the ras-related protein gene Ypt1, respectively. Specificity of the designed primers was demonstrated using 68 isolates, including Phytophthora spp., Pythium spp., and other soilborne pathogens. Multiplex PCR discriminated between P. nicotianae and P. cactorum in DNA mixtures of mycelia of the two species. Moreover, both species were detected in artificially and naturally infested soils, indicating that these markers can be used in diagnosis of strawberry diseases. For investigation of the geographic distribution of the two pathogens in Japan, soil samples were collected in 89 strawberry fields from eight prefectures (Gifu, Saga, Nara, Tochigi, Chiba, Shizuoka, Yamanashi, and Hokkaido) of Japan. The method that was developed was successfully applied to survey P. nicotianae and P. cactorum, and distribution of the two pathogens in strawberry plantings in Japan was determined.


The thyroxine-binding properties of serum proteins. A competitive binding technique employing sephadex G-25.
A competitive binding technique is described for the estimation of the thyroxine (T4)-binding properties of serum proteins in dilute blood serum and lymph. When used in conjunction with an assay for total T4 the following parameters can be estimated: the number of functionally different T4 binding proteins, their individual association constants and binding capacities for T4, the amount of T4 which is bound to each binding species, and the concentration of unbound (free) T4. Both human and sheep serum have three functionally different T4-binding proteins. The association constants for the three human proteins were 9.5x10(9), 1.6x10(8) and 3.1x10(5) 1/mol for T4-binding globulin (TBG), T4-binding prealbumin (TBPA) and serum albumin, respectively. The corresponding sheep proteins, TBG, TBP-2 and albumin, had association constants of 8.9x10(9), 1-4 X 10(8) and 3.5x10(5) 1/mol. Human TBG had a mean binding capacity of 21.3 mug/100 ml and that of ovie TBG was 12.8 mug/100 ml. The other specific binding proteins (TBPA in man and TBP-2 in sheep) had mean binding capacities of 307 and 359 mug/100 ml respectively. Two functionally different T4-binding proteins were identified in rat serum.


Application of a new image analysis technique to study brain asymmetry in schizophrenia.
The hypothesis that normal brain torque (i.e. rightward frontal and leftward occipital asymmetry) is anomalous in schizophrenia (Crow, 1997. Trends in Neuroscience, 20, 339-343) was tested by application of a novel image analysis technique on three-dimensional magnetic resonance images obtained in 26 adult patients with chronic schizophrenia (18 males, 8 females) and 24 controls (14 males, 10 females). Right and left cerebral hemisphere tissue was extracted via non-linear co-registration with a mask image, and maps were computed of inter-hemispheric differences in tissue volume in an array of columns of voxels orthogonal to the mid-plane (2D), and profiles of coronal slice volumes (1D). Furthermore, integration of two-dimensional column maps gave approximate lobar asymmetries, and occipital and frontal asymmetries were combined to give a volumetric measure of brain torque. Significant brain torque was revealed in male and female control and patient groups, and did not correlate with brain size. Frontal and occipital asymmetries were significantly correlated in all groups. Both frontal and occipital components of torque were significantly increased in males than females. Patients tended to have reduced torque, particularly the leftward occipital component. Furthermore, 3/26 patients (but no controls) had reversed torque (leftward frontal and rightward occipital asymmetry). Contrary to Crow's hypothesis, brain torque was not significantly reduced in patients with schizophrenia relative to controls, although reversal of torque was found in three cases. Future studies with larger sample sizes should consider sexual dimorphism and specific symptoms in relation to asymmetry.


Consortium neuroscience of attention deficit/hyperactivity disorder and autism spectrum disorder: The ENIGMA adventure.
Neuroimaging has been extensively used to study brain structure and function in individuals with attention deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) over the past decades. Two of the main shortcomings of the neuroimaging literature of these disorders are the small sample sizes employed and the heterogeneity of methods used. In 2013 and 2014, the ENIGMA-ADHD and ENIGMA-ASD working groups were respectively, founded with a common goal to address these limitations. Here, we provide a narrative review of the thus far completed and still ongoing projects of these working groups. Due to an implicitly hierarchical psychiatric diagnostic classification system, the fields of ADHD and ASD have developed largely in isolation, despite the considerable overlap in the occurrence of the disorders. The collaboration between the ENIGMA-ADHD and -ASD working groups seeks to bring the neuroimaging efforts of the two disorders closer together. The outcomes of case-control studies of subcortical and cortical structures showed that subcortical volumes are similarly affected in ASD and ADHD, albeit with small effect sizes. Cortical analyses identified unique differences in each disorder, but also considerable overlap between the two, specifically in cortical thickness. Ongoing work is examining alternative research questions, such as brain laterality, prediction of case-control status, and anatomical heterogeneity. In brief, great strides have been made toward fulfilling the aims of the ENIGMA collaborations, while new ideas and follow-up analyses continue that include more imaging modalities (diffusion MRI and resting-state functional MRI), collaborations with other large databases, and samples with dual diagnoses.


Pseudoangiomatous stromal hyperplasia of the breast: sonographic features with histopathologic correlation.
The objective of this study was to evaluate the spectrum of sonographic findings in pseudoangiomatous stromal hyperplasia (PASH) of the breast when it presents as a tumoral mass with pathologic correlation. Breast sonogram studies of 13 patients with 13 pathologically proven PASH lesions were retrospectively reviewed. The morphologic characteristics of the lesions as seen on ultrasound were evaluated and correlated with histopathologic findings. Sonography demonstrated most lesions, 11 of 13, to be hypoechoic in echotexture. One lesion was isoechoic in echotexture, also demonstrating small internal cysts, and one was predominantly hyperechoic. Two of the 11 hypoechoic lesions also demonstrated a complex heterogeneous pattern with a central hypoechoic area and a peripheral echogenic rim. All lesions were oval in shape with the long axis of the lesion parallel to the chest wall. None of the lesions demonstrated posterior acoustic shadowing. PASH lesions of the breast have a varied sonographic appearance. Knowledge of the spectrum of morphologic features shown on sonography can be helpful in the diagnosis of this entity.


Muscle size explains low passive skeletal muscle force in heart failure patients.
Alterations in skeletal muscle function and architecture have been linked to the compromised exercise capacity characterizing chronic heart failure (CHF). However, how passive skeletal muscle force is affected in CHF is not clear. Understanding passive force characteristics in CHF can help further elucidate the extent to which altered contractile properties and/or architecture might affect muscle and locomotor function. Therefore, the aim of this study was to investigate passive force in a single muscle for which non-invasive measures of muscle size and estimates of fiber force are possible, the soleus (SOL), both in CHF patients and age- and physical activity-matched control participants. Passive SOL muscle force and size were obtained by means of a novel approach combining experimental data (dynamometry, electromyography, ultrasound imaging) with a musculoskeletal model. We found reduced passive SOL forces (∼30%) (at the same relative levels of muscle stretch) in CHF vs. healthy individuals. This difference was eliminated when force was normalized by physiological cross sectional area, indicating that reduced force output may be most strongly associated with muscle size. Nevertheless, passive force was significantly higher in CHF at a given absolute muscle length (non length-normalized) and likely explained by the shorter muscle slack lengths and optimal muscle lengths measured in CHF compared to the control participants. This later factor may lead to altered performance of the SOL in functional tasks such gait. These findings suggest introducing exercise rehabilitation targeting muscle hypertrophy and, specifically for the calf muscles, exercise that promotes muscle lengthening.


Influence of ANKK1 and DRD2 polymorphisms in response to haloperidol.
The present study explores whether ankyrin repeat and kinase domain containing 1 (ANKK1) and dopamine receptor D2 (DRD2) variants could predict efficacy and tolerability of haloperidol in the treatment of psychotic patients. We also attempted to replicate findings in a group of schizophrenic patients from the Clinical Antipsychotic Trials in Intervention Effectiveness (CATIE) study. Eighty-eight acutely psychotic patients were genotyped for 9 ANKK1 and 27 DRD2 SNPs. Treatment efficacy and tolerability were assessed using the Positive and Negative Symptoms Scale and the Udvalg for Kliniske Undersogelser side effects rating scales, respectively. Multivariate analyses were employed to test possible influences of single-nucleotide polymorphisms on clinical and safety variables. Analysis of haplotypes was also performed. Outcomes in the replication sample were response versus nonresponse and the presence versus absence of motor side effects at 1 month of treatment. rs2242592 within ANKK1 gene and rs1124493 within DRD2 gene were associated with clinical improvement (p = 0.008 and p = 0.001, respectively). Results were confirmed in the allelic analysis. Three haplotype blocks, one among ANKK1 and two among DRD2 gene were associated with better clinical improvement. Our results were not replicated in the CATIE sample, although rs11604671, which is in strong linkage disequilibrium with rs2242592, was associated with response in the replication sample. Our findings support a possible role of ANKK1 and DRD2 variability on haloperidol efficacy. However, due to the discrepancies between the results in the two samples, our results need further validation.


Influence of the central venous site on the transpulmonary thermodilution parameters in critically ill burn patients.
The aim of this study was to verify the measurement concordance of cardiac index (CI), extra-vascular lung water index (EVLWI) and global end diastolic volume index (GEDVI) with transpulmonary thermodilution (TPTD) between the jugular and femoral access with catheters inserted ipsilaterally in critically ill burn patients. Correlations were excellent and the concordance was good for the CI, EVLW and GEDVI (mean bias -0.11 L/min/m², -0.3 mL/kg and -20 mL/m² for CI, EVLW and GEDVI, respectively). We conclude that ipsilateral arterial and venous femoral and jugular measurement of TPTD parameters can be used interchangeably if catheters with different lengths on the femoral site are used.


Craniocerebral aspergillosis in immunocompetent hosts: surgical perspective.
Craniocerebral aspergillosis is a rare but dangerous variety of central nervous system infections. Surgery is being widely recognized as the cornerstone of management. Due to the rarity of the disease, difficulty and delay in diagnosis and poor outcome, there is very little in the literature regarding the various surgical strategies that may be adopted in these patients. Early aggressive surgery followed by chemotherapy offers the best chances. Surgical planning would depend upon the type and location of the disease process as well as the condition of the patient. Perioperative care holds immense importance and knowledge of possible complications is essential. Aspergillosis of the central nervous system is difficult to diagnose and equally difficult to treat. Surgery remains the cornerstone of management followed by systemic antifungal medications. Results are better in immunocompetent patients as compared to those who are immunocompromised.


Teriparatide treatment increases Hounsfield units in the lumbar spine out of proportion to DEXA changes.
The authors sought to assess whether Hounsfield units (HU) increase following teriparatide treatment and to compare HU increases with changes in bone mineral density (BMD) as measured by dual-energy x-ray absorptiometry (DEXA). A retrospective chart review was performed from 1997 to 2018 across all campuses at our institution. The authors identified patients who had been treated with at least 6 months of teriparatide and compared HU and BMD as measured on DEXA scans before and after treatment. Fifty-two patients were identified for analysis (46 women and 6 men, average age 67 years) who underwent an average of 20.9 ± 6.5 months of teriparatide therapy. The mean ± standard deviation HU increase throughout the lumbar spine (L1-4) was from 109.8 ± 53 to 133.9 ± 61 HU (+22%, 95% CI 1.2-46, p value = 0.039). Based on DEXA results, lumbar spine BMD increased from 0.85 to 0.93 g/cm2 (+9%, p value = 0.044). Lumbar spine T-scores improved from -2.4 ± 1.5 to -1.7 ± 1.5 (p value = 0.03). Average femoral neck T-scores improved from -2.5 ± 1.1 to -2.3 ± 1.0 (p value = 0.31). Teriparatide treatment increased both HU and BMD on DEXA in the lumbar spine, without a change in femoral BMD. The 22% improvement in HU surpassed the 9% improvement determined with DEXA. These results support some surgeons' subjective sense that intraoperative bone quality following teriparatide treatment is better than indicated by DEXA results. To the authors' knowledge, this is the first study demonstrating an increase in HU with teriparatide treatment.


Sphingolipids and glycoproteins are differentially trafficked to the Chlamydia trachomatis inclusion.
Chlamydia trachomatis is an obligate intracellular pathogen that multiples within the confines of a membrane-bound vacuole called an inclusion. Approximately 40-50% of the sphingomyelin synthesized from exogenously added NBD-ceramide is specifically transported from the Golgi apparatus to the chlamydial inclusion (Hackstadt, T., M.A. Scidmore, and D.D. Rockey. 1995. Proc. Natl. Acad. Sci. USA. 92: 4877-4881). Given this major disruption of a cellular exocytic pathway and the similarities between glycolipid and glycoprotein exocytosis, we wished to determine whether the processing and trafficking of glycoproteins through the Golgi apparatus to the plasma membrane in chlamydia-infected cells was also disrupted. We analyzed the processing of several model glycoproteins including vesicular stomatitis virus G-protein, transferrin receptor, and human histocompatibility leukocyte class I antigen. In infected cells, the posttranslational processing and trafficking of these specific proteins through the Golgi apparatus and subsequent transport to the plasma membrane was not significantly impaired, nor were these glycoproteins found associated with the chlamydial inclusion membrane. Studies of receptor recycling from endocytic vesicles employing fluorescently and HRP-tagged transferrin and anti-transferrin receptor antibody revealed an increased local concentration of transferrin and transferrin receptor around but never within the chlamydial inclusion. However, Scatchard analysis failed to show either an increased intracellular accumulation of transferrin receptor or a decreased number of plasma membrane receptors in infected cells. Furthermore, the rate of exocytosis from the recycling endosomes to the plasma membrane was not altered in chlamydia-infected cells. Thus, although C. trachomatis disrupts the exocytosis of sphingolipids and the Golgi apparatus appears physically distorted, glycosylation and exocytosis of representative secreted and endocytosed proteins are not disrupted. These results suggest the existence of a previously unrecognized sorting of sphingolipids and glycoproteins in C. trachomatis-infected cells.


Steady-state diffusion-weighted imaging: theory, acquisition and analysis.
Steady-state diffusion-weighted imaging (DWI) has long been recognized to offer potential benefits over conventional spin-echo methods. This family of pulse sequences is highly efficient and compatible with three-dimensional acquisitions, which could enable high-resolution, low-distortion images. However, the same properties that lead to its efficiency make steady-state imaging highly susceptible to motion and create a complicated signal with dependence on T(1), T(2) and flip angle. Recent developments in gradient hardware, motion-mitigation techniques and signal analysis offer potential solutions to these problems, reviving interest in steady-state DWI. This review offers a description of steady-state DWI signal formation and provides an overview of the current methods for steady-state DWI acquisition and analysis.


Breaking of symmetry in graphene growth on metal substrates.
In graphene growth, island symmetry can become lower than the intrinsic symmetries of both graphene and the substrate. First-principles calculations and Monte Carlo modeling explain the shapes observed in our experiments and earlier studies for various metal surface symmetries. For equilibrium shape, edge energy variations δE manifest in distorted hexagons with different ground-state edge structures. In growth or nucleation, energy variation enters exponentially as ∼e(δE/k(B)T), strongly amplifying the symmetry breaking, up to completely changing the shapes to triangular, ribbonlike, or rhombic.


Sequence-specific potent induction of IFN-alpha by short interfering RNA in plasmacytoid dendritic cells through TLR7.
Short interfering RNA (siRNA) is used in RNA interference technology to avoid non-target-related induction of type I interferon (IFN) typical for long double-stranded RNA. Here we show that in plasmacytoid dendritic cells (PDC), an immune cell subset specialized in the detection of viral nucleic acids and production of type I IFN, some siRNA sequences, independent of their GU content, are potent stimuli of IFN-alpha production. Localization of the immunostimulatory motif on the sense strand of a potent IFN-alpha-inducing siRNA allowed dissection of immunostimulation and target silencing. Injection into mice of immunostimulatory siRNA, when complexed with cationic liposomes, induced systemic immune responses in the same range as the TLR9 ligand CpG, including IFN-alpha in serum and activation of T cells and dendritic cells in spleen. Immunostimulation by siRNA was absent in TLR7-deficient mice. Thus sequence-specific TLR7-dependent immune recognition in PDC needs to be considered as an additional biological activity of siRNA, which then should be termed immunostimulatory RNA (isRNA).


A single HIV-1 cluster and a skewed immune homeostasis drive the early spread of HIV among resting CD4+ cell subsets within one month post-infection.
Optimizing therapeutic strategies for an HIV cure requires better understanding the characteristics of early HIV-1 spread among resting CD4+ cells within the first month of primary HIV-1 infection (PHI). We studied the immune distribution, diversity, and inducibility of total HIV-DNA among the following cell subsets: monocytes, peripheral blood activated and resting CD4 T cells, long-lived (naive [TN] and central-memory [TCM]) and short-lived (transitional-memory [TTM] and effector-memory cells [TEM]) resting CD4+T cells from 12 acutely-infected individuals recruited at a median 36 days from infection. Cells were sorted for total HIV-DNA quantification, phylogenetic analysis and inducibility, all studied in relation to activation status and cell signaling. One month post-infection, a single CCR5-restricted viral cluster was massively distributed in all resting CD4+ subsets from 88% subjects, while one subject showed a slight diversity. High levels of total HIV-DNA were measured among TN (median 3.4 log copies/million cells), although 10-fold less (p = 0.0005) than in equally infected TCM (4.5), TTM (4.7) and TEM (4.6) cells. CD3-CD4+ monocytes harbored a low viral burden (median 2.3 log copies/million cells), unlike equally infected resting and activated CD4+ T cells (4.5 log copies/million cells). The skewed repartition of resting CD4 subsets influenced their contribution to the pool of resting infected CD4+T cells, two thirds of which consisted of short-lived TTM and TEM subsets, whereas long-lived TN and TCM subsets contributed the balance. Each resting CD4 subset produced HIV in vitro after stimulation with anti-CD3/anti-CD28+IL-2 with kinetics and magnitude varying according to subset differentiation, while IL-7 preferentially induced virus production from long-lived resting TN cells. In conclusion, within a month of infection, a clonal HIV-1 cluster is massively distributed among resting CD4 T-cell subsets with a flexible inducibility, suggesting that subset activation and skewed immune homeostasis determine the conditions of viral dissemination and early establishment of the HIV reservoir.


Open access: implications for scholarly publishing and medical libraries.
The paper reviews and analyzes the evolution of the open access (OA) publishing movement and its impact on the traditional scholarly publishing model. A literature survey and analysis of definitions of OA, problems with the current publishing model, historical developments, funding agency responses, stakeholder viewpoints, and implications for scientific libraries and publishing are performed. The Internet's transformation of information access has fueled interest in reshaping what many see as a dysfunctional, high-cost system of scholarly publishing. For years, librarians alone advocated for change, until relatively recently when interest in OA and related initiatives spread to the scientific community, governmental groups, funding agencies, publishers, and the general public. Most stakeholders acknowledge that change in the publishing landscape is inevitable, but heated debate continues over what form this transformation will take. The most frequently discussed remedies for the troubled current system are the "green" road (self-archiving articles published in non-OA journals) and the "gold" road (publishing in OA journals). Both movements will likely intensify, with a multiplicity of models and initiatives coexisting for some time.


A personal glimpse of clinical infectious diseases: 1949-1999.
We have witnessed the advent of the antibiotic era and the development of potent immunization agents in the second half of the 20th century. These remarkable scientific tools enable us to treat and control infectious diseases effectively. Yet the development of microbial resistance to antimicrobial agents and the emergence of new or previously unrecognized infectious diseases continue to challenge the medical and public health professionals. Most ominously, the ill-natured terrorists and mistrustful administrators in certain nations have capitalized on the modern microbial technology to create means for bioterrorism and biological warfare. When will humans ever learn?


A hybrid BCI for enhanced control of a telepresence robot.
Motor-disabled end users have successfully driven a telepresence robot in a complex environment using a Brain-Computer Interface (BCI). However, to facilitate the interaction aspect that underpins the notion of telepresence, users must be able to voluntarily and reliably stop the robot at any moment, not just drive from point to point. In this work, we propose to exploit the user's residual muscular activity to provide a fast and reliable control channel, which can start/stop the telepresence robot at any moment. Our preliminary results show that not only does this hybrid approach increase the accuracy, but it also helps to reduce the workload and was the preferred control paradigm of all the participants.


Self-assembled silica-carbonate structures and detection of ancient microfossils.
We have synthesized inorganic micron-sized filaments, whose microstucture consists of silica-coated nanometer-sized carbonate crystals, arranged with strong orientational order. They exhibit noncrystallographic, curved, helical morphologies, reminiscent of biological forms. The filaments are similar to supposed cyanobacterial microfossils from the Precambrian Warrawoona chert formation in Western Australia, reputed to be the oldest terrestrial microfossils. Simple organic hydrocarbons, whose sources may also be abiotic and indeed inorganic, readily condense onto these filaments and subsequently polymerize under gentle heating to yield kerogenous products. Our results demonstrate that abiotic and morphologically complex microstructures that are identical to currently accepted biogenic materials can be synthesized inorganically.


Intracranial pressure monitoring in severe traumatic brain injury in latin america: process and methods for a multi-center randomized controlled trial.
In patients with severe traumatic brain injury (TBI), the influence on important outcomes of the use of information from intracranial pressure (ICP) monitoring to direct treatment has never been tested in a randomized controlled trial (RCT). We are conducting an RCT in six trauma centers in Latin America to test this question. We hypothesize that patients randomized to ICP monitoring will have lower mortality and better outcomes at 6-months post-trauma than patients treated without ICP monitoring. We selected three centers in Bolivia to participate in the trial, based on (1) the absence of ICP monitoring, (2) adequate patient accession and data collection during the pilot phase, (3) preliminary institutional review board approval, and (4) the presence of equipoise about the value of ICP monitoring. We conducted extensive training of site personnel, and initiated the trial on September 1, 2008. Subsequently, we included three additional centers. A total of 176 patients were entered into the trial as of August 31, 2010. Current enrollment is 81% of that expected. The trial is expected to reach its enrollment goal of 324 patients by September of 2011. We are conducting a high-quality RCT to answer a question that is important globally. In addition, we are establishing the capacity to conduct strong research in Latin America, where TBI is a serious epidemic. Finally, we are demonstrating the feasibility and utility of international collaborations that share resources and unique patient populations to conduct strong research about global public health concerns.


Coeliac disease and the risk of fractures - a general population-based cohort study.
Earlier studies have suggested that untreated coeliac disease may be associated with osteoporosis, but results are contradictory for the risk of long-term fractures. To study the association between coeliac disease and fractures. We used Cox regresson to examine the future risk of hip fracture and fracture of any type in more than 13 000 individuals with coeliac disease and 65 000 age- and sex-matched reference individuals in a general population-based cohort. During follow-up, 1365 first hip fractures and 4847 fractures of any type occurred. Coeliac disease was positively associated with subsequent hip fracture (hazard ratio = 2.1; 95% CI = 1.8-2.4) (in children: hazard ratio = 2.6; 95% CI = 1.1-6.2) and fractures of any type (hazard ratio = 1.4; 95% CI = 1.3-1.5) (in children: hazard ratio = 1.1; 95% CI = 1.0-1.2). The absolute excess risk of hip fractures in children with coeliac disease was 4/100 000 person-years. Incidence ratios for hip fracture in individuals with CD were around two both prior to diagnosis of coeliac disease and afterwards; this risk increase remained 20 years after diagnosis of coeliac disease. Individuals with coeliac disease, including children with coeliac disease, may be at increased risk of hip fracture and fracture of any type. Coeliac disease may be positively associated with long-term hip fracture risk.


Genome-wide meta-analyses identifies novel taxane-induced peripheral neuropathy-associated loci.
Taxane containing chemotherapy extends survival for breast cancer patients. However, taxane-induced peripheral neuropathy (TIPN) cannot be predicted, prevented or effectively treated. Using genome-wide analyses, we sought to identify common risk variants for TIPN. Women with high-risk breast cancer enrolled in SWOG 0221 were genotyped using the Illumina 1M chip. Genome-wide analyses were performed in relation to ≥grade 3 Common Terminology Criteria for Adverse Events (CTCAE) neuropathy in European and African Americans. Data were meta-analyzed with GW associations of CTCAE ≥grade 3 versus <grade 3 in CALGB 40101 assuming a fixed effects model. The percentage of ≥grade 3 TIPN in 1269 European Americans and 139 African Americans in S0221, was 11.6 and 22.3%, respectively. CALGB 40101 ≥grade 3 TOPN was 7.2%. The most significant association with ≥grade 3 TIPN was the G allele of rs1858826 in GNGT1 (Pmeta=1.1×10), which showed a decrease in risk of ≥grade 3 TIPN (odds ratio=0.29, 95% confidence interval: 0.18-0.46). The genetic variants associated with ≥grade 3 TIPN are hypothesized to have biochemical functions and reside in and near genes involved in diabetes and diabetic neuropathy. This finding is consistent with results from CALGB 40101 pathway analyses. Larger homogeneous trials with similar dosing and criteria for defining neuropathy are needed to properly assess the relationship of genomics with the neuropathy spectrum.


Communal nursing in mexican free-tailed bat maternity colonies.
Examination of genotypes of female-pup nursing pairs taken from large maternity colonies of the Mexican free-tailed bat in Texas demonstrates that nursing is nonrandom and selective along genetic (kinship) lines. This is contrary to previous reports that nursing in these colonies is indiscriminate. Although nursing is nonrandom, an estimated 17 percent of the females sampled were nursing pups that could not be their offspring. This "nonparental" nursing is an apparent result of the difficulties females face in consistently relocating and selectively nursing their own pups within these enormous colonies.


A giant thrombosed aneurysm of the petrous carotid artery presenting with cavernous sinus syndrome: case report.
Aneurysms involving the petrous Carotid artery are rare and a review of the literature demonstrates that the mode of clinical presentation depends on the direction of expansion of the aneurysmal sac. The eighth nerve is the most commonly affected, followed by the fifth nerve, sixth nerve and seventh nerve, respectively. There has not been reported to date a lesion presenting with cavernous sinus syndrome. We present the case of a 46-year-old woman who complained of left facial pain and pan-ophthalmoplegia, and was shown to have a giant thrombosed aneurysm of the petrous carotid artery extending into the cavernous sinus. Because preoperative evaluation of the patient revealed good collateral flow, proximal balloon occlusion of the left internal carotid artery was performed. Neurological symptoms of the patient resolved 2 months after surgery except for the size of the left pupil. We conclude that an aneurysm of the petrous carotid artery should be included in the differential diagnosis of cases presenting with a cavernous sinus syndrome. Early diagnosis followed by definitive treatment is important for the alleviation of clinical symptoms associated with this lesion.


Motor strategies for initiating downward-oriented movements during standing in adults.
Sitting down and squatting are routine activities in daily living that lower the body mass by flexing the trunk and legs, but they obviously require different motor strategies for each goal posture. The former action must transfer the supporting surface onto a seat, whereas the latter must maintain the center of mass within the same base of both feet. By comparing the performance of both maneuvers, the mechanisms involved in initiating the downward-oriented movements and the process of optimizing the performance during their repetitions were studied. Twelve healthy subjects were asked to perform sitting-down and squatting actions immediately when a light cue was given, but at a natural speed. Electromyograms, angular movements of the joints of the right leg, and center of pressure (COP) displacement were recorded before and during each task. The initial mechanisms to initiate the break from the upright posture and the changes of postural adjustments during repetitive movements were analyzed separately. The sitting-down movement was achieved by a stereotyped motor strategy characterized by a gastrocnemius muscle burst coupled with deactivation of the erector spinae muscle. The former produced a transient COP displacement in the forward direction, and simultaneous unlocking of the trunk prevented a fall backward. By contrast, because of the absence of any need to produce momentum in a given direction, a variety of motor strategies were available to initiate squatting. The direction of initial COP displacement to initiate squatting varied with the muscles involved in unlocking the upright posture. During repetition of sitting down, the average COP position of the initial standing posture in the preparatory period was immediately shifted forward after the second trial. Simultaneously, the erector spinae muscle was deactivated earlier in the later trials. These resulted in a decreased momentum in the backward direction while the subjects were transferring themselves onto the seat. In the squatting task, however, these changes could not be identified, except for a slight flexed position of the knee during standing in the first trial. These findings suggest that in the case of transferring the body-mass to another supporting base the central nervous system immediately adjusts the size of the initial impetus to optimize the performance.


Psidium guajava leaf extract prevents intestinal colonization of Citrobacter rodentium in the mouse model.
Diarrheal diseases are the second highest cause of mortality of children under 5 years worldwide. There is a continuous search for developing a cost-effective treatment for diarrhea as the present ones are facing challenges. Medicinal plants can be explored further as an alternative treatment for diarrhea. Psidium guajava leaves have been used as an antidiarrheal globally. Citrobacter rodentium, a common mouse pathogen, is known to mimic the pathogenecity of enteropathogenic and enterohemorrhagic E. coli. It can thus present an effective model to study infectious diarrhea. In the present study, the P. guajava leaf extract was tested for its efficacy in treating infectious diarrhea using a C. rodentium mouse model. The mice in the test group (treated with P. guajava leaf extract) showed quicker clearance of infection as compared with the control group. The bacterial load in the fecal sample of the mice in the test group was high on Day 4 as compared with that in the control group, suggesting a flush out of the bacteria. In the test group, 6/7 (85.71%) mice showed clearance of infection by Day 19. The control group continued to show infection till Day 29. P. guajava leaf extract thus has the potential for use in the treatment of infectious diarrhea.


Sustained Cerebrovascular and Cognitive Benefits of Resveratrol in Postmenopausal Women.
Deficits in the cerebral microcirculation contribute to age-related cognitive decline. In a pilot study of postmenopausal women, we found that supplementation with a low dose of resveratrol, a phytoestrogen, for 14 weeks improved cerebrovascular and cognitive functions. We have since undertaken a larger, longer term study to confirm these benefits. Postmenopausal women aged 45-85 years (n = 129) were randomized to take placebo or 75 mg trans-resveratrol twice daily for 12 months. Effects on cognition, cerebral blood flow, cerebrovascular responsiveness (CVR) and cardiometabolic markers (blood pressure, diabetes markers and fasting lipids) were assessed. Compared to placebo, resveratrol improved overall cognitive performance (P < 0.001) and attenuated the decline in CVR to cognitive stimuli (P = 0.038). The latter effect was associated with reduction of fasting blood glucose (r = -0.339, P = 0.023). This long-term study confirms that regular consumption of resveratrol can enhance cognitive and cerebrovascular functions in postmenopausal women, with the potential to slow cognitive decline due to ageing and menopause.


Mobile Apps for Eye Care in Canada: An Analysis of the iTunes Store.
Mobile phone screens can facilitate stimulation to various components of the visual system and many mobile apps are accepted as a means of providing clinical assessments for the oculo-visual system. Although many of these apps are intended for use in clinical settings, there is a growing number of apps in eye care developed for self-tests and eye exercises for lay people. These and other features, however, have not yet been well described. Our objective was to identify, describe, and categorize mobile apps related to eye care that are available to users in the Canadian iTunes market. We conducted an extensive search of the Apple iTunes Store for apps related to eye care. We used the terms "eye," "eye care," "vision," and "eye test" and included apps that are targeted at both lay people and medical professionals. We excluded apps whose primary function is not related to eye care. Eligible apps were categorized by primary purpose, based on how they were described by their developers in the iTunes Store. Our search yielded 10,657 apps, of which 427 met our inclusion criteria. After removing duplicates, 355 unique apps were subject to further review. We assigned the eligible apps to three distinct categories: 39/355 apps (11.0%) were intended for use by medical professionals, 236 apps (66.5%, 236/355) were intended for use by lay people, and 80 apps (22.5%, 80/355) were intended for marketing eye care and eye-care products. We identified 9 subcategories of apps based on the descriptions of their primary functions. Apps for medical professionals fell into three subcategories: clinical calculators (n=6), clinical diagnostic tools (n=18), and education and networking apps for professionals (n=15). Apps for lay people fell into four subcategories: self-testing (n=153), eye exercises (n=30), patient tools and low vision aids (n=35), and apps for patient education (n=18). Mixed-use apps (n=80) were placed into two subcategories: marketing of individual practitioners or eye-care products (n=72) and marketing of multiple eye-care products or professional services. The most extensive subcategory pertaining to eye care consisted of apps for use by lay people, especially for conducting self-tests (n=236). This study revealed a previously uncharacterized category of apps intended for use by doctors and patients, of which the primary goal is marketing of eye-care services and products (n=80).


Cytoreductive surgery and intraperitoneal chemotherapy for colorectal peritoneal and hepatic metastases: a case-control study.
Concomitant treatment of colorectal peritoneal metastases (PM) and hepatic metastases (HM) remains controversial. This study compares the cytoreductive surgery (CRS) and intraperitoneal chemotherapy (IPC) treatment of colorectal peritoneal metastases (PM) with the CRS/IPC/hepatic resection treatment of colorectal PM and HM. All patients from a prospective PM registry at the Uppsala institution treated concomitantly for PM/HM with CRS/IPC/hepatic resections were included in a PM/HM-group, n=11. They were matched 1(:)2 with patients from the registry being treated only for PM with CRS/IPC, n=22. Overall survival (OS), disease-free survival (DFS), morbidity, mortality, and recurrences were compared. The PM/HM-group had median OS of 15 months (95% CI: 6-46 months) and the PM-group had a median OS of 34 months (95% CI: 19-37 months), P=0.2. The DFS was 10 months (95% CI: 3-14 months) and 24 months (95% CI: 10-32 months) respectively, P=0.1. Morbidity was 27% in both groups and one postoperative death in the PM/HM-group. Currently, 1/10 (10%) patients with an R1 resection are disease-free in the PM/HM group while 9/20 (45%) are disease-free in the PM group (P=0.05). Concomitant treatment of PM and HM with CRS/IPC/hepatic resections is feasible with no significant increase in morbidity compared to CRS/IPC. The risk of recurrences is higher in the PM/HM group with a tendency towards worse DFS.


Carcinogenic nickel silences gene expression by chromatin condensation and DNA methylation: a new model for epigenetic carcinogens.
A transgenic gpt+ Chinese hamster cell line (G12) was found to be susceptible to carcinogenic nickel-induced inactivation of gpt expression without mutagenesis or deletion of the transgene. Many nickel-induced 6-thioguanine-resistant variants spontaneously reverted to actively express gpt, as indicated by both reversion assays and direct enzyme measurements. Since reversion was enhanced in many of the nickel-induced variant cell lines following 24-h treatment with the demethylating agent 5-azacytidine, the involvement of DNA methylation in silencing gpt expression was suspected. This was confirmed by demonstrations of increased DNA methylation, as well as by evidence indicating condensed chromatin and heterochromatinization of the gpt integration site in 6-thioguanine-resistant cells. Upon reversion to active gpt expression, DNA methylation and condensation are lost. We propose that DNA condensation and methylation result in heterochromatinization of the gpt sequence with subsequent inheritance of the now silenced gene. This mechanism is supported by direct evidence showing that acute nickel treatment of cultured cells, and of isolated nuclei in vitro, can indeed facilitate gpt sequence-specific chromatin condensation. Epigenetic mechanisms have been implicated in the actions of some nonmutagenic carcinogens, and DNA methylation changes are now known to be important in carcinogenesis. This paper further supports the emerging theory that nickel is a human carcinogen that can alter gene expression by enhanced DNA methylation and compaction, rather than by mutagenic mechanisms.


Professional roller hockey injuries.
To study the incidence and types of injuries sustained by professional roller hockey players in practices and games, and to compare these statistics with those from ice hockey. This injury survey used a strict definition of injury, standardized reporting strategies, and diagnosis by a team physician as standards by which to analyze the characteristics of roller hockey injuries. The injuries were recorded after the players had been examined by a team physician at the game or practice site or in the physician's office. During three seasons for one roller hockey team and one season for another team, an average of 22 players per team participated in the study. Due to personnel changes, the team rosters were modified between seasons. Each player injury was included in the study. An injury was defined as any physical impairment caused during a practice or game that eliminated the player from that practice or game or the next day's practice session or contest, or any physical ailment that necessitated a physical examination by the team physicians. Injury data were categorized and injury rates were calculated. 122 injuries were recorded during four professional roller hockey seasons, resulting in an overall participation injury rate of 14.4 per 1,000 player hours. The game injury rate was 304.9 per 1,000 player hours. The players were 105.1 times more likely to be injured during a game than during practice. Preseason practices produced 4.5 times more injuries than regular season practices. In comparison, sample data from the only other published study of roller hockey injuries and from several studies of ice hockey have indicated game injury rates of 139.0 (roller hockey), 119.0, 96.1, 78.4, 78.8, and 66.0 per 1,000 player hours, respectively. Results of this study demonstrate that roller hockey produces a higher rate of both contact and noncontact injuries than ice hockey; this contradicts the findings of the only other published research study on injuries in roller versus ice hockey. This increased incidence of injury may be due in part to the differences in surfaces, and can prove hazardous to even the recreational roller hockey player or in-line skater.


The combinatorics of overlapping genes.
Overlapping genes exist in all domains of life and are much more abundant than expected upon their first discovery in the late 1970s. Assuming that the reference gene is read in frame +0, an overlapping gene can be encoded in two reading frames in the sense strand, denoted by +1 and +2, and in three reading frames in the opposite strand, denoted by -0, -1, and -2. This motivated numerous researchers to study the constraints induced by the genetic code on the various overlapping frames, mostly based on information theory. Our focus in this paper is on the constraints induced on two overlapping genes in terms of amino acids, as well as polypeptides. We show that simple linear constraints bind the amino-acid composition of two proteins encoded by overlapping genes. Novel constraints are revealed when polypeptides are considered, and not just single amino acids. For example, in double-coding sequences with an overlapping reading frame -2, each Tyrosine (denoted as Tyr or Y) in the overlapping frame overlaps a Tyrosine in the reference frame +0 (and reciprocally), whereas specific words (e.g. YY) never occur. We thus distinguish between null constraints (YY = 0 in frame -2) and non-null constraints (Y in frame +0 ⇔ Y in frame -2). Our equivalence-based constraints are symmetrical and thus enable the characterization of the joint composition of overlapping proteins. We describe several formal frameworks and a graph algorithm to characterize and compute these constraints. As expected, the degrees of freedom left by these constraints vary drastically among the different overlapping frames. Interestingly, the biological meaning of constraints induced on two overlapping proteins (hydropathy, forbidden di-peptides, expected overlap length …) is also specific to the reading frame. We study the combinatorics of these constraints for overlapping polypeptides of length n, pointing out that, (i) except for frame -2, non-null constraints are deduced from the amino-acid (length = 1) constraints and (ii) null constraints are deduced from the di-peptide (length = 2) constraints. These results yield support for understanding the mechanisms and evolution of overlapping genes, and for developing novel overlapping gene detection methods.


Chromosomal bands affected by acute oil exposure and DNA repair errors.
In a previous study, we showed that individuals who had participated in oil clean-up tasks after the wreckage of the Prestige presented an increase of structural chromosomal alterations two years after the acute exposure had occurred. Other studies have also reported the presence of DNA damage during acute oil exposure, but little is known about the long term persistence of chromosomal alterations, which can be considered as a marker of cancer risk. We analyzed whether the breakpoints involved in chromosomal damage can help to assess the risk of cancer as well as to investigate their possible association with DNA repair efficiency. Cytogenetic analyses were carried out on the same individuals of our previous study and DNA repair errors were assessed in cultures with aphidicolin. Three chromosomal bands, 2q21, 3q27 and 5q31, were most affected by acute oil exposure. The dysfunction in DNA repair mechanisms, expressed as chromosomal damage, was significantly higher in exposed-oil participants than in those not exposed (p= 0.016). The present study shows that breaks in 2q21, 3q27 and 5q31 chromosomal bands, which are commonly involved in hematological cancer, could be considered useful genotoxic oil biomarkers. Moreover, breakages in these bands could induce chromosomal instability, which can explain the increased risk of cancer (leukemia and lymphomas) reported in chronically benzene-exposed individuals. In addition, it has been determined that the individuals who participated in clean-up of the oil spill presented an alteration of their DNA repair mechanisms two years after exposure.


Establishing an Inpatient Gym for Recipients of Stem Cell Transplantation: A Multidisciplinary Collaborative.
Evidence suggests that exercise can have a profound impact on physiologic and quality-of-life outcomes for patients undergoing hematopoietic stem cell transplantation (HSCT). Despite this, implementation of a gym on inpatient HSCT units may be limited because of space, infrastructure, and budget. This article presents the design, implementation, and evaluation of the gym and highlights its use for individual and group patient activities. An interprofessional team at a National Cancer Institute-designated comprehensive cancer center collaborated to design and implement gym space on an inpatient HSCT unit servicing as many as 86 beds. Informal feedback from patients, as well as metrics on use of the space, indicates that the gym is well received and frequently used. Limitations include the absence of a designated physical therapy technician to supervise individual activity, which may limit patient access when a staff member is unavailable. The cost associated with the implementation of such space may be offset by benefits to patients, including enhanced conditioning, quality of life, and time to discharge, as evidenced in the literature.


Evaluation of upper extremity reachable workspace using Kinect camera.
In clinical evaluation of upper extremity, there is a lack of assessment methods that are quantitative, reliable, and informative of the overall functional capability of an individual. We present new methodology for the assessment of upper extremity impairments based on the concept of 3-dimensional reachable workspace using Microsoft Kinect. We quantify the reachable workspace by the relative surface area representing the portion of the unit hemi-sphere that is covered by the hand movement. We examine accuracy of joint positions, joint angles, and reachable workspace computation between the Kinect and motion capture system. The results of our analysis in 10 healthy subjects showed that the accuracy of the joint positions was within 66.3 mm for our experimental protocol. We found that the dynamic angle measurements had relatively large deviations (between 9° to 28°). The acquired reachable workspace envelope showed high agreement between the two systems with high repeatability between trials (correlation coefficients between 0.86 and 0.93). The findings indicate that the proposed Kinect-based 3D reachable workspace analysis provides sufficiently accurate and reliable results as compared to motion capture system. The proposed method could be promising for clinical evaluation of upper extremity in neurological or musculoskeletal conditions.


Do our methods lead to insomniacs' madness?: Daytime testing after laboratory and home-based polysomnographic studies.
Complaints of daytime dysfunction are common among chronic insomniacs, but laboratory comparisons of insomniacs and age-matched and gender-matched normal controls have generally failed to document these complaints. However, a few studies, which allowed subjects to sleep in their homes on the nights before daytime testing, have shown some relative diurnal deficits among insomniacs. The current study compared the effects of nocturnal laboratory and home polysomnogram (PSG) studies on subsequent daytime test results among older insomniacs and normal sleepers. Insomniacs (n = 32) and normal sleepers (n = 32) were randomly assigned to first undergo three nights of nocturnal PSG monitoring either in the sleep laboratory (16 insomniacs, 16 normal sleepers) or in their homes (16 insomniacs, 16 normal sleepers). Following the third night of PSG monitoring, subjects spent 1 day in the sleep laboratory, where they completed a four-trial multiple sleep latency test along with four trials of a computer-administered performance test battery. Results showed that insomniacs, as a group, were slightly, albeit consistently, sleepier than were normal sleepers following nights of home sleep monitoring, but a reverse of this trend was found among subjects who underwent nocturnal laboratory PSG before daytime testing. Furthermore, normal sleepers showed faster reaction times on a signal detection task than did insomniacs within the subgroup who underwent home PSGs prior to such testing. However, within the subgroup that underwent nocturnal laboratory PSGs, insomniacs' signal detection reaction times were significantly faster than those shown by normal sleepers. Results provide some support for the speculation that the nocturnal PSG monitoring site, used as a precursor to daytime testing, may systematically affect daytime comparisons between insomniacs and matched controls. Moreover, these results suggest that the use of home-based nocturnal PSG monitoring prior to daytime testing may provide an enhanced understanding of insomniacs' diurnal complaints.


Mode of action of lipoprotein modification enzymes-Novel antibacterial targets.
Lipoproteins are characterized by a fatty acid moiety at their amino-terminus through which they are anchored into membranes. They fulfill a variety of essential functions in bacterial cells, such as cell wall maintenance, virulence, efflux of toxic elements including antibiotics, and uptake of nutrients. The posttranslational modification process of lipoproteins involves the sequential action of integral membrane enzymes and phospholipids as acyl donors. In recent years, the structures of the lipoprotein modification enzymes have been solved by X-ray crystallography leading to a greater insight into their function and the molecular mechanism of the reactions. The catalytic domains of the enzymes are exposed to the periplasm or external milieu and are readily accessible to small molecules. Since the lipoprotein modification pathway is essential in proteobacteria, it is a potential target for the development of novel antibiotics. In this review, we discuss recent literature on the structural characterization of the enzymes, and the in vitro activity assays compatible with high-throughput screening for inhibitors, with perspectives on the development of new antimicrobial agents.