Three-dimensional imaging in the context of minimally invasive and transcatheter cardiovascular interventions using multi-detector computed tomography: from pre-operative planning to intra-operative guidance.
The rapid expansion of less invasive surgical and transcatheter cardiovascular procedures for a wide range of cardiovascular conditions, including coronary, valvular, structural cardiac, and aortic disease has been paralleled by novel three-dimensional (3-D) approaches to imaging. Three-dimensional imaging allows acquisition of volumetric data sets and subsequent off-line reconstructions along unlimited 2-D planes and 3-D volumes. Pre-procedural 3-D imaging provides detailed understanding of the operative field for surgical/interventional planning. Integration of imaging modalities during the procedure allows real-time guidance. Because computed tomography routinely acquires 3-D data sets, it has been one of the early imaging modalities applied in the context of surgical and interventional planning. This review describes the continuum of applications from pre-operative planning to procedural integration, based on the emerging experience with computed tomography and rotational angiography, respectively. At the same time, the potential adverse effects of imaging with X-ray-based tomographic or angiographic modalities are discussed. It is emphasized that the role of imaging guidance in this context remains unclear and will need to be evaluated in clinical trials. This is in particular true, because data showing improved outcome or even non-inferiority for most of the emerging transcatheter procedures are still lacking.


Correlates of disrupted sleep-wake variables in patients with advanced cancer.
High rates of sleep difficulties have been found in patients with advanced cancer. However, not much is known about factors that are associated with sleep impairments in this population and that could constitute their potential risk factors or consequences. This study conducted in patients with cancer receiving palliative care aimed to evaluate the relationships of subjective (sleep diary; Insomnia Severity Index, ISI) and objective (actigraphy) sleep-wake variables with several physical and psychological symptoms, maladaptive sleep behaviours, erroneous beliefs about sleep, quality of life, time to death and environmental factors. The sample was composed of 57 community-dwelling patients with cancer receiving palliative care and with an Eastern Cooperative Oncology Group Scale score of 2 or 3. Actigraphic, light and sound recording and a daily sleep and pain diary were completed for seven consecutive days. A battery of self-report scales was also administered. Greater disruptions of subjective and objective sleep-wake variables were more consistently associated with worse physical symptoms than with psychological variables. Disrupted objective sleep-wake parameters were also associated with a greater frequency of maladaptive sleep behaviours. Finally, a greater nocturnal noise in the bedroom was correlated with more impairments in subjective and objective sleep-wake variables while a lower 24-hour light exposure was associated with more disruption of subjectively assessed sleep only. Although longitudinal studies are needed to establish the etiology of sleep-wake difficulties in patients with advanced cancer, our findings suggest that physical symptoms, maladaptive sleep behaviours and environmental factors can contribute to their development or their persistence and need to be adequately addressed.


Developing health systems research capacities through north-south partnership: an evaluation of collaboration with South Africa and Thailand.
Over the past ten years, calls to strengthen health systems research capacities in low and middle income countries have increased. One mechanism for capacity development is the partnering of northern and southern institutions. However, detailed case-studies of north-south partnerships, at least in the domain of health systems research, remain limited.This study aims to evaluate the partnerships developed between the Health Economics and Financing Programme of the London School of Hygiene and Tropical Medicine and three research partners in South Africa and Thailand to strengthen health economics-related research capacity. Data from programme documents were collected over five years to measure quantitative indicators of capacity development. Qualitative data were obtained from 25 in-depth interviews with programme staff from South Africa, Thailand and London. Five years of formal partnership resulted in substantial strengthening of individual research skills and moderate instituonalised strengthening in southern partner institutions. Activities included joint proposals, research and articles, staff exchange and post-graduate training. In Thailand, individual capacities were built through post-graduate training and the partner institution developed this as part of a package aimed at retaining young researchers at the institution. In South Africa, local post-graduate teaching programs were strengthened, regular staff visits/exchanges initiated and maintained and funding secured for several large-scale, multi-partner projects. These activities could not have been achieved without good personal relationships between members of the partner institutions, built on trust developed over twenty years. In South Africa, a critical factor was the joint appointment of a London staff member on long-term secondment to one of the partner institutions. As partnerships mature the needs of partners change and new challenges emerge. Partners' differing research priorities (national v international; policy-led v academic-led) need to be balanced and equitable funding mechanisms developed recognising the needs and constraints faced by both southern and northern partners. Institutionalising partnerships (through long-term development of trust, engagement of a broad range of staff in joint activities and joint appointment of staff), and developing responsive mechanisms for governing these partnerships (through regular joint negotiation of research priorities and funding issues), can address these challenges in mutually acceptable ways. Indeed, by late 2005 the partnership under scrutiny in this paper had evolved into a wider consortium involving additional partners, more explicit mechanisms for managing institutional relationships and some core funding for partners. Most importantly, this study has shown that it is possible for long-term north-south partnership commitments to yield fruit and to strengthen the capacities of public health research and training institutions in less developed countries.


Growth and development in preterm infants fed long-chain polyunsaturated fatty acids: a prospective, randomized controlled trial.
A randomized, masked, controlled trial was conducted to assess effects of supplementing premature infant formulas with oils containing the long-chain polyunsaturated fatty acids, arachidonic acid (AA; 20:4 n6), and docosahexaenoic acid (DHA; 22:6 n3) on growth, visual acuity, and multiple indices of development. Infants (N = 470) with birth weights 750 to 1800 g were assigned within 72 hours of the first enteral feeding to 1 of 3 formula groups with or without long-chain polyunsaturated fatty acids: 1) control (N = 144), 2) AA+DHA from fish/fungal oil (N = 140), and 3) AA+DHA from egg-derived triglyceride (egg-TG)/fish oil (N = 143). Infants were fed human milk and/or Similac Special Care with or without 0.42% AA and 0.26% DHA to term corrected age (CA), then fed human milk or NeoSure with or without 0.42% AA and 0.16% DHA to 12 months' CA. Infants fed exclusively human milk to term CA (EHM-T; N = 43) served as a reference. Visual acuity measured by acuity cards at 2, 4, and 6 months' CA was not different among groups. Visual acuity measured by swept-parameter visual-evoked potentials in a subgroup from 3 sites (45 control, 50 AA+DHA [fish/fungal]; 39 AA+DHA [egg-TG/fish]; and 23 EHM-T) was better in both the AA+DHA (fish/fungal; least square [LS] means [cycle/degree] +/- standard error [SE; octaves] 11.4 +/- 0.1) and AA+DHA (egg-TG/fish; 12.5 +/- 0.1) than control (8.4 +/- 0.1) and closer to that of the EHM-T group (16.0 +/- 0.2) at 6 months' CA. Visual acuity improved from 4 to 6 months' CA in all but the control group. Scores on the Fagan test of novelty preference were greater in AA+DHA (egg-TG/fish; LS means +/- SE, 59.4 +/- 7.7) than AA+DHA (fish/fungal; 57.0 +/- 7.5) and control (57.5 +/- 7.4) at 6 months' CA, but not at 9 months' CA. There were no differences in the Bayley Mental Development Index at 12 months' CA. However, the Bayley motor development index was higher for AA+DHA (fish/fungal; LS means +/- SE, 90.6 +/- 4.4) than control (81.8 +/- 4.3) for infants </=1250 g. When Spanish-speaking infants and twins were excluded from the analyses, the MacArthur Communicative Development Inventory revealed that control infants (LS means +/- SE, 94.1 +/- 2.9) had lower vocabulary comprehension at 14 months' CA than AA+DHA (fish/fungal) infants (100.6 +/- 2.9) or AA+DHA (egg-TG/fish) infants (102.2 +/- 2.8). There were no consistent differences in weight, length, head circumference, or anthropometric gains. These results showed a benefit of supplementing formulas for premature infants with AA and DHA from either a fish/fungal or an egg-TG/fish source from the time of first enteral feeding to 12 months' CA.


Epidemiology of alcohol-related emergency hospital admissions in children and adolescents: An e-cohort analysis in Wales in 2006-2011.
Harmful levels of alcohol consumption in young people are prevalent and of increasing public concern in the western world. Rates of alcohol-related emergency hospital admissions in children and young people between 10 to 17 years were described, and the reasons for these admissions and their association with socio-demographic factors were examined. E-cohort data were extracted from the Secure Anonymised Information Linkage Databank, which contained alcohol-related emergency hospital admissions (N = 2968) from 2006 to 2011 in children and adolescents aged 10 to 17 years in Wales. A generalised linear mixed model was fitted using a log-link with a population offset to the data to calculate incident rate ratios (IRRSs). There was a general decreasing trend from 2006 to 2011 in the number and rate of alcohol-related emergency hospital admissions; the mean age of admission was 15.4 (standard deviation 1.4) years. In each of the four youngest age groups (10-13,14,15,16 years), females had higher IRRs than males. Males had slightly higher IRR compared to females only in the oldest age group (17 years). IRRs increased with increasing deprivation. The majority (92%) of the admissions lasted one day and most of the admissions (70%) occured during the last three days of the week with a peak on Saturday. The length of stay in hospital was longer in cases when self-harm were present. Multiple admissions showed high prevalance of serious self-harm cases in females. The number of admissions with injuries and falls were higher for males than females. Female children and adolescents were more likely to be admitted to hospital for alcohol-related reasons. These data illustrate the significant burden of alcohol-related harm in young people and highlight the need for interventions and policies that promote safe drinking practices among young people to prevent future alcohol-related harm during the life-course.


Overweight, obesity, and neighborhood characteristics among postpartum Latinas.
Weight gain during the childbearing years and failure to lose pregnancy weight after birth contribute to the development of obesity in Latinas. Madres para la Salud (Mothers for Health) is a 12-month prospective, randomized controlled trial exploring a social support intervention with moderate-intensity physical activity to effect changes in body fat, systemic and fat tissue inflammation, and depression symptoms in sedentary postpartum Latinas. This paper describes the initial body composition of the sample, social support, and neighborhood contextual correlations of overweight and obese Latina mothers within the first 6 months after birth. The mean body mass index was 29.68 with 38.56% bioelectrical impedence analysis for body fat. Elements of the environment (e.g., opportunities to walk) received middle or high scores. Access to healthy food was positively related to favorability of the walking environment. Waist-to-hip ratio was uncorrelated with other obesity-related indices. The body adiposity of these Latina mothers was coupled with low levels of social support from family and friends and neighborhood characteristics that were unfavorable to walking.


Antiplatelet and anticoagulant therapy to prevent bypass graft thrombosis in patients with lower extremity arterial occlusive disease.
The incidence of graft failure for above knee femoropopliteal grafts is described by the European Consensus Document on Critical Limb Ischaemia. It occurs in approximately 15% of patients when vein is used for the grafting procedure and in 20% of patients when PTFA (polytetrafluoroethylene) or other prosthetic material is used. Femorodistal grafts have a much poorer outcome with 45% and 75% failure rates for vein and prosthetic grafts, respectively. Prevention of primary graft failure and thus the need for surgical reintervention is of major clinical and economic importance. Early failure, occurring within one month of operation, is usually due to technical error such as poor patient selection or operative technique. Approximately 10% of graft failures will fall into this time period. When grafts thrombose after two years, progression of native atherosclerosis either proximally or distally is the usual cause. This accounts for 2-3% of all graft failures each year. The most common time for grafts to fail is between one month and two years (80% of all failures) and this is the same period in which graft stenoses are now known to develop. There are few evidence-based recommendations for the use of pharmacological agents in maintaining graft patency following peripheral vascular surgery. This article reviews the evidence for or against the use of anticoagulant and antiplatelet therapy for the prevention of bypass graft thrombosis in patients with peripheral arterial occlusive disease.


Prevalence and burden of comorbidities in Chronic Obstructive Pulmonary Disease.
The classical definition of Chronic Obstructive Pulmonary Disease (COPD) as a lung condition characterized by irreversible airway obstruction is outdated. The systemic involvement in patients with COPD, as well as the interactions between COPD and its comorbidities, justify the description of chronic systemic inflammatory syndrome. The pathogenesis of COPD is closely linked with aging, as well as with cardiovascular, endocrine, musculoskeletal, renal, and gastrointestinal pathologies, decreasing the quality of life of patients with COPD and, furthermore, complicating the management of the disease. The most frequently described comorbidities include skeletal muscle wasting, cachexia (loss of fat-free mass), lung cancer (small cell or non-small cell), pulmonary hypertension, ischemic heart disease, hyperlipidemia, congestive heart failure, normocytic anemia, diabetes, metabolic syndrome, osteoporosis, obstructive sleep apnea, depression, and arthritis. These complex interactions are based on chronic low-grade systemic inflammation, chronic hypoxia, and multiple common predisposing factors, and are currently under intense research. This review article is an overview of the comorbidities of COPD, as well as their interaction and influence on mutual disease progression, prognosis, and quality of life.


Evaluation of the immunomodulatory and antiviral effects of the cytokine combination IFN-α and IL-7 in the lymphocytic choriomeningitis virus and Friend retrovirus mouse infection models.
Existing therapies for chronic viral infections are still suboptimal or have considerable side effects, so new therapeutic strategies need to be developed. One option is to boost the host's immune response with cytokines. We have recently shown in an acute ex vivo HIV infection model that co-administration of interferon (IFN)-α and interleukin (IL)-7 allows us to combine the potent anti-HIV activity of IFN-α with the beneficial effects of IL-7 on T-cell survival and function. Here we evaluated the effect of combining IFN-α and IL-7 on viral replication in vivo in the chronic lymphocytic choriomeningitis virus (LCMV) and acute Friend retrovirus (FV) infection models. In the chronic LCMV model, cytokine treatment was started during the early replication phase (i.e., on day 7 post-infection [pi]). Under the experimental conditions used, exogenous IFN-α inhibited FV replication, but had no effect on viral replication in the LCMV model. There was no therapeutic benefit of IL-7 either alone or in combination with IFN-α in either of the two infection models. In the LCMV model, dose-dependent effects of the cytokine combination on T-cell phenotype/function were observed. It is possible that these effects would translate into antiviral activity in re-challenged mice. It is also possible that another type of IFN-α/β or induction of endogenous IFN-α/β alone or in combination with IL-7 would have antiviral activity in the LCMV model. Furthermore, we cannot exclude that some effect on viral titers would have been seen at later time points not investigated here (i.e., beyond day 34 pi). Finally, IFN-α/IL-7 may inhibit the replication of other viruses. Thus it might be worth testing these cytokines in other in vivo models of chronic viral infections.


Inhibition of phagocytosis by Haemophilus ducreyi requires expression of the LspA1 and LspA2 proteins.
Haemophilus ducreyi previously has been shown to inhibit the phagocytosis of both secondary targets and itself by certain cells in vitro. Wild-type H. ducreyi strain 35000HP contains two genes, lspA1 and lspA2, whose encoded protein products are predicted to be 456 and 543 kDa, respectively. An isogenic mutant of H. ducreyi 35000HP with inactivated lspA1 and lspA2 genes has been shown to exhibit substantially decreased virulence in the temperature-dependent rabbit model for chancroid. This lspA1 lspA2 mutant was tested for its ability to inhibit phagocytosis of immunoglobulin G-opsonized particles by differentiated HL-60 and U-937 cells and by J774A.1 cells. The wild-type strain H. ducreyi 35000HP readily inhibited phagocytosis, whereas the lspA1 lspA2 mutant was unable to inhibit phagocytosis. Similarly, the wild-type strain was resistant to phagocytosis, whereas the lspA1 lspA2 mutant was readily engulfed by phagocytes. This inhibitory effect of wild-type H. ducreyi on phagocytic activity was primarily associated with live bacterial cells but could also be found, under certain conditions, in concentrated H. ducreyi culture supernatant fluids that lacked detectable outer membrane fragments. Both the wild-type strain and the lspA1 lspA2 mutant attached to phagocytes at similar levels. These results indicate that the LspA1 and LspA2 proteins of H. ducreyi are involved, directly or indirectly, in the antiphagocytic activity of this pathogen, and they provide a possible explanation for the greatly reduced virulence of the lspA1 lspA2 mutant.


Implications of artefacts reduction in the planning CT originating from implanted fiducial markers.
The efficacy of metal artefact reduction (MAR) software to suppress artefacts in reconstructed computed tomography (CT) images originating from small metal objects, like tumor markers and surgical clips, was evaluated. In addition, possible implications of using digital reconstructed radiographs (DRRs), based on the MAR CT images, for setup verification were analyzed. A phantom and 15 patients with different tumor sites and implanted markers were imaged with a multislice CT scanner. The raw image data was reconstructed both with the clinically used filtered-backprojection (FBP) and with the MAR software. Using the MAR software, improvements in image quality were often observed in CT slices with markers or clips. Especially when several markers were located near to each other, fewer streak artefacts were observed than with the FBP algorithm. In addition, the shape and size of markers could be identified more accurately, reducing the contoured marker volumes by a factor of 2. For the phantom study, the CT numbers measured near to the markers corresponded more closely to the expected values. However, the MAR images were slightly more smoothed compared with the images reconstructed with FBP. For 8 prostate cancer patients in this study, the interobserver variation in 3D marker definition was similar (<0.4 mm) when using DRRs based on either FBP or MAR CT scans. Automatic marker matches also showed a similar success rate. However, differences in automatic match results up to 1 mm, caused by differences in the marker definition, were observed, which turned out to be (borderline) statistically significant (p = 0.06) for 2 patients. In conclusion, the MAR software might improve image quality by suppressing metal artefacts, probably allowing for a more reliable delineation of structures. When implanted markers or clips are used for setup verification, the accuracy may slightly be improved as well, which is relevant when using very tight clinical target volume (CTV) to planning target volume (PTV) margins for planning.


Causes and treatments of lag screw's cut out after intramedullary nailing osteosinthesis for trochanteric fractures.
Background. Superior cut-out of a lag screw remains a serious complication in the treatment of trochanteric or subtrochanteric fractures and it is related to many factors: the type of fracture, osteoporosis and the stability of fracture reduction. Little is known about the outcome after revision surgery for complications of the gamma nail. We assessed the outcome in patients who had revision surgery because of lag screw's cut out after gamma nailing for a trochanteric fracture.Material and Method. We present a study of 20 consecutive patients who underwent treatment after 20 cut-out of the lag screw fixation of a trochanteric fracture with Gamma Locking Nail from September 2004 to November 2010. In 16 patients hip prothesis was performed, in 1 the removal of the implant and in 3 the reosteosynthesis. We reviewed 13 patients: 10 total hip arthroplasty, 2 endoprothesis and 1 reosteosynthesis of nail and lag screw (mean follow up: 26 months, mean age: 73 years old), 7 patients died. Patients were reviewed retrospectively by an independent observer. Clinical evaluation was performed, Oxford score and Harris Hip score were measured. X-Ray examination was performed after a minimum of 12 months of follow up.Results. Mean Harris Hip Score mean was 67 and mean Oxford score was 32 in hip prothesis group (12 patients). We had several complications, Implant-related complications were: 2 ipometria > 2cm, 2 recurrent hip arthroplasty dislocations (1 reoperated), 4 persistent thigh pain. In only 4 patients none complications were observed. Another patient, who had been subjected to reosteosinthesis, obtained better results (HHS:95, Oxford score:45) but with a 2 cm ipometria and occasional pain in the thigh.Conclusion. Cut out after gamma nail is consequent to biological or mechanical causes. Treatment of this complication is hip prosthesis (parzial or total hip arthroplasty), reosteosynthesis of the lag screw and/or the nail and the removal of the implant. Conversion to total/parzial hip arthroplasty may be a demanding operation with a higher complication rate respect to the standard, while reosteosynthesis is possible in selected patients and early cutting out.


Prevention of adverse effects of noise on children.
This article presents findings from a European project co-ordinated by the National Institute of Public Health, Denmark. The project "Children and noise--prevention of adverse effects" was partly financed by the European Commission Programme on Pollution-related Diseases and included partners or consultants from six European Union Member States: Denmark, Germany, Italy, the Netherlands, Sweden and the United Kingdom. The project used a definition of noise based on children's special development and provides examples of good practice on how to prevent the harmful effects of noise in children's daily settings. The settings analysed were day-care centres, primary schools and discotheques. Two methods were applied to obtain the effective examples of noise prevention or noise reduction: reviewing existing research and interviewing key people with knowledge and experience that has not yet appeared in the literature. A range of cases of preventing the adverse effects of noise assessed before and after the intervention provide a number of good practices, including information and awareness-raising campaigns and the identification of key concepts and key players in the prevention of noise. The examples of good practice have been effective in reducing noise, reducing the effects of noise, increasing the awareness of the importance of noise reduction or increasing action to reduce noise. The examples are based on a common format for reviewing preventive measures and can serve as direct inspiration for action to prevent noise in children's daily settings.


Molluscan phylogeny: the paleontological viewpoint.
Stasek (1) theorized that the extant mollusks are the progeny of three separate lineages that separated before the phylum was well established. He wrote that no known intermediate forms, fossil or living, bridge the "enormous gaps between any two of the three lineages," and therefore treated each as a separate subphylum. These subphyla are (i) the subphylum Aculifera Hatscheck 1891, containing only the class Aplacophora, derived from the most primitive ancestors of the Mollusca; (ii) the subphylum Placophora von Jhering 1876, containing only the class Polyplacophora, and emphasizing the pseudometamerism of its more advanced premollusk ancestor; and (iii) the subphylum Conchifera Gegenbaur 1878, containing the Monoplacophora and the other classes derived from it. We point out that the Polyplacophora may be derived from the Monoplacophora instead of a more primitive ancestral stock. We also suggest that the Conchifera can be separated into two major lineages, each worthy of the rank of subphylum. The fossil record indicates that the Monoplacophora gave rise to the Gastropoda, Cephalopoda, Rostroconchia, and possibly Polyplacophora, and that the Pelecypoda and Scaphopoda are derived from the Rostroconchia. These last three classes thus form a lineage that diverged from the Monoplacophora in the Early Cambrian. They emphasized a shell form that in all groups is primitively open at both ends, allowing the gut to remain relatively straight, with an anterior mouth and posterior anus. They became burrowing (infaunal) deposit or filter feeders. We coin the term Diasoma (through-body) for the subphylum containing these three classes (Rostroconchia, Pelecypoda, and Scaphopoda). The remaining three classes (Monoplacophora, Gastropoda, and Cephalopoda) emphasize a conical univalved shell, usually twisted into a spiral. The relatively small single aperture forces the anus to lie close to the mouth, and the gut is bent into a "U." Most are surface-dwelling (epifaunal) grazers or carnivores. We coin the name Cyrtosoma (hunchback-body) for the subphylum containing these three classes. Strictly speaking, the cyrtosomes are the ancestors of the diasomes but, in fact, both subphyla appeared and began to diversify within a few million years in the Early Cambrian. Note added in proof: After proofs were corrected we were informed that the new genus Opikella (40) is preoccupied by (Opikella = Oepikella) Thorslund 1940, an Ordovican ostracod. We rename the mollusk genus Oepikila.


Syngas Production From the Reforming of Typical Biogas Compositions in an Inert Porous Media Reactor.
Syngas production by inert porous media combustion of rich biogas-air mixtures was studied experimentally, focusing on carbon dioxide utilization and process efficiency. Different gas mixtures of natural gas and carbon dioxide, which simulated a typical biogas composition of 100:0, 70:30, 55:45, and 40:60 (CH4:CO2), were comparatively analyzed considering combustion waves temperatures and velocities, and chemical concentrations products, at high equivalence ratios of φ = 1.5 and φ = 2.0. Different CO2 concentrations on biogas composition showed higher H2 productions than on pure methane (100:0), mainly due to CO2 reforming reactions. Also, syngas production, hydrogen yields, and process efficiency by means of biogas filtration combustion were higher than under methane filtration combustion. Results of the thermochemical conversion of biogas show an alternative and promising non-catalytic technique to CO2 utilization.


K5/K14-positive cells contribute to salivary gland-like breast tumors with myoepithelial differentiation.
Salivary gland-like tumors of the breast show a great variety of architectural patterns and cellular differentiations such as glandular, myoepithelial, squamous, and even mesenchymal phenotypes. However, currently little is known about the evolution and cellular differentiation of these tumors. For that reason, we performed an in situ triple immunofluorescence lineage/differentiation tracing (isTILT) and qRT-PCR study of basal (K5/K14), glandular (K7/K8/18), and epidermal-specific squamous (K10) keratins, p63, and smooth muscle actin (SMA; myoepithelial marker) with the aim to construct and trace different cell lineages and define their cellular hierarchy in tumors with myoepithelial differentiation. isTILT analysis of a series of 28 breast, salivary, and lacrimal gland tumors, including pleomorphic adenomas (n=8), epithelial-myoepithelial tumors (n=9), and adenoid cystic carcinomas (n=11) revealed that all tumor types contained K5/K14-positive progenitor cells in varying frequencies from a few percent up to 15%. These K5/K14-positive tumor cells were found to differentiate to glandular- (K8/18-positive) and myoepithelial-lineage (SMA-positive)-specific cells and were also shown to generate various heterologeous cell differentiations such as squamous and mesenchymal progenies. p63 was co-expressed with K5/K14 in basal-like progenitor cells, myoepithelial, and squamous cells but not in glandular cells. Our results show that the corresponding counterpart tumors of breast and salivary/lacrimal glands have identical cellular compositions. Taken together, our isTILT and RNA-expression data indicate that look-alike tumors of the breast represent a special subgroup of basal-type tumors with benign or usually low malignant potential.


The Benefits and Risks of Prophylactic Central Neck Dissection for Papillary Thyroid Carcinoma: Prospective Cohort Study.
Objectives. This study evaluated the benefits of performing prophylactic central neck dissection (CND) with total thyroidectomy (TT) in management of papillary thyroid carcinoma (PTC) patients who were clinically node-negative at presentation. Methods. A total of 257 patients with stage T1 or T2 PTC and without preoperative evidence of lymph node involvement (N0) were enrolled in this prospective study. The patients were randomly assigned to two groups: (1) a total thyroidectomy (TT) group (n = 104) or (2) a TT plus CND group (n = 153). The two groups were compared for their perioperative data, complication rates, disease recurrence rates, and clinical outcomes. Results. The two groups of patients were similar in age, sex ratio, follow-up duration, and tumor size (P = 0.227, 0.359, 0.214, and 0.878, resp.). The two groups showed similar rates of disease recurrence (3.9% in the TT group versus 3.3% in the TT plus CND group); however, complications occurred more frequently in the TT plus CND group; especially transient hypocalcemia (P = 0.043). Conclusions. Patients treated with TT plus CND had a higher rate of complications with similar recurrence rate. We believe that CND may not be routinely recommended when treating patients with PTC.


A novel transposon trap for mycobacteria: isolation and characterization of IS1096.
In the course of developing strategies to obtain a mutation in the aspartate semialdehyde dehydrogenase (asd) gene of Mycobacterium smegmatis, an efficient transposon trap was constructed which may be generally useful for the identification of transposable elements in mycobacteria. A DNA fragment containing the asd gene was replaced with an aminoglycoside phosphotransferase gene (aph) to generate a delta asd::aph allele. Attempts to replace the wild-type asd gene with the delta asd::aph allele were unsuccessful, suggesting that this deletion was lethal to the growth of M. smegmatis. The plasmid, pYUB215, which contains beta-galactosidase expressed from a mycobacteriophage promoter and delta asd::aph, was integrated into the chromosome of M. smegmatis by a homologous, single-crossover, recombination event. Visual screening for inactivation of the beta-galactosidase gene in the resulting strain allowed the isolation of a novel mycobacterial insertion element from M. smegmatis. This insertion element, which is unique to M. smegmatis, was designated IS1096 and transposes at a frequency of 7.2 x 10(-5) per cell in an apparently random fashion. IS1096 is 2,275 bp in length and contains two open reading frames which are predicted to encode proteins involved in transposition. This insertion element exhibits several characteristics that suggest it may be a useful tool for genetic analysis of mycobacteria, possibly including the study of mechanisms of pathogenesis.


Normal human epidermis contains an interferon-like protein.
Interferons have been postulated to participate in growth regulation of normal body tissues and are known to inhibit growth of human epidermal keratinocytes in vitro. Polyclonal antibodies to recombinant human interferon-alpha, purified by passage over an affinity column (Sepharose coupled to the recombinant interferon), used in the indirect immunofluorescent method specifically stained the proliferative (basal) compartment of human epidermis in histological cross-sections of normal skin and in cultured keratinocyte colonies. Extracts prepared from healthy nonvirally infected keratinocyte cultures contained interferon activity as determined by viral plaque inhibition assay. Using the Western blotting technique column-purified antibodies and antisera to recombinant human interferon-alpha recognized a band of approximately 40 kD when reacted with both extracted keratinocyte proteins and recombinant human interferon-alpha standards, that gave in addition a band of approximately 20 kD. The above findings suggest that interferon or a closely related protein is present in the proliferative compartment of normal epidermis in the absence of viral infection and therefore may serve as a physiological modulator of epidermal growth.


Retinotopic fMRI Reveals Visual Dysfunction and Functional Reorganization in the Visual Cortex of Mild to Moderate Glaucoma Patients.
To investigate retinotopic functional representation in the visual cortex of mild to moderate primary open-angle glaucoma (POAG) participants and age-matched normal volunteers using high-resolution retinotopic blood oxygenation level dependent (BOLD) functional magnetic resonance imaging (fMRI). fMRI was performed on 9 POAG participants (61±11 y old) and 9 age-matched controls (58±5 y old) were studied. A wide-view visual presentation (±55 degrees) was used to evaluate central and peripheral vision. Cortical magnification factors and BOLD% changes as a function of eccentricity. Correlation analysis between BOLD% changes and visual field scores, and between BOLD% changes and retinal nerve fiber layer thicknesses was performed. Comparison of BOLD% changes for individual visual field quadrants between POAG subgroups and normal group was performed. BOLD% changes of POAG participants in peripheral visual regions were reduced compared to normals but similar in central visual regions, consistent with the notion of peripheral vision being affected first and more compared to central vision. fMRI retinotopic mapping revealed enlarged representation of the parafovea in the visual cortex of POAG participants compared to normals. Cortical magnification of the central, but not peripheral, visual representation in the visual cortex was larger in POAG participants, suggesting functional remapping. BOLD% changes of individual visual field quadrants were significantly correlated with visual field scores and with retinal nerve fiber layer thickness in the corresponding quadrants. These results support the hypothesis that there are functional alteration and remapping in the topographic representation of the visual cortex in POAG participants, and these changes are correlated with disease severity.


Usability and Acceptability of a Corneal-Plane α-Opic Light Logger in a 24-h Field Trial.
Exposure to light fundamentally influences human physiology and behaviour by synchronising our biological clock to the external light-dark cycle and controlling melatonin production. In addition to well-controlled laboratory studies, more naturalistic approaches to examining these "non-visual" effects of light have been developed in recent years. As naturalistic light exposure is quite unlike well-controlled stimulus conditions in the laboratory, it is critical to measure light exposure in a person-referenced way, the "spectral diet." To this end, light loggers have been developed to capture personalised light exposure. As an alternative to light sensors integrated into wrist-worn actimeters, pendants, or brooch-based light loggers, a recently developed wearable light logger laterally attached to spectacle frames enables the measurement of biologically relevant quantities in the corneal plane. Here, we examine the usability and acceptability of using the light logger in an undergraduate student sample (n = 18, mean±1SD: 20.1 ± 1.7 years; 9 female; Oxford, UK) in real-world conditions during a 24-h measurement period. We probed the acceptability of the light logger using rating questionnaires and open-ended questions. Our quantitative results show a modest acceptability of the light logger. A thematic analysis of the open-ended questions reveals that the form factor of the device, in particular, size, weight, and stability, and reactions from other people to the wearer of the light logger, were commonly mentioned aspects. In sum, the results indicate the miniaturisation of light loggers and "invisible" integration into extant everyday objects as key areas for future technological development, facilitating the availability of light exposure data for developing personalised intervention strategies in both research, clinical and consumer contexts.


Optimizing infectious disease interventions during an emerging epidemic.
The emergence and global impact of the novel influenza A(H1N1)v highlights the continuous threat to public health posed by a steady stream of new and unexpected infectious disease outbreaks in animals and humans. Once an emerging epidemic is detected, public health authorities will attempt to mitigate the epidemic by, among other measures, reducing further spread as much as possible. Scarce and/or costly control measures such as vaccines, anti-infective drugs, and social distancing must be allocated while epidemiological characteristics of the disease remain uncertain. Here we present first principles for allocating scarce resources with limited data. We show that under a broad class of assumptions, the simple rule of targeting intervention measures at the group with the highest risk of infection per individual will achieve the largest reduction in the transmission potential of a novel infection. For vaccination of susceptible persons, the appropriate risk measure is force of infection; for social distancing, the appropriate risk measure is incidence of infection. Unlike existing methods that rely on detailed knowledge of group-specific transmission rates, the method described here can be implemented using only data that are readily available during an epidemic, and allows ready adaptation as the epidemic progresses. The need to observe risk of infection helps to focus the ongoing planning and design of new infectious disease surveillance programs; from the presented first principles for allocating scarce resources, we can adjust the prioritization of groups for intervention when new observations on an emerging epidemic become available.


A cell-type-specific role for murine Commd1 in liver inflammation.
The transcription factor NF-κB plays a critical role in the inflammatory response and it has been implicated in various diseases, including non-alcoholic fatty liver disease (NAFLD). Although transient NF-κB activation may protect tissues from stress, a prolonged NF-κB activation can have a detrimental effect on tissue homeostasis and therefore accurate termination is crucial. Copper Metabolism MURR1 Domain-containing 1 (COMMD1), a protein with functions in multiple pathways, has been shown to suppress NF-κB activity. However, its action in controlling liver inflammation has not yet been investigated. To determine the cell-type-specific contribution of Commd1 to liver inflammation, we used hepatocyte and myeloid-specific Commd1-deficient mice. We also used a mouse model of NAFLD to study low-grade chronic liver inflammation: we fed the mice a high fat, high cholesterol (HFC) diet, which results in hepatic lipid accumulation accompanied by liver inflammation. Depletion of hepatocyte Commd1 resulted in elevated levels of the NF-κB transactivation subunit p65 (RelA) but, surprisingly, the level of liver inflammation was not aggravated. In contrast, deficiency of myeloid Commd1 exacerbated diet-induced liver inflammation. Unexpectedly we observed that hepatic and myeloid Commd1 deficiency in the mice both augmented hepatic lipid accumulation. The elevated levels of proinflammatory cytokines in myeloid Commd1-deficient mice might be responsible for the increased level of steatosis. This increase was not seen in hepatocyte Commd1-deficient mice, in which increased lipid accumulation appeared to be independent of inflammation. Our mouse models demonstrate a cell-type-specific role for Commd1 in suppressing liver inflammation and in the progression of NAFLD.


Aggressive EBV-associated lymphoproliferative disorder: a prodrome to diffuse large B-cell lymphoma?
A 19-year-old male patient presented with intermittent high fever and left cervical lymphadenopathy. The lymph node biopsy findings were interpreted as "Epstein-Barr virus (EBV)-associated lymphoproliferative disorder consistent with infectious mononucleosis." No molecular studies were performed at that time. The patient was followed without treatment. Five months later, the patient again presented with fever, lymphadenopathy, and splenomegaly. The lymph node biopsy showed features of a diffuse large B-cell lymphoma. Molecular studies on this lymph node biopsy showed a clonal EBV population, although polymerase chain reaction studies failed to reveal a clonal B-cell or T-cell population. A concurrent bone marrow biopsy showed features consistent with hemophagocytic syndrome. He had elevated ferritin, soluble interleukin-2 receptors and persistent EBV viremia. The patient responded to Rituxan for a short period with undetectable EBV levels. Subsequent right cervical lymph node, liver, and jejunal biopsies showed involvement by diffuse large B-cell lymphoma and the patient expired soon thereafter.


Fosfomycin: A First-Line Oral Therapy for Acute Uncomplicated Cystitis.
Fosfomycin is a new agent to Canada approved for the treatment of acute uncomplicated cystitis (AUC) in adult women infected with susceptible isolates of E. coli and Enterococcus faecalis. We reviewed the literature regarding the use of oral fosfomycin for the treatment of AUC. All English-language references from 1975 to October 2015 were reviewed. In Canada, fosfomycin tromethamine is manufactured as Monurol® and is available as a 3-gram single dose sachet. Fosfomycin has a unique chemical structure, inhibiting peptidoglycan synthesis at an earlier site compared to β-lactams with no cross-resistance with other agents. Fosfomycin displays broad-spectrum activity against ESBL-producing, AmpC-producing, carbapenem-non-susceptible, and multidrug-resistant (MDR) E. coli. Resistance to fosfomycin in E. coli is rare (<1%). Fosfomycin is excreted unchanged in the urine by glomerular filtration with peak urinary concentration ~4000 µg/mL and remains at concentrations >100 µg/mL for 48 hours after a single 3-gram oral dose. No dosage adjustments are required in elderly patients, in pregnant patients, or in either renal or hepatic impairment. Fosfomycin demonstrates a favorable safety profile, and clinical trials have demonstrated efficacy in AUC that is comparable to ciprofloxacin, nitrofurantoin, and trimethoprim-sulfamethoxazole. Fosfomycin's in vitro activity against common uropathogens, including MDR isolates, its favorable safety profile including pregnancy patients, drug interactions, and clinical trials data demonstrating efficacy in AUC, has resulted in Canadian, US, and European guidelines/authorities recommending fosfomycin as a first line agent for the treatment of AUC.


Mechanism of action of cerebral epoxyeicosatrienoic acids on cerebral arterial smooth muscle.
Microsomal preparations of cat brain incubated with [14C]arachidonic acid produced epoxyeicosatrienoic acids (EETs) that eluted with the same retention times as synthetically prepared 5,6-, 8,9-, and 11,12-EETs. These compounds dilated serotonin-preconstricted, pressurized cat cerebral arteries in a dose-dependent fashion. Epoxide formation was not found in mitochondrial fractions and was dependent on the presence of NADPH. The maximum effects of 8,9-EET and 11,12-EET were greater than those of 5,6-EET. The cellular basis of this vasodilation was further investigated by examining the effects of 8,9-EET and 11,12-EET on K+ channel activity in vascular muscle cells freshly isolated from cat cerebral arteries. Both 8,9-EET and 11,12-EET increased the frequency of opening, mean open time, and open-state probability of a 98-pS K+ channel recorded in the cell-attached mode with 145 mM KCl in the pipette and 4.7 mM KCl in the bath. Blockade of K+ channel activity with tetraethylammonium attenuated the vasodilatory effects of 11,12-EET on serotonin-preconstricted cat cerebral arteries. These results suggest that endogenously formed EETs may participate in local regulation of cerebral blood flow by dilating cerebral arteries through a mechanism that involves activation of K+ channels.


Tunable Multiband Halide Perovskite Tandem Photodetectors with Switchable Response.
Photodetectors with multiple spectral response bands have shown promise to improve imaging and communications through the switchable detection of different photon energies. However, demonstrations to date have been limited to only two bands and lack capability for fast switching in situ. Here, we exploit the band gap tunability and capability of all-perovskite tandem solar cells to demonstrate a new device concept realizing four spectral bands of response from a single multijunction device, with fast, optically controlled switching between the bands. The response to monochromatic light is highly selective and narrowband without the need for additional filters and switches to broader response bands on applying bias light. Sensitive photodetection above 6 × 1011 Jones is demonstrated in all modes, with rapid switching response times of <250 ns. We demonstrate proof of principle on how the manipulation of the modular multiband detector response through light conditions enables diverse applications in optical communications with secure encryption.


CIRCULATORY ADAPTATION TO DIVING IN THE FRESHWATER TURTLE.
The heart of the freshwater turtle has a functional ventricular septal defect. In ambient air there is some shunting of blood from the left to the right ventricle through the defect. During prolonged diving or N(2) inhalation, the shunt is reversed and blood from the tissues bypasses the lung and enters the aorta directly. This adaptation appears to be based on the exclusive use of anaerobic glycolysis as an energy source during prolonged diving.


Individual variability of venom from the European adder (Vipera berus berus) from one locality in Eastern Hungary.
We have revealed intra-population variability among venom samples from several individual European adders (Vipera berus berus) within a defined population in Eastern Hungary. Individual differences in venom pattern were noticed, both gender-specific and age-related, by one-dimensional electrophoresis. Gelatin zymography demonstrated that these individual venoms have different degradation profiles indicating varying protease activity in the specimens from adders of different ages and genders. Some specimens shared a conserved region of substrate degradation, while others had lower or extremely low protease activity. Phospholipase A2 activity of venoms was similar but not identical. Interspecimen diversity of the venom phospholipase A2-spectra (based on the components' molecular masses) was detected by MALDI-TOF MS. The lethal toxicity of venoms (LD50) also showed differences among individual snakes. Extracted venom samples had varying neuromuscular paralysing effect on chick biventer cervicis nerve-muscle preparations. The paralysing effect of venom was lost when calcium in the physiological salt solution was replaced by strontium; indicating that the block of twitch responses to nerve stimulation is associated with the activity of a phospholipase-dependent neurotoxin. In contrast to the studied V. b. berus venoms from different geographical regions so far, this is the first V. b. berus population discovered to have predominantly neurotoxic neuromuscular activity. The relevance of varying venom yields is also discussed. This study demonstrates that individual venom variation among V. b. berus living in particular area of Eastern Hungary might contribute to a wider range of clinical manifestations of V. b. berus envenoming than elsewhere in Europe.


Spectral characteristics and photosensitization of TiO2 nanoparticles in reverse micelles by perylenes.
We report on the photosensitization of titanium dioxide nanoparticles (TiO2 NPs) synthesized inside AOT (bis(2-ethylhexyl) sulfosuccinate sodium salt) reverse micelles following photoexcitation of perylene derivatives with dicarboxylate anchoring groups. The dyes, 1,7-dibromoperylene-3,4,9,10-tetracarboxy dianhydride (1), 1,7-dipyrrolidinylperylene-3,4,9,10-tetracarboxy dianhydride (2), and 1,7-bis(4-tert-butylphenyloxy)perylene-3,4,9,10-tetracarboxy dianhydride (3), have considerably different driving forces for photoinduced electron injection into the TiO2 conduction band, as estimated by electrochemical measurements and quantum mechanical calculations. Fluorescence anisotropy measurements indicate that dyes 1 and 2 are preferentially solubilized in the micellar structure, creating a relatively large local concentration that favors the attachment of the dye to the TiO2 surface. The binding process was followed by monitoring the hypsochromic shift of the dye absorption spectra over time for 1 and 2. Photoinduced electron transfer from the singlet excited state of 1 and 2 to the TiO2 conduction band (CB) is indicated by emission quenching of the TiO2-bound form of the dyes and confirmed by transient absorption measurements of the radical cation of the dyes and free carriers (injected electrons) in the TiO2 semiconductor. Steady state and transient spectroscopy indicate that dye 3 does not bind to the TiO2 NPs and does not photosensitize the semiconductor. This observation was rationalized as a consequence of the bulky t-butylphenyloxy groups which create a strong steric impediment for deep access of the dye within the micelle structure to reach the semiconductor oxide surface.


A robust measure of food web intervality.
Intervality of a food web is related to the number of trophic dimensions characterizing the niches in a community. We introduce here a mathematically robust measure for food web intervality. It has previously been noted that empirical food webs are not strictly interval; however, upon comparison to suitable null hypotheses, we conclude that empirical food webs actually do exhibit a strong bias toward contiguity of prey, that is, toward intervality. Further, our results strongly suggest that empirically observed species and their diets can be mapped onto a single dimension. This finding validates a critical assumption in the recently proposed static niche model and provides guidance for ongoing efforts to develop dynamic models of ecosystems.


Long-term outcomes after transcatheter aortic valve implantation: insights on prognostic factors and valve durability from the Canadian multicenter experience.
This study sought to evaluate the long-term outcomes after transcatheter aortic valve implantation (TAVI) in the Multicenter Canadian Experience study, with special focus on the causes and predictors of late mortality and valve durability. Very few data exist on the long-term outcomes associated with TAVI. This was a multicenter study including 339 patients considered to be nonoperable or at very high surgical risk (mean age: 81 ± 8 years; Society of Thoracic Surgeons score: 9.8 ± 6.4%) who underwent TAVI with a balloon-expandable Edwards valve (transfemoral: 48%, transapical: 52%). Follow-up was available in 99% of the patients, and serial echocardiographic exams were evaluated in a central echocardiography core laboratory. At a mean follow-up of 42 ± 15 months 188 patients (55.5%) had died. The causes of late death (152 patients) were noncardiac (59.2%), cardiac (23.0%), and unknown (17.8%). The predictors of late mortality were chronic obstructive pulmonary disease (hazard ratio [HR]: 2.18, 95% confidence interval [CI]: 1.53 to 3.11), chronic kidney disease (HR: 1.08 for each decrease of 10 ml/min in estimated glomerular filtration rate, 95% CI: 1.01 to 1.19), chronic atrial fibrillation (HR: 1.44, 95% CI: 1.02 to 2.03), and frailty (HR: 1.52, 95% CI: 1.07 to 2.17). A mild nonclinically significant decrease in valve area occurred at 2-year follow-up (p < 0.01), but no further reduction in valve area was observed up to 4-year follow-up. No changes in residual aortic regurgitation and no cases of structural valve failure were observed during the follow-up period. Approximately one-half of the patients who underwent TAVI because of a high or prohibitive surgical risk profile had died at a mean follow-up of 3.5 years. Late mortality was due to noncardiac comorbidities in more than one-half of patients. No clinically significant deterioration in valve function was observed throughout the follow-up period.


Small molecule peptidomimetics containing a novel phosphotyrosine bioisostere inhibit protein tyrosine phosphatase 1B and augment insulin action.
Protein tyrosine phosphatase 1B (PTP1B) attenuates insulin signaling by catalyzing dephosphorylation of insulin receptors (IR) and is an attractive target of potential new drugs for treating the insulin resistance that is central to type II diabetes. Several analogues of cholecystokinin(26)(-)(33) (CCK-8) were found to be surprisingly potent inhibitors of PTP1B, and a common N-terminal tripeptide, N-acetyl-Asp-Tyr(SO(3)H)-Nle-, was shown to be necessary and sufficient for inhibition. This tripeptide was modified to reduce size and peptide character, and to replace the metabolically unstable sulfotyrosyl group. This led to the discovery of a novel phosphotyrosine bioisostere, 2-carboxymethoxybenzoic acid, and to analogues that were >100-fold more potent than the CCK-8 analogues and >10-fold selective for PTP1B over two other PTP enzymes (LAR and SHP-2), a dual specificity phosphatase (cdc25b), and a serine/threonine phosphatase (calcineurin). These inhibitors disrupted the binding of PTP1B to activated IR in vitro and prevented the loss of tyrosine kinase (IRTK) activity that accompanied PTP1B-catalyzed dephosphorylation of IR. Introduction of these poorly cell permeant inhibitors into insulin-treated cells by microinjection (oocytes) or by esterification to more lipophilic proinhibitors (3T3-L1 adipocytes and L6 myocytes) resulted in increased potency, but not efficacy, of insulin. In some instances, PTP1B inhibitors were insulin-mimetic, suggesting that in unstimulated cells PTP1B may suppress basal IRTK activity. X-ray crystallography of PTP1B-inhibitor complexes revealed that binding of an inhibitor incorporating phenyl-O-malonic acid as a phosphotyrosine bioisostere occurred with the mobile WPD loop in the open conformation, while a closely related inhibitor with a 2-carboxymethoxybenzoic acid bioisostere bound with the WPD loop closed, perhaps accounting for its superior potency. These CCK-derived peptidomimetic inhibitors of PTP1B represent a novel template for further development of potent, selective inhibitors, and their cell activity further justifies the selection of PTP1B as a therapeutic target.


Parental influence on a child's autistic traits.
Robbie is a 4-year-old boy whose parents are concerned about his speech, social skills, and repetitive behaviors. He has poor articulation; at time, he is difficult to understand. On the other hand, he has a fair vocabulary, and he has good intent to communicate. He is generally able to communicate his needs and wants. He likes to tell his parents about his day. When he begins the day at preschool, Robbie initially stands by himself and watches. He slowly warms up and eventually participates in activities. He engages in parallel play or follows other children. He knows names of children at preschool, and he is well liked. He is affectionate with his parents. When Robbie is excited, he wiggles his fingers, flaps his arms, and grimaces. He can be quite rigid; for example, he gets very distressed when his mother sets his cup down on his right side instead of his left. However, in general, Robbie has a sunny personality. He likes to watch children's television shows. He pretends plays with action figures. Robbie is an only child who lives with both parents. His mother works full-time, and his father is in home with Robbie during the day. When examined in the office, Robbie had a bright affect, good eye contact, and social referencing. He demonstrated good communicative intent, but poor articulation and some jargoning. He frequently wiggled his fingers and flapped his hands with excitement. Robbie had a borderline score on the Autism Diagnostic Observation Schedule. During the visit, the pediatrician noted that Robbie's father was rather quiet and rarely responded to questions. When he did respond, he had a monotone quality to his voice. He maintained either a flat or nervous affect throughout the visit. He made limited eye contact, and occasionally he stared excessively.


Can we turn down autonomous wishes to donate anonymously?
Imagine a Samaritan living kidney donor, who some time ago has anonymously donated one of his kidneys to a patient on top of the waiting list. He now contacts the transplantation centre once again, to donate part of his liver. The Centre, startled by this idea, refers him to the regular screening procedure for all Samaritan donations. It turns out that his wish is well-informed, voluntarily made and that he is competent to decide. We acknowledge that a donor's wish should not be followed in all cases, even though this wish is a clear expression of his own free will. However, a refusal must be based on sound moral reasons and it is less clear what reasons these might be. We outline the most common arguments for refusal, assess these arguments in terms of strengths and weaknesses, and show which arguments, if any at all, are most promising. We conclude, firstly, that we should only assess risks (which include motivations), not judge relationships, and secondly, that it is not a transplant centre's mission to carry out a donor's life project.


Validation of a Test Method for Collection and Analysis of Chloroform Emissions From Stationary Sources.
A test method based upon the adsorption of chloroform onto charcoal was evaluated for the collection and analysis of chloroform emissions from stationary sources. In this method, a source gas sample is pulled through adsorption tubes containing activated charcoal (to adsorb the chloroform), and chloroform is extracted from the charcoal with a hexane/methanol mixture. The extract is analyzed by gas chromatography with an electron capture detector. Procedures in Environmental Protection Agency (EPA) Method 301 were utilized to test the suitability of the method under field conditions at two sampling sites (paper mills). EPA Method 301 requires that four separate trains ("quad train") operate simultaneously in each run. During each run, two of the four sampling trains were spiked with a known amount of gaseous chloroform. The quad train sampling was performed six or more times. In the first field test, the stack emissions of chloroform were approximately 300 ppm, the mean spike recovery was 82%, the precision of the method for unspiked samples was within 5%, and the sampling bias was -43 ppm. Modifications were made to the sampling method and the spike gas introduction system. The revised method was then tested at a second field site which had chloroform emissions of approximately 220 ppm. The mean spike recovery improved to 95%, the unspiked sample precision was within 5%, and the sampling bias improved to -8.5 ppm.


Absence of long-term gonadotoxicity in primates receiving extracorporeal shock wave application.
Extracorporeal shock wave lithotripsy (SWL) is becoming popular in the management of lower ureteral calculi; however, the quantity of data on its potential gonadotoxic effects are limited. Eight nonhuman primates had baseline measurements of testicular volume, semen analysis, serum testosterone and FSH assays, and DNA flow cytometric analysis of testicular aspirates. The anesthetized primates were lowered into a Dornier XL-1 lithotripter and at a 20 kV power setting had various numbers of shocks (0, 500, 1500) directed at each testis. Sequential studies were done at 6-week intervals for 9 months. The control group showed no significant change in any measure. Semen analysis, testosterone, and FSH results were variable and without statistically significant differences. There were changes in the DNA histograms, with the tetraploid (4N) group of cells being the most sensitive. All changes caused by SWL application returned to baseline by 9 months. Data from this primate study document no apparent long-term male gonadotoxicity from SWL, but the authors suggest measures to protect the testis during clinical use.


Temporal Dynamics of Natural Static Emotional Facial Expressions Decoding: A Study Using Event- and Eye Fixation-Related Potentials.
This study aims at examining the precise temporal dynamics of the emotional facial decoding as it unfolds in the brain, according to the emotions displayed. To characterize this processing as it occurs in ecological settings, we focused on unconstrained visual explorations of natural emotional faces (i.e., free eye movements). The General Linear Model (GLM; Smith and Kutas, 2015a,b; Kristensen et al., 2017a) enables such a depiction. It allows deconvolving adjacent overlapping responses of the eye fixation-related potentials (EFRPs) elicited by the subsequent fixations and the event-related potentials (ERPs) elicited at the stimuli onset. Nineteen participants were displayed with spontaneous static facial expressions of emotions (Neutral, Disgust, Surprise, and Happiness) from the DynEmo database (Tcherkassof et al., 2013). Behavioral results on participants' eye movements show that the usual diagnostic features in emotional decoding (eyes for negative facial displays and mouth for positive ones) are consistent with the literature. The impact of emotional category on both the ERPs and the EFRPs elicited by the free exploration of the emotional faces is observed upon the temporal dynamics of the emotional facial expression processing. Regarding the ERP at stimulus onset, there is a significant emotion-dependent modulation of the P2-P3 complex and LPP components' amplitude at the left frontal site for the ERPs computed by averaging. Yet, the GLM reveals the impact of subsequent fixations on the ERPs time-locked on stimulus onset. Results are also in line with the valence hypothesis. The observed differences between the two estimation methods (Average vs. GLM) suggest the predominance of the right hemisphere at the stimulus onset and the implication of the left hemisphere in the processing of the information encoded by subsequent fixations. Concerning the first EFRP, the Lambda response and the P2 component are modulated by the emotion of surprise compared to the neutral emotion, suggesting an impact of high-level factors, in parieto-occipital sites. Moreover, no difference is observed on the second and subsequent EFRP. Taken together, the results stress the significant gain obtained in analyzing the EFRPs using the GLM method and pave the way toward efficient ecological emotional dynamic stimuli analyses.


Malignant salivary gland tumours of the larynx: a single institution review.
Malignant salivary gland tumours of the larynx are very rare, with limited reports of clinical outcomes. We present the decade-long experience of a single institution. A 10-year retrospective chart review of a tertiary head and neck cancer centre was performed. Index patients were identified from a review of a pathology database, and reviewed by a head and neck pathologist. Patient demographics, presenting signs and symptoms, treatment modalities and clinical outcomes were extracted from electronic medical records. Six patients were included, with an age range of 44 to 69. All six had malignant laryngeal salivary gland tumours. Pathologies included: three adenoid cystic carcinoma (2 supraglottic, 1 subglottic), one mucoepidermoid carcinoma (supraglottic), one epithelial-myoepithelial carcinoma (supraglottic) and one adenocarcinoma (transglottic). All were treated with surgery (2 endolaryngeal, 4 open) and five of six with the addition of adjuvant therapy (4 radiotherapy, 1 concurrent chemoradiation). One patient had smoking history; no patients had significant alcohol history. With 4.5 years of median follow-up, none of the patients has had recurrence or local/distant metastasis. Salivary gland tumours of the larynx present in mid to late-age, and can be successfully managed with a multi-modality approach, resulting in excellent local and regional control rates.


Automatic classification of mammography reports by BI-RADS breast tissue composition class.
Because breast tissue composition partially predicts breast cancer risk, classification of mammography reports by breast tissue composition is important from both a scientific and clinical perspective. A method is presented for using the unstructured text of mammography reports to classify them into BI-RADS breast tissue composition categories. An algorithm that uses regular expressions to automatically determine BI-RADS breast tissue composition classes for unstructured mammography reports was developed. The algorithm assigns each report to a single BI-RADS composition class: 'fatty', 'fibroglandular', 'heterogeneously dense', 'dense', or 'unspecified'. We evaluated its performance on mammography reports from two different institutions. The method achieves >99% classification accuracy on a test set of reports from the Marshfield Clinic (Wisconsin) and Stanford University. Since large-scale studies of breast cancer rely heavily on breast tissue composition information, this method could facilitate this research by helping mine large datasets to correlate breast composition with other covariates.


The number of x chromosomes causes sex differences in adiposity in mice.
Sexual dimorphism in body weight, fat distribution, and metabolic disease has been attributed largely to differential effects of male and female gonadal hormones. Here, we report that the number of X chromosomes within cells also contributes to these sex differences. We employed a unique mouse model, known as the "four core genotypes," to distinguish between effects of gonadal sex (testes or ovaries) and sex chromosomes (XX or XY). With this model, we produced gonadal male and female mice carrying XX or XY sex chromosome complements. Mice were gonadectomized to remove the acute effects of gonadal hormones and to uncover effects of sex chromosome complement on obesity. Mice with XX sex chromosomes (relative to XY), regardless of their type of gonad, had up to 2-fold increased adiposity and greater food intake during daylight hours, when mice are normally inactive. Mice with two X chromosomes also had accelerated weight gain on a high fat diet and developed fatty liver and elevated lipid and insulin levels. Further genetic studies with mice carrying XO and XXY chromosome complements revealed that the differences between XX and XY mice are attributable to dosage of the X chromosome, rather than effects of the Y chromosome. A subset of genes that escape X chromosome inactivation exhibited higher expression levels in adipose tissue and liver of XX compared to XY mice, and may contribute to the sex differences in obesity. Overall, our study is the first to identify sex chromosome complement, a factor distinguishing all male and female cells, as a cause of sex differences in obesity and metabolism.


Impact of whey proteins on the systemic and local intestinal level of mice with diet induced obesity.
Obesity is a serious public health problem and being multifactorial is difficult to tackle. Since the intestinal ecosystem's homeostasis is, at least partially, diet-dependent, its modulation may be triggered by food components that are designed to exert a modulatory action leading to a health-promoting effect. Milk whey proteins, are considered as such promising factors since they influence satiation as well as body weight and constitute the source of biologically active peptides which may modulate health status locally and systemically. This way, whey proteins are associated with obesity. Therefore, this paper is aimed at the estimation of the impact of whey proteins using a commercially available whey protein isolate on the physiological response of mice with diet-induced obesity. The physiological response was evaluated on the local-intestinal level, scrutinizing intestinal microbiota as one of the important factors in obesity and on the systemic level, analyzing the response of the organism. Whey proteins brought about the decrease of the fat mass with a simultaneous increase of the lean mass of animals with diet induced obesity, which is a promising, health-promoting effect. Whey proteins also proved to act beneficially helping restore the number of beneficial bifidobacteria in obese animals and decreasing the calorie intake and fat mass as well as the LDL level. Overall, supplementation of the high fat diet with whey proteins acted locally by restoration of the intestinal ecosystem, thus preventing dysbiosis and its effects and also acted systemically by strengthening the organism increasing the lean mass and thus hindering obesity-related detrimental effects.


Complex Optical Surfaces Formed by Replica Molding Against Elastomeric Masters
Complex, optically functional surfaces in organic polymers can be fabricated by replicating relief structures present on the surface of an elastomeric master with an ultraviolet or thermally curable organic polymer, while the master is deformed by compression, bending, or stretching. The versatility of this procedure for fabricating surfaces with complex, micrometer- and submicrometer-scale patterns was demonstrated by the production of (i) diffraction gratings with periods smaller than the original grating; (ii) chirped, blazed diffraction gratings (where the period of a chirped grating changes continuously with position) on planar and curved surfaces; (iii) patterned microfeatures on the surfaces of approximately hemispherical objects (for example, an optical surface similar to a fly's eye); and (iv) arrays of rhombic microlenses. These topologically complex, micropatterned surfaces are difficult to fabricate with other techniques.


Cell death in the pathogenesis of heart disease: mechanisms and significance.
Cell death was once viewed as unregulated. It is now clear that at least a portion of cell death is a regulated cell suicide process. This type of death can exhibit multiple morphologies. One of these, apoptosis, has long been recognized to be actively mediated, and many of its underlying mechanisms have been elucidated. Moreover, necrosis, the traditional example of unregulated cell death, is also regulated in some instances. Autophagy is usually a survival mechanism but can occur in association with cell death. Little is known, however, about how autophagic cells die. Apoptosis, necrosis, and autophagy occur in cardiac myocytes during myocardial infarction, ischemia/reperfusion, and heart failure. Pharmacological and genetic inhibition of apoptosis and necrosis lessens infarct size and improves cardiac function in these disorders. The roles of autophagy in ischemia/reperfusion and heart failure are unresolved. A better understanding of these processes and their interrelationships may allow for the development of novel therapies for the major heart syndromes.


Calcium-dependent regulation of airway epithelial chloride channels.
To determine how cell calcium ([Ca2+]c) regulates apical Cl- channels, we measured the rate of 125-Iodide (125I-) efflux to assay Cl- channel activity in intact cells and examined cell-free membrane patches from cultured canine tracheal epithelial cells. The Ca2+ elevating agonist bradykinin and the calcium ionophore A23187 increased 125I- efflux. This response did not require prostaglandin production. Under several conditions, changes in [Ca2+]c were temporally dissociated from changes in channel activation: a transient increase in [Ca2+]c caused a prolonged stimulation of 125I- efflux. Neither Cl- channel activation nor open-channel probability was affected by varying internal [Ca2+] in excised membrane patches. Adenosine 3',5'-cyclic monophosphate (cAMP)- and Ca2(+)-dependent channel activation may be independent: cAMP-stimulated 125I- efflux did not require an increase in [Ca2+]c, Ca2(+)-stimulated efflux did not require an increase in cAMP, and simultaneous addition of A23187 and isoproterenol produced additive effects on 125I- efflux. The data suggest that an increase in [Ca2+]c activates Cl- channels, however, the effect of Ca2+ appears to be indirect, not involving a ligand-type interaction with the channel.


IL-1β-dependent extravasation of preexisting lung-restricted autoantibodies during lung transplantation activates complement and mediates primary graft dysfunction.
Preexisting lung-restricted autoantibodies (LRAs) are associated with a higher incidence of primary graft dysfunction (PGD), although it remains unclear whether LRAs can drive its pathogenesis. In syngeneic murine left lung transplant recipients, preexisting LRAs worsened graft dysfunction, which was evident by impaired gas exchange, increased pulmonary edema, and activation of damage-associated pathways in lung epithelial cells. LRA-mediated injury was distinct from ischemia-reperfusion injury since deletion of donor nonclassical monocytes and host neutrophils could not prevent graft dysfunction in LRA-pretreated recipients. Whole LRA IgG molecules were necessary for lung injury, which was mediated by the classical and alternative complement pathways and reversed by complement inhibition. However, deletion of Fc receptors in donor macrophages or mannose-binding lectin in recipient mice failed to rescue lung function. LRA-mediated injury was localized to the transplanted lung and dependent on IL-1β-mediated permeabilization of pulmonary vascular endothelium, which allowed extravasation of antibodies. Genetic deletion or pharmacological inhibition of IL-1R in the donor lungs prevented LRA-induced graft injury. In humans, preexisting LRAs were an independent risk factor for severe PGD and could be treated with plasmapheresis and complement blockade. We conclude that preexisting LRAs can compound ischemia-reperfusion injury to worsen PGD for which complement inhibition may be effective.


Neuronal cell depolarization induces intragenic chromatin modifications affecting NCAM alternative splicing.
In search for physiological pathways affecting alternative splicing through its kinetic coupling with transcription, we found that membrane depolarization of neuronal cells triggers the skipping of exon 18 from the neural cell adhesion molecule (NCAM) mRNA, independently of the calcium/calmodulin protein kinase IV pathway. We show that this exon responds to RNA polymerase II elongation, because its inclusion is increased by a slow polymerase II mutant. Depolarization affects the chromatin template in a specific way, by causing H3K9 hyper-acetylation restricted to an internal region of the NCAM gene surrounding the alternative exon. This intragenic histone hyper-acetylation is not paralleled by acetylation at the promoter, is associated with chromatin relaxation, and is linked to H3K36 tri-methylation. The effects on acetylation and splicing fully revert when the depolarizing conditions are withdrawn and can be both duplicated and potentiated by the histone deacetylase inhibitor trichostatin A. Our results are consistent with a mechanism involving the kinetic coupling of splicing and transcription in response to depolarization through intragenic epigenetic changes on a gene that is relevant for the differentiation and function of neuronal cells.


Rheumatoid arthritis. The two faces of Rsk2 in hyperplastic disease.
Given the established role of 90 kDa ribosomal S6 kinases (Rsk) in oncogenesis, and the promise of new Rsk-blocking cancer treatments, it is perhaps surprising that Rsk2-mediated inhibition of hyperplasia has now been demonstrated to occur in the arthritic synovium. Does this functional duality make Rsk2 a risky target for the treatment of rheumatoid arthritis?


SMAD signaling and redox imbalance cooperate to induce prostate cancer cell dormancy.
Metastasis involves the dissemination of single or small clumps of cancer cells through blood or lymphatic vessels and their extravasation into distant organs. Despite the strong regulation of metastases development by a cell dormancy phenomenon, the dormant state of cancer cells remains poorly characterized due to the difficulty of in vivo studies. We have recently shown in vitro that clonogenicity of prostate cancer cells is regulated by a dormancy phenomenon that is strongly induced when cells are cultured both at low cell density and in a slightly hypertonic medium. Here, we characterized by RT-qPCR a genetic expression signature of this dormant state which combines the presence of both stemness and differentiation markers. We showed that both TFGβ/BMP signaling and redox imbalance are required for the full induction of this dormancy signature and cell quiescence. Moreover, reconstruction experiments showed that TFGβ/BMP signaling and redox imbalance are sufficient to generate a pattern of genetic expression displaying all characteristic features of the dormancy signature. Finally, we observed that low cell density was sufficient to activate TGFβ/BMP signaling and to generate a slight redox imbalance thus priming cells for dormancy that can be attained with a co-stimulus like hypertonicity, most likely through an increased redox imbalance. The identification of a dual regulation of dormancy provides a framework for the interpretation of previous reports showing a restricted ability of BMP signaling to regulate cancer cell dormancy in vivo and draws attention on the role of oxidative stress in the metastatic process.


Adjudin disrupts spermatogenesis by targeting drug transporters: Lesson from the breast cancer resistance protein (BCRP).
For non-hormonal male contraceptives that exert their effects in the testis locally instead of via the hypothalamic-pituitary-testicular axis, such as adjudin that disrupts germ cell adhesion, a major hurdle in their development is to improve their bioavailability so that they can be efficiently delivered to the seminiferous epithelium by transporting across the blood-testis barrier (BTB). If this can be done, it would widen the gap between their efficacy and general toxicity. However, Sertoli cells that constitute the BTB, peritubular myoid cells in the tunica propria, germ cells at different stages of their development, as well as endothelial cells that constitute the microvessels in the interstitium are all equipped with multiple drug transporters, most notably efflux drug transporters, such as P-glycoprotein, multidrug resistance-related protein 1 (MRP1) and breast cancer resistance protein (BCRP) that can actively prevent drugs (e.g., adjudin) from entering the seminiferous epithelium to exert their effects. Recent studies have shown that BCRP is highly expressed by endothelial cells of the microvessels in the interstitium in the testis and also peritubular myoid cells in tunica propria even though it is absent from Sertoli cells at the site of the BTB. Furthermore, BCRP is also expressed spatiotemporally by Sertoli cells and step 19 spermatids in the rat testis and stage-specifically, limiting to stage VII‒VIII of the epithelial cycle, and restricted to the apical ectoplasmic specialization [apical ES, a testis-specific F-actin-rich adherens junction (AJ)]. Interestingly, adjudin was recently shown to be capable of downregulating BCRP expression at the apical ES. In this Opinion article, we critically discuss the latest findings on BCRP; in particular, we provide some findings utilizing molecular modeling to define the interacting domains of BCRP with adjudin. Based on this information, it is hoped that the next generation of adjudin analogs to be synthesized can improve their efficacy in downregulating BCRP and perhaps other drug efflux transporters in the testis to improve their efficacy to traverse the BTB by modifying their interacting domains.


Metabolic therapy with Deanna Protocol supplementation delays disease progression and extends survival in amyotrophic lateral sclerosis (ALS) mouse model.
Amyotrophic Lateral Sclerosis (ALS), also known as Lou Gehrig's disease, is a neurodegenerative disorder of motor neurons causing progressive muscle weakness, paralysis, and eventual death from respiratory failure. There is currently no cure or effective treatment for ALS. Besides motor neuron degeneration, ALS is associated with impaired energy metabolism, which is pathophysiologically linked to mitochondrial dysfunction and glutamate excitotoxicity. The Deanna Protocol (DP) is a metabolic therapy that has been reported to alleviate symptoms in patients with ALS. In this study we hypothesized that alternative fuels in the form of TCA cycle intermediates, specifically arginine-alpha-ketoglutarate (AAKG), the main ingredient of the DP, and the ketogenic diet (KD), would increase motor function and survival in a mouse model of ALS (SOD1-G93A). ALS mice were fed standard rodent diet (SD), KD, or either diets containing a metabolic therapy of the primary ingredients of the DP consisting of AAKG, gamma-aminobutyric acid, Coenzyme Q10, and medium chain triglyceride high in caprylic triglyceride. Assessment of ALS-like pathology was performed using a pre-defined criteria for neurological score, accelerated rotarod test, paw grip endurance test, and grip strength test. Blood glucose, blood beta-hydroxybutyrate, and body weight were also monitored. SD+DP-fed mice exhibited improved neurological score from age 116 to 136 days compared to control mice. KD-fed mice exhibited better motor performance on all motor function tests at 15 and 16 weeks of age compared to controls. SD+DP and KD+DP therapies significantly extended survival time of SOD1-G93A mice by 7.5% (p = 0.001) and 4.2% (p = 0.006), respectively. Sixty-three percent of mice in the KD+DP and 72.7% of the SD+DP group lived past 125 days, while only 9% of the control animals survived past that point. Targeting energy metabolism with metabolic therapy produces a therapeutic effect in ALS mice which may prolong survival and quality of life in ALS patients.


Regulatory T Cell Responses in Participants with Type 1 Diabetes after a Single Dose of Interleukin-2: A Non-Randomised, Open Label, Adaptive Dose-Finding Trial.
Interleukin-2 (IL-2) has an essential role in the expansion and function of CD4+ regulatory T cells (Tregs). Tregs reduce tissue damage by limiting the immune response following infection and regulate autoreactive CD4+ effector T cells (Teffs) to prevent autoimmune diseases, such as type 1 diabetes (T1D). Genetic susceptibility to T1D causes alterations in the IL-2 pathway, a finding that supports Tregs as a cellular therapeutic target. Aldesleukin (Proleukin; recombinant human IL-2), which is administered at high doses to activate the immune system in cancer immunotherapy, is now being repositioned to treat inflammatory and autoimmune disorders at lower doses by targeting Tregs. To define the aldesleukin dose response for Tregs and to find doses that increase Tregs physiologically for treatment of T1D, a statistical and systematic approach was taken by analysing the pharmacokinetics and pharmacodynamics of single doses of subcutaneous aldesleukin in the Adaptive Study of IL-2 Dose on Regulatory T Cells in Type 1 Diabetes (DILT1D), a single centre, non-randomised, open label, adaptive dose-finding trial with 40 adult participants with recently diagnosed T1D. The primary endpoint was the maximum percentage increase in Tregs (defined as CD3+CD4+CD25highCD127low) from the baseline frequency in each participant measured over the 7 d following treatment. There was an initial learning phase with five pairs of participants, each pair receiving one of five pre-assigned single doses from 0.04 × 106 to 1.5 × 106 IU/m2, in order to model the dose-response curve. Results from each participant were then incorporated into interim statistical modelling to target the two doses most likely to induce 10% and 20% increases in Treg frequencies. Primary analysis of the evaluable population (n = 39) found that the optimal doses of aldesleukin to induce 10% and 20% increases in Tregs were 0.101 × 106 IU/m2 (standard error [SE] = 0.078, 95% CI = -0.052, 0.254) and 0.497 × 106 IU/m2 (SE = 0.092, 95% CI = 0.316, 0.678), respectively. On analysis of secondary outcomes, using a highly sensitive IL-2 assay, the observed plasma concentrations of the drug at 90 min exceeded the hypothetical Treg-specific therapeutic window determined in vitro (0.015-0.24 IU/ml), even at the lowest doses (0.040 × 106 and 0.045 × 106 IU/m2) administered. A rapid decrease in Treg frequency in the circulation was observed at 90 min and at day 1, which was dose dependent (mean decrease 11.6%, SE = 2.3%, range 10.0%-48.2%, n = 37), rebounding at day 2 and increasing to frequencies above baseline over 7 d. Teffs, natural killer cells, and eosinophils also responded, with their frequencies rapidly and dose-dependently decreased in the blood, then returning to, or exceeding, pretreatment levels. Furthermore, there was a dose-dependent down modulation of one of the two signalling subunits of the IL-2 receptor, the β chain (CD122) (mean decrease = 58.0%, SE = 2.8%, range 9.8%-85.5%, n = 33), on Tregs and a reduction in their sensitivity to aldesleukin at 90 min and day 1 and 2 post-treatment. Due to blood volume requirements as well as ethical and practical considerations, the study was limited to adults and to analysis of peripheral blood only. The DILT1D trial results, most notably the early altered trafficking and desensitisation of Tregs induced by a single ultra-low dose of aldesleukin that resolves within 2-3 d, inform the design of the next trial to determine a repeat dosing regimen aimed at establishing a steady-state Treg frequency increase of 20%-50%, with the eventual goal of preventing T1D. ISRCTN Registry ISRCTN27852285; ClinicalTrials.gov NCT01827735.


On the selection of non-invasive methods based on speech analysis oriented to automatic Alzheimer disease diagnosis.
The work presented here is part of a larger study to identify novel technologies and biomarkers for early Alzheimer disease (AD) detection and it focuses on evaluating the suitability of a new approach for early AD diagnosis by non-invasive methods. The purpose is to examine in a pilot study the potential of applying intelligent algorithms to speech features obtained from suspected patients in order to contribute to the improvement of diagnosis of AD and its degree of severity. In this sense, Artificial Neural Networks (ANN) have been used for the automatic classification of the two classes (AD and control subjects). Two human issues have been analyzed for feature selection: Spontaneous Speech and Emotional Response. Not only linear features but also non-linear ones, such as Fractal Dimension, have been explored. The approach is non invasive, low cost and without any side effects. Obtained experimental results were very satisfactory and promising for early diagnosis and classification of AD patients.


A novel sequencing-based vaginal health assay combining self-sampling, HPV detection and genotyping, STI detection, and vaginal microbiome analysis.
The composition of the vaginal microbiome, including both the presence of pathogens involved in sexually transmitted infections (STI) as well as commensal microbiota, has been shown to have important associations for a woman's reproductive and general health. Currently, healthcare providers cannot offer comprehensive vaginal microbiome screening, but are limited to the detection of individual pathogens, such as high-risk human papillomavirus (hrHPV), the predominant cause of cervical cancer. There is no single test on the market that combines HPV, STI, and microbiome screening. Here, we describe a novel inclusive vaginal health assay that combines self-sampling with sequencing-based HPV detection and genotyping, vaginal microbiome analysis, and STI-associated pathogen detection. The assay includes genotyping and detection of 14 hrHPV types, 5 low-risk HPV types (lrHPV), as well as the relative abundance of 31 bacterial taxa of clinical importance, including Lactobacillus, Sneathia, Gardnerella, and 3 pathogens involved in STI, with high sensitivity, specificity, and reproducibility. For each of these taxa, reference ranges were determined in a group of 50 self-reported healthy women. The HPV sequencing portion of the test was evaluated against the digene High-Risk HPV HC2 DNA test. For hrHPV genotyping, agreement was 95.3% with a kappa of 0.804 (601 samples); after removal of samples in which the digene hrHPV probe showed cross-reactivity with lrHPV types, the sensitivity and specificity of the hrHPV genotyping assay were 94.5% and 96.6%, respectively, with a kappa of 0.841. For lrHPV genotyping, agreement was 93.9% with a kappa of 0.788 (148 samples), while sensitivity and specificity were 100% and 92.9%, respectively. This novel assay could be used to complement conventional cervical cancer screening, because its self-sampling format can expand access among women who would otherwise not participate, and because of its additional information about the composition of the vaginal microbiome and the presence of pathogens.


Two domains of anosognosia in Alzheimer's disease.
To examine the presence of different dimensions of unawareness in patients with probable Alzheimer's disease. A consecutive series of 170 patients with probable Alzheimer's disease were assessed with the anosognosia questionnaire-dementia (AQ-D) which includes items related to cognitive deficits and behavioural problems. A factor analysis of the AQ-D produced two factors: a "cognitive unawareness" factor, which loaded on items of memory, spatial and temporal orientation, calculation, abstract reasoning, and praxis, and a "behavioural unawareness" factor which loaded on items of irritability, selfishness, inappropriate emotional display, and instinctive disinhibition. A stepwise forward regression analysis showed significant correlations between the cognitive unawareness factor and more severe cognitive deficits, delusions, and apathy, but less depression. On the other hand, the behavioural unawareness factor correlated significantly with higher mania and pathological laughing scores. Whereas the cognitive unawareness factor showed a significant correlation with cognitive tests assessing verbal comprehension and long term memory, and was significantly associated with a longer duration of illness, no significant correlations were found between the behavioural unawareness factor and the neuropsychological tasks. Unawareness of cognitive deficits and unawareness of behavioural problems may constitute independent phenomena in Alzheimer's disease. Whereas unawareness of cognitive deficits is related to the severity of intellectual impairment and the presence of delusional apathetic mood, unawareness of behavioural problems may be part of a disinhibition syndrome.


Improving diet, physical activity and other lifestyle behaviours using computer-tailored advice in general practice: a randomised controlled trial.
The adoption and maintenance of healthy behaviours is essential in the primary prevention of chronic non-communicable diseases. This study evaluated the effectiveness of a minimal intervention on multiple lifestyle factors such as diet, physical activity, smoking and alcohol, delivered through general practice, using computer-tailored feedback. Adult patients visiting 21 general practitioners in Brisbane, Australia, were surveyed about ten health behaviours that are risk factors for chronic, non-communicable diseases. Those who completed the self-administered baseline questionnaire entered a randomised controlled trial, with the intervention group receiving computer-tailored printed advice, targeting those health behaviours for which respondents were not meeting current recommendations. The primary outcome was change in summary lifestyle score (Prudence Score) and individual health behaviours at three months. A repeated measures analysis compared change in these outcomes in intervention and control groups after adjusting for age and education. 2306 patients were randomised into the trial. 1711 (76%) returned the follow-up questionnaire at 3 months. The Prudence Score (10 items) in the intervention group at baseline was 5.88, improving to 6.25 at 3 months (improvement = 0.37), compared with 5.84 to 5.96 (improvement = 0.12) in the control group (F = 13.3, p = 0.01). The intervention group showed improvement in meeting recommendations for all individual health behaviours compared with the control group. However, these differences were significant only for fish intake (OR 1.37, 95% CI 1.11-1.68), salt intake (OR 1.19, 95% CI 1.05-1.38), and type of spread used (OR 1.28, 95% CI 1.06-1.51). A minimal intervention using computer-tailored feedback to address multiple lifestyle behaviours can facilitate change and improve unhealthy behaviours. Although individual behaviour changes were modest, when implemented on a large scale through general practice, this intervention appears to be an effective and practical tool for population-wide primary prevention. The Australian New Zealand Clinical Trials Registry: ACTRN12611001213932.


NR5A2 regulates Lhb and Fshb transcription in gonadotrope-like cells in vitro, but is dispensable for gonadotropin synthesis and fertility in vivo.
Successful mammalian reproduction depends on proper synthesis of the pituitary-derived glycoprotein hormones, luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Several transcription factors cooperate to activate cell-specific and hormone-regulated expression of the gonadotropin beta subunits (Lhb and Fshb). Among these, NR5A1 (steroidogenic factor 1; SF1) has been shown to directly bind to the Lhb promoter, mediate basal and gonadotropin-releasing hormone (GnRH)-stimulated Lhb transcription, and possibly directly regulate Fshb expression. Recently, the closely-related NR5A2 was shown to activate the rat Lhb promoter in vitro. Here, we further characterized the role of NR5A2 in regulating gonadotropin synthesis. Ectopically expressed NR5A2 directly activated the murine Lhb promoter in a manner identical to that of NR5A1, whereas neither factor activated the murine Fshb promoter. In LβT2 gonadotrope-like cells, depletion of endogenous NR5A1 or NR5A2 impaired basal and GnRH-stimulated Lhb and Fshb transcription. To analyze the physiological role of NR5A2 in gonadotropes in vivo, we generated mice with a gonadotrope-specific deletion of Nr5a2. In contrast with our in vitro data, these mice had normal pituitary Lhb and Fshb expression and intact fertility. Together, our data establish that NR5A2 can act in a non-redundant manner to regulate Lhb and Fshb transcription in vitro, but is dispensable in vivo.


Efficient Algorithms for Sequence Analysis with Entropic Profiles.
Entropy, being closely related to repetitiveness and compressibility, is a widely used information-related measure to assess the degree of predictability of a sequence. Entropic profiles are based on information theory principles, and can be used to study the under-/over-representation of subwords, by also providing information about the scale of conserved DNA regions. Here, we focus on the algorithmic aspects related to entropic profiles. In particular, we propose linear time algorithms for their computation that rely on suffix-based data structures, more specifically on the truncated suffix tree (TST) and on the enhanced suffix array (ESA). We performed an extensive experimental campaign showing that our algorithms, beside being faster, make it possible the analysis of longer sequences, even for high degrees of resolution, than state of the art algorithms.