Identification of potential human respiratory syncytial virus and metapneumovirus T cell epitopes using computational prediction and MHC binding assays.
Human respiratory syncytial virus (RSV) and human metapneumovirus (MPV) are two of the most common causes of serious viral lower respiratory tract illness in humans. CD8+ T cells have been shown to be important in animal models and human clinical studies for the clearance of viral infection, and they may contribute in part to protection against severe disease during reinfections. Precise enumeration and accurate phenotyping of RSV- or MPV-specific CD8+ T cells in humans is currently limited by the relatively small number of T cell epitopes that have been mapped with accompanying identification of MHC restriction patterns. We sought to expand the number of potential RSV and MPV epitopes for use in clinical and translational studies by identifying an expanded set of MHC-binding peptides based on RSV and MPV wild-type virus strain protein sequences. We interrogated the full protein sequences of all 9 or 11 proteins of MPV or RSV respectively using four established epitope prediction algorithms for human HLA A*0101, A*0201, or B*0702 binding and attempted to synthesize the top-scoring 150-152 peptides for each of the two viruses. Synthesis resulted in 442 synthesized and soluble peptides of the 452 predicted epitopes for MPV or RSV. We then determined the binding of the synthetic peptides to recombinant human HLA A*0101, A*0201 or B*0702 molecules with the predicted restriction using a commercially available plate-based assay, iTopia. A total of 230 of the 442 peptides tested exhibited binding to the appropriate MHC molecule. The binding results suggested that existing algorithms for prediction of MHC A*0201 binding are particularly robust. The binding results also provided a large benchmarking data collection for comparison of new prediction algorithms.


CoRESTed development of regulatory T cells.
Tregs require specific epigenetic signatures to induce and maintain their suppressive function in the context of inflammation and cancer surveillance. In this issue of the JCI, Xiong and colleagues identify a critical role for the epigenetic repressor REST corepressor 1 (CoREST) in promoting Treg suppressive transcriptional and functional programs. Pharmacologic inhibition and genetic loss of CoREST in Tregs impaired organ allograft tolerance and unleashed antitumor immunity via epigenetic activation of effector T cell programs. We propose that exploiting epigenetic control mechanisms will further the translation of Treg-based therapeutics to target inflammatory and malignant disorders.


Overexpression of vascular endothelial growth factor isoforms drives oxygenation and growth but not progression to glioblastoma multiforme in a human model of gliomagenesis.
Vascular endothelial growth factor (VEGF) is thought to promote tumor growth and angiogenesis. Whereas VEGF is up-regulated in only a portion of anaplastic astrocytoma (AA), it is overexpressed in most glioblastoma multiforme (GBM), and the level of expression is correlated with grade of glioma. To explore the possibility that VEGF may act as a driving force in the progression of AA to GBM, the VEGF isoforms VEGF(121) and VEGF(165) were overexpressed in genetically modified, mutant H-Ras-transformed human astrocytes that on intracranial implantation form AA-like tumors. The ability of the VEGF isoforms to stimulate growth, angiogenesis, oxygenation, and the formation of necrotic GBM-like tumors was then monitored. The parental mutant H-Ras-modified astrocytes expressed four times more endogenous VEGF than normal human astrocytes, but on intracranial implantation formed hypovascular, hypoxic, small AA-like tumors. Whereas these modest levels of VEGF overexpression were insufficient to drive oxygenation and GBM formation, an additional 8-fold increase in VEGF expression mediated by retroviral infection with constructs encoding either VEGF (121) or VEGF (165) resulted in cells which, after intracranial implantation, formed tumors that were larger, more vascular, and better oxygenated than those formed by the mutant H-ras parental cells. However, the tumors formed by the cells expressing exogenous VEGF (121) or VEGF (165) retained the phenotype of AA, lacking areas of necrosis that are the hallmark of the GBM phenotype. These results suggest that whereas the VEGF(121) and VEGF(165) isoforms can contribute to glioma vascularization, oxygenation, and growth, they do not in and of themselves drive the formation of the GBM phenotype.


Animal welfare chauvinism in Brexit Britain: a genealogy of care and control.
This paper uses the deployment of animal welfare as an issue during the 'Brexit' referendum as a lens through which to explore the mutual shaping of discourses about care for animals in Britain and the British nation, or the nationalism of animal welfare. Adopting a genealogical outlook, it uses one political advertisement in particular-paid for by the official Vote Leave campaign-as a focalising image and means of opening up the issues, leading to an empirical emphasis on the issue of live animal export as it has mediated ideas about Europe and British identity. Introducing the idea of 'animal welfare chauvinism', the paper suggests that animal welfare messages in the context of this constitutional debate were products of chauvinistic and caring impulses which are mutually constitutive and crystallised through discourses formed in relation to contingent historical struggles. Analytically, stress is placed on the constructive role of situated and repeated discursive exchanges, occurring between animal advocates and other national political elites, within which 'care for animals' as a national ideal is forged. In this light, the article concludes with reflections on the stakes of entering into an already existing conversation on the 'national culture of care' for animals in Britain.


Macular translocation: histopathologic findings in swine eyes.
Macular translocation has been proposed as an alternative technique in the treatment of some cases of choroidal neovascularization. The purpose of the paper is to report the histopathologic findings in the retina of swine eyes undergone macular translocation. Ten eyes of ten Yucatan pigs underwent posterior pars plana vitrectomy and scleral imbrication to achieve macular translocation. Mattress sutures were preplaced at the equator of the eyes. After a pars plana vitrectomy, balanced saline solution was injected under the temporal retina to produce a retinal detachment. Scleral imbrication was achieved by tightening the mattress sutures. An air-fluid exchange was performed and the eye was filled with sulfur hexafluoride 18%. The eyes were enucleated 2, 4, 8 and 12 weeks after surgery and analyzed under light and electron microscopy. Macular translocation was achieved in all cases. The major findings consist of a minimal decrease in the number of photoreceptors outer segments; also a change in the morphology was noted. This included some degree of loss of vertical alignment and an increase in the interphotoreceptor space. There was a recovery in the morphology of the photoreceptors over time. Minimal changes in the photoreceptors and retinal pigment epithelium are observed when macular translocation is performed with recovery of these changes over time. Scleral imbrication is an effective technique to achieve translocation of the fovea.


[Health situation of prisoners at a prison compliance centre, Chile].
There are population groups nowadays that are regarded as vulnerable, one of which is the prison population, considered to have major health needs. Nonetheless, people deprived of liberty maintain inherent human rights such as that of health care, which in some situations may take second place. Cross-sectional descriptive study, carried out at El Manzano Prison compliance centre, Concepción, from October 2011 to February 2012 with the implementation of a preventive health exam and a socio-demographic and health questionnaire, for 18+, female and male prisoners in a closed system, on reception of written informed consent. in the study, the population was 85% men, the average age was 34 years, 91.2% receive visits, average term of imprisonment 38 months. At least 45% have a diagnosed disease, prioritizing mental disorders, and respiratory and circulatory system diseases. 56% of prisoners have requested health care infrequently, 33% of which were very satisfied and 32% satisfied with prison health services. The health of the prison population is more impaired than that of the general population, with a larger number of needs that are also different, but there is a positive perception of health by prisoners and a high degree of satisfaction with health services.


Less extensive treatment and inferior prognosis for breast cancer patient with comorbidity: a population-based study.
The prevalence of coexistent diseases in addition to breast cancer becomes increasingly important in an ageing population. However, the clinical implications are unclear. The age-specific prevalence of serious comorbidity among all new breast cancer patients diagnosed from 1995 to 2001 (n=8966) in the South of the Netherlands was analysed in relation to age, stage and treatment. Independent prognostic effects of age and comorbidity were evaluated (follow-up was continued until 1 January 2004). The prevalence of comorbidity increased from 9% for those aged <50 years to 56% for patients aged 80+ years. The most frequent conditions were cardiovascular disease (7%), diabetes mellitus (7%), and previous cancer (6%). In the presence of comorbidity, fewer patients received radiotherapy (51% vs. 66%, P<0.0001) and fewer patients who underwent breast-conserving surgery also had axillary dissection (P<0.0001). Relative 5-year survival rates for patients without comorbidity (87%) were significantly higher (P<0.01) than those for patients with previous cancer (77%), diabetes mellitus (78%), and for patients with 2+ coexistent diseases (59%). Relative survival of patients without comorbidity increased with age to 93% for patients older than 70 years. Comorbidity negatively affected prognosis, independent of age, stage of disease, and treatment (Hazard Ratio (HR)=1.3, P=0.0001 for one coexistent disease and HR=1.4, P=0.0001 for 2+ coexistent diseases). The most important effects were found for previous cancer (HR=1.4, P=0.003), cerebrovascular disease (HR=1.6, P<0.004) or dementia (HR=2.3, P<0.0001). Elderly breast cancer patients can be divided in those without other diseases, who have a relatively good prognosis, and those who have at least one other serious coexistent disease and significantly poorer prognosis.


Improvement in balance from diagnosis to return-to-play initiation following a sport-related concussion: BESS scores vs center-of-pressure measures.
Accurate assessment of balance recovery throughout treatment of a sport-related concussion is imperative. This study examined differences in balance from diagnosis to return-to-play initiation in adolescent patients post-concussion. Second, this study investigated the extent to which the Balance Error Scoring System (BESS) correlated with center-of-pressure (COP) measures. Forty participants performed the BESS while standing on a force platform such that COP data were obtained simultaneously. Spatial and velocity COP-based measures were computed for the double-stance conditions. BESS scores and COP-based measures indicated improved balance performance between visits. Specifically, 62.5/65.0% of participants exhibited improved firm/foam BESS final scores, respectively, and 56.4-71.8% exhibited improved COP-based measures. However, once normative ranges were referenced to identify maintained performance, the percentage of participants who substantially improved differed from initial findings (BESS: 2.5/7.5%, COP: 48.7-69.2%). Additionally, positive correlations between balance measures were primarily found at diagnosis (r=0.33-0.53), while only three correlations were maintained at return-to-play initiation (r=0.34-0.39). BESS scores successfully identified poor balance performance at diagnosis when symptoms were most pronounced, but failed to accurately depict performance once balance impairment, indicated by COP-based measures, became less apparent. Further work is needed to implement more advanced balance assessments into clinical environments.


Morphometry and histochemistry of the semitendinosus muscle of tufted capuchin monkeys (Cebus apella Linnaeus, 1758).
Considering monkeys are animals closely related to the human, and semitendinosus muscle has been used in many postural research experiments, we have decided to study its histochemical characteristics. Samples were removed from the proximal, middle and distal regions of the semitendinosus muscles of five adult male tufted capuchin monkeys and observed for reaction with m-ATPase (with alkaline and acid pre-incubation), nicotinamide adenine dinucleotide tetrazolium reductase, and haematoxylin and eosin. The muscle fibres were classified as fast glycolytic (FG), fast oxidative glycolytic (FOG) and slow oxidative (SO) and quantified in terms of frequency and area. The three regions of the semitendinosus muscle showed no significant differences in frequency or area of the respective fibre types, and therefore the muscle can be considered histoenzymologically homogeneous. FG fibres presented higher frequencies and larger areas. The sum of FOG and SO fibres was 57.5%, suggesting that the semitendinosus muscle of the tufted capuchin monkey is adapted to an action involved in posture maintenance and in long arboreal dislocation. The present data agrees with the notion of differentiated quadrupedalism in some primates, which support a lower percentage of their weight on the fore limbs.


The Holo-Diagram. VI: Practical Device in Coherent Optics.
Ordinary interferometry, hologram interferometry, contouring, speckle, moiré, ordinary radar, Doppler radar, optical Doppler velocimeter, Doppler holography, and gated viewing are all discussed, and it is vdemonstrated how closely these methods are related to each other. One single diagram, the holo-diagram, can be used for the evaluation of each method and even for combinations of the methods. The diagram is constructed for the study of interference patterns when an object is placed in the vicinity of two focal points representing either one point of illumination and one point of observation or two points of illumination or two points of observation. It reveals interference surfaces in space and how ordinary interference fringes are formed where an object intersects these surfaces. With a common moiré analogy the three-dimensional sensitivity distribution and the fringe patterns of each of the methods can be simulated. Finally it is pointed out that the diagram demonstrates the interference limits and diffraction limits of any method of optical information retrieval.


Cognitive enhancement and antipsychotic-like activity following repeated dosing with the selective M4 PAM VU0467154.
Although selective activation of the M1 muscarinic acetylcholine receptor (mAChR) subtype has been shown to improve cognitive function in animal models of neuropsychiatric disorders, recent evidence suggests that enhancing M4 mAChR function can also improve memory performance. Positive allosteric modulators (PAMs) targeting the M4 mAChR subtype have shown therapeutic potential for the treatment of multiple symptoms observed in schizophrenia, including positive and cognitive symptoms when assessed in acute preclinical dosing paradigms. Since the cholinergic system has been implicated in multiple stages of learning and memory, we evaluated the effects of repeated dosing with the highly selective M4 PAM VU0467154 on either acquisition and/or consolidation of learning and memory when dosed alone or after pharmacologic challenge with the N-methyl-d-aspartate subtype of glutamate receptors (NMDAR) antagonist MK-801. MK-801 challenge represents a well-documented preclinical model of NMDAR hypofunction that is thought to underlie some of the positive and cognitive symptoms observed in schizophrenia. In wildtype mice, 10-day, once-daily dosing of VU0467154 either prior to, or immediately after daily testing enhanced the rate of learning in a touchscreen visual pairwise discrimination task; these effects were absent in M4 mAChR knockout mice. Following a similar 10-day, once-daily dosing regimen of VU0467154, we also observed 1) improved acquisition of memory in a cue-mediated conditioned freezing paradigm, 2) attenuation of MK-801-induced disruptions in the acquisition of memory in a context-mediated conditioned freezing paradigm and 3) reversal of MK-801-induced hyperlocomotion. Comparable efficacy and plasma and brain concentrations of VU0467154 were observed after repeated dosing as those previously reported with an acute, single dose administration of this M4 PAM. Together, these studies are the first to demonstrate that cognitive enhancing and antipsychotic-like activity are not subject to the development of tolerance following repeated dosing with a selective M4 PAM in mice and further suggest that activation of M4 mAChRs may modulate both acquisition and consolidation of memory functions.


Computational models in the service of X-ray and cryo-electron microscopy structure determination.
Critical assessment of structure prediction (CASP) conducts community experiments to determine the state of the art in computing protein structure from amino acid sequence. The process relies on the experimental community providing information about not yet public or about to be solved structures, for use as targets. For some targets, the experimental structure is not solved in time for use in CASP. Calculated structure accuracy improved dramatically in this round, implying that models should now be much more useful for resolving many sorts of experimental difficulties. To test this, selected models for seven unsolved targets were provided to the experimental groups. These models were from the AlphaFold2 group, who overall submitted the most accurate predictions in CASP14. Four targets were solved with the aid of the models, and, additionally, the structure of an already solved target was improved. An a posteriori analysis showed that, in some cases, models from other groups would also be effective. This paper provides accounts of the successful application of models to structure determination, including molecular replacement for X-ray crystallography, backbone tracing and sequence positioning in a cryo-electron microscopy structure, and correction of local features. The results suggest that, in future, there will be greatly increased synergy between computational and experimental approaches to structure determination.


[Echoes from the 22nd annual applied research meeting on chagas disease and the 10th annual applied research meeting on leishmaniasis].
Chagas disease and leishmaniasis are important conditions that still affect millions of people, with significant medical, social and economic implications. The annual meetings on Chagas disease and leishmaniasis are outstanding forums for discussing new findings regarding different aspects of these diseases and for planning control strategies, which involve large numbers of young and senior researchers. Thus, such meetings must continue to vigorously represent the struggle against these diseases.


Successive depth variations in microvascular distribution of rat somatosensory cortex.
Although hemodynamic-based functional brain imaging techniques are powerful tools to explore the brain functions noninvasively, hemodynamic-based signal is strongly affected by spatial configuration of microvessels. Understanding the quantitative relations between microvascular structure and functional activity is therefore significant to make a valid signal interpretation for the imaging techniques. In the present study, we evaluated depth profiles of microvascular distributions in rat somatosensory subfields (barrel field, forelimb region, trunk region and hindlimb region) and characterized depth variations in microvascular structures, such as locations, lengths and directions of microvessels, throughout the cortical layers (I-VI). To obtain the accurate microvascular structure, we made a customized casting method by using confocal laser scanning microscope. We observed that microvascular distribution successively varied throughout the cortical layers (I-VI) and that the maximum number density of microvessels was consistently found in middle layers (III-V). In addition, superficial layers had relatively long microvessels, almost perpendicular to the cortical surface, whereas middle layers had short microvessels propagating in all directions. These regional differences in microvascular structures were closely related to the somatosensory subfields, e.g., barrel field was the greatest number density of microvessels among the investigated subfields. Based on these observations, we compared microvascular profiles with previously reported distribution patterns of tissue partial pressure of oxygen (pO2). The results showed that tissue pO2 was correlated with microvascular distribution in some but not all of the subfields. This finding shows that detailed microvascular profiles are helpful to investigate causal relationships between microvascular structure and functional activities in cerebral cortex.


Oral antimicrobial rinse to reduce mycobacterial culture contamination among tuberculosis suspects in Uganda: a prospective study.
Contamination by bacterial or fungal organisms reduces the effectiveness of mycobacterial culture for diagnosis of pulmonary tuberculosis (TB). We evaluated the effect of an anti-microbial and an anti-fungal oral rinse prior to expectoration on culture-contamination rates. We enrolled a consecutive random sample of adults with cough for ≥ 2 weeks and suspected TB admitted to Mulago Hospital (Kampala, Uganda) between October 2008 and June 2009. We randomly assigned patients to oral rinse (60 seconds with chlorhexidine followed by 60 seconds with nystatin) vs. no oral rinse prior to initial sputum collection. Uganda National Tuberculosis Reference Laboratory technicians blinded to the method of sputum collection (with or without oral rinse) processed all sputum specimens for smear microscopy (direct Ziehl-Neelsen) and mycobacterial culture (Lowenstein-Jensen media). Of 220 patients enrolled, 177 (80%) were HIV-seropositive (median CD4-count 37 cells/uL, IQR 13-171 cells/uL). Baseline characteristics were similar between patients in the oral-rinse (N = 110) and no oral-rinse (N = 110) groups. The proportion of contaminated cultures was significantly lower in the oral-rinse group compared to the no oral-rinse group (4% vs. 15%, risk difference -11%, 95% CI -18 to -3%, p = 0.005). Oral rinse significantly reduced the proportion of contaminated cultures among HIV-infected patients (3% vs. 18%, risk difference -14%, 95% CI -23 to -6%, p = 0.002) but not HIV-uninfected (6% vs. 4%, risk difference 2%, 95% CI -12 to +15%, p = 0.81) patients. However, the proportion of smear-positive specimens (25% vs. 35%, p = 0.10) and culture-positive specimens (48% vs. 56%, p = 0.24) were lower in the oral-rinse compared to the no oral-rinse group, although the differences were not statistically significant. Oral rinse prior to sputum expectoration is a promising strategy to reduce mycobacterial culture contamination in areas with high HIV prevalence, if strategies can be devised to reduce the adverse impact of oral rinse on smear- and culture-positivity.


Nuclear Imaging Study of the Pharmacodynamic Effects of Debio 1143, an Antagonist of Multiple Inhibitor of Apoptosis Proteins (IAPs), in a Triple-Negative Breast Cancer Model.
Debio 1143, a potent orally available SMAC mimetic, targets inhibitors of apoptosis proteins (IAPs) members and is currently in clinical trials. In this study, nuclear imaging evaluated the effects of Debio 1143 on tumor cell death and metabolism in a triple-negative breast cancer (TNBC) cell line (MDA-MB-231)-based animal model. Apoptosis induced by Debio 1143 was assessed by FACS (caspase-3, annexin 5 (A5)), binding of 99mTc-HYNIC-Annexin V, and a cell proliferation assay. 99mTc-HYNIC-Annexin V SPECT and [18F]-FDG PET were also performed in mice xenografted with MDA-MB-231 cells. Debio 1143 induced early apoptosis both in vitro and in vivo 6 h after treatment. Debio 1143 inhibited tumor growth, which was associated with a decreased tumor [18F]-FDG uptake when measured during treatment. This imaging study combining SPECT and PET showed the early proapoptotic effects of Debio 1143 resulting in a robust antitumor activity in a preclinical TNBC model. These imaging biomarkers represent valuable noninvasive tools for translational and clinical research in TNBC.


Effect of parity on sexual function: an identical twin study.
To assess the impact of childbirth on female sexual function by using an identical twin study design. A survey including the Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire (PISQ-12) was administered to 542 twin sisters, and PISQ-12 scores of 29 twin pairs discordant for parity were compared. Multiple linear regression models were used to evaluate impact on total PISQ-12 scores in 276 identical, sexually active twins. Three models were used 1) to evaluate the effect of parity and general risk factors, 2) to examine the impact of birth mode, and 3) to examine the role of episiotomy and operative delivery. Mean PISQ-12 scores were significantly higher for discordant nulliparous twins than for parous twins (102.5 versus 93.5, P < .001). The mean (standard deviation) PISQ-12 score was 99.3 (11.7). Age of 50 years or older (difference in mean scores -5.4, P = .019), stress urinary incontinence (-3.3, P = .02), urge urinary incontinence (-5.9, P < .001), parity (-6.5, P < .001), and fecal incontinence (-5.7, P = .048) were associated with decreased mean PISQ scores in the univariable analysis. Parity (-4.9, P < .001) and urge urinary incontinence (-4.3, P = .009) were the only factors remaining independently predictive of diminished sexual function in the multivariable analysis. Mode of delivery did not significantly affect mean PISQ scores (P = .763). Among women who had vaginal deliveries only, neither episiotomy nor operative delivery was associated with change in PISQ scores (P = .553). Nulliparous women reported superior sexual satisfaction scores compared with parous women, regardless of age and mode of delivery. Childbirth appears to have a lasting impact on sexual function, due to psychological more than physical factors, well beyond the postpartum period. II-2.


Milk yield, milk composition, eating behavior, and lamb performance of ewes fed diets containing soybean hulls replacing coastcross (Cynodon species) hay.
The objective of this experiment was to evaluate the effects of replacing coastcross hay NDF by soybean hull (SH) NDF on the lactation performance and eating behavior of ewes and also on the performance of their lambs. Fifty-six Santa Inês lactating ewes (56.1 +/- 6.8 kg of initial BW; mean +/- SD) were penned individually and used in a randomized complete block design with 14 blocks and 4 treatments. Diets were formulated to provide similar concentrations of NDF (56%) and CP (16%). The SH NDF replaced 33 (SH33), 67 (SH67), or 100% (SH100) of the NDF contributed by coastcross hay in a 70% forage-based diet (SH0), resulting in SH inclusion rates of 0, 25, 54, and 85% of the dietary DM. Once a week, from the second to the eighth week of lactation (weaning time), ewes were separated from their lambs, stimulated by a 6-IU i.v. oxytocin injection, and hand milked to empty the udder. After 3 h, milk production was obtained after the same procedure. Quadratic effect for milk production (142.4, 179.8, 212.6, and 202.9 g/3 h) and cubic effect for DMI (2.27, 2.69, 3.25, and 3.00 kg/d) were observed as SH inclusion increased from 0 to 85% of the dietary DM. Milk fat (7.59, 7.86, 7.59, and 7.74%), protein (4.53, 4.43, 4.40, and 4.55%), and total solids (18.24, 18.54, 18.39, and 18.64%) did not differ among the 70% forage-based diet and diets with SH NDF replacing 33, 67, or 100% of the NDF. A linear increase in lactose concentration was observed with SH inclusion. Ewe BW gain during the trial showed a cubic response (0.37, 0.03, 4.80, and 2.80 kg) with SH inclusion. The preweaning ADG of lambs increased linearly, and ADG of lambs after weaning decreased linearly with SH inclusion. Final BW of lambs (2 wk after weaning) did not differ among treatments. Eating behavior observations were conducted with 44 ewes. The same facilities, experimental design, dietary treatments, and feeding management were used. Observations were visually recorded every 5 min for a 24-h period when ewes were 46 +/- 6.8 d in milk. Eating time (min/d, min/g of DMI, and min/g of NDF intake) and time expended in rumination and chewing activities (min/g of DMI and min/g of NDF intake) decreased linearly with the addition of SH in the diets. The inclusion of SH improved DMI and milk production, also reflecting on the BW of lambs at weaning. Milk performance was not affected when SH NDF replaced 100% of hay NDF.


[Genetics of isoenzymes and development].
Possibilities of utilization of isozymes as markers of the activity of genes in ontogenesis are considered. There are cases of both the synchronous and asynchronous activation of paternal and maternal genes controlling the synthesis of appropriate isozymes. The asynchronous activation is peculiar, mainly, of interspecific hybrids. The organospecific pattern of isozymes in ontogenesis is determined not only by the activity of structural genes controlling their syntheses, but also by numerous genes-modificators active at the translation and posttranslation levels.


A murine model of asbestosis.
Balb/c mice were exposed to aerosolized chrysotile fibers and evaluated as a host for the study of asbestos-induced pulmonary disease. Histologically, an initial macrophage reaction was found to progress to "asbestos body" formation and diffuse focal interstitial fibrosis within 1 year of a chronic exposure period. This reaction was most intense in areas adjacent to respiratory bronchioles and alveolar ducts. Two morphologically distinct tumors at the pulmonary visceral surface were also discovered among a high percentage of asbestos-exposed mice. Bronchoalveolar lavage demonstrated an eventual alteration of the retrievable cell populations among the dusted animals. Evaluation of systemic B-lymphocyte activity suggested a stimulation of this cell subset following chrysotile inhalation. These results demonstrate that subsequent to chronic asbestos exposure, the mouse develops pulmonary and immunologic changes very similar to those noted in human asbestosis.


Optimal timing for cardiac surgery in infective endocarditis: is earlier better?
All patients with infective endocarditis should be transferred to a hospital with cardiac surgery facilities. Once the decision to operate on a patient with infective endocarditis has been made, the timing of surgery is very often a difficult decision. Literature on this topic is very scarce. The European Society of Cardiology guidelines include recommendations on the timing of surgery. Heart failure, uncontrolled infection and prevention of embolic risk are the three main indications for surgery. Most often, when the decision to operate has been made, there is no benefit and potentially harm in delaying surgery. If cardiac surgery is indicated after an ischemic stroke, it should not be delayed. Discussion should be multidisciplinary and involve at least a cardiologist, a cardiac surgeon and an infectious diseases specialist, and any other specialist as needed (for example a neurologist).


[The mineral dietary composition affects glucose metabolism and modulates insulin effect in intact rats].
The experiments on intact rats showed that an excess sodium chloride consumption and the use of giposol (NaCl substitute) produce a hypoglycemic effect. Giposol increases, whereas NaCl decreases, the glucose tolerance. Giposol activates hexokinase and glucose-6-phosphate dehydrogenase (the key enzymes of the glucose metabolism in tissues) and reduces the effect of insulin. Both giposol and NaCl increase the level of glucose absorption in small intestine. The gastric motility is activated by NaCl and not affected by giposol.


Additive hazards regression and partial likelihood estimation for ecological monitoring data across space.
We develop continuous-time models for the analysis of environmental or ecological monitoring data such that subjects are observed at multiple monitoring time points across space. Of particular interest are additive hazards regression models where the baseline hazard function can take on flexible forms. We consider time-varying covariates and take into account spatial dependence via autoregression in space and time. We develop statistical inference for the regression coefficients via partial likelihood. Asymptotic properties, including consistency and asymptotic normality, are established for parameter estimates under suitable regularity conditions. Feasible algorithms utilizing existing statistical software packages are developed for computation. We also consider a simpler additive hazards model with homogeneous baseline hazard and develop hypothesis testing for homogeneity. A simulation study demonstrates that the statistical inference using partial likelihood has sound finite-sample properties and offers a viable alternative to maximum likelihood estimation. For illustration, we analyze data from an ecological study that monitors bark beetle colonization of red pines in a plantation of Wisconsin.


A new method based on deep learning and image processing for detection of strabismus with the Hirschberg test.
Strabismus is a condition in which one or both eyes do not work in parallel or in harmony. People with strabismus have one eye looking straight ahead while the other eye looks inwards, outwards, upwards or downwards. This condition can affect both eyes. Strabismus is a common eye condition that affects about 4 % of the world's population. Tests such as Hirschberg, Cover and Krimsky are used to detect strabismus. In the Hirschberg test, a light source is held at a distance of 50 cm so that it falls on the centre of each eye. The horizontal and vertical distance between the centre of gravity of the light reflected from the cornea and the centre of the pupil indicates the degree of strabismus. In this study, deep learning and image processing algorithms are used to detect the eye, corneal reflection, iris and pupil on a patient's facial image. Based on the Hirschberg test, the horizontal and vertical shifts for both eyes were measured to determine the patient's degree of strabismus. In this way, the Hirschberg test used in strabismus screening was performed automatically by software. The correct detection of the pupil and the light reflected from the cornea by the algorithm means that the eye has been measured correctly. The software was tested on the facial images of 88 strabismic patients of different sexes and ages. 91 % of the 88 patients, or 80 patients, had their left eye measured correctly. 90 % of the 88 patients, or 79 patients, had their right eye measured correctly. The results for each eye obtained from the correct measurements were found to have an error of maximum ± 2°. This error is due to the fact that a real eye is in three-dimensional space, while the digital eye image is in two-dimensional space, and was only observed in the test results of some patients. This algorithm can be tested on patients of all ages and is not affected by morphological differences in the patients' faces. Successful results have been observed experimentally that this newly proposed method can be used in strabismus screening.


Seborrheic dermatitis and malignancy. An investigation of the skin flora.
The skin flora of patients with disseminated malignant disease and seborrheic dermatitis has been investigated and compared with controls as well as with otherwise healthy patients suffering from seborrheic dermatitis. Although significant differences were detected in both bacterial and yeast counts between different sites on the body, no significant qualitative or quantitative differences were found between the three groups of subjects. Whereas abnormalities of the skin flora have been described in seriously ill patients and in individuals subjected to occlusion, we were unable to demonstrate any changes in skin flora in patients with malignant disease and seborrheic dermatitis. Our results do not support the view that increased numbers of Pityrosporum yeasts are important in the pathogenesis of seborrheic dermatitis.


Chemical modification of arginine residues of lung galaptin and fibronectin. Effects on fibroblast binding.
Lung galaptin bound to lung fibroblasts with a Kd of 190 nM, and this binding could be inhibited by 20 mM-lactose. Selective modifications of the arginine residues of galaptin with cyclohexane-1,2-dione did not change its lectin activity or its binding to fibroblasts. By contrast, modification of the arginine residues of plasma fibronectin resulted in a marked diminution of protein-fibroblast binding. Selective modification of arginine residues may provide a useful probe for -Arg-Gly-Asp-Xaa cell-binding sequences of proteins.


A case of epithelial-myoepithelial carcinoma of the parotid gland.
Epithelial-myoepithelial carcinomas comprise approximately 1% of all salivary gland neoplasms. Most tumors arise in the major salivary glands, especially in the parotid gland. We present a case of epithelial-myoepithelial carcinoma of the parotid gland in a 65-year-old male patient. Magnetic resonance imaging showed an irregular and heterogeneous mass in the left parotid gland. Superficial parotidectomy was performed. There was no evidence of recurrence during a 21-month follow-up.


Breathlessness clinics within specialist palliative care settings can improve the quality of life and functional capacity of patients with lung cancer.
This paper is a development on recent research that proved the value of non-pharmacological techniques and strategies in the management of breathlessness in lung cancer. It evaluates the intervention in a specialist palliative care setting using an outpatient clinic at Lewis-Manning House. Referrals were made by the patients' physician or specialist nurse. Patients (n = 30) were assessed and treated by the senior physiotherapist in charge of the clinic over three sessions. A number of outcomes were measured at various stages of the patients' treatment. The results have confirmed and strengthened the previous published results. Highly significant improvements in patients' breathlessness, functional capacity, activity levels and distress levels have been shown. For example, the percentage of patients experiencing breathlessness several times or more per day was reduced from 73% to 27% four weeks later. In addition, this project has been able to demonstrate significant improvements in quality of life and high levels of satisfaction with the interventions. Qualitative data enhanced the findings of objective measurements.


High-resolution crossover maps for each bivalent of Zea mays using recombination nodules.
Recombination nodules (RNs) are closely correlated with crossing over, and, because they are observed by electron microscopy of synaptonemal complexes (SCs) in extended pachytene chromosomes, RNs provide the highest-resolution cytological marker currently available for defining the frequency and distribution of crossovers along the length of chromosomes. Using the maize inbred line KYS, we prepared an SC karyotype in which each SC was identified by relative length and arm ratio and related to the proper linkage group using inversion heterozygotes. We mapped 4267 RNs on 2080 identified SCs to produce high-resolution maps of RN frequency and distribution on each bivalent. RN frequencies are closely correlated with both chiasma frequencies and SC length. The total length of the RN recombination map is about twofold shorter than that of most maize linkage maps, but there is good correspondence between the relative lengths of the different maps when individual bivalents are considered. Each bivalent has a unique distribution of crossing over, but all bivalents share a high frequency of distal RNs and a severe reduction of RNs at and near kinetochores. The frequency of RNs at knobs is either similar to or higher than the average frequency of RNs along the SCs. These RN maps represent an independent measure of crossing over along maize bivalents.


[Detection of autoimmune changes in white mice as a method of studying the biological properties of Shigella sonnei].
An attempt was made of using for the purpose of studying the virulence of Sh. sonnei of the method of determination of autoimmune plaque-forming cells in infected albino mice. By the mentioned method a total of 231 strains of Sh. sonnei of various biochemical types were examined. The virulence of 103 strains was checked in paralled by the keratoconjunctival test. It was shown that the method of determination of the autoimmune plaque-forming cells in the blood of infected mice could be used as a test for the virulence of Sh. sonnei, which was more sensitive than the keratoconjunctival test. Among the cultures studied 14.7% proved to be avirulent, 51.5%-of low virulence, 21.2%-moderately virulent, and 12.6%-highly virulent. Strains of the II biotype proved to be the most virulent, and strains of the III biotype-the least. The virulence of the cultures isolated from the patients with acute dysentery was more than double that of the cultures isolated from persons who came in contact with the patients.


The effect of prolactin (PRL) on the growth of Toxoplasma gondii tachyzoites in vitro.
During the development and effector phases of the anti-Toxoplasma response, the immunological system of a host is involved in several complex interactions with the endocrine system, and prolactin (PRL) is one of the most important hormones involved in immunoregulation. In this work, the influence of the recombinant human prolactin (rhPRL) on the viability, penetration, and intensity of intracellular proliferation of Toxoplasma gondii BK strain in vitro was evaluated. Using one murine (L929) and two human cell lines (Hs27 and HeLa), no toxic effect of the rhPRL on host cells was found (by determining cellular viability using MTT assay). A similar lack of rhPRL cytotoxic activity was found in the case of the extracellular tachyzoites of T. gondii BK. Replication of parasites in the presence of rhPRL was analyzed first by simultaneous addition of the hormone and the parasites into a microculture of the host cells (treatment during infection). No statistically significant changes in the intensity of parasite proliferation in all used host cells were found for a wide range of the hormone concentrations. However, pre-incubation of the tachyzoites with rhPRL resulted in a significant reduction (up to 36.15%) in the replication abilities of the parasite. Further experiments revealed that in fact, the inhibition of replication was caused by a limited capacity of the parasites to penetrate host's cells as demonstrated by the reduced number of infected cells.


Log in and breathe out: efficacy and cost-effectiveness of an online sleep training for teachers affected by work-related strain--study protocol for a randomized controlled trial.
Insomnia and work-related stress often co-occur. Both are associated with personal distress and diminished general functioning, as well as substantial socio-economic costs due to, for example, reduced productivity at the work place and absenteeism. Insomnia complaints by people experiencing work-related stress are correlated with a deficient cognitive detachment from work. Diffuse boundaries between work and private life can additionally complicate the use of recreational activities that facilitate cognitive detachment.Cognitive behavioral therapy for insomnia is effective but rarely implemented. Internet-based cognitive behavioral therapy for insomnia could potentially reduce this deficit given its demonstrated effectiveness. Less is known, however, about the efficacy of internet-based cognitive behavioral therapy for insomnia in populations affected by high work stress. Thus, the aim of the present study is to evaluate the efficacy and cost-effectiveness of a newly developed, guided online training which is based on Cognitive Behavioral Therapy for insomnia and tailored to teachers affected by occupational stress. In a two-arm randomized controlled trial (N = 128), the effects of a guided online sleep training will be compared to a waitlist-control condition. German teachers with significant clinical insomnia complaints (Insomnia Severity Index ≥ 15) and work-related rumination (Irritation Scale, subscale Cognitive Irritation ≥ 15) will be included in the study. The primary outcome measure will be insomnia severity. Additionally, an economic evaluation from a societal perspective will be conducted. Data from the intention-to-treat sample will be analyzed two and six months after randomization. To the best of our knowledge, this is the first study to evaluate an online sleep training tailored to a specific population with work stress, that is, teachers. If this type of intervention is effective, it could reduce the paucity of cognitive behavioral therapy for insomnia and augment the support for teachers in coping with their insomnia problems. German Clinical Trial Register (DRKS): DRKS00004700.


Penetration of oxygen into bacterial colonies.
Previous estimates of the depth of oxygen penetration into bacterial colonies were made after measuring actual and potential respiration rates of whole colonies, or by calculation from kinetic values determined from the growth of bacteria in liquid culture. This paper reports the use of microelectrodes to measure oxygen penetration directly. Oxygen became undetectable 25-30 microns below the surface of a 120 microns deep, 18 h colony of Bacillus cereus. The colony was grown on a nutrient-rich agar medium incubated at 30 degrees C in a water-saturated atmosphere.


Irisin inhibits CCK-8-induced TNF-α production via integrin αVβ5-NF-κB signaling pathways in Nile tilapia (Oreochromis niloticus).
Irisin, a secreted myokine generated by fibronectin type III domain-containing protein 5, has recently shown the potential to alleviate inflammation. Cholecystokinin-octapeptide (CCK-8) is closely associated with the inflammatory factor TNF-α, a central cytokine in inflammatory reactions. However, the interactions between irisin and CCK-8 in regulating TNF-α production and the underlying mechanism have not yet been elucidated. In the present study, irisin treatment inhibited the basal and the CCK-8-induced TNF-α production in vivo. Additionally, neutralizing circulating irisin using an irisin antiserum significantly augmented the CCK-8-induced stimulation of TNF-α levels. Moreover, the incubation of head kidney cells with irisin or CCK-8 has opposite effects on TNF-α secretion. Notably, irisin treatment inhibited basal and CCK-8-stimulated TNF-α release and gene transcription in head kidney cells. Mechanistically, the inhibitory actions of irisin on basal and CCK-8-induced TNF-α production could be negated by co-administered with the selective integrin αVβ5 inhibitor cilengitide. In addition, the inhibitory effect of irisin on basal and CCK-8-triggered TNF-α production could be abolished by the inhibition of the nuclear factor-kappa B (NF-κB) signaling pathway. Furthermore, irisin impeded CCK-8-induced phosphorylation and degradation of IκBα, simultaneously inhibiting NF-κB phosphorylation, preventing its translocation into the nucleus, and suppressing its DNA-binding activity induced by CCK-8. Collectively, these results suggest that the inhibitory effect of irisin on TNF-α production caused by CCK-8 is mediated via the integrin αVβ5-NF-κB signaling pathways in tilapia.


The longevity of the antimicrobial response in rainbow trout (Oncorhynchus mykiss) fed a peptidoglycan (PG) supplemented diet.
This study builds upon previous work studying antimicrobial peptide (AMP) gene expression in rainbow trout (Oncorhynchus mykiss) fed a peptidoglycan (PG) enriched diet. The aims here were 1) to evaluate how long AMP expression is elevated in skin with continuous feeding of fish with the PG enriched diet for 21 or 28 days, and 2) to assess the impact of stopping PG feeding at day 14 when sampled at day 21 or 28. The rainbow trout were divided into 6 groups, with two fed a control commercial diet for the duration of the experiment and the other four given the same diet enriched with 10 mg PG/Kg for 14 days (PG 1-14) or continuously (PG continuous), the former reverting back to the commercial diet at day 14. No mortalities occurred during the study and there were no significant differences in growth among the fish in the different diet groups. The expression of six AMP genes was studied by real-time PCR in the skin, since these genes were shown to be induced in response to the PG enriched diets in a previous experiment. We show that continuous PG treatment for 21 or 28 days maintained high levels of AMP expression, although in general the levels decreased with time on the diets. Withdrawal of the PG diets at day 14 resulted in a fall in expression level especially apparent with omCATH-1, omCATH-2 and omLEAP-2a, but with omDB-3 and omDB-4 remaining at elevated levels (x10) in comparison to fish given a control diet. These results confirm that orally administered PG clearly enhances the trout innate immune system and could be used as a means to boost fish defences. Future studies should be conducted to verify the impact on survival after pathogen challenge in trout fed PG enriched diets under these regimes.


[Immune tolerance after renal transplantation].
Progress in immunosuppressive therapy has improved short-term survival of renal allografts by decreasing the frequency of acute rejections. However, the long-term survival of renal grafts has not improved. Transplanted kidneys are lost in the late period after transplantation as a result of vasculopathy and chronic rejection. Immunological tolerance means the lack of immunological activity towards certain antigens while the response towards others remains correct. The induction of immunological tolerance of donor antigens (transplant tolerance) is examined intensively to work out treatment methods which will allow prevention of chronic allograft rejection. The paper includes an overview of current knowledge on allograft tolerance. Immune response to alloantigens is described and the mechanisms of immunological tolerance induction (including clonal deletion, anergy connected with the microchimerism phenomenon, and active suppression caused by regulatory lymphocytes) are characterized. The role of dendritic cells in the process of inducing and maintaining tolerance is highlighted. Tolerance-inducing strategies in renal transplant recipients and clinically applied evaluation methods are presented. At present, optimizing recipient matching is used to decrease the risk of graft rejection. Hopefully, gene therapy will be possible in the near future. However, before introducing such a procedure into clinical studies, optimal therapy conditions and risk evaluation must be defined in tests on animals.


[Multiple pilomatrixomas associated with Steinert disease].
A rare case of pilomatrixomas associated with Steinert's disease is reported. The patient had 14 tumors which were surgically excised and analyzed under the microscope. Such association seems to be much more common than in the general population. Besides these patients usually have multiple tumours and a positive familial history. This suggest a predisposition to the appearance of these tumours.


Non-dexamethasone-suppressible, pituitary-dependent hyperadrenocorticism in a dog.
A 5-year-old female dog with hyperadrenocorticism was determined to have pituitary-dependent hyperadrenocorticism even though plasma cortisol concentrations were not suppressed after high-dosage dexamethasone administration. The diagnosis was based on a supranormal response of plasma cortisol to ACTH administration and a lack of suppression of plasma cortisol concentration after administration of 0.1 mg of dexamethasone/kg. Although a higher dosage of dexamethasone (1 mg/kg) did not cause suppression of plasma cortisol, plasma ACTH concentrations in the dog were increased above those in clinically normal dogs, supporting a diagnosis of pituitary-dependent hyperadrenocorticism. During treatment with mitotane, the dog became unconscious and died. Necropsy revealed a pituitary tumor that had compressed and displaced the hypothalamus. Although high-dosage dexamethasone suppression tests often are useful in the differential diagnosis of hyperadrenocorticism, a lack of suppression of plasma cortisol does not necessarily exclude pituitary-dependent hyperadrenocorticism.


The mechanism of cell cycle arrest front progression explained by a KLUH/CYP78A5-dependent mobile growth factor in developing leaves of Arabidopsis thaliana.
The size and shape of leaves are influenced by the progression of the cell cycle arrest front (AF). However, the AF progression with leaf growth has not been characterized quantitatively. Moreover, the mechanism linking AF progression and genetic factors is not fully understood. Recently, it was proposed that a KLUH/CYP78A5 (KLU)-dependent signal acts as a mobile growth factor (MGF) for cell proliferation and controls the lateral organ size of Arabidopsis. This study examines this hypothesis under the assumption that the gradient field dynamics of the KLU-dependent MGF provide the mechanism of AF progression using molecular markers and computer simulations. First, we measured the exact AF position with leaf growth using the pCYCB1;1::CYCB1;1::GUS expression pattern, which visualizes mitotic cells. As a result, we found that the AF stayed at an almost constant distance from the leaf blade base (stage 1) and then progressed towards the base and disappeared relatively quickly (stage 2), which previously had not been identified. Secondly, we showed that KLU may generate a concentration gradient of MGF in leaves, if KLU really controls cell division via the biosynthesis of MGF, by comparing the expression patterns of pKLU::GUS and pCYCB1;1::CYCB1;1::GUS. Finally, we built a simulation model using a diffusion equation with a decay term, in which the rate of MGF production estimated from the KLU expression level was included in the boundary condition. Our simulation model successfully reproduced both stages 1 and 2 of the AF, suggesting that the proposed mechanism does explain the AF progression under some restricted conditions.


Endocrine expression of the active form of TGF-beta1 in the TGF-beta1 null mice fails to ameliorate lethal phenotype.
TGF-beta1 null mice die by 3 to 4 weeks of age due to a severe autoimmune-mediated multifocal inflammation resulting in multi-organ failure. To assess the therapeutic potential of circulating levels of active TGF-beta1, we generated mice with endocrine expression of active TGF-beta1 on a TGF-beta1 null background (TGF-beta1 (-/-/TG)) by crossing TGF-beta1(+/-) mice with transgenic mice (TG) that express recombinant TGF-beta1 specifically in the liver and secrete it in the blood. The TGF-beta1 (-/-/TG) mice exhibit a survival profile similar to the TGF-beta1 (-/-) mice indicating a failure to rescue the lethal phenotype. However, serum TGF-beta1 levels in the TGF-beta1 (-/-/TG) mice were restored to near normal levels with expression in all the tissues, notably in the kidney and spleen. Histopathology showed reduced inflammation in the target tissues, especially in the heart. Interestingly, unlike TGF-beta1 (-/-) mice, the TGF-beta1 (-/-/TG) mice have glomerulonephritis in their kidneys similar to the TG mice. Thus, the phenotype of TGF-beta1 (-/-/TG) animal model indicates the potential role of circulating active-TGF-beta1 in reducing inflammation, but its failure to rescue lethality in TGF-beta1 null mice indicates a critical autocrine role of TGF-beta1.


The Role of the Contextual Cohort to Resolve Some Challenges and Limitations of Comparisons in Pharmacoepidemiology.
In pharmacoepidemiology, comparison studies can provide a useful estimate of the level of increased or decreased risk of specific events with a medication (through a measure of effect). A key focus of pharmacoepidemiological studies is the safety and effectiveness of medicines in their real-world use, and adequate comparisons of effect estimates are critical. However, consideration of guidelines, pharmacoeconomic assessments, and policies for reimbursement have made comparisons in pharmacoepidemiological studies far more difficult to conduct in recent years. Where certain subject characteristics influence the probability of being exposed to a treatment, this can introduce issues of selection bias and confounding. Methodologies are available to minimise selection bias (through case-only and randomised study designs) and deal with confounding (such as regression modelling or propensity score matching methods), however these each have their own limitations. Where prescribing guidelines are present, conducting comparisons in pharmacoepidemiology produces many challenges and not all of these can be easily overcome. Patient channelling can be more frequent with adherence to clinical guidelines compared with when prescribing decisions by doctors are based predominantly on their clinical judgement. Use of a contextual cohort could be considered as an option to characterise the adoption of new medications into clinical practice and describe the prevalence of clinical characteristics and risk factors in the two cohorts, rather than compare event rates and produce an estimate of effect.


Maternal Immune Activation and Autism Spectrum Disorder: From Rodents to Nonhuman and Human Primates.
A subset of women who are exposed to infection during pregnancy have an increased risk of giving birth to a child who will later be diagnosed with a neurodevelopmental or neuropsychiatric disorder. Although epidemiology studies have primarily focused on the association between maternal infection and an increased risk of offspring schizophrenia, mounting evidence indicates that maternal infection may also increase the risk of autism spectrum disorder. A number of factors, including genetic susceptibility, the intensity and timing of the infection, and exposure to additional aversive postnatal events, may influence the extent to which maternal infection alters fetal brain development and which disease phenotype (autism spectrum disorder, schizophrenia, other neurodevelopmental disorders) is expressed. Preclinical animal models provide a test bed to systematically evaluate the effects of maternal infection on fetal brain development, determine the relevance to human central nervous system disorders, and to evaluate novel preventive and therapeutic strategies. Maternal immune activation models in mice, rats, and nonhuman primates suggest that the maternal immune response is the critical link between exposure to infection during pregnancy and subsequent changes in brain and behavioral development of offspring. However, differences in the type, severity, and timing of prenatal immune challenge paired with inconsistencies in behavioral phenotyping approaches have hindered the translation of preclinical results to human studies. Here we highlight the promises and limitations of the maternal immune activation model as a preclinical tool to study prenatal risk factors for autism spectrum disorder, and suggest specific changes to improve reproducibility and maximize translational potential.


Neural correlates of affective task switching and asymmetric affective task switching costs.
The control of emotions is of potentially great clinical relevance. Accordingly, there has been increasing interest in understanding the cognitive mechanisms underlying the ability to switch efficiently between the processing of affective and non-affective information. Reports of asymmetrically increased switch costs when switching toward the more salient emotion task indicate specific demands in the flexible control of emotion. The neural mechanisms underlying affective task switching, however, are so far not fully understood. Using functional Magnetic Resonance Imaging (MRI) (N = 57), we observed that affective task switching was accompanied by increased activity in domain-general fronto-parietal control systems. Blood-oxygen-level-dependent (BOLD) activity in the posterior medial frontal and anterolateral prefrontal cortex was directly related to affective switch costs, indicating that these regions play a particular role in individual differences in (affective) task-switching ability. Asymmetric switch costs were associated with increased activity in the right inferior frontal and dorsal anterior medial prefrontal cortex, two brain regions critical for response inhibition. This suggests that asymmetric switch costs might-to a great extent-reflect higher demands on inhibitory control of the dominant emotion task. These results contribute to a refined understanding of brain systems for the flexible control of emotions and thereby identify valuable target systems for future clinical research.


Chemical composition, anti-biofilm activity and potential cytotoxic effect on cancer cells of Rosmarinus officinalis L. essential oil from Tunisia.
Rosmarinus officinalis L. from Tunisia, popularly known as rosemary, is of a considerable importance for its medicinal uses and aromatic value. The aim of this study was to examine the chemical composition of Rosmarinus officinalis essential oil (ROEO) and to evaluate its antibiofilm activity on biofilm-forming bacterium and its anticancer activity on cancer cell lines. The chemical composition of Rosmarinus officinalis essential oil (ROEO) was analyzed by GC-MS and its antibacterial activity was evaluated by micro-dilution method. The antibofilm activity of ROEO was evaluated using the crystal violet test and the cytotoxicity activity was determined by the MTT assay. In this research, thirty-six compounds were identified in ROEO using GC-MS analyses. The main components were 1,8-cineole (23.56%), camphene (12.78%), camphor (12.55%) and β-pinene (12.3%). The antibacterial activity of ROEO was evaluated by micro-dilution method. The oil exhibited inhibition and bactericidal effect against two strains: Staphylococcus aureus ATCC 9144 and Staphylococcus epidermidis S61. It was found that the minimum inhibitory concentration (MIC) obtained for S. aureus and S. epidermidis ranged from 1.25 to 2.5 and from 0.312 to 0.625 μl ml-1, respectively and the minimum bactericidal concentration (MBC) were in the order of 5 and 2.5 μl ml-1, respectively. Furthermore, this oil showed a S. epidermidis biofilm inhibition more than 57% at a concentration of 25 μl ml-1. The eradication of 67% of the established biofilm was observed at a concentration of 50 μl ml-1 of ROEO, whereas the dose of 25 μl ml-1 removed only 38% of preformed biofilm. ROEO strongly inhibited the proliferation of Hela and MCF-7 cells with IC50 values of 0.011 and 0.253 μl ml-1, respectively. Our results demonstrate that ROEO could have a potential role in the treatment of diseases related to infection by microorganisms or proliferation of cancer cells.


[Diagnosis of liver abscesses].
The author observed 298 patients with abscesses of the liver of different etiology. The frequency of symptoms detected by clinical, laboratory abd roentgenological examinations is analysed. The value of special methods of examination (such as scanning and radiography of the liver, electrorentgenoscanography, echography, laparoscopy) is shown.


Dual-specificity phosphatase 14 (DUSP14/MKP6) negatively regulates TCR signaling by inhibiting TAB1 activation.
T cell activation is dependent upon phosphorylation of MAPKs, which play a critical role in the regulation of immune responses. Dual-specificity phosphatase 14 (DUSP14; also known as MKP6) is classified as a MAPK phosphatase. The in vivo functions of DUSP14 remain unclear. Thus, we generated DUSP14-deficient mice and characterized the roles of DUSP14 in T cell activation and immune responses. DUSP14 deficiency in T cells resulted in enhanced T cell proliferation and increased cytokine production upon T cell activation. DUSP14 directly interacted with TGF-β-activated kinase 1 (TAK1)-binding protein 1 (TAB1) and dephosphorylated TAB1 at Ser(438), leading to TAB1-TAK1 complex inactivation in T cells. The phosphorylation levels of the TAB1-TAK1 complex and its downstream molecules, including JNK and IκB kinase, were enhanced in DUSP14-deficient T cells upon stimulation. The enhanced JNK and IκB kinase activation in DUSP14-deficient T cells was attenuated by TAB1 short hairpin RNA knockdown. Consistent with that, DUSP14-deficient mice exhibited enhanced immune responses and were more susceptible to experimental autoimmune encephalomyelitis induction. Thus, DUSP14 negatively regulates TCR signaling and immune responses by inhibiting TAB1 activation.


A randomized controlled trial protocol for engaging distress tolerance and working memory to aid smoking cessation in low socioeconomic status (SES) adults.
Low income and low educational attainment are among the strongest predictors of both smoking prevalence and lapse (i.e., return) to smoking after cessation attempts. Treatment refinement is limited by inadequate knowledge of the specific lapse- or relapse-relevant vulnerabilities characteristic of populations that should be the target of treatment. In the context of a randomized clinical trial design, we describe an experimental medicine approach for evaluating the role of 2 specific lapse-relevant targets relative to the higher stress characteristic of low-socioeconomic contexts: low distress tolerance and low working memory capacity. Furthermore, we use an innovative approach for understanding risk of smoking lapse in smokers undergoing a quit attempt to examine candidate mechanistic targets assessed not only during nicotine use, but also during the conditions smokers will face upon a cessation attempt-during stressful nicotine-deprivation windows. This study is designed to show the incremental value of assessments during deprivation windows, in part because of the way in which specific vulnerabilities are modified by, and interact with, the heightened stress and withdrawal symptoms inherent to nicotine-deprivation states. Specifically, the study is designed to evaluate whether a novel mindfulness intervention (mindfulness combined with interoceptive exposure) can improve upon existing mindfulness interventions and extend therapeutic gains to the modification of mechanistic targets assessed in high-stress or negative affectivity contexts. The overall goal is to validate mechanistic targets and associated interventions for the purpose of expanding treatment options for at-risk smokers. (PsycInfo Database Record (c) 2020 APA, all rights reserved).


A novel classification and management scheme for craniocervical junction disorders with ventral neural element compression.
Craniocervical junction (CCJ) pathologies with ventral neural element compression are poorly understood, and appropriate management requires accurate understanding, description, and a more uniform nomenclature. The aim of this study was to evaluate patients to identify anatomical clusters and better classify CCJ disorders with ventral compression and guide treatment. A retrospective review of adult and pediatric patients with ventral CCJ compression from 2008 to 2022 at a single center was performed. The incidence of anatomical abnormalities and compressive etiologies was assessed. Surgical approach, radiographic data, and outcomes were recorded. Association rules analysis (ARA) was used to assess variable clustering. Among 51 patients, the main causes of compression were either purely bony (retroflexed dens [n = 18]; basilar invagination [BI; n = 13]) or soft tissue (degenerative pannus [n = 16]; inflammatory pannus [n = 2]). The primary cluster in ARA was a retroflexed dens, platybasia, and Chiari malformation (CM), and the secondary cluster was BI, C1-2 subluxation, and reducibility. These, along with degenerative pannus, formed the three major classes. In assessing the optimal treatment strategy, reducibility was evaluated. Of the BI cases, 12 of the 13 patients had anterolisthesis of C1 that was potentially reducible, compared with 2 of the 18 patients with a retroflexed dens (both with concomitant BI), and no pannus cases. The mean C1-2 facet angle was significantly higher in BI at 32.4°, compared with -2.3° in retroflexed dens and 8.1° in degenerative pannus (p < 0.05). Endonasal decompression with posterior fixation was performed in 48 (94.0%) of the 51 patients, whereas posterior reduction/fixation alone was performed in 3 patients (6.0%). Of 16 reducible cases, open posterior reduction alone was successful in 3 (60.0%) of 5 cases, with all successes containing isolated BI. Reduction was not attempted if vertebral anatomy was unfavorable (n = 9) or the C1 lateral mass was absent (n = 5). The mean follow-up was 28 months. Symptoms improved in 88.9% of patients and were stable in the remaining 11.1%. Tracheostomy and percutaneous G-tube placement occurred in 7.8% and 11.8% of patients, respectively. Reoperation for an endonasal CSF leak repair or posterior cervical wound revision both occurred in 3.9% of patients. In classifying, one cluster caused decreased posterior fossa volume due to an anatomical triad of retroflexed dens, platybasia, and CM. The second cluster caused pannus formation due to degenerative hypertrophy. For both, endonasal decompression with posterior fixation was ideal. The third group contained C1 anterolisthesis characterized by a steep C1-2 facet angle causing reducible BI. Posterior reduction/fixation is the first-line treatment when anatomically feasible or endonasal decompression with in situ posterior fixation when anatomical constraints exist.


Successful management of prolonged gamma-hydroxybutyrate and alcohol withdrawal.
A 27-year-old man was admitted with tremulousness, diaphoresis, tachypnea (28 breaths/min), full-body rigidity, irritability, paranoia, and auditory and visual hallucinations 2 days after stopping long-term gamma-hydroxybutyrate (GHB) and 8 hours after stopping alcohol intake. He received intravenous fluids and tapering dosages of lorazepam to control agitation and rigidity, and recovered with no significant sequelae after 8 days. Abrupt cessation of GHB after high-dosage abuse can precipitate a clinically significant withdrawal syndrome. Lorazepam should be considered for treatment of GHB withdrawal. Concomitant alcohol abuse may mask early GHB withdrawal symptoms and exacerbate withdrawal.


Muscle architecture and force-velocity characteristics of cat soleus and medial gastrocnemius: implications for motor control.
1. Isometric and isotonic contractile parameters of the soleus (SOL) and medial gastrocnemius (MG) muscles of seven adult cats were studied. In addition, architectural characteristics of six contralateral pairs of these ankle extensors were determined. 2. The in situ peak isometric tetanic tension developed by the MG at the Achilles tendon is nearly 5 times (9,846 vs 2,125 g) that of the SOL muscle. However, when differences between the MG and SOL in fiber length (2.01 vs 3.66 cm), muscle mass (9.80 vs. 3.31 g), and angle of pinnation (21.4 vs. 6.4 degrees) are considered, the specific tensions of these muscles are similar (approximately 2.3 kg x cm-2). 3. When the effects of muscle architecture are eliminated, the nearly threefold greater maximum isotonic shortening velocity (Vmax) of sarcomeres of the MG (38.2 micron/s) relative to the SOL (13.4 micron/s) is presumably due to intrinsic differences in the biochemical properties of these muscle. However, the Vmax developed by the MG at the Achilles tendon (258.6 mm/s) during a shortening contraction is only 1.5 times that of the SOL (176.3 mm/s) due to the influence of these muscles' specific architectures. 4. Variations in geometrical characteristics of the SOL and MG are consonant with the relative amounts of participation of these muscles during posture, locomotion, and jumping. Posture requires the development of low forces for prolonged periods for which the SOL seems best suited both architecturally and physiologically. The MG, relatively inactive during quiet standing, becomes responsible for a greater percentage of tension and shortening speed during plantar flexion (E3) as gait speeds increase, which is consistent with this muscle's greater tension- and velocity-generating capacity. 5. At high speeds of locomotion (3.0 m/s) and jumping, the shortening velocities developed at the end of E3 (approximately 20-40 ms before paw off) exceed Vmax of the SOL. Consequently, the SOL, although electrically active, cannot contribute to the tensions required to generate the shortening velocities dictated by these movements. 6. These data demonstrate the influence of the differing geometries of the SOL and MG on the roles of these muscles in generating forces at varying velocities, as demanded by the dynamics of the movement.


Pleiotropic genetic association analysis with multiple phenotypes using multivariate response best-subset selection.
Genetic pleiotropy refers to the simultaneous association of a gene with multiple phenotypes. It is widely distributed in the whole genome and can help to understand the common genetic mechanism of diseases or traits. In this study, a multivariate response best-subset selection (MRBSS) model based pleiotropic association analysis method is proposed. Different from the traditional genetic association model, the high-dimensional genotypic data are viewed as response variables while the multiple phenotypic data as predictor variables. Moreover, the response best-subset selection procedure is converted into an 0-1 integer optimization problem by introducing a separation parameter and a tuning parameter. Furthermore, the model parameters are estimated by using the curve search under the modified Bayesian information criterion. Simulation experiments show that the proposed method MRBSS remarkably reduces the computational time, obtains higher statistical power under most of the considered scenarios, and controls the type I error rate at a low level. The application studies in the datasets of maize yield traits and pig lipid traits further verifies the effectiveness.


Paternal Occupational Exposure to Heavy Metals and Welding Fumes and Testicular Germ Cell Tumours in Sons in France.
Testicular cancer is the most common cancer in young men. Its causes are largely unknown, although prenatal occupational and environmental exposures have been suggested. We investigated paternal occupational exposure to heavy metals and welding fumes and the risk of testicular germ cell tumors (TGCT) in their offspring. A total of 454 cases and 670 controls were included from a French nationwide case-control study. The INTEROCC job exposure matrix was used to assign occupational exposures (cadmium, chromium, iron, nickel, lead, and welding fumes) to the fathers' jobs. Odds ratios (ORs) for TGCT were estimated using conditional logistic regression models for frequency-matched sets. Three complementary analytical approaches were used: (1) single-agent analysis, (2) analysis by groups, and (3) principal component analysis (PCA). The proportion of paternal exposure to different heavy metals and welding fumes ranged from 0.7% (cadmium) to 11.3% (lead). Based on PCA, three principal components explained 93.5% of the cumulative variance. No associations were found between heavy metals or welding fumes and TGCT. In this study, paternal occupational exposure to heavy metals or welding fumes was not associated with TGCT development in their sons.


Mask TextSpotter: An End-to-End Trainable Neural Network for Spotting Text with Arbitrary Shapes.
Unifying text detection and text recognition in an end-to-end training fashion has become a new trend for reading text in the wild, as these two tasks are highly relevant and complementary. In this paper, we investigate the problem of scene text spotting, which aims at simultaneous text detection and recognition in natural images. An end-to-end trainable neural network named as Mask TextSpotter is presented. Different from the previous text spotters that follow the pipeline consisting of a proposal generation network and a sequence-to-sequence recognition network, Mask TextSpotter enjoys a simple and smooth end-to-end learning procedure, in which both detection and recognition can be achieved directly from two-dimensional space via semantic segmentation. Further, a spatial attention module is proposed to enhance the performance and universality. Benefiting from the proposed two-dimensional representation on both detection and recognition, it easily handles text instances of irregular shapes, for instance, curved text. We evaluate it on four English datasets and one multi-language dataset, achieving consistently superior performance over state-of-the-art methods in both detection and end-to-end text recognition tasks. Moreover, we further investigate the recognition module of our method separately, which significantly outperforms state-of-the-art methods on both regular and irregular text datasets for scene text recognition.


Uptake and distribution of cis-unsaturated fatty acids and their effect on free radical generation in normal and tumor cells in vitro.
We have previously shown that cis-unsaturated fatty acids (c-UFAs) possess a selective tumoricidal action that can be blocked by antioxidants. This property of c-UFAs might be due to various factors, including increased uptake, unusual distribution, or an ability to alter free radical generation in tumor but not normal cells. 14C-labelled linoleic acid (LA) uptake was almost the same in normal and tumor cells, whereas that of 14C-labelled arachidonic acid (AA) and 14C-labelled eicosapentaenoic acid (EPA) in tumor cells was substantially less than in normal cells. Tumor cells incorporate major portions of the fatty acids in the ether lipid and phospholipid fractions, whereas normal cells incorporate the fatty acids primarily in the phospholipid fraction. LA, AA, and EPA augmented nitroblue tetrazolium reduction, an indication of free radical generation, selectively in the tumor cells. These results suggest that there are significant differences between normal and tumor cells in fatty acid uptake and distribution, and in the ability of fatty acids to generate free radicals.


Proportion and risk factors for death by euthanasia in dogs in the UK.
The loss of a pet can be particularly distressing for owners, whether the method of death is euthanasia or is unassisted. Using primary-care clinical data, this study aimed to report the demographic and clinical factors associated with euthanasia, relative to unassisted death, in dogs. Method of death (euthanasia or unassisted) and clinical cause of death were extracted from a random sample of 29,865 dogs within the VetCompass Programme from a sampling frame of 905,544 dogs under UK veterinary care in 2016. Multivariable logistic regression modelling was used to evaluate associations between risk factors and method of death. Of the confirmed deaths, 26,676 (89.3%) were euthanased and 2,487 (8.3%) died unassisted. After accounting for confounding factors, 6 grouped-level disorders had higher odds in euthanased dogs (than dogs that died unassisted), using neoplasia as the baseline. The disorders with greatest odds included: poor quality of life (OR 16.28), undesirable behaviour (OR 11.36) and spinal cord disorder (OR 6.00). Breed, larger bodyweight and increasing age were additional risk factors for euthanasia. The results highlight that a large majority of owners will face euthanasia decisions and these findings can support veterinarians and owners to better prepare for such an eventuality.


[Short biography of an actor of the institutionalisation of orthopaedics (1830-1850)].
Parts of the socioscientific career of Jules Guérin, an orthopaedic surgeon, are presented in this article. The aim is to deepen the comprehension of intricate processes like specialisation and professionalisation of medicine and development of medical gymnastics. From this point of view Guérin's biography is very informative. The intention is to highlight the institutionalisation process of orthopaedics during two decades: the 1830s and 1840s. For the analysis the author tries to associate historical elements taken from the medical field and the socioeconomic context, however, without digressing too far from Guérin himself. First, Guérin's part in the institutionalisation process will be studied, second, his influence as a surgeon and theorist of spinal deformities and then his role as a controversial figure in the medical field.


Quercetin Mitigates Hepatic Insulin Resistance in Rats with Bile Duct Ligation Through Modulation of the STAT3/SOCS3/IRS1 Signaling Pathway.
Insulin resistance (IR) and inflammatory mediators are correlated with hepatic fibrosis. Quercetin is a bioflavonoid with well-known antidiabetic and antifibrotic properties. Bile duct ligation (BDL) is a surgical model performed on animals to produce a murine model in which increased oxidative stress occurs, which results in liver fibrosis. Our study aimed to determine whether quercetin improves hepatic IR as well as hepatic fibrosis in rats experiencing BDL. Male Wistar rats were allocated to four groups according to a random pattern, including a sham group, a sham and quercetin group (30 mg/kg/day), a BDL alone group, and a BDL and quercetin group (30 mg/kg/day). Evaluation of STAT3, SOCS3, IRS1, Rac1, Rac1-GTP, Sp1, NOX1, HIF-1α, and ERK1 expression was performed by RT-PCR along with the western blot analytical technique in liver tissue. The antidiabetic impact of quercetin was associated with reduction in mRNA and expression of protein in STAT3 and SOCS3, along with an increase in IRS1. The antifibrotic effect of quercetin was also determined by downregulation of mRNA or the levels of protein expression of Rac1-GTP, Rac1, HIF-1α, NOX1, and Sp1, along with ERK1. Our study indicates that quercetin may improve hepatic fibrosis via inhibiting ROS-associated inflammation as well as ameliorating hepatic IR by beneficial regulation of the STAT3/SOCS3/IRS1 signaling pathway.


Microwave magnetoelectric fields and their role in the matter-field interaction.
We show that in a source-free subwavelength region of microwave fields, there can exist field structures with a local coupling between the time-varying electric and magnetic fields differing from the electric-magnetic coupling in regular-propagating free-space electromagnetic waves. To distinguish such field structures from regular electromagnetic (EM) field structures, we term them as magnetoelectric (ME) fields. We study a structure and conservation laws of microwave ME near fields. We show that there exist sources of microwave ME near fields-the ME particles. These particles are represented by small quasi-two-dimensional ferrite disks with magnetic-dipolar-oscillation spectra. The near fields originating from such particles are characterized by topologically distinctive power-flow vortices, nonzero helicity, and a torsion degree of freedom. The paper consists of two main parts. In the first one, we give a theoretical background of properties of the electric and magnetic fields inside and outside of a ferrite particle with magnetic-dipolar-oscillation spectra resulting in the appearance of microwave ME near fields. In the second main part, we represent numerical and experimental studies of the microwave ME near fields and their interactions with matter. Based on the obtained properties of the ME near fields, we discuss possibilities for effective microwave sensing of natural and artificial chiral structures.


UWA-121, a mixed dopamine and serotonin re-uptake inhibitor, enhances L-DOPA anti-parkinsonian action without worsening dyskinesia or psychosis-like behaviours in the MPTP-lesioned common marmoset.
L-3,4-Dihydroxyphenylalanine (L-DOPA) is the most effective treatment for Parkinson's disease (PD), but its long-term administration is complicated by wearing-off and dyskinesia. UWA-101, a dual, equipotent inhibitor of dopamine (DAT) and serotonin (SERT) transporters, has previously been shown to successfully extend duration of anti-parkinsonian benefit of L-DOPA (ON-time), without exacerbating dyskinesia, in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmoset. However, UWA-101 is racemic and it is unclear whether one or both enantiomers contribute to its actions, and whether a better therapeutic effect might be attained by using a single antipode. In the current study, we synthesised the two enantiomers of UWA-101, R-101 (UWA-121) and S-101 (UWA-122), characterised their pharmacological profiles and administered them to MPTP-lesioned marmosets. Parkinsonism, dyskinesia, psychosis-like behaviours and duration of ON-time were evaluated. UWA-121 is a dual DAT > SERT inhibitor, with an approximate 10:1 DAT:SERT affinity ratio (inhibitory constants (Ki) of 307 and 3830 nM, respectively). In combination with L-DOPA, UWA-121 extended duration of ON-time when compared to L-DOPA/vehicle treatment (by 40%, P < 0.01). UWA-121 also extended duration of ON-time without dyskinesia (by 215%, P < 0.05) and ON-time without psychosis-like behaviours when compared to L-DOPA/vehicle treatment (by 345%, P < 0.01). UWA-121 did not worsen the severity of dyskinesia or psychosis-like behaviours (P > 0.05). UWA-122 is a selective SERT inhibitor (Ki 120 nM, Ki at DAT > 50 μM) and, in combination with L-DOPA, had no effect on ON-time, dyskinesia or psychosis-like behaviours (P > 0.05). These data indicate that dual DAT and SERT inhibitors effectively enhance L-DOPA anti-parkinsonian action without worsening dyskinesia and that compounds with such a pharmacological profile represent promising agents against wearing-off in PD.


COX-2 modulates mammary tumor progression in response to collagen density.
High breast density is linked to an increased risk of breast cancer, and correlates with changes in collagen. In a mouse model of mammary carcinoma in the context of increased collagen deposition, the MMTV-PyMT/Col1a1 (tm1jae) , there is accelerated mammary tumor formation and progression. Previous gene expression analysis suggests that increased collagen density elevates expression of PTGS2 (prostaglandin-endoperoxide synthase 2), the gene for cyclooxygenase-2 (COX-2). To understand the role of COX-2 in tumor progression within a collagen-dense microenvironment, we treated MMTV-PyMT or MMTV-PyMT/Col1a1 (tm1jae) tumors prior to and after tumor formation. Animals received treatment with celecoxib, a specific COX-2 inhibitor, or placebo. Mammary tumors were examined for COX-2, inflammatory and stromal cell components, and collagen deposition through immunohistochemical analysis, immunofluorescence, multiplex cytokine ELISA and tissue imaging techniques. PyMT/Col1a1 (tm1jae) tumors were larger, more proliferative, and expressed higher levels of COX-2 and PGE2 than PyMT tumors in wild type (WT) mice. Treatment with celecoxib significantly decreased the induced tumor size and metastasis of the PyMT/Col1a1 tumors, such that their size was not different from the smaller PyMT tumors. Celecoxib had minimal effect on the PyMT tumors. Celecoxib decreased expression levels of COX-2, PGE2, and Ki-67. Several cytokines were over-expressed in PyMT/Col1a1 compared to PyMT, and celecoxib treatment prevented their over-expression. Furthermore, macrophage and neutrophil recruitment were enhanced in PyMT/Col1a1 tumors, and this effect was inhibited by celecoxib. Notably, COX-2 inhibition reduced overall collagen deposition. Finally, when celecoxib was used prior to tumor formation, PyMT/Col1a1 tumors were fewer and smaller than in untreated animals. These findings suggest that COX-2 has a direct role in modulating tumor progression in tumors arising within collagen-dense microenvironments, and suggest that COX-2 may be an effective therapeutic target for women with dense breast tissue and early-stage breast cancer.


Gallbladder cancer in South America: epidemiology and prevention.
The incidence and the mortality of gallbladder cancer (GBC) show significant variation worldwide, with high age-standardized rates in western South America (SA). Due to the lack of effective measures for prevention, the late diagnosis and the small benefit of systemic treatment, GBC has an ominous prognosis and became an important public health problem in this part of the continent, where the most important risk factors are gallstone disease, female gender, age, ethnic groups, and low socioeconomic status. Many genetic abnormalities have been described in series from SA, some of them similar and others unique in comparison to gene alterations in GBC from other regions of the world. Prophylactic cholecystectomy (PC) is one of the strategies to decrease the mortality but its cost-effectiveness is questionable. A way to improve the performance of PC is to identify molecular risk factors that in combination with currently known ones detect patients with very high risk for developing GBC. Also, more research studies are required to better understand the epidemiology and molecular biology in order to improve the prevention and treatment of this lethal disease.


Antipsychotic Use Among 1144 Patients After Aneurysmal Subarachnoid Hemorrhage.
Background and Purpose- At acute phase and neurointensive care, patients with aneurysmal subarachnoid hemorrhage (aSAH) may become agitated or delirious. We found no previous studies on psychotic disorders or antipsychotic drug (APD) use by long-term aSAH survivors. We defined the APD use and its risk factors among 12-month survivors of aSAH in an Eastern Finnish population-based cohort with long-term follow-up. Methods- We analyzed APD use in 1144 consecutive patients with aSAH alive at 12 months of the Kuopio intracranial aneurysm patient and family database and their age, sex, and birth municipality matched controls (3:1; n=3432) from 1995 to 2013 and median follow-up of 9 years. Using the Finish nationwide health registries, we obtained drug purchase and hospital discharge data. Results- In total, 140 (12%) of the 1144 patients started APD use first time after aSAH (index date), in contrast to 145 (4%) of the 3432 matched population controls. The cumulative rate of starting APD was 6% at 1 year and 9% at 5 years, in contrast to 1% and 2% in the controls, respectively. The rates at 1 and 5 years were only 1% and 2% in the 489 patients with a good condition (modified Rankin Scale score, 0 or 1 at 12 months; no shunt, intracerebral hemorrhage, or intraventricular hemorrhage). Instead, the highest rate of APD use, 23% at 5 years was among the 192 patients shunted for hydrocephalus after aSAH. Eighty-eight (63%) of the 140 aSAH patients with APD use had also concomitant antidepressant or antiepileptic drug use. Conclusions- The 12-month survivors of aSAH were significantly more likely to be started on APD after aSAH than their matched population controls. These patients often used antidepressant and antiepileptic drugs concomitantly. The use of APDs strongly correlated with signs of brain injury after aSAH, with low use if no signs of significant brain injury were present.


Thermal response of a dental tissue induced by femtosecond laser pulses.
This paper reports a theoretical and experimental study for thermal transport in a thin slice of human tooth induced by a 120 fs, 800 nm pulse laser at a repetition rate of 1 kHz. The surface reflectivity of enamel and the convection heat transfer coefficient were determined using an inverse heat transfer analysis. Instead of a fully three-dimensional modeling, two simplified two-dimensional (2D) planar and axisymmetric heat conduction models were proposed to simulate the temperature fields. The temperature responses obtained from the 2D planar and axisymmetric model agree well with the experimental measurements. On the other hand, the one-dimensional (1D) result significantly differs from the 2D axisymmetric one, suggesting that care should be taken when a 1D thermal model is considered for estimating temperature response.


Introduction to spin-polarized ballistic hot electron injection and detection in silicon.
Ballistic hot electron transport overcomes the well-known problems of conductivity and spin lifetime mismatch that plague spin injection attempts in semiconductors using ferromagnetic ohmic contacts. Through the spin dependence of the mean free path in ferromagnetic thin films, it also provides a means for spin detection after transport. Experimental results using these techniques (consisting of spin precession and spin-valve measurements) with silicon-based devices reveals the exceptionally long spin lifetime and high spin coherence induced by drift-dominated transport in the semiconductor. An appropriate quantitative model that accurately simulates the device characteristics for both undoped and doped spin transport channels is described; it can be used to recover the transit-time distribution from precession measurements and determine the spin current velocity, diffusion constant and spin lifetime, constituting a spin 'Haynes-Shockley' experiment without time-of-flight techniques. A perspective on the future of these methods is offered as a summary.


Rupture of the rectosigmoid colon with evisceration of the small bowel through the anus.
Spontaneous rupture of the rectosigmoid colon and herniation of the small intestine through the rupture site and eventual evisceration through the anus is a very rare event. In the literature, only 42 cases have been reported. The majority of them occurred in patients with rectal prolapse and one case was reported in association with a third-degree uterine prolapse. We experienced an 81-year-old female patient with rectal prolapse and second-degree uterine prolapse complicated by spontaneous perforation of the rectosigmoid colon and anal evisceration of the small intestine. Segmental resection of the nonviable small intestine, primary repair of the ruptured rectosigmoid colon, and sigmoid loop colostomy were performed, and the patient recovered well. In our patient, both rectal and uterine prolapses cooperatively damaged the anterior wall of the rectosigmoid colon and resulted in perforation. So, rectal and uterine prolapses should be treated before the complication develops. In this patient, uterine prolapse should be treated because of the recurrence of this rare episode.


Combined anterior and rotational laxity measurements allow characterizing personal knee laxity profiles in healthy individuals.
The aim of this study was to quantify sagittal and rotational knee laxity profiles taking into account individual influencing factors. Linear regression models were used to determine which individual characteristics (age, height, body mass and sex) influenced the outcome in a group of 104 healthy subjects. The standardized residuals were used as individualized (corrected) laxity scores and were combined to determine knee laxity profiles. Anterior knee laxity was not influenced by individual characteristics. Rotational knee laxity was higher in females and inversely related to body mass. The correlation between anterior laxity and internal rotation scores was weak (r = 0.24, p = 0.02). The proportion of knees concerned by increased laxity scores (scores >1) was similar for anterior displacement, internal and external rotation (15 %). Only 32 % of the tested subjects showed a normal profile (score >-1 and <1) for all three directions, 33 % were concerned by hyperlaxity, 40 % by hypolaxity and 5 % by both. The diversity of laxity profiles found here highlights that the interpretation of multidirectional knee laxity is complex and suggests the necessity for individualized care of knee diseases and injuries. These results contribute to the understanding of knee laxity and throw the basis for prevention strategies and improvement of treatment outcomes in injuries and diseases. Case series with no comparison groups, Level IV.


Small molecule immunomodulation: the tumor microenvironment and overcoming immune escape.
Immunotherapy has led to a paradigm shift in the treatment of many advanced malignancies. Despite the success in treatment of tumors like non-small cell lung cancer (NSCLC) and melanoma, checkpoint inhibition-based immunotherapy has limitations. Many tumors, such as pancreatic cancer, are less responsive to checkpoint inhibitors, where patients tend to have a limited duration of benefit and where clinical responses are more robust in patients who are positive for predictive biomarkers. One of the critical factors that influence the efficacy of immunotherapy is the tumor microenvironment (TME), which contains a heterogeneous composition of immunosuppressive cells. Myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) alter the immune landscape of the TME and serve as facilitators of tumor proliferation, metastatic growth and immunotherapy resistance. Small molecule inhibitors that target these components of the TME have been developed. This special issue review focuses on two promising classes of immunomodulatory small molecule inhibitors: colony stimulating factor-1 receptor (CSF-1R) and focal adhesion kinase (FAK). Small molecule inhibitors of CSF-1R reprogram the TME and TAMs, and lead to enhanced T-cell-mediated tumor eradication. FAK small molecule inhibitors decrease the infiltration MDSCs, TAMs and regulatory T-cells. Additionally, FAK inhibitors are implicated as modulators of stromal density and cancer stem cells, leading to a TME more conducive to an anti-tumor immune response. Immunomodulatory small molecule inhibitors present a unique opportunity to attenuate immune escape of tumors and potentiate the effectiveness of immunotherapy and traditional cytotoxic therapy.