Diabetes Distress and Associations With Demographic and Clinical Variables: A Nationwide Population-Based Registry Study of 10,186 Adults With Type 1 Diabetes in Norway.
To estimate diabetes distress prevalence and associations with demographic and clinical variables among adults with type 1 diabetes in Norway. In this nationwide population-based registry study, the Problem Areas in Diabetes (PAID-20) questionnaire was sent to 16,255 adults with type 1 diabetes. Linear regression models examined associations of demographic and clinical variables with distress. In total, 10,186 individuals (62.7%) completed the PAID-20, with a mean score of 25.4 (SD 18.4) and 21.7% reporting high distress. Respondents endorsed worrying about the future and complications as the most problematic item (23.0%). Female sex, younger age, non-European origin, primary education only, unemployment, smoking, continuous glucose monitoring use, more symptomatic hypoglycemia, reduced foot sensitivity, treated retinopathy, and higher HbA1c were associated with higher distress. Diabetes distress is common among adults with type 1 diabetes and associated with clinically relevant factors, underlining that regular care should include efforts to identify and address distress.


Beneficial effects of garlic (Allium sativum) oil in experimental corrosive esophageal burns effects of garlic oil in esophageal burns.
Corrosive esophageal burns, particularly common in developing countries, lead to different problems in different age groups. The ingestion of corrosive substances can cause such problems as stricture of the esophagus, to acute perforation, and even death. Because stricture formation is related to the severity of the initial injury, the prevention of stricture constitutes a main goal of treatment. The aim of this study was to investigate the protective and anti-inflammatory effects of garlic (Allium sativum) oil in corrosive esophageal burn. Twenty-eight rats were randomly divided into 4 equal groups: group 1 (sham), group 2 (control), group 3 (topical treatment), and group 4 (topical and systemic treatment). In groups 2, 3, and 4, corrosive esophageal burns were generated by applying sodium hydroxide to a 1.5-cm segment of the abdominal esophagus. Normal saline was applied to group 2, topical garlic oil to group 3, and topical and systemic garlic oil were used in group 4. The level of hydroxyproline was lower in the topical treatment groups than in the control group (p=0.023). There was difference in tumor necrosis factor alpha level between the systemic treatment groups and the control group (p=0.044). Treatment with garlic oil decreased stenosis index (SI) and histopathological damage score (HDS) in corrosive esophageal burn rats. The SI in the topical treatment group was significantly lower than that of the control group (p=0.016). The HDS was significantly lower in group 4 when compared with the control group (p=0.019). Garlic oil is an effective agent in promoting the regression of esophageal stenosis and tissue damage caused by corrosive burns. While the protective effect of garlic oil on tissue damage is more significant when applied topically, the anti-inflammatory effect is more pronounced when applied systemically. Therefore, we believe that the application of garlic oil in patients with corrosive esophageal burns can reduce complication rates.


Contaminants in ospreys from the Pacific Northwest: II. Organochlorine pesticides, polychlorinated biphenyls, and mercury, 1991-1997.
Eggs of ospreys (Pandion haliaetus) were collected over the period 1991 to 1997 at 111 nests in the Fraser and Columbia River drainage systems of British Columbia, Washington, and Oregon. Contents were analyzed for organochlorine (OC) pesticides, polychlorinated biphenyls (PCBs), and total mercury. Blood samples were taken from nestling ospreys at two time points during the 1992 breeding season on the Thompson River and analyzed for non-ortho PCBs. Concentrations of DDE and related compounds showed high variability among individual eggs within study areas and no significant differences in mean concentrations among study areas. Some eggs contained high concentrations of DDE, up to 20 mg/kg (wet weight), for which there were no evident local sources, suggesting that exposure occurred outside of the breeding grounds. Most other OC pesticides measured in osprey eggs showed a similar distribution, although mean concentrations of chlordane-related compounds were generally, and in some cases significantly, higher in samples collected from the Columbia River sites compared to elsewhere. Significantly greater concentrations of PCBs were found in eggs from the Columbia River basin compared to the Fraser. This was attributed to extensive development of hydroelectric generation and related industries on the Columbia system. Significant differences among sites were also found in the pattern of PCB congeners, e.g., eggs from the lower Columbia River site had proportionally greater concentrations of less chlorinated, Aroclor 1242-type PCBs compared to other sites. In contrast, eggs from upper reaches of the Columbia River had relatively greater amounts of Aroclor 1254 and 1260 congeners. Mercury concentrations in osprey eggs tended to be uniform among sites and comparable to those reported in the literature for ospreys nesting on naturally formed lakes and rivers. There were no significant temporal changes in mean concentrations of any of the measured compounds at sites monitored from 1991 to 1997.


Lesional-targeting of neuroprotection to the inflammatory penumbra in experimental multiple sclerosis.
Progressive multiple sclerosis is associated with metabolic failure of the axon and excitotoxicity that leads to chronic neurodegeneration. Global sodium-channel blockade causes side effects that can limit its use for neuroprotection in multiple sclerosis. Through selective targeting of drugs to lesions we aimed to improve the potential therapeutic window for treatment. This was assessed in the relapsing-progressive experimental autoimmune encephalomyelitis ABH mouse model of multiple sclerosis using conventional sodium channel blockers and a novel central nervous system-excluded sodium channel blocker (CFM6104) that was synthesized with properties that selectively target the inflammatory penumbra in experimental autoimmune encephalomyelitis lesions. Carbamazepine and oxcarbazepine were not immunosuppressive in lymphocyte-driven autoimmunity, but slowed the accumulation of disability in experimental autoimmune encephalomyelitis when administered during periods of the inflammatory penumbra after active lesion formation, and was shown to limit the development of neurodegeneration during optic neuritis in myelin-specific T cell receptor transgenic mice. CFM6104 was shown to be a state-selective, sodium channel blocker and a fluorescent p-glycoprotein substrate that was traceable. This compound was >90% excluded from the central nervous system in normal mice, but entered the central nervous system during the inflammatory phase in experimental autoimmune encephalomyelitis mice. This occurs after the focal and selective downregulation of endothelial p-glycoprotein at the blood-brain barrier that occurs in both experimental autoimmune encephalomyelitis and multiple sclerosis lesions. CFM6104 significantly slowed down the accumulation of disability and nerve loss in experimental autoimmune encephalomyelitis. Therapeutic-targeting of drugs to lesions may reduce the potential side effect profile of neuroprotective agents that can influence neurotransmission. This class of agents inhibit microglial activity and neural sodium loading, which are both thought to contribute to progressive neurodegeneration in multiple sclerosis and possibly other neurodegenerative diseases.


Hydration Repulsion Difference between Ordered and Disordered Membranes Due to Cancellation of Membrane-Membrane and Water-Mediated Interactions.
Hydration repulsion acts between all sufficiently polar surfaces in water at small separations and prevents dry adhesion up to kilobar pressures. Yet it remained unclear whether this ubiquitous force depends on surface structure or is a sole water property. We demonstrate that previous deviations among different experimental measurements of hydration pressures in phospholipid bilayer stacks disappear when plotting data consistently as a function of repeat distance or membrane surface distance. The resulting pressure versus distance curves agree quantitatively with our atomistic simulation results and exhibit different decay lengths in the ordered gel and the disordered fluid states. This suggests that hydration forces are not caused by water ordering effects alone. Splitting the simulated total pressure into membrane-membrane and water-mediated parts shows that these contributions are opposite in sign and of similar magnitude, thus they are equally important. The resulting net hydration pressure between membranes is what remains from the near-cancellation of these ambivalent contributions.


Field-quadrature and photon-number correlations produced by parametric processes.
In a previous paper [Opt. Express 13, 4986 (2005)], formulas were derived for the field-quadrature and photon-number variances produced by multiple-mode parametric processes. In this paper, formulas are derived for the quadrature and number correlations. The number formulas are used to analyze the properties of basic devices, such as two-mode amplifiers, attenuators and frequency convertors, and composite systems made from these devices, such as cascaded parametric amplifiers and communication links. Amplifiers generate idlers that are correlated with the amplified signals, or correlate pre-existing pairs of modes, whereas attenuators decorrelate pre-existing modes. Both types of device modify the signal-to-noise ratios (SNRs) of the modes on which they act. Amplifiers decrease or increase the mode SNRs, depending on whether they are operated in phase-insensitive (PI) or phase-sensitive (PS) manners, respectively, whereas attenuators always decrease these SNRs. Two-mode PS links are sequences of transmission fibers (attenuators) followed by two-mode PS amplifiers. Not only do these PS links have noise figures that are 6-dB lower than those of the corresponding PI links, they also produce idlers that are (almost) completely correlated with the signals. By detecting the signals and idlers, one can eliminate the effects of electronic noise in the detectors.


Effects of antiplatelet therapy after stroke due to intracerebral haemorrhage (RESTART): a randomised, open-label trial.
Antiplatelet therapy reduces the risk of major vascular events for people with occlusive vascular disease, although it might increase the risk of intracranial haemorrhage. Patients surviving the commonest subtype of intracranial haemorrhage, intracerebral haemorrhage, are at risk of both haemorrhagic and occlusive vascular events, but whether antiplatelet therapy can be used safely is unclear. We aimed to estimate the relative and absolute effects of antiplatelet therapy on recurrent intracerebral haemorrhage and whether this risk might exceed any reduction of occlusive vascular events. The REstart or STop Antithrombotics Randomised Trial (RESTART) was a prospective, randomised, open-label, blinded endpoint, parallel-group trial at 122 hospitals in the UK. We recruited adults (≥18 years) who were taking antithrombotic (antiplatelet or anticoagulant) therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage, discontinued antithrombotic therapy, and survived for 24 h. Computerised randomisation incorporating minimisation allocated participants (1:1) to start or avoid antiplatelet therapy. We followed participants for the primary outcome (recurrent symptomatic intracerebral haemorrhage) for up to 5 years. We analysed data from all randomised participants using Cox proportional hazards regression, adjusted for minimisation covariates. This trial is registered with ISRCTN (number ISRCTN71907627). Between May 22, 2013, and May 31, 2018, 537 participants were recruited a median of 76 days (IQR 29-146) after intracerebral haemorrhage onset: 268 were assigned to start and 269 (one withdrew) to avoid antiplatelet therapy. Participants were followed for a median of 2·0 years (IQR [1·0- 3·0]; completeness 99·3%). 12 (4%) of 268 participants allocated to antiplatelet therapy had recurrence of intracerebral haemorrhage compared with 23 (9%) of 268 participants allocated to avoid antiplatelet therapy (adjusted hazard ratio 0·51 [95% CI 0·25-1·03]; p=0·060). 18 (7%) participants allocated to antiplatelet therapy experienced major haemorrhagic events compared with 25 (9%) participants allocated to avoid antiplatelet therapy (0·71 [0·39-1·30]; p=0·27), and 39 [15%] participants allocated to antiplatelet therapy had major occlusive vascular events compared with 38 [14%] allocated to avoid antiplatelet therapy (1·02 [0·65-1·60]; p=0·92). These results exclude all but a very modest increase in the risk of recurrent intracerebral haemorrhage with antiplatelet therapy for patients on antithrombotic therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage. The risk of recurrent intracerebral haemorrhage is probably too small to exceed the established benefits of antiplatelet therapy for secondary prevention. British Heart Foundation.


Feasibility and acceptability of daily testing at school as an alternative to self-isolation following close contact with a confirmed case of COVID-19: a qualitative analysis.
Daily testing using a rapid Lateral Flow Device (LFD) has been suggested as an alternative to self-isolation. A randomised trial comparing daily contact testing (DCT) in schools with self-isolation found that SARS-CoV-2 transmission within school was comparable and low in both groups. However, if this approach is to be adopted widely, it is critical that we understand the perspective of those who will be delivering and receiving DCT. The aim of this qualitative process study embedded in the randomised controlled trial (RCT) was to improve understanding of a range of behavioural factors that could influence implementation. Interviews were conducted with 63 participants, including staff, students, and parents of students who had been identified as being in close contact with someone with COVID-19. The topic guide explored perceptions of daily testing, understanding of positive and negative test results, and adherence to guidance. Data were analysed using an inductive thematic approach. Results were organised under three main headings: (1) factors influencing daily testing (2) interpretation of test results (3) behaviour during testing period. Participants recognized that daily testing may allow students to remain in school, which was viewed as necessary for both education and social needs. Whilst some felt safer as a result of daily testing, others raised concerns about safety. Participants did not always understand how to interpret and respond to test results, and although participants reported high levels of adherence to the guidance, improved communications were desired. Daily testing may be a feasible and acceptable alternative to self-isolation among close contacts of people who test positive. However, improved communications are needed to ensure that all students and parents have a good understanding of the rationale for testing, what test results mean, how test results should be acted on, and how likely students are to test positive following close contact. Support is needed for students and parents of students who have to self-isolate and for those who have concerns about the safety of daily testing.


Assessing executive function using a computer game: computational modeling of cognitive processes.
Early and reliable detection of cognitive decline is one of the most important challenges of current healthcare. In this project, we developed an approach whereby a frequently played computer game can be used to assess a variety of cognitive processes and estimate the results of the pen-and-paper trail making test (TMT)--known to measure executive function, as well as visual pattern recognition, speed of processing, working memory, and set-switching ability. We developed a computational model of the TMT based on a decomposition of the test into several independent processes, each characterized by a set of parameters that can be estimated from play of a computer game designed to resemble the TMT. An empirical evaluation of the model suggests that it is possible to use the game data to estimate the parameters of the underlying cognitive processes and using the values of the parameters to estimate the TMT performance. Cognitive measures and trends in these measures can be used to identify individuals for further assessment, to provide a mechanism for improving the early detection of neurological problems, and to provide feedback and monitoring for cognitive interventions in the home.


Characterization of a cytoplasmic trehalase of Escherichia coli.
Escherichia coli can synthesize trehalose in response to osmotic stress and is able to utilize trehalose as a carbon source. The pathway of trehalose utilization is different at low and high osmolarity. At high osmolarity, a periplasmic trehalase (TreA) is induced that hydrolyzes trehalose in the periplasm to glucose. Glucose is then taken up by the phosphotransferase system. At low osmolarity, trehalose is taken up by a trehalose-specific enzyme II of the phosphotransferase system as trehalose-6-phosphate and then is hydrolyzed to glucose and glucose-6-phosphate. Here we report a novel cytoplasmic trehalase that hydrolyzes trehalose to glucose. treF, the gene encoding this enzyme, was cloned under ara promoter control. The enzyme (TreF) was purified from extracts of an overexpressing strain and characterized biochemically. It is specific for trehalose exhibiting a Km of 1.9 mM and a Vmax of 54 micromol of trehalose hydrolyzed per min per mg of protein. The enzyme is monomeric, exhibits a broad pH optimum at 6.0, and shows no metal dependency. TreF has a molecular weight of 63,703 (549 amino acids) and is highly homologous to TreA. The nonidentical amino acids of TreF are more polar and more acidic than those of TreA. The expression of treF as studied by the expression of a chromosomal treF-lacZ fusion is weakly induced by high osmolarity of the medium and is partially dependent on RpoS, the stationary-phase sigma factor. Mutants producing 17-fold more TreF than does the wild type were isolated.


Revealing the brain's adaptability and the transcranial direct current stimulation facilitating effect in inhibitory control by multiscale entropy.
The abilities to inhibit impulses and withdraw certain responses are critical for human's survival in a fast-changing environment. These processes happen fast, in a complex manner, and sometimes are difficult to capture with fMRI or mean electrophysiological brain signal alone. Therefore, an alternative measure that can reveal the efficiency of the neural mechanism across multiple timescales is needed for the investigation of these brain functions. The present study employs a new approach to analyzing electroencephalography (EEG) signal: the multiscale entropy (MSE), which groups data points with different timescales to reveal any occurrence of repeated patterns, in order to theoretically quantify the complexity (indicating adaptability and efficiency) of neural systems during the process of inhibitory control. From this MSE perspective, EEG signals of successful stop trials are more complex and information rich than that of unsuccessful stop trials. We further applied transcranial direct current stimulation (tDCS), with anodal electrode over presupplementary motor area (preSMA), to test the relationship between behavioral modification with the complexity of EEG signals. We found that tDCS can further increase the EEG complexity of the frontal lobe. Furthermore, the MSE pattern was found to be different between high and low performers (divided by their stop-signal reaction time), where the high-performing group had higher complexity in smaller scales and less complexity in larger scales in comparison to the low-performing group. In addition, this between-group MSE difference was found to interact with the anodal tDCS, where the increase of MSE in low performers benefitted more from the anodal tDCS. Together, the current study demonstrates that participants who suffer from poor inhibitory control can efficiently improve their performance with 10min of electrical stimulation, and such cognitive improvement can be effectively traced back to the complexity within the EEG signals via MSE analysis, thereby offering a theoretical basis for clinical intervention via tDCS for deficits in inhibitory control.


Physiological and histopathological responses following closed rotational head injury depend on direction of head motion.
Rotational inertial forces are thought to be the underlying mechanism for most severe brain injuries. However, little is known about the effect of head rotation direction on injury outcomes, particularly in the pediatric population. Neonatal piglets were subjected to a single non-impact head rotation in the horizontal, coronal, or sagittal direction, and physiological and histopathological responses were observed. Sagittal rotation produced the longest duration of unconsciousness, highest incidence of apnea, and largest intracranial pressure increase, while coronal rotation produced little change, and horizontal rotation produced intermediate and variable derangements. Significant cerebral blood flow reductions were observed following sagittal but not coronal or horizontal injury compared to sham. Subarachnoid hemorrhage, ischemia, and brainstem pathology were observed in the sagittal and horizontal groups but not in a single coronal animal. Significant axonal injury occurred following both horizontal and sagittal rotations. For both groups, the distribution of injury was greater in the frontal and parietotemporal lobes than in the occipital lobes, frequently occurred in the absence of ischemia, and did not correlate with regional cerebral blood flow reductions. We postulate that these direction-dependent differences in injury outcomes are due to differences in tissue mechanical loading produced during head rotation.


Prevalence and causes of musculoskeletal impairment in Fundong District, North-West Cameroon: results of a population-based survey.
Epidemiological data on musculoskeletal conditions such as degenerative joint diseases and bone fractures are lacking in low- and middle-income countries. This survey aimed to estimate the prevalence and causes of musculoskeletal impairment in Fundong Health District, North-West Cameroon. Fifty-one clusters of 80 people (all ages) were selected using probability proportionate to size sampling. Households within clusters were selected by compact segment sampling. Six screening questions were asked to identify participants likely to have a musculoskeletal impairment (MSI). Participants screening positive to any screening question underwent a standardised examination by a physiotherapist to assess presence, cause, diagnosis and severity of impairment. In total, 3567 of 4080 individuals enumerated for the survey were screened (87%). The all-age prevalence of MSI was 11.6% (95% CI: 10.1-13.3). Prevalence increased with age, from 2.9% in children to 41.2% in adults 50 years and above. The majority of MSI cases (70.4%) were classified as mild, 27.2% as moderate and 2.4% as severe. Acquired non-trauma comprised 67% of the diagnoses. The remainder included trauma (14%), neurological (11%), infection (5%) and congenital (3%). The most common individual diagnosis was degenerative joint disease (43%). Over one-third (38%) of individuals with MSI had never received medical care or rehabilitation for their condition. This survey contributes to the epidemiological data on MSI in low- and middle-income countries. Nearly half of adults aged over 50 years had an MSI. There is a need to address the treatment and rehabilitative service gap for people with MSI in Cameroon.


Protective Effects of Minor Components of Curcuminoids on Hydrogen Peroxide-Treated Human HaCaT Keratinocytes.
Hydrogen peroxide, one of the reactive oxygen species (ROS), can cause intracellular oxidative stress associated with skin aging and/or photoaging. Curcumin, a polyphenol in turmeric, has been reported to exhibit biological activity. In this study, five naturally occurring curcuminoids [curcumin, demethoxycurcumin (DMC), bisdemethoxycurcumin (BDMC), monohydroxy-DMC, and monohydroxy-BDMC] were used to investigate their protective roles against hydrogen peroxide-induced oxidative stress in the immortalized human keratinocyte cell lines (HaCaT cells). These five curcuminoids at 10 μM, but not at 5 μM, were shown to exhibit cytotoxicities toward HaCaT keratinocytes. Therefore, a 5 μM concentration of the five curcuminoids was selected for further investigations. Cells were pretreated with or without curcuminoids for 2.5 h before 24-h hydrogen peroxide (150 μM) treatments. Pretreatments with the minor components monohydroxy-DMC or monohydroxy-BDMC, but not curcumin, DMC, and BDMC, showed protective activity, elevating cell viability compared to cells with direct hydrogen peroxide treatments. Pretreatments with monohydroxy-DMC and monohydroxy-BDMC showed the best protective effects, reducing apoptotic cell populations and intracellular ROS, as demonstrated by flow cytometry, as well as reducing the changes of the mitochondrial membrane potential compared to cells with direct hydrogen peroxide treatments. The pretreatments with monohydroxy-DMC and monohydroxy-BDMC reduced c-jun and c-fos mRNA expression and p53 tumor suppressor protein expression and increased HO-1 protein expression and glutathione peroxidase (GPx) activity, respectively, compared to cells with direct hydrogen peroxide treatments. The five curcuminoids exhibited similar hydrogen peroxide-scavenging activity in vitro. It was proposed that monohydroxy-DMC and monohydroxy-BDMC could induce antioxidant defense systems better than curcumin, DMC, or BDMC could against hydrogen peroxide-induced oxidative stress and apoptosis of HaCaT keratinocytes and that they may have potential as ingredients in antiaging cosmetics for skin care.


Penile vascular diagnostic categorization using penile duplex Doppler ultrasound: Differences in vascular hemodynamics parameters by differences in anatomic sampling location.
In 2013 the International Society for Sexual Medicine(ISSM) published the guidelines regarding the standard operating procedure (SOP) for penile duplex Doppler ultrasound (PDDU). Although ISSM-SOP have given important strides in reducing interobserver variability in PDDU by procedural protocol and parameters these guidelines do not address the anatomic location along the penis at which hemodynamic measurements have to be done. In our opinion a "double sampling" may be interesting to detect the arteriogenic or venogenic nature of the erectile dysfunction (ED). In particular sampling measurements at the "crus" (at the level of the peno-scrotal junction) may be significative for detection of veno-occlusive dysfunction (VOD),whereas an evaluation at "mid penis" (1/2 distance between peno-scrotal junction and coronal sulcus), may be useful to diagnose an arterial insufficiency (AI). We evalued 90 men, mean age 56.3, affected with ED of medium degree, responder to PDE5-I that urdergone to PDDU and also responder after pharmacologic intracavernosal injection (PII)of prostaglandin E1 20 mcg, with rigid erection and normal maintenance. We moreover evalued 90 men in youthful age (mean 35.2), in absence of vascular risk factors, no responder to PDE5-I that undergone to PDDU by PII at high dosage (bimix: prostaglandin E1 20 mcg, papaverine 20 mg). In the first pool the sampling at "mid penis" resulted significative for arterial insuffciency (AI) in 81% (73), in presence of normal or borderline end diastolic velocity (EDV). Sampling at the "crus" resulted negative for VOD in 90% (81). In the second pool, 66.6% (60) resulted responder with rigid erection and normal maintenance in presence of normal hemodynamic parameters: peak systolic velocity (PSV) and end diastolic velocity (EDV) both at the "crus" and at "mid penis" sampling. 33.4% (30) responded with a semirigid erection and manifested a constant deficit of maintenance; at the "crus"and at "mid penis" the hemodynamic arterial parameters resulted normal. At the "crus" the EDV resulted significantly augmented (VOD index) in 96.6% (29); at "mid penis" augmented EDV was founded in 50% (15). These observational data would be able to confirm the utility of a routinary "double sampling" procedure, at the "crus" and at "md penis", during PDDU in order to better distinguish between VOD or AI or in any case to be useful to stimulate a future more precise standardization in execution of PDDU examination.


Onchocerca volvulus: immunization of chimpanzees with X-irradiated third-stage (L3) larvae.
To provide a theoretical basis for the potential development of vaccines against Onchocerca volvulus (Ov) a trial has been conducted to assess the protective efficacy of immunization of chimpanzees with X-irradiated L3 larvae. Approximately 1000 larvae were injected at 0, 1, and 7 months. The immunized animals, and unimmunized controls, were then challenged with 250 live L3. In order to provide possibly protective exposure to the immunologically distinct L4 epicuticle, a radiation dose (45 krad) was chosen which preserved about 50% of the molting ability of unirradiated larvae. Despite the presence of a strong immune response to crude adult worm extracts, and to cloned Ov antigens, at the time of challenge little or no significant protection against patent infection was observed: three of four immunized animals developed patent infection as compared to four of four controls. One immunized animal failed to become patent or to manifest the late antibody response to adult worm antigens seen in both subpatent and patent infections in this model, and may have been protected from infection. The implications of these studies for future attempts to immunize against O. volvulus are discussed.


Mining rare associations between biological ontologies.
The constantly increasing volume and complexity of available biological data requires new methods for their management and analysis. An important challenge is the integration of information from different sources in order to discover possible hidden relations between already known data. In this paper we introduce a data mining approach which relates biological ontologies by mining cross and intra-ontology pairwise generalized association rules. Its advantage is sensitivity to rare associations, for these are important for biologists. We propose a new class of interestingness measures designed for hierarchically organized rules. These measures allow one to select the most important rules and to take into account rare cases. They favor rules with an actual interestingness value that exceeds the expected value. The latter is calculated taking into account the parent rule. We demonstrate this approach by applying it to the analysis of data from Gene Ontology and GPCR databases. Our objective is to discover interesting relations between two different ontologies or parts of a single ontology. The association rules that are thus discovered can provide the user with new knowledge about underlying biological processes or help improve annotation consistency. The obtained results show that produced rules represent meaningful and quite reliable associations.


Prevalence of thalassemia in patients with microcytosis referred for hemoglobinopathy investigation in Ontario: a prospective cohort study.
In Ontario, Canada, beta-thalassemia is easily detected through measurement of hemoglobin A2, but most laboratories do not do exhaustive DNA investigations for alpha-thalassemia. Therefore, the prevalence of thalassemia in microcytic samples for hemoglobinopathy investigation in Ontario is unknown. To address this, we performed a prospective cohort study in which samples referred for hemoglobinopathy investigation were also evaluated for alpha-thalassemia by DNA testing. Of 800 samples submitted, 664 were evaluable. Of the 664 patients represented, 163 (24.5%) were beta-thalassemia major carriers, 68 (10.2%) were hemoglobin Bart's hydrops fetalis carriers and, in total, 361 (54.4%) had some form of thalassemia. We conclude that microcytosis due to thalassemia is common in Ontario and that major forms of thalassemia, including forms predisposing to hemoglobin Bart's hydrops fetalis and beta-thalassemia major, are frequent. This illustrates the importance of adequate prenatal and laboratory investigation for these abnormalities in Ontario and other similar multiethnic jurisdictions worldwide.


The effect of different atrioventricular delays on left atrium and left atrial appendage function in patients with DDD pacemaker.
Although it has been known that optimization of atrioventricular delay (AVD) has favorable effect on the left ventricular functions in patients with DDD pacemaker, the effect of different AVDs on left atrium (LA) and left atrial appendage (LAA) functions has not been exactly evaluated. The aim of the present study was to assess the effect of different AVDs on LA and LAA functions in DDD pacemaker implanted patients with atrioventricular block. Forty-eight patients with DDD pacemaker were enrolled into the study. Patients were divided into two groups according to the echocardiographic diastolic function: Group I (normal diastolic function) and Group II (diastolic dysfunction). LAA emptying velocity on pulsed wave Doppler and LAA late systolic wave velocity by using tissue Doppler were recorded. Patients were paced for five successive continuous pacing periods of 10 minutes duration using five selective AVDs (80-250 ms). Significant effect on LA and LAA functions has not been observed by the setting of AVD in Group I. However, when the AVD was gradually shortened form 150 ms to 80 ms, LA and LAA functions gradually decreased in Group II patients. When AVD increased to 200 ms, LA and LAA functions were improved. Further increase in AVD resulted in decreased LA and LAA functions. Setting of AVD has not significant effect on the LA and LAA functions in patients with normal diastolic function, but moderate prolongation of AVD in physiological limits improved LA and LAA functions in DDD pacemaker implanted patients with diastolic dysfunction.


[Global gender policies in prevention and tobacco control].
Later stages of the smoking epidemic show that social and gender inequalities increase tobacco use among women and more deprived social groups. Given that smoking prevalence among women is increasing adding gender perspective in the design of prevention and tobacco control policies is a priority. After a brief description of the overall frame of tobacco control, different policies including minimum strategies that should incorporate gender specific aspects are described. Among them, empowerment measures addressed to reduce gender inequities are included; legislative measures; health care measures; and lastly measures related to research and evaluation aiming to add gender perspective in tobacco policy implementation and analysis.


A genome-wide association study identifies rs2000999 as a strong genetic determinant of circulating haptoglobin levels.
Haptoglobin is an acute phase inflammatory marker. Its main function is to bind hemoglobin released from erythrocytes to aid its elimination, and thereby haptoglobin prevents the generation of reactive oxygen species in the blood. Haptoglobin levels have been repeatedly associated with a variety of inflammation-linked infectious and non-infectious diseases, including malaria, tuberculosis, human immunodeficiency virus, hepatitis C, diabetes, carotid atherosclerosis, and acute myocardial infarction. However, a comprehensive genetic assessment of the inter-individual variability of circulating haptoglobin levels has not been conducted so far.We used a genome-wide association study initially conducted in 631 French children followed by a replication in three additional European sample sets and we identified a common single nucleotide polymorphism (SNP), rs2000999 located in the Haptoglobin gene (HP) as a strong genetic predictor of circulating Haptoglobin levels (P(overall) = 8.1 × 10(-59)), explaining 45.4% of its genetic variability (11.8% of Hp global variance). The functional relevance of rs2000999 was further demonstrated by its specific association with HP mRNA levels (β = 0.23 ± 0.08, P = 0.007). Finally, SNP rs2000999 was associated with decreased total and low-density lipoprotein cholesterol in 8,789 European children (P(total cholesterol) = 0.002 and P(LDL) = 0.0008).Given the central position of haptoglobin in many inflammation-related metabolic pathways, the relevance of rs2000999 genotyping when evaluating haptoglobin concentration should be further investigated in order to improve its diagnostic/therapeutic and/or prevention impact.


I2-Catalyzed cross dehydrogenative coupling: rapid access to benzoxazinones and quinazolinones.
An efficient and applicable I2-catalyzed intramolecular dehydrogenative C-O/C-N coupling reaction via activating the C-H bond adjacent to the N atom has been developed to provide dozens of substituted benzoxazinones (31 examples) and quinazolinones (5 examples) in good to excellent yields (up to 98%). This one-pot methodology has significant advantages, including a metal-free process, broad substrate scope, high atom economy, and simple operation. This strategy goes through an iminium intermediate followed by nucleophilic attack to provide the desired products.


Effects of Lactobacillus casei on the expression and the activity of cytochromes P450 and on the CYP mRNA level in the intestine and the liver of male rats.
The aim of the study was to find whether probiotic Lactobacillus casei influences the expression or the activity of cytochromes P450 (CYP) and whether it has an influence on the level of CYP mRNA in male rats. Live bacterial suspension of L. casei was administered orally (gavage) to healthy male Wistar rats daily for 7 days. Control group of rats was treated with the saline solution. Sections of the duodenum, jejunum, ileum, caecum and colon were dissected from each experimental animal. In all individual samples, the expression of selected CYPs was determined by Western blotting. The levels of expression of CYPs were also evaluated by mRNA using the real-time PCR method. There were changes observed in the expression of CYP enzymes and in the CYP mRNA levels along the intestine after application of L. casei. The expression of CYP1A1 enzyme was found to be decreased in the proximal part of the jejunum and colon, CYP1A1 mRNA level was decreased in the distal part of the jejunum, ileum and caecum. Thus, the changes in CYP1A1 protein or mRNA were observed along the intestine of male rats. Similarly, a decreased expression of the caecal CYP2E1 mRNA and of the duodenal CYP3A9 mRNA after treatment of rats with L. casei was found. Probiotic L. casei might be able to contribute to prevention against colorectal cancer by decreasing levels of certain forms of xenobiotic-metabolizing enzymes; moreover, in general, there is a possibility of interactions with concomitantly taken pharmacotherapeutic agents.


Congo Red Fluorescence for Rapid In Situ Characterization of Synthetic Curli Systems.
Curli are amyloid proteins that are assembled into extracellular polymeric fibers by bacteria during biofilm formation. The beta-sheet-rich protein CsgA, the primary structural component of the fibers, is secreted through dedicated machinery and self-assembles into cell-anchored fibers many times longer than the cell. Here, we have developed an in situ fluorescence assay for curli production that exploits the fluorescent properties of Congo red (CR) dye when bound to amyloid, allowing for rapid and robust curli quantification. We initially evaluated three amyloid-binding dyes for the fluorescent detection of curli in bacterial culture and found only Congo red compatible with in situ quantification. We further characterized the fluorescent properties of the dye directly in bacterial culture and calibrated the fluorescence using purified CsgA protein. We then used the Congo red assay to rapidly develop and characterize inducible curli-producing constructs in both an MC4100-derived lab strain of Escherichia coli and a derivative of the probiotic strain E. coli Nissle. This technique can be used to evaluate curli production in a minimally invasive manner using a range of equipment, simplifying curli quantification and the development of novel engineered curli systems.IMPORTANCE Curli are proteins produced by many bacteria as a structural component of biofilms, and they have recently emerged as a platform for fabrication of biological materials. Curli fibers are very robust and resistant to degradation, and the curli subunits can tolerate many protein fusions, facilitating the biosynthesis of novel functional materials. A serious bottleneck in the development of more sophisticated engineered curli systems is the rapid quantification of curli production by the bacteria. In this work we address this issue by developing a technique to monitor curli production directly in bacterial cultures, allowing for rapid curli quantification in a manner compatible with many powerful high-throughput techniques that can be used to engineer complex biological material systems.


Does hugging provide stress-buffering social support? A study of susceptibility to upper respiratory infection and illness.
Perceived social support has been hypothesized to protect against the pathogenic effects of stress. How such protection might be conferred, however, is not well understood. Using a sample of 404 healthy adults, we examined the roles of perceived social support and received hugs in buffering against interpersonal stress-induced susceptibility to infectious disease. Perceived support was assessed by questionnaire, and daily interpersonal conflict and receipt of hugs were assessed by telephone interviews on 14 consecutive evenings. Subsequently, participants were exposed to a virus that causes a common cold and were monitored in quarantine to assess infection and illness signs. Perceived support protected against the rise in infection risk associated with increasing frequency of conflict. A similar stress-buffering effect emerged for hugging, which explained 32% of the attenuating effect of support. Among infected participants, greater perceived support and more-frequent hugs each predicted less-severe illness signs. These data suggest that hugging may effectively convey social support.


Early versus delayed treatment of relapsed ovarian cancer (MRC OV05/EORTC 55955): a randomised trial.
Serum CA125 concentration often rises several months before clinical or symptomatic relapse in women with ovarian cancer. In the MRC OV05/EORTC 55955 collaborative trial, we aimed to establish the benefits of early treatment on the basis of increased CA125 concentrations compared with delayed treatment on the basis of clinical recurrence. Women with ovarian cancer in complete remission after first-line platinum-based chemotherapy and a normal CA125 concentration were registered for this randomised controlled trial. Clinical examination and CA125 measurement were done every 3 months. Patients and investigators were masked to CA125 results, which were monitored by coordinating centres. If CA125 concentration exceeded twice the upper limit of normal, patients were randomly assigned (1:1) by minimisation to early or delayed chemotherapy. Patients and clinical sites were informed of allocation to early treatment, and treatment was started as soon as possible within 28 days of the increased CA125 measurement. Patients assigned to delayed treatment continued masked CA125 measurements, with treatment commencing at clinical or symptomatic relapse. All patients were treated according to standard local practice. The primary outcome was overall survival. Analysis was by intention to treat. This study is registered, ISRCTN87786644. 1442 patients were registered for the trial, of whom 529 were randomly assigned to treatment groups and were included in our analysis (265 early, 264 delayed). With a median follow-up of 56·9 months (IQR 37·4-81·8) from randomisation and 370 deaths (186 early, 184 delayed), there was no evidence of a difference in overall survival between early and delayed treatment (HR 0·98, 95% CI 0·80-1·20, p=0·85). Median survival from randomisation was 25·7 months (95% CI 23·0-27·9) for patients on early treatment and 27·1 months (22·8-30·9) for those on delayed treatment. Our findings showed no evidence of a survival benefit with early treatment of relapse on the basis of a raised CA125 concentration alone, and therefore the value of routine measurement of CA125 in the follow-up of patients with ovarian cancer who attain a complete response after first-line treatment is not proven. UK Medical Research Council and the European Organisation for Research and Treatment of Cancer.


De novo-designed translation-repressing riboregulators for multi-input cellular logic.
Efforts to construct synthetic biological circuits with more complex functions have often been hindered by the idiosyncratic behavior, limited dynamic range and crosstalk of commonly utilized parts. Here, we employ de novo RNA design to develop two high-performance translational repressors with sensing and logic capabilities. These synthetic riboregulators, termed toehold repressors and three-way junction (3WJ) repressors, detect transcripts with nearly arbitrary sequences, repress gene expression by up to 300-fold and yield orthogonal sets of up to 15 devices. Automated forward engineering is used to improve toehold repressor dynamic range and SHAPE-Seq is applied to confirm the designed switching mechanism of 3WJ repressors in living cells. We integrate the modular repressors into biological circuits that execute universal NAND and NOR logic and evaluate the four-input expression NOT ((A1 AND A2) OR (B1 AND B2)) in Escherichia coli. These capabilities make toehold and 3WJ repressors valuable new tools for biotechnological applications.


The novel prostaglandin I2 mimetic ONO-1301 escapes desensitization in an antiplatelet effect due to its inhibitory action on thromboxane A2 synthesis in mice.
ONO-1301 [(E)-[5-[2-[1-phenyl-1-(3-pyridyl)methylidene-aminooxy]ethyl]-7,8-dihydronaphthalene-1-yloxy]acetic acid] is a novel prostaglandin (PG) I2 mimetic with inhibitory activity on the thromboxane (TX) A2 synthase. Interestingly, ONO-1301 retains its inhibitory effect on platelet aggregation after repeated administration, while beraprost, a representative agonist for the PGI2 receptor (IP), loses its inhibitory effect after repeated administration. In the present study, we intended to clarify the mechanism by which ONO-1301 escapes desensitization of an antiplatelet effect. In platelets prepared from wild-type mice, ONO-1301 inhibited collagen-induced aggregation and stimulated cAMP production in an IP-dependent manner. In addition, ONO-1301 inhibited arachidonic acid-induced TXA2 production in platelets lacking IP. Despite the decrease in stimulatory action on cAMP production, the antiplatelet effect of ONO-1301 hardly changed after repeated administration for 10 days in wild-type mice. Noteworthy, beraprost could retain its antiplatelet effect after repeated administration in combination with a low dose of ozagrel, a TXA2 synthase inhibitor. Therefore, we hypothesized that chronic IP stimulation by beraprost induces an increase in TXA2 production, leading to reduction in the antiplatelet effect. As expected, repeated administration of beraprost increased the plasma and urinary levels of a TXA2 metabolite, while ONO-1301 did not increase them significantly. In addition, beraprost could retain the ability to inhibit platelet aggregation after repeated administration in mice lacking the TXA2 receptor (TP). These results indicate that TP-mediated signaling participates in platelet desensitization against IP agonists and that simultaneous inhibition of TXA2 production confers resistance against desensitization on IP agonists.


Wavelet-transform analysis for group delay extraction of white light spectral interferograms.
We proposed a simple and straightforward technique, wavelet-transform analysis, for group delay extraction from the white light spectral interferograms. In this paper, we demonstrated that the extracted group delay dispersion by wavelet-transform was insensitive to the path length balancing of the interferometer. This promises a flexible and robust technique for chirped mirror characterization.


Guidelines for imaging and staging of neuroblastic tumors: consensus report from the International Neuroblastoma Risk Group Project.
Neuroblastoma is an enigmatic disease entity; some tumors disappear spontaneously without any therapy, while others progress with a fatal outcome despite the implementation of maximal modern therapy. However, strong prognostic factors can accurately predict whether children have "good" or "bad" disease at diagnosis, and the clinical stage is currently the most significant and clinically relevant prognostic factor. Therefore, for an individual patient, proper staging is of paramount importance for risk assessment and selection of optimal treatment. In 2009, the International Neuroblastoma Risk Group (INRG) Project proposed a new staging system designed for tumor staging before any treatment, including surgery. Compared with the focus of the International Neuroblastoma Staging System, which is currently the most used, the focus has now shifted from surgicopathologic findings to imaging findings. The new INRG Staging System includes two stages of localized disease, which are dependent on whether image-defined risk factors (IDRFs) are or are not present. IDRFs are features detected with imaging at the time of diagnosis. The present consensus report was written by the INRG Imaging Committee to optimize imaging and staging and reduce interobserver variability. The rationales for using imaging methods (ultrasonography, magnetic resonance imaging, computed tomography, and scintigraphy), as well as technical guidelines, are described. Definitions of the terms recommended for assessing IDRFs are provided with examples. It is anticipated that the use of standardized nomenclature will contribute substantially to more uniform staging and thereby facilitate comparisons of clinical trials conducted in different parts of the world.


Chronic nitrogen deposition alters tree allometric relationships: implications for biomass production and carbon storage.
As increasing levels of nitrogen (N) deposition impact many terrestrial ecosystems, understanding the potential effects of higher N availability is critical for forecasting tree carbon allocation patterns and thus future forest productivity. Most regional estimates of forest biomass apply allometric equations, with parameters estimated from a limited number of studies, to forest inventory data (i.e., tree diameter). However most of these allometric equations cannot account for potential effects of increased N availability on biomass allocation patterns. Using 18 yr of tree diameter, height, and mortality data collected for a dominant tree species (Acer saccharum) in an atmospheric N deposition experiment, we evaluated how greater N availability affects allometric relationships in this species. After taking into account site and individual variability, our results reveal significant differences in allometric parameters between ambient and experimental N deposition treatments. Large trees under experimental N deposition reached greater heights at a given diameter; moreover, their estimated maximum height (mean ± standard deviation: 33.7 ± 0.38 m) was significantly higher than that estimated under the ambient condition (31.3 ± 0.31 m). Within small tree sizes (5-10 cm diameter) there was greater mortality under experimental N deposition, whereas the relative growth rates of small trees were greater under experimental N deposition. Calculations of stemwood biomass using our parameter estimates for the diameter-height relationship indicated the potential for significant biases in these estimates (~2.5%), with under predictions of stemwood biomass averaging 4 Mg/ha lower if ambient parameters were to be used to estimate stem biomass of trees in the experimental N deposition treatment. As atmospheric N deposition continues to increase into the future, ignoring changes in tree allometry will contribute to the uncertainty associated with aboveground carbon storage estimates across a forest with a large geographic distribution in eastern North America.


[Diagnosis and treatment of chronic hepatitis B and D. National consensus guideline in Hungary from 15 October 2016].
Diagnosis and treatment of HBV/HDV infection means for the patient to be able to maintain working capacity, to increase quality of life, to prevent cancer, and to prolong life expectancy, while society benefits from eliminating the chances of further transmission of the viruses, and decreasing the overall costs of serious complications. The guideline delineates the treatment algorithms for 2017 set by a consensus meeting of physicians involved in the treatment of these diseases. The prevalence of HBV infection in the Hungarian general population is 0.5-0.7%. The indications of treatment is based upon viral examinations (including viral nucleic acid determination), determinations of disease activity and stage (including biochemical, pathologic, and/or non-invasive methods), and excluding contraindications. To avoid unnecessary side effects and for cost-effective approach the guideline stresses the importance of quick and detailed virologic evaluations, the applicability of elastography as an acceptable alternative of liver biopsy in this regard, as well as the relevance of appropriate consistent follow up schedule for viral response during therapy. The first choice of therapy in chronic hepatitis B infection can be pegylated interferon for 48 weeks or continuous entecavir or tenofovir therapy. The latter two must be continued for at least 12 months after hepatitis B surface antigen seroconversion. Adefovir dipivoxil is recommended mainly in combination therapy. Lamivudine is no longer a first choice; patients currently taking lamivudine must switch if response is inadequate. Appropriate treatment of patients taking immunosuppressive medications is highly recommended. Pegylated interferon based therapy is recommended for the treatment of concomitant hepatitis D infection. Orv. Hetil., 2017, 158(Suppl. 1) 23-35.


Fusion of an immunoglobulin variable gene and a T cell receptor constant gene in the chromosome 14 inversion associated with T cell tumors.
An inversion of chromosome 14, inv(14)(q11,q32), is frequently observed in human T cell tumors; the cytogenetic breakpoints are of interest because the T cell receptor alpha-chain and immunoglobulin heavy chain genes reside on chromosome bands 14q11 and 14q32, respectively. We have investigated the structure of the alpha-chain genes in a T cell line harboring the chromosome 14 inversion. On the normal chromosome 14, a V alpha segment has rearranged nonproductively with a J alpha segment. In contrast, the inverted chromosome features an unprecedented rearrangement in which an immunoglobulin heavy chain variable gene segment (VH) on chromosome band 14q32 has joined with a J alpha segment from band 14q11. The VH-J alpha C alpha rearrangement is productive at the genomic level and therefore may encode a hybrid immunoglobulin/T cell receptor polypeptide.


Decreases in community viral load are accompanied by reductions in new HIV infections in San Francisco.
At the individual level, higher HIV viral load predicts sexual transmission risk. We evaluated San Francisco's community viral load (CVL) as a population level marker of HIV transmission risk. We hypothesized that the decrease in CVL in San Francisco from 2004-2008, corresponding with increased rates of HIV testing, antiretroviral therapy (ART) coverage and effectiveness, and population-level virologic suppression, would be associated with a reduction in new HIV infections. We used San Francisco's HIV/AIDS surveillance system to examine the trends in CVL. Mean CVL was calculated as the mean of the most recent viral load of all reported HIV-positive individuals in a particular community. Total CVL was defined as the sum of the most recent viral loads of all HIV-positive individuals in a particular community. We used Poisson models with robust standard errors to assess the relationships between the mean and total CVL and the primary outcome: annual numbers of newly diagnosed HIV cases. Both mean and total CVL decreased from 2004-2008 and were accompanied by decreases in new HIV diagnoses from 798 (2004) to 434 (2008). The mean (p = 0.003) and total CVL (p = 0.002) were significantly associated with new HIV cases from 2004-2008. Reductions in CVL are associated with decreased HIV infections. Results suggest that wide-scale ART could reduce HIV transmission at the population level. Because CVL is temporally upstream of new HIV infections, jurisdictions should consider adding CVL to routine HIV surveillance to track the epidemic, allocate resources, and to evaluate the effectiveness of HIV prevention and treatment efforts.


Functional reorganisation and recovery following cortical lesions: A preliminary study in macaque monkeys.
Damage following traumatic brain injury or stroke can often extend beyond the boundaries of the initial insult and can lead to maladaptive cortical reorganisation. On the other hand, beneficial cortical reorganisation leading to recovery of function can also occur. We used resting state FMRI to investigate how cortical networks in the macaque brain change across time in response to lesions to the prefrontal cortex, and how this reorganisation correlated with changes in behavioural performance in cognitive tasks. After prelesion testing and scanning, two monkeys received a lesion to regions surrounding the left principal sulcus followed by periodic testing and scanning. Later, the animals received another lesion to the opposite hemisphere and additional testing and scanning. Following the first lesion, we observed both a behavioural impairment and decrease in functional connectivity, predominantly in frontal-frontal networks. Approximately 8 weeks later, performance and connectivity patterns both improved. Following the second lesion, we observed a further behavioural deficit and decrease in connectivity that showed little recovery. We discuss how different mechanisms including alternate behavioural strategies and reorganisation of specific prefrontal networks may have led to improvements in behaviour. Further work will be needed to confirm these mechanisms.


Effects of diets with different calcium and phosphorus contents on the skeletal development and blood chemistry of growing great danes.
The skeletal development of three groups of great dane dogs, fed a diet composed according to the published nutritional requirements for dogs (controls) or with increased calcium or calcium and phosphorus content, was examined radiographically, histologically and biochemically. The diets were fed from the time the dogs first began eating food in addition to their dam's milk, until they were 17 weeks old. Thereafter, the calcium and phosphorus intakes of the dogs in the high calcium groups were normalised for a further 10 weeks. The dogs fed the high calcium diet without a proportionally high phosphorus intake became hypercalcaemic and hypophosphataemic, and had severe disturbances in skeletal development, growth, and mineralisation which were typical for rickets. After their calcium intake was normalised the lesions of rickets resolved but osteochondrotic lesions became apparent. The dogs fed the high calcium and phosphorus diet became slightly hypophosphataemic, their growth was retarded, and they had disturbances in skeletal development resembling osteochondrosis, which had only partly resolved after 10 weeks on the normal calcium and phosphorus diet.


Crossmodal links between audition and touch in covert endogenous spatial attention.
We report three experiments designed to investigate the nature of any crossmodal links between audition and touch in sustained endogenous covert spatial attention, using the orthogonal spatial cuing paradigm. Participants discriminated the elevation (up vs. down) of auditory and tactile targets presented to either the left or the right of fixation. In Experiment 1, targets were expected on a particular side in just one modality; the results demonstrated that the participants could spatially shift their attention independently in both audition and touch. Experiment 2 demonstrated that when the participants were informed that targets were more likely to be on one side for both modalities, elevation judgments were faster on that side in both audition and touch. The participants were also able to "split" their auditory and tactile attention, albeit at some cost, when targets in the two modalities were expected on opposite sides. Similar results were also reported in Experiment 3 when participants adopted a crossed-hands posture, thus revealing that crossmodal links in audiotactile attention operate on a representation of space that is updated following posture change. These results are discussed in relation to previous findings regarding crossmodal links in audiovisual and visuotactile covert spatial attentional orienting.


Solid-State Dynamic Nuclear Polarization at 9.4 and 18.8 T from 100 K to Room Temperature.
Efficient dynamic nuclear polarization (DNP) in solids, which enables very high sensitivity NMR experiments, is currently limited to temperatures of around 100 K and below. Here we show how by choosing an adequate solvent, (1)H cross effect DNP enhancements of over 80 can be obtained at 240 K. To achieve this we use the biradical TEKPol dissolved in a glassy phase of ortho-terphenyl (OTP). We study the solvent DNP enhancement of both TEKPol and BDPA in OTP in the range from 100 to 300 K at 9.4 and 18.8 T. Surprisingly, we find that the DNP enhancement decreases only relatively slowly for temperatures below the glass transition of OTP (Tg = 243 K), and (1)H enhancements around 15-20 at ambient temperature can be observed. We use this to monitor molecular dynamic transitions in the pharmaceutically relevant solids Ambroxol and Ibuprofen.


Ellagic acid inhibits adipocyte differentiation through coactivator-associated arginine methyltransferase 1-mediated chromatin modification.
Chromatin remodeling is a key mechanism in adipocyte differentiation. However, it is unknown whether dietary polyphenols are epigenetic effectors for adiposity control. Ellagic acid (EA) is a naturally occurring polyphenol in numerous fruits and vegetables. Recently, EA-containing foods have been reported to reduce adiposity. In the present study, we sought to determine whether EA inhibits adipogenesis by modifying chromatin remodeling in human adipogenic stem cells (hASCs). qPCR microarray of chromatin modification enzymes revealed that 10 μmol/L of EA significantly inhibits histone deacetylase (HDAC)9 down-regulation. In addition, EA was associated with up-regulation of HDAC activity and a marked reduction of histone acetylation levels. However, chemical inhibition of HDAC activity or depletion of HDAC9 by siRNA were not sufficient to reverse the antiadipogenic effects of EA. Intriguingly, EA treatment was also associated with reduced histone 3 arginine 17 methylation levels (H3R17me2), implying the inhibitory role of EA in coactivator-associated arginine methyltransferase 1 (CARM)1 activity during adipogenesis. Boosting CARM1 activity by delivering cell-penetrating peptides of CARM1 not only recovered H3R17me2 but also restored adipogenesis evidenced by H3 acetylation at lysine 9, HDAC9 down-regulation, PPARγ expression and triglyceride accumulation. Taken together, our data suggest that reduced CARM1 activity by EA results in a decrease of H3R17me2 levels, which may interrupt consecutive histone remodeling steps for adipocyte differentiation including histone acetylation and HDAC9 dissociation from chromatin. Our work provides the mechanistic insights into how EA, a polyphenol ubiquitously found in fruits and vegetables, attenuates human adipocyte differentiation by altering chromatin remodeling.


Phase 2 clinical trial of a recombinant adeno-associated viral vector expressing α1-antitrypsin: interim results.
Recombinant adeno-associated virus (rAAV) vectors offer promise for the gene therapy of α(1)-antitrypsin (AAT) deficiency. In our prior trial, an rAAV vector expressing human AAT (rAAV1-CB-hAAT) provided sustained, vector-derived AAT expression for >1 year. In the current phase 2 clinical trial, this same vector, produced by a herpes simplex virus complementation method, was administered to nine AAT-deficient individuals by intramuscular injection at doses of 6.0×10(11), 1.9×10(12), and 6.0×10(12) vector genomes/kg (n=3 subjects/dose). Vector-derived expression of normal (M-type) AAT in serum was dose dependent, peaked on day 30, and persisted for at least 90 days. Vector administration was well tolerated, with only mild injection site reactions and no serious adverse events. Serum creatine kinase was transiently elevated on day 30 in five of six subjects in the two higher dose groups and normalized by day 45. As expected, all subjects developed anti-AAV antibodies and interferon-γ enzyme-linked immunospot responses to AAV peptides, and no subjects developed antibodies to AAT. One subject in the mid-dose group developed T cell responses to a single AAT peptide unassociated with any clinical effects. Muscle biopsies obtained on day 90 showed strong immunostaining for AAT and moderate to marked inflammatory cell infiltrates composed primarily of CD3-reactive T lymphocytes that were primarily of the CD8(+) subtype. These results support the feasibility and safety of AAV gene therapy for AAT deficiency, and indicate that serum levels of vector-derived normal human AAT >20 μg/ml can be achieved. However, further improvements in the design or delivery of rAAV-AAT vectors will be required to achieve therapeutic target serum AAT concentrations.


Effects of Orientations, Aspect Ratios, Pavement Materials and Vegetation Elements on Thermal Stress inside Typical Urban Canyons.
The analysis of local climate conditions to test artificial urban boundaries and related climate hazards through modelling tools should become a common practice to inform public authorities about the benefits of planning alternatives. Different finishing materials and sheltering objects within urban canyons (UCs) can be tested, predicted and compared through quantitative and qualitative understanding of the relationships between the microclimatic environment and subjective thermal assessment. This process can work as support planning instrument in the early design phases as has been done in this study that aims to analyze the thermal stress within typical UCs of Bilbao (Spain) in summertime through the evaluation of Physiologically Equivalent Temperature using ENVI-met. The UCs are characterized by different orientations, height-to-width aspect ratios, pavement materials, trees' dimensions and planting pattern. Firstly, the current situation was analyzed; secondly, the effects of asphalt and red brick stones as streets' pavement materials were compared; thirdly, the benefits of vegetation elements were tested. The analysis demonstrated that orientation and aspect ratio strongly affect the magnitude and duration of the thermal peaks at pedestrian level; while the vegetation elements improve the thermal comfort up to two thermophysiological assessment classes. The outcomes of this study, were transferred and visualized into green planning recommendations for new and consolidated urban areas in Bilbao.


Improving our understanding of metal implant failures: Multiscale chemical imaging of exogenous metals in ex-vivo biological tissues.
Biological exposures to micro- and nano-scale exogenous metal particles generated as a consequence of in-service degradation of orthopaedic prosthetics can result in severe adverse tissues reactions. However, individual reactions are highly variable and are not easily predicted, due to in part a lack of understanding of the speciation of the metal-stimuli which dictates cellular interactions and toxicity. Investigating the chemistry of implant derived metallic particles in biological tissue samples is complicated by small feature sizes, low concentrations and often a heterogeneous speciation and distribution. These challenges were addressed by developing a multi-scale two-dimensional X-ray absorption spectroscopic (XAS) mapping approach to discriminate sub-micron changes in particulate chemistry within ex-vivo tissues associated with failed CoCrMo total hip replacements (THRs). As a result, in the context of THRs, we demonstrate much greater variation in Cr chemistry within tissues compared with previous reports. Cr compounds including phosphate, hydroxide, oxide, metal and organic complexes were observed and correlated with Co and Mo distributions. This variability may help explain the lack of agreement between biological responses observed in experimental exposure models and clinical outcomes. The multi-scale 2D XAS mapping approach presents an essential tool in discriminating the chemistry in dilute biological systems where speciation heterogeneity is expected. SIGNIFICANCE: Metal implants are routinely used in healthcare but may fail following degradation in the body. Although specific implants can be identified as 'high-risk', our analysis of failures is limited by a lack of understanding of the chemistry of implant metals within the peri-prosthetic milieu. A new approach to identify the speciation and variability in speciation at sub-micron resolution, of dilute exogenous metals within biological tissues is reported; applied to understanding the failure of metallic (CoCrMo) total-hip-replacements widely used in orthopedic surgery. Much greater variation in Cr chemistry was observed compared with previous reports and included phosphate, hydroxide, oxide, metal and organic complexes. This variability may explain lack of agreement between biological responses observed in experimental exposure models and clinical outcomes.


Angiotensin II AT(1) receptor blockers ameliorate inflammatory stress: a beneficial effect for the treatment of brain disorders.
Excessive allostatic load as a consequence of deregulated brain inflammation participates in the development and progression of multiple brain diseases, including but not limited to mood and neurodegenerative disorders. Inhibition of the peripheral and brain Renin-Angiotensin System by systemic administration of Angiotensin II AT(1) receptor blockers (ARBs) ameliorates inflammatory stress associated with hypertension, cold-restraint, and bacterial endotoxin administration. The mechanisms involved include: (a) decreased inflammatory factor production in peripheral organs and their release to the circulation; (b) reduced progression of peripherally induced inflammatory cascades in the cerebral vasculature and brain parenchyma; and (c) direct anti-inflammatory effects in cerebrovascular endothelial cells, microglia, and neurons. In addition, ARBs reduce bacterial endotoxin-induced anxiety and depression. Further pre-clinical experiments reveal that ARBs reduce brain inflammation, protect cognition in rodent models of Alzheimer's disease, and diminish brain inflammation associated with genetic hypertension, ischemia, and stroke. The anti-inflammatory effects of ARBs have also been reported in circulating human monocytes. Clinical studies demonstrate that ARBs improve mood, significantly reduce cognitive decline after stroke, and ameliorate the progression of Alzheimer's disease. ARBs are well-tolerated and extensively used to treat cardiovascular and metabolic disorders such as hypertension and diabetes, where inflammation is an integral pathogenic mechanism. We propose that including ARBs in a novel integrated approach for the treatment of brain disorders such as depression and Alzheimer's disease may be of immediate translational relevance.


CT-measured skeletal muscle mass used to assess frailty in patients with head and neck cancer.
Skeletal muscle depletion or sarcopenia is related to multiple adverse clinical outcome. However, frailty questionnaires are currently applied in the daily practice to identify patients who are potentially (un)suitable for treatment but are time consuming and straining for patients and the clinician. Screening for sarcopenia in patients with head and neck cancer (HNC) could be a promising fast biomarker for frailty. Our objective was to quantify sarcopenia with pre-treatment low skeletal muscle mass from routinely obtained neck computed tomography scans at level of third cervical vertebra in patients diagnosed with HNC and evaluate its association with frailty. A total of 112 HNC patients with Stages III and IV disease were included from a prospective databiobank. The amount of skeletal muscle mass was retrospectively defined using the skeletal muscle index (SMI). Correlation analysis between SMI and continuous frailty data and the observer agreement were analysed with Pearson's r correlation coefficients. Sarcopenia was present when SMI felt below previously published non-gender specific thresholds (<43.2 cm2 /m2 ). Frailty was evaluated by Geriatrics 8 (G8), Groningen Frailty Indicator, Timed Up and Go test, and Malnutrition Universal Screening Tool. A univariate and multivariate logistic regression analysis was performed for all patients and men separately to obtain odds ratios (ORs) and 95% confidence intervals (95% CIs). The cohort included 82 men (73%) and 30 women (27%), with a total mean age of 63 (±9) years. The observer agreement for cross-sectional measurements was excellent for both intra-observer variability (r = 0.99, P < 0.001) and inter-observer variability (r = 0.98, P < 0.001). SMI correlated best with G8 frailty score (r = 0.38, P < 0.001) and did not differ per gender. Sarcopenia was present in 54 (48%) patients, whereof 25 (46%) men and 29 (54%) women. Prevalence of frailty was between 5% and 54% depending on the used screening tool. The multivariate regression analysis for all patients and men separately isolated the G8 questionnaire as the only independent variable associated with sarcopenia (OR 0.76, 95% CI 0.66-0.89, P < 0.001 and OR 0.76, 95% CI 0.66-0.88, P < 0.001, respectively). This is the first study that demonstrates that sarcopenia is independently associated with frailty based on the G8 questionnaire in HNC patients. These results suggest that in the future, screening for sarcopenia on routinely obtained neck computed tomography scans may replace time consuming frailty questionnaires and help to select the (un)suitable patients for therapy, which is highly clinically relevant.


BRIT1 regulates early DNA damage response, chromosomal integrity, and cancer.
BRIT1, initially identified as an hTERT repressor, has additional functions at DNA damage checkpoints. Here, we demonstrate that BRIT1 formed nuclear foci minutes after irradiation. The foci of BRIT1 colocalized with 53BP1, MDC1, NBS1, ATM, RPA, and ATR. BRIT1 was required for activation of these elements, indicating that BRIT1 is a proximal factor in the DNA damage response pathway. Depletion of BRIT1 increased the accumulation of chromosomal aberrations. In addition, decreased levels of BRIT1 were detected in several types of human cancer, with BRIT1 expression being inversely correlated with genomic instability and metastasis. These results identify BRIT1 as a crucial DNA damage regulator in the ATM/ATR pathways and suggest that it functions as a tumor suppressor gene.


Differences in the chromatin structure and cis-element organization of the human and mouse GATA1 loci: implications for cis-element identification.
Cis-element identification is a prerequisite to understand transcriptional regulation of gene loci. From analysis of a limited number of conserved gene loci, sequence comparison has proved a robust and efficient way to locate cis-elements. Human and mouse GATA1 genes encode a critical hematopoietic transcription factor conserved in expression and function. Proper control of GATA1 transcription is critical in regulating myeloid lineage specification and maturation. Here, we compared sequence and systematically mapped position of DNase I hypersensitive sites, acetylation status of histone H3/H4, and in vivo binding of transcription factors over approximately 120 kilobases flanking the human GATA1 gene and the corresponding region in mice. Despite lying in approximately 10 megabase (Mb) conserved syntenic segment, the chromatin structures of the 2 homologous loci are strikingly different. The 2 previously unidentified hematopoietic cis-elements, one in each species, are not conserved in position and sequence and have enhancer activity in erythroid cells. In vivo, they both bind the transcription factors GATA1, SCL, LMO2, and Ldb1. More broadly, there are both species- and regulatory element-specific patterns of transcription factor binding. These findings suggest that some cis-elements regulating human and mouse GATA1 genes differ. More generally, mouse human sequence comparison may fail to identify all cis-elements.


Comparing upper gastrointestinal X-ray and endoscopy for gastric cancer diagnosis in Korea.
To compare the cost and accuracy of upper gastrointestinal (GI) X-ray and upper endoscopy for diagnosis of gastric cancer using data from the 2002-2004 Korean National Cancer Screening Program (NCSP). The study population included 1,503,646 participants in the 2002-2004 stomach cancer screening program who underwent upper GI X-ray or endoscopy. The accuracy of screening was defined as the probability of detecting gastric cancer. We calculated the probability by merging data from the NCSP and the Korea Central Cancer Registry. We estimated the direct costs of the medical examination and the tests for upper GI X-ray, upper endoscopy, and biopsy. The probability of detecting gastric cancer via upper endoscopy was 2.9-fold higher than via upper GI X-ray. The unit costs of screening using upper GI X-ray and upper endoscopy were $32.67 and $34.89, respectively. In 2008, the estimated cost of identifying one case of gastric cancer was $53,094.64 using upper GI X-ray and $16,900.43 using upper endoscopy. The cost to detect one case of gastric cancer was the same for upper GI X-ray and upper endoscopy at a cost ratio of 1:3.7. Upper endoscopy is slightly more costly to perform, but the cost to detect one case of gastric cancer is lower.


Surgical survival benefits for coronary disease patients with left ventricular dysfunction.
Controversy still exists about the proper selection of patients with coronary artery disease and left ventricular dysfunction for coronary bypass surgery. To examine this issue, we studied 710 patients with significant coronary artery disease and left ventricular dysfunction (ejection fraction less than or equal to 40%). Of 301 patients treated surgically, 232 had bypass grafts; 17, left ventricular surgery; and 52, both procedures. At 3 years after treatment, unadjusted survival was 84% for surgical patients and 64% for medical patients. At baseline, medical patients had more left ventricular dysfunction than surgical patients, but surgical patients had more coronary artery disease and angina than medical patients. In Cox survival models, two invasive factors (ejection fraction and extent of coronary artery disease) and three noninvasive indexes (assessment of myocardial infarction, angina, and conduction disturbances) were the five best predictors of survival (p less than 0.001). After adjustment for these factors between the two treatment groups, overall surgical survival at 3 years after treatment was 86%, and medical survival was 68%. Long-term surgical survival benefits appeared greatest in patients with the most severe left ventricular dysfunction, most extensive coronary artery disease, and most severe anginal symptoms. We conclude that surgery provides significant survival benefits for coronary disease patients with left ventricular dysfunction; in general, the sicker the patient, the greater the benefit.


Combination therapy with amphotericin B and fluconazole against invasive candidiasis in neutropenic-mouse and infective-endocarditis rabbit models.
Although there are an increasing number of new antifungal agents available, the morbidity and mortality due to invasive mycoses remain high. The high rates of polyene toxicities and the development of azole resistance have raised the issue of using antifungal agents of these classes in combination, despite theoretical concerns regarding antagonism between such agents. This study was designed to evaluate the in vivo efficacy of combined therapy with amphotericin B and fluconazole against Candida albicans. Two distinct animal models were used in this study: a neutropenic-mouse model of hematogenously disseminated candidiasis and the infective-endocarditis rabbit model. Treatment efficacy was assessed by determining reductions in mortality as well as decreases in tissue fungal densities. In the neutropenic-mouse model, amphotericin B, as well as combination therapy, significantly prolonged survival compared to untreated controls (P < 10(-5) and P = 0.001, respectively). The fungal densities in the kidneys of neutropenic mice were significantly reduced with either amphotericin B monotherapy or amphotericin B-fluconazole combined therapy compared to those of controls (P < 10(-6)). Fluconazole monotherapy also reduced fungal densities in the kidneys; however, this decrease was not statistically significant (P = 0.17). In contrast, treatment with either fluconazole alone or combined with amphotericin B (but not amphotericin B monotherapy) significantly decreased fungal densities in the brain (P = 0.025). In the rabbit endocarditis model, amphotericin B monotherapy or combined therapy significantly decreased fungal densities in cardiac vegetations (P < 0.01 versus the controls). Although no significant antagonism was seen when fluconazole was given in combination with amphotericin B, combination therapy did not augment the antifungal activity of amphotericin B.


Prediction of fractional flow reserve with angiographic DILEMMA score.
Angiographic assessment of stenosis has limited predictive value for functionally significant lesions compared with fractional flow reserve (FFR). The recently developed angiographic DILEMMA score, which consists of minimal lumen diameter (MLD), lesion length (LL) and Bypass Angioplasty Revascularization Investigation (BARI) Myocardial Jeopardy Index (MJI) was found to have diagnostic value in predicting FFR ≤0.80. The present study was an investigation of prediction of FFR ≤0.80 using DILEMMA score and its relationship to resting distal coronary artery pressure/aortic pressure (Pd/Pa). Records of consecutive patients who underwent coronary angiography and FFR were retrospectively analyzed. Assessment of MLD and LL was performed using quantitative coronary angiography. BARI MJI was calculated using angiographic calculation index. A total of 185 pressure wire analysis data sets from 150 patients were analyzed retrospectively. There were 82 lesions in FFR >0.80 group and 103 lesions in FFR ≤0.80 group. Negative correlation was found between FFR and DILEMMA score (r=-0.494; p<0.001), FFR and BARI-MJI (r=-0.378; p<0.001), and between FFR and LL (r=-0.314; p<0.001). Positive correlation was found between FFR and baseline Pd/Pa (r=0.713; p<0.001), and between FFR and MLD (r=0.415; p<0.001). DILEMMA score had negative correlation with resting Pd/Pa (r=-0.389; p<0.001). In receiver operating characteristic analysis for diagnosing FFR≤0.80, area under curve values of resting Pd/Pa, DILEMMA score, MLD, BARI-MJI, and LL were 0.862, 0.793, 0.780, 0.728, and 0.686, respectively. DILEMMA score had moderately strong correlation with FFR and good accuracy in diagnosing significant FFR, but it had weak correlation with resting Pd/Pa.


Kernels for longitudinal data with variable sequence length and sampling intervals.
We develop several kernel methods for classification of longitudinal data and apply them to detect cognitive decline in the elderly. We first develop mixed-effects models, a type of hierarchical empirical Bayes generative models, for the time series. After demonstrating their utility in likelihood ratio classifiers (and the improvement over standard regression models for such classifiers), we develop novel Fisher kernels based on mixture of mixed-effects models and use them in support vector machine classifiers. The hierarchical generative model allows us to handle variations in sequence length and sampling interval gracefully. We also give nonparametric kernels not based on generative models, but rather on the reproducing kernel Hilbert space. We apply the methods to detecting cognitive decline from longitudinal clinical data on motor and neuropsychological tests. The likelihood ratio classifiers based on the neuropsychological tests perform better than than classifiers based on the motor behavior. Discriminant classifiers performed better than likelihood ratio classifiers for the motor behavior tests.


In vivo Effects of Repeated Thyronamine Administration in Male C57BL/6J Mice.
Thyronamines are decarboxylated and deiodinated metabolites of thyroid hormones (THs). Of all possible thyronamine variants, only 3-iodothyronamine (3-T1AM) and iodine-free thyronamine (T0AM) have been detected in vivo. While intensive research has been done on the (patho-)physiological action of 3-T1AM, the role of T0AM has been studied less intensively. We determined whether a single pharmacological dose (50 mg/kg, i.p.) or repeated administration (5 mg/kg/day, i.p., for 7 days) of T0AM affects metabolism, cardiovascular function, or thermoregulation in male C57BL/6J mice. Since selenium (Se) is important for proper TH function and Se metabolism is affected by TH, we additionally analyzed Se concentrations in liver, serum, and kidney using total reflection X-ray analysis. A single injection of T0AM had no effect on heart rate, temperature, or activity as assessed by radio telemetry. Likewise, daily administration of T0AM did not alter body weight, food or water intake, heart rate, blood pressure, brown adipose tissue thermogenesis, or body temperature, and no significant differences in hepatic glycogen content or mRNA expression of genes involved in cardiovascular function or metabolic control were determined. Also, the X-ray analysis of Se concentrations revealed no significant changes. However, hepatic T0AM was significantly increased in the treated animals. In summary, our data demonstrate that T0AM elicits no obvious metabolic, cardiovascular, or thermoregulatory activities in mice. As T0AM does also not interfere with TH or Se metabolism, we conclude that the deiodination of 3-T1AM to T0AM constitutes an efficient inactivation mechanism, terminating the actions of the more powerful precursor.


Ubiquitin - omics reveals novel networks and associations with human disease.
Human neurodegenerative and infectious diseases and tumorigenesis are associated with alterations in ubiquitin pathways. Over 10% of the genome encode for genes that either bind or manipulate ubiquitin to affect a large proportion of biological processes. This has been the basis for the development of approaches allowing the enrichment of ubiquitinated proteins for comparisons using proteomics and mass spectrometry. Tools such as tagged tandem ubiquitin binding domains, chemically derivatized ubiquitin or anti-gly-gly-lys antibodies combined with mass spectrometry have contributed to surveys of poly-ubiquitinated proteins, poly-ubiquitin linkage diversity and protein ubiquitination sites and their relation to other posttranslational modifications at a proteome wide level, providing insights in to how dynamic alterations in ubiquitination and deubiquitination steps are associated with normal physiology and pathogenesis.


Type I aortic dissection in a patient with human immunodeficiency virus infection.
The use of highly active antiretroviral therapy in patients with HIV infection has significantly reduced HIV-related infectious complications and improved their survival. With effective antiretroviral therapy, cardiovascular disease has gained prominence as a cause of morbidity and mortality in HIV-infected persons. Aortic dissection is an uncommon but potentially fatal disease with catastrophic complications. The spread of AIDS is a major public health problem in China, but there is scant literature regarding the clinical outcome for HIV/AIDS patients with aortic dissection in China. This case report describes a patient with HIV and type I aortic dissection who survived without surgical repair. This report is provided to describe a detailed and successful outcome for a patient with type I aortic dissection and HIV in China.


Filtering Web pages for quality indicators: an empirical approach to finding high quality consumer health information on the World Wide Web.
The World Wide Web is an increasingly popular source for consumer health information, but many authors have expressed concerns about the quality of health information present on the Internet. We have developed a prototype system that responds to a consumer health query by returning a list of Web pages that are ranked according to the likely quality of the page contents. A computer program identifies some of the criteria that have been suggested for assessing the quality of health information on the Internet. It also identifies characteristics that may serve as proxies for desirable (or undesirable) qualities that are difficult to assess directly using an algorithm. Intervening in the search process and automatically analyzing the contents of each page returned by a general search engine may facilitate the search for high quality consumer health information on the Web.


Space closure using aligners.
Due to the search for more aesthetic and comfortable alternatives to perform orthodontic treatments and to the great technological development, orthodontic aligners have assumed great importance. More and more complex treatments have been carried out with these appliances without, however, having all aspects involved in their use being studied in depth. Its biomechanical planning requires different approaches than those used in fixed orthodontics, as the force systems involved in movements, responses and side effects are distinct, and the professional must be prepared when opting for the technique. The objective of this article is to perform an evaluation of the force systems created on the space closure with aligners, its characteristics, and problems, as well as make some suggestions to overcome the difficulties inherent to its use. Space closure with aligners is possible, but depends on the correct selection of the patient, in addition to requiring the proper planning of the applied forces. The use of auxiliary resources and overcorrections to address the deficiencies of the aligner systems should always be considered. Digital planning should be used as a map of the force systems that will be applied, and not just as a marketing tool, keeping in mind that determining the objectives and the way to achieve them is the responsibility of the orthodontist, and that treatment plans must be individualized for each situation, following appropriate biomechanical precepts.


A study of depressive symptoms and smoking behavior in adult male twins from the NHLBI twin study.
Self-report measures of depressive symptoms, such as the Center for Epidemiological Studies-Depression Scale (CES-D), correlate with current and lifetime smoking status. In one previous study of adult female twins, genetic factors accounted for the covariation of liability to a diagnosis of major depressive disorder and liability to lifetime smoking (Kendler, Neale, MacLean, Heath, Eaves, & Kessler, 1993b, Archives of General Psychiatry, 50, 36-43); however, it remained unclear whether genetic effects also account for the covariation between subclinical depressive symptomology and smoking behavior. In this study, we use twin structural equation modeling to explore whether genetic and/or environmental influences contribute to the covariation between depressive symptoms, as measured by the CES-D, and current and lifetime smoking status among 120 monozygotic and 114 dizygotic Caucasian male twin pairs (aged 59-69). In this sample, depressive symptoms showed small but significant correlations with current and lifetime smoking status. Univariate twin analyses indicated that additive genetic and non-shared environmental factors contributed significantly to liability to current and lifetime smoking. However, the majority of variance in CES-D scores was attributable to non-shared (individual) environment. In bivariate analyses, non-shared environmental factors accounted for the majority of covariation between liability to depressive symptoms (CES-D scores > or = 8; above the 75th percentile) and liability to current and lifetime smoking status. Taken together with the previous literature, these results suggest that the etiology of covariation among depressive symptoms and smoking behavior may vary by measurement and severity of depressive symptomology.


Edward Ballard and the Practice of Epidemiology in the 19th-Century United Kingdom.
This article recovers the history of Victorian epidemiology through the career of British physician Edward Ballard (1820-1897). Ballard's career provides a useful window into the practices of epidemiology in the 19th century because he held notable public health posts as medical officer of health for Islington and inspector at the Medical Department of the Local Government Board. By the time of his death, in 1897, he typified the transition toward professional epidemiology. In exploring some of the most important environmental and health-related problems in preventive medicine in the 19th century, Ballard was part of a group of influential epidemiologists who studied infectious disease. In particular, he was noted for his research into typhoid fever and industrial health. Yet Ballard's career has largely been forgotten. In this article, I explore Ballard's work as a window into the everyday practices of Victorian epidemiology and suggest that the process of professionalizing epidemiology in the 20th century was about forgetting epidemiology's Victorian past as much as it was about championing it.


Dysfunctional stem and progenitor cells impair fracture healing with age.
Successful fracture healing requires the simultaneous regeneration of both the bone and vasculature; mesenchymal stem cells (MSCs) are directed to replace the bone tissue, while endothelial progenitor cells (EPCs) form the new vasculature that supplies blood to the fracture site. In the elderly, the healing process is slowed, partly due to decreased regenerative function of these stem and progenitor cells. MSCs from older individuals are impaired with regard to cell number, proliferative capacity, ability to migrate, and osteochondrogenic differentiation potential. The proliferation, migration and function of EPCs are also compromised with advanced age. Although the reasons for cellular dysfunction with age are complex and multidimensional, reduced expression of growth factors, accumulation of oxidative damage from reactive oxygen species, and altered signaling of the Sirtuin-1 pathway are contributing factors to aging at the cellular level of both MSCs and EPCs. Because of these geriatric-specific issues, effective treatment for fracture repair may require new therapeutic techniques to restore cellular function. Some suggested directions for potential treatments include cellular therapies, pharmacological agents, treatments targeting age-related molecular mechanisms, and physical therapeutics. Advanced age is the primary risk factor for a fracture, due to the low bone mass and inferior bone quality associated with aging; a better understanding of the dysfunctional behavior of the aging cell will provide a foundation for new treatments to decrease healing time and reduce the development of complications during the extended recovery from fracture healing in the elderly.


Cryo-electron microscopy--a primer for the non-microscopist.
Cryo-electron microscopy (cryo-EM) is increasingly becoming a mainstream technology for studying the architecture of cells, viruses and protein assemblies at molecular resolution. Recent developments in microscope design and imaging hardware, paired with enhanced image processing and automation capabilities, are poised to further advance the effectiveness of cryo-EM methods. These developments promise to increase the speed and extent of automation, and to improve the resolutions that may be achieved, making this technology useful to determine a wide variety of biological structures. Additionally, established modalities for structure determination, such as X-ray crystallography and nuclear magnetic resonance spectroscopy, are being routinely integrated with cryo-EM density maps to achieve atomic-resolution models of complex, dynamic molecular assemblies. In this review, which is directed towards readers who are not experts in cryo-EM methodology, we provide an overview of emerging themes in the application of this technology to investigate diverse questions in biology and medicine. We discuss the ways in which these methods are being used to study structures of macromolecular assemblies that range in size from whole cells to small proteins. Finally, we include a description of how the structural information obtained by cryo-EM is deposited and archived in a publicly accessible database.