Anti-idiotypic antibodies recognizing stable epitopes limit the emergence of idiotype variants in a murine B cell lymphoma.
The emergence of Id variants is a major escape mechanism from anti-Id therapy of human B cell malignancies and of the murine B cell lymphoma 38C13. To determine what impact the epitope specificity of anti-Id antibodies has on the prevention of emergence of such Id variants in the 38C13 lymphoma, anti-Id mAb of varying epitope specificity for the Id of 38C13 tumor cells were produced and studied. Some antibodies, produced by immunizing mice with both the wild-type 38C13 IgM and variant IgM, cross-reacted with wild-type 38C13 IgM and with all four members of a panel of variant IgM. These anti-Id did not react with separated 38C13 IgM H or L chains by Western blot, but did react with the cytoplasmic H chain of the surface Ig- variant cell line T2D that expresses the same H chain as wild-type 38C13 in its cytoplasm but does not express any associated L chain. In contrast, anti-Id of narrower specificity did not react with this H chain. This indicated that the broadly cross-reactive antibodies recognized a stable epitope on 38C13 H chain. When a broadly cross-reactive antibody MS11G6 was compared to S1C5, an antibody of narrower specificity, MS11G6, was superior at preventing tumor growth in mice inoculated with 38C13 cells. Moreover, no surface Ig+ variants emerged in escaping tumors in the MS11G6-treated group, whereas such variants were common in the S1C5 treated group. Both anti-Id were of equal efficacy in eliminating wild-type 38C13 cells by using 38C13 cells in tumor inoculums that had just been cloned in vitro, but MS11G6 was also capable of preventing the growth of several surface Ig+ variant cell lines in vivo. We conclude that anti-Id recognizing more stable Id determinants can limit the emergence of Id variants and therefore be more effective therapeutic agents. This finding is of additional importance as additional in vivo and immunophenotypic studies demonstrated that the generation of Id variants was an ongoing process both in cloned parental 38C13 cells and its variants.


Elastin degradation product isodesmosine is a chemoattractant for Pseudomonas aeruginosa.
Previous studies have demonstrated that Pseudomonas aeruginosa PAO1 is chemotactic towards proteinogenic amino acids, however, the chemotaxis response of this strain towards non-proteinogenic amino acids and the specific chemoreceptors involved in this response are essentially unknown. In this study, we analysed the chemotactic response of PAO1 towards two degradation products of elastin, the lysine-rich, non-proteinogenic amino acids, desmosine and isodesmosine. We observed that isodesmosine, a potential biomarker for different diseases, served as a chemoattractant for PAO1. A screen of 251methyl-accepting chemotaxis proteins mutants of PAO1 identified PctA as the chemoreceptor for isodesmosine. We also showed that the positive chemotactic response to isodesmosine is potentially common by demonstrating chemoattraction in 12 of 15 diverse (in terms of source of isolation) clinical isolates, suggesting that the chemotactic response to this non-proteinogenic amino acid might be a conserved feature of acute infection isolates and thus could influence the colonization of potential infection sites.


Fatigue recovery and connected factors following paediatric concussion.
Using a biopsychosocial framework and the three-factor fatigue model, we aimed to (1) plot recovery of fatigue over the 3 months following paediatric concussion and (2) explore factors associated with persisting fatigue during the first 3 months postconcussion. 240 children and adolescents aged 5-18 years (M=11.64, SD=3.16) completed assessments from time of injury to 3 months postinjury. Separate linear mixed effects models were conducted for child and parent ratings on the PedsQL-Multidimensional Fatigue Scale to plot recovery across domains (General, Cognitive, Sleep/Rest) and Total fatigue, from 1 week to 3 months postinjury. Two-block hierarchical regression analyses were then conducted for parent and child ratings of fatigue at each time point, with age, sex and acute symptoms in block 1 and child and parent mental health variables added to block 2. There was a significant reduction in both child and parent ratings across the 3 months postinjury for all fatigue domains (all p<0.001). For both child and parent fatigue ratings, child mental health was the most significant factor associated with fatigue at all time points. Adding child and parent mental health variables in the second block of the regression substantially increased the variance explained for both child and parent ratings of fatigue. Our findings confirm that fatigue improves during the first 3 months postconcussion and highlights the importance of considering child and parent mental health screening when assessing patients with persisting postconcussive symptoms.


[Biomaterial regulation (biostoffverordnung) - aspects of the practical conversion].
German Biomaterial regulation (Biostoffverordnung) applies for activities with biological materials (BM). The purpose of this regulation is protection of employees working with BM. BM are micro organisms, inclusively genetically changed micro organisms, cell cultures and human pathogene endoparasits, which cause infections, sensitizing or toxic effects on humans. This regulation describes the necessary organizational, safety-relevant, personally and hygiene measures for the prevention of the diseases and damages caused by BA.


Nasal tip-suspending suture technique: cat's nape suture.
Variation in nasal-tip deformity is the most common complaint of the patients requesting rhinoplastic surgery, and the goal of nearly every rhinoplasty is to achieve ideal nasal-tip rotation and projection. We describe a procedure that allows the surgeon to secure nasal-tip rotation and projection through a suspension suture technique. Preserving the interalar soft tissues over the dorsal caudal septum and interdomal ligaments during the surgery is the major basis of this technique. We use the soft tissues as a suspending material for the tip complex, which acts like one whole part.


Requirement of the Pseudomonas aeruginosa tonB gene for high-affinity iron acquisition and infection.
To investigate the contribution of the TonB protein to high-affinity iron acquisition in Pseudomonas aeruginosa, we constructed tonB-inactivated mutants from strain PAO1 and its derivative deficient in producing the siderophores pyoverdin and pyochelin. The tonB mutants could not grow in a free-iron-restricted medium prepared by apotransferrin addition, even though the medium was supplemented with each purified siderophore or with a heme source (hemoglobin or hemin). The tonB inactivation was shown to make P. aeruginosa unable to acquire iron from the transferrin with either siderophore. Introduction of a plasmid carrying the intact tonB gene restored growth of the tonB mutant of PAO1 in the free-iron-restricted medium without any supplements and restored growth of the tonB mutant of the siderophore-deficient derivative in the medium supplemented with pyoverdin, pyochelin, hemoglobin, or hemin. In addition, animal experiments showed that, in contrast to PAO1, the tonB mutant of PAO1 could not grow in vivo, such as in the muscles and lungs of immunosuppressed mice, and could not kill any of the animals. The in vivo growth ability and lethal virulence were also restored by introduction of the tonB-carrying plasmid in the tonB mutant. These results indicate clearly that the intact tonB gene-and, therefore, the TonB protein encoded by it-is essential for iron acquisition mediated by pyoverdin and pyochelin and via heme uptake in P. aeruginosa and suggest that the TonB-dependent iron acquisition may be essential for P. aeruginosa to infect the animal host.


Cord Blood Metabolome Is Highly Associated with Birth Weight, but Less Predictive for Later Weight Development.
Fetal metabolism may be changed by the exposure to maternal factors, and the route to obesity may already set in utero. Cord blood metabolites might predict growth patterns and later obesity. We aimed to characterize associations of cord blood with birth weight, postnatal weight gain, and BMI in adolescence. Over 700 cord blood samples were collected from infants participating in the German birth cohort study LISAplus. Glycerophospholipid fatty acids (GPL-FA), polar lipids, non-esterified fatty acids (NEFA), and amino acids were analyzed with a targeted, liquid chromatography-tandem mass spectrometry based metabolomics platform. Cord blood metabolites were related to growth factors by linear regression models adjusted for confounding variables. Cord blood metabolites were highly associated with birth weight. Lysophosphatidylcholines C16:1, C18:1, C20:3, C18:2, C20:4, C14:0, C16:0, C18:3, GPL-FA C20:3n-9, and GPL-FA C22:5n-6 were positively related to birth weight, while higher cord blood concentrations of NEFA C22:6, NEFA C20:5, GPL-FA C18:3n-3, and PCe C38:0 were associated with lower birth weight. Postnatal weight gain and BMI z-scores in adolescents were not significantly associated with cord blood metabolites after adjustment for multiple testing. Potential long-term programming effects of the intrauterine environment and metabolism on later health cannot be predicted with profiling of the cord blood metabolome.


Dissociating the contributions of human frontal eye fields and posterior parietal cortex to visual search.
Imaging, lesion, and transcranial magnetic stimulation (TMS) studies have implicated a number of regions of the brain in searching for a target defined by a combination of attributes. The necessity of both frontal eye fields (FEF) and posterior parietal cortex (PPC) in task performance has been shown by the application of TMS over these regions. The effects of stimulation over these two areas have, thus far, proved to be remarkably similar and the only dissociation reported being in the timing of their involvement. We tested the hypotheses that 1) FEF contributes to performance in terms of visual target detection (possibly by modulation of activity in extrastriate areas with respect to the target), and 2) PPC is involved in translation of visual information for action. We used a task where the presence (and location) of the target was indicated by an eye movement. Task disruption was seen with FEF TMS (with reduced accuracy on the task) but not with PPC stimulation. When a search task requiring a manual response was presented, disruption with PPC TMS was seen. These results show dissociation of FEF and PPC contributions to visual search performance and that PPC involvement seems to be dependent on the response required by the task, whereas this is not the case for FEF. This supports the idea of FEF involvement in visual processes in a manner that might not depend on the required response, whereas PPC seems to be involved when a manual motor response to a stimulus is required.


Comparison of Cell Preparations between Commercially Available Filter Cards of the Cytospin with Custom Made Filter Cards.
Cytological evaluation of body fluids is an important diagnostic technique. Cytocentrifuge has contributed immensely to improve the diagnostic yield of the body fluids. Cytocentrifuge requires a filter card for absorbing the cell free fluid. This is the only consumable which needs to be purchased from the manufacturer at a significant cost. To compare the cell density in cytocentrifuge preparations made from commercially available filter cards with custom made filter cards. This was a prospective analytical study undertaken in department of pathology of a tertiary care centre. A 300 GSM handmade paper with the absorbability similar to the conventional card was obtained and fashioned to suit the filter card slot of the cytospin. Thirty seven body fluids were centrifuged using both conventional and custom made filter card. The cell density was measured as number of cells per 10 high power fields. The median cell density was compared using Mann-Whitney U test. The agreement between the values was analysed using Bland Altman analysis. The median cell count per 10 High power field (HPF) with conventional card was 386 and that with custom made card was 408. The difference was not statistically significant (p = 0.66). There was no significant difference in the cell density and alteration in the morphology between the cell preparations using both the cards. Custom made filter card can be used for cytospin cell preparations of body fluids without loss of cell density or alteration in the cell morphology and at a very low cost.


Percutaneous transcatheter aortic valve implantation: present and future perspective.
Transcatheter aortic-valve implantation is becoming the standard of care for inoperable patients with severe aortic stenosis and a valid alternative for those at high surgical risk. Since the first percutaneous transcatheter aortic-valve implantation in humans in 2002, over 50,000 transcatheter aortic valves have been implanted in the last decade, with progressive improvement in the available devices. Overall, there are two main families of transcatheter prosthesis: self-expandable and nonself-expandable. The self-expandable devices, for which CoreValve(®) (Medtronic CV Luxembourg S.a.r.l., Luxembourg) represents the prototype, are characterized by a structure composed of shape memory materials, usually nitinol, which acquire its final shape once released. By contrast, the non-self-expandable prostheses, mainly represented by the Edwards(®) valve (Edwards Life Sciences, Inc., CA, USA), require balloon dilatation to reach its final shape. Although several publications have already provided positive data on both technologies, new clinical studies with improved systems are currently being conducted in order to provide more solid data and potentially expand the spectrum of patients who can benefit from this therapy. Thus, the aim of the present paper is to review the salient features of the two most used systems today (third-generation CoreValve and Edwards SAPIEN XT(®)) as well as to provide data on other emerging valves and future perspectives.


Emerging Screening Approaches in the Development of Nrf2-Keap1 Protein-Protein Interaction Inhibitors.
Due to role of the Keap1-Nrf2 protein-protein interaction (PPI) in protecting cells from oxidative stress, the development of small molecule inhibitors that inhibit this interaction has arisen as a viable approach to combat maladies caused by oxidative stress, such as cancers, neurodegenerative disease and diabetes. To obtain specific and genuine Keap1-Nrf2 inhibitors, many efforts have been made towards developing new screening approaches. However, there is no inhibitor for this target entering the clinic for the treatment of human diseases. New strategies to identify novel bioactive compounds from large molecular databases and accelerate the developmental process of the clinical application of Keap1-Nrf2 protein-protein interaction inhibitors are greatly needed. In this review, we have summarized virtual screening and other methods for discovering new lead compounds against the Keap1-Nrf2 protein-protein interaction. We also discuss the advantages and limitations of different strategies, and the potential of this PPI as a drug target in disease therapy.


Prognostic and therapeutic relevance of FLIP and procaspase-8 overexpression in non-small cell lung cancer.
Non-small cell lung carcinoma remains by far the leading cause of cancer-related deaths worldwide. Overexpression of FLIP, which blocks the extrinsic apoptotic pathway by inhibiting caspase-8 activation, has been identified in various cancers. We investigated FLIP and procaspase-8 expression in NSCLC and the effect of HDAC inhibitors on FLIP expression, activation of caspase-8 and drug resistance in NSCLC and normal lung cell line models. Immunohistochemical analysis of cytoplasmic and nuclear FLIP and procaspase-8 protein expression was carried out using a novel digital pathology approach. Both FLIP and procaspase-8 were found to be significantly overexpressed in tumours, and importantly, high cytoplasmic expression of FLIP significantly correlated with shorter overall survival. Treatment with HDAC inhibitors targeting HDAC1-3 downregulated FLIP expression predominantly via post-transcriptional mechanisms, and this resulted in death receptor- and caspase-8-dependent apoptosis in NSCLC cells, but not normal lung cells. In addition, HDAC inhibitors synergized with TRAIL and cisplatin in NSCLC cells in a FLIP- and caspase-8-dependent manner. Thus, FLIP and procaspase-8 are overexpressed in NSCLC, and high cytoplasmic FLIP expression is indicative of poor prognosis. Targeting high FLIP expression using HDAC1-3 selective inhibitors such as entinostat to exploit high procaspase-8 expression in NSCLC has promising therapeutic potential, particularly when used in combination with TRAIL receptor-targeted agents.


Impact of strengths model training and supervision on the therapeutic practice of Australian mental health clinicians.
This study explored the impact of Strengths Model training, supervision and mentorship on the practice of a group of multi-disciplinary mental health clinicians that included mental health nurses, social workers, psychologists, and occupational therapists. A qualitative approach that combined critical realism and grounded theory was used. The findings demonstrated how a substantive category, Getting to Know Clients Better, facilitated participants' progression through a basic social psychological process, Becoming a Strengths-Informed Practitioner. This process consisted of a discernible and sustained change towards more person-centred, hopeful, and recovery-oriented practice. The findings also described an underlying generative mechanism for this, the Client Becomes Visible, which accorded with theoretical models of empathy, based on enhanced cognitive processing. The strength-based approach to practice facilitated the establishment of a collaborative relationship and a stronger therapeutic alliance between the client and clinician. The research demonstrated that Strengths Model is an effective vehicle for improving recovery-orientated mental health services.


Early application of airway pressure release ventilation may reduce the duration of mechanical ventilation in acute respiratory distress syndrome.
Experimental animal models of acute respiratory distress syndrome (ARDS) have shown that the updated airway pressure release ventilation (APRV) methodologies may significantly improve oxygenation, maximize lung recruitment, and attenuate lung injury, without circulatory depression. This led us to hypothesize that early application of APRV in patients with ARDS would allow pulmonary function to recover faster and would reduce the duration of mechanical ventilation as compared with low tidal volume lung protective ventilation (LTV). A total of 138 patients with ARDS who received mechanical ventilation for <48 h between May 2015 to October 2016 while in the critical care medicine unit (ICU) of the West China Hospital of Sichuan University were enrolled in the study. Patients were randomly assigned to receive APRV (n = 71) or LTV (n = 67). The settings for APRV were: high airway pressure (Phigh) set at the last plateau airway pressure (Pplat), not to exceed 30 cmH2O) and low airway pressure ( Plow) set at 5 cmH2O; the release phase (Tlow) setting adjusted to terminate the peak expiratory flow rate to ≥ 50%; release frequency of 10-14 cycles/min. The settings for LTV were: target tidal volume of 6 mL/kg of predicted body weight; Pplat not exceeding 30 cmH2O; positive end-expiratory pressure (PEEP) guided by the PEEP-FiO2 table according to the ARDSnet protocol. The primary outcome was the number of days without mechanical ventilation from enrollment to day 28. The secondary endpoints included oxygenation, Pplat, respiratory system compliance, and patient outcomes. Compared with the LTV group, patients in the APRV group had a higher median number of ventilator-free days {19 [interquartile range (IQR) 8-22] vs. 2 (IQR 0-15); P < 0.001}. This finding was independent of the coexisting differences in chronic disease. The APRV group had a shorter stay in the ICU (P = 0.003). The ICU mortality rate was 19.7% in the APRV group versus 34.3% in the LTV group (P = 0.053) and was associated with better oxygenation and respiratory system compliance, lower Pplat, and less sedation requirement during the first week following enrollment (P < 0.05, repeated-measures analysis of variance). Compared with LTV, early application of APRV in patients with ARDS improved oxygenation and respiratory system compliance, decreased Pplat and reduced the duration of both mechanical ventilation and ICU stay.


Reactivation of human herpesvirus 6 during pregnancy.
Reactivation of human herpesvirus 6 (HHV-6) and cytomegalovirus (CMV) during pregnancy and transmission of the viruses to the fetus were investigated by polymerase chain reaction (PCR) and serology. In all, 104 blood samples were obtained 3 times during pregnancy and once at delivery. In another 107 women, samples were obtained only at delivery. Cord blood samples were obtained from both groups of women. HHV-6 DNA was detected in 41%-44% of the samples during months 3-8 of pregnancy, in 25% at delivery, and in 24% of age-matched controls. HHV-6 DNA was found in 1.0% of the cord blood samples. CMV DNA was detected in 1.7% of leukocytes from 104 pregnant women but in no cord blood sample. IgG antibodies to HHV-6 were found in 96% and CMV IgG in 62.5% of the women. HHV-6 IgG titers were significantly higher in HHV-6 PCR-positive women. Thus, HHV-6 reactivation seems common during pregnancy, and transfer of HHV-6 to the fetus may occur in approximately 1% of pregnancies.


[Psychopathology and classification of depressive disorders].
Depressive disorders are a heterogeneous group of conditions in terms of their etiology, symptom composition and outcome, which has resulted in difficulties in the definition of the axial depressive syndrome and its clinical forms. This gives rise to a number of problems regarding their definition and delimitation from other mental disorders and from normality. As a result, changing and to some extent overlapping definitions of depressive disorders have been proposed over time. A definition of axial depressive syndrome is proposed based on the differentiation between disturbances of mood and affect. The two main classificatory approaches (categorical and dimensional) are examined with regard to their appropriateness in classifying depressive disorders. Although the two approaches possess pros and cons, the dimensional approach has a number of characteristics that makes it more appropriate than the categorical approach for classifying mental disorders in general and depressive disorders in particular. A multidimensional model for classifying depressive disorders is proposed. The model includes etiological, symptomatological and course/outcome components, each of which is composed of a number of dimensions that have clinical and therapeutical relevance.


Concurrent radiotherapy and ipilimumab immunotherapy for patients with melanoma.
Ipilimumab and radiotherapy are commonly used to treat unresectable and metastatic melanoma. Results from preclinical studies and case reports suggest a biologic interaction between these two treatments. To understand the clinical implications of the interaction, we carried out a retrospective study reviewing records of patients treated with ipilimumab and radiotherapy for melanoma at our institution between 2005 and 2011. The review included details of treatment, response, adverse events (AE), and overall survival (OS). Twenty-nine patients underwent 33 courses of non-brain radiotherapy between their first and last dose of ipilimumab. Immune-related AEs (ir-AEs) were observed in 43% of patients receiving ipilimumab at 10 mg/kg and in 22% of patients receiving 3 mg/kg; the frequency of ir-AEs was not significantly different compared with previous studies of ipilimumab alone. Radiotherapy-related AEs were significantly more common in patients receiving higher doses of radiation. Palliation of symptoms was reported by 77% of patients after radiotherapy. Median OS was 9 and 39 months in patients receiving radiotherapy during induction and maintenance with ipilimumab, respectively. In this retrospective study, concurrent ipilimumab and radiotherapy was neither associated with higher than expected rates of AEs nor did it abrogate palliative effects of radiotherapy or survival benefits of ipilimumab. Further studies to prospectively explore the efficacy of this therapeutic combination are warranted.


Management of NSAID-related gastrointestinal mucosal injury.
The three therapeutic goals in patients with NSAID-induced gastroduodenopathy are treatment of dyspeptic symptoms, management of NSAID-related ulcers and their complications, and prophylaxis against recurrent gastrointestinal toxicity. Both H(2)-receptor antagonists and proton pump inhibitors (PPIs) appear to be helpful in relieving the symptoms associated with NSAID use, while treatment of NSAID-induced gastroduodenal ulcers, whether the NSAID is continued or not, is best achieved by the use of PPIs. However, because symptoms do not often predict the presence of gastroduodenal ulcers, the goal of prevention has become paramount in the treatment of patients with an increased likelihood of gastrointestinal toxicity. The best prophylaxis against NSAID-related toxicity is the use of an alternative agent such as salsalate or paracetamol (acetaminophen). However, if an NSAID is to be used, prophylaxis is best accomplished with a PPI or misoprostol, a prostaglandin E1 analogue. The use of misoprostol is limited by its frequent dosing, at least 200 microg three times a day, and its own gastrointestinal side effects. Future therapy will include NSAIDs that maintain their antiinflammatory effects, while possessing superior safety profiles, and include preferential and highly selective COX-2 inhibitors and nitric oxide releasing compounds.


Intestinal rehabilitation and the short bowel syndrome: part 1.
The management of patients with intestinal failure due to short bowel syndrome (SBS) is complex, requiring a comprehensive approach that frequently necessitates long-term, if not life-long, use of parenteral nutrition (PN). Despite tremendous advances in the provision of PN over the past three decades, which have allowed significant improvements in the survival and quality of life of these patients, this mode of nutritional support carries with it significant risks to the patient, is very costly and, ultimately, does not attempt to improve the function of the remaining bowel. Intestinal rehabilitation refers to the process of restoring enteral autonomy and, thus, allowing freedom from parenteral nutrition, usually by means of dietary, medical, and, occasionally, surgical strategies. While recent investigations have focused on the use of trophic substances to increase the absorptive function of the remaining gut, whether intestinal rehabilitation occurs as a consequence of enhanced bowel adaptation or is simply a result of an optimized, comprehensive approach to the care of these patients remains unclear. In Part 1 of this review, an overview of SBS and pathophysiological considerations related to the remaining bowel anatomy in these patients will be provided. Additionally, a review of intestinal adaptation and factors that may enhance the adaptive process, focusing on evidence derived from animal studies, will also be discussed. In Part 2, relevant data on the development of intestinal adaptation in studies involving humans will be reviewed as will the general management of SBS. Lastly, the potential benefits of a multidisciplinary intestinal rehabilitation program in the care of these patients will also be discussed.


Temporal feeding pattern may influence reproduction efficiency, the example of breeding mares.
Discomfort in farm animals may be induced by inappropriate types or timing of food supplies. Thus, time restriction of meals and lack of roughage have been shown to be one source of emergence of oral stereotypies and abnormal behaviour in horses which have evolved to eat high-fibre diets in small amounts over long periods of time. This feeding pattern is often altered in domestic environment where horses are often fed low fibre meals that can be rapidly consumed. This study aimed at determining the effect of the temporal pattern of feeding on reproductive efficiency of breeding mares, One hundred Arab breeding mares were divided into two groups that differed only in the temporal pattern of roughage availability: only at night for the standard feeding pattern group (SFP mares), night and day for the "continuous feeding" group (CF mares). The total amount of roughage provided was the same as the CF mares received half of the hay during the day while in paddock (haynets). Mares were tested for oestrus detection by teasing with one stallion and were then examined clinically by rectal palpations and ultrasound before being mated naturally or inseminated by fresh or frozen semen. Multivariate logistic regression was used to analyse data. The treatment affected significantly the reproductive efficiency of the mares with fewer oestrus abnormalities (p = 0.0002) and more fertility (p = 0.024) in CF mares (conception rate = 81% versus 55% in SFP mares). Ensuring semi-continous feeding by providing roughage may be a way of fulfilling the basic physiological needs of the horses' digestive system, reducing stress and associated inhibitors of reproduction. To our knowledge, this study provides the first evidence of an impact of temporal feeding patterns on reproductive success in a Mammal. Temporal patterns of feeding may be a major and underestimated factor in breeding.


Delta-Notch lateral inhibitory patterning in the emergence of ciliated cells in Xenopus: experimental observations and a gene network model.
In diverse vertebrate and invertebrate systems, lateral inhibition through the Delta-Notch signaling pathway can lead to cells in initially uniform epithelial tissues differentiating in "salt-and-pepper", regular spacing patterns. In this paper we examine lateral inhibition during the emergence of ciliated cells in Xenopus embryonic skin, using experimental manipulations of the Delta-Notch pathway and a connectionist gene-network model of the process. The results of our model are in agreement with previous models of regular patterning through lateral inhibition and reproduce the observations of our experimental assays. Moreover, the model provides an account for the variability of embryonic responses to the experimental assays, points to a component of lateral inhibition that may be the chief source of this variability, and suggests ways to control it. Our model could thus serve as a tool to generate predictions about this and other regular patterning systems governed by lateral inhibition.


Housing gaps, mosquitoes and public viewpoints: a mixed methods assessment of relationships between house characteristics, malaria vector biting risk and community perspectives in rural Tanzania.
House improvement and environmental management can significantly improve malaria transmission control in endemic communities. This study assessed the influence of physical characteristics of houses and surrounding environments on mosquito biting risk in rural Tanzanian villages, and examined knowledge and perceptions of residents on relationships between these factors and malaria transmission. The study further assessed whether people worried about these risks and how they coped. Entomological surveys of indoor mosquito densities were conducted across four villages in Ulanga district, south-eastern Tanzania. The survey involved 48 sentinel houses sampled monthly and other sets of 48 houses randomly recruited each month for one-off sampling over 12 months. Physical characteristics of the houses and surrounding environments were recorded. Questionnaire surveys were administered to 200 household heads to assess their knowledge and concerns regarding the observed housing and environmental features, and whether they considered these features when constructing houses. Focus group discussions, were conducted to clarify emergent themes on people's perceptions on relationships between housing or environmental factors and malaria transmission. The entomological surveys showed statistically higher indoor densities of the malaria vectors (Anopheles arabiensis and Anopheles funestus) in houses with mud walls compared to plastered or brick walls, open eaves compared to closed eaves and unscreened windows compared to screened windows. Most respondents reported that their houses allowed mosquito entry, at least partially. Participants were aware that house structure and environmental characteristics influenced indoor mosquito densities and consequently malaria transmission. They were concerned about living in poorly-constructed houses with gaps on eaves, walls, windows and doors but were constrained by low income. In rural south-eastern Tanzania, significant proportions of people still live in houses with open eaves, unscreened windows and gaps on doors. Though they are fully aware of associated mosquito biting and pathogen transmission risks, they are constrained by low-income levels. The study proposes that community-based house improvement initiatives combined with targeted subsidies could lower the financial barriers, improve access to essential construction materials or designs, and significantly accelerate malaria transmission control in these communities.


Layer-dependent multiplicative effects of spatial attention on contrast responses in human early visual cortex.
Attention mechanisms at different cortical layers of human visual cortex remain poorly understood. Using submillimeter-resolution fMRI at 7 Tesla, we investigated the effects of top-down spatial attention on the contrast responses across different cortical depths in human early visual cortex. Gradient echo (GE) T2* weighted BOLD signal showed an additive effect of attention on contrast responses across cortical depths. Compared to the middle cortical depth, attention modulation was stronger in the superficial and deep depths of V1, and also stronger in the superficial depth of V2 and V3. Using ultra-high resolution (0.3 mm in-plane) balanced steady-state free precession (bSSFP) fMRI, a multiplicative scaling effect of attention was found in the superficial and deep layers, but not in the middle layer of V1. Attention modulation of low contrast response was strongest in the middle cortical depths, indicating baseline enhancement or contrast gain of attention modulation on feedforward input. Finally, the additive vs. scaling effect of attention from GE-EPI and bSSFP signals can be explained by stronger nonlinearity of BOLD signals from large than small blood vessels, suggesting multiplicative effect of attention on neural activity. These findings support that top-down spatial attention mainly operates through feedback connections from higher order cortical areas, and a distinct mechanism of attention may also be associated with feedforward input through subcortical pathway.


Patterns of Arterial Disease in Takayasu Arteritis and Giant Cell Arteritis.
To identify and validate, using computer-driven methods, patterns of arterial disease in Takayasu arteritis (TAK) and giant cell arteritis (GCA). Patients with TAK or GCA were studied from the Diagnostic and Classification Criteria for Vasculitis (DCVAS) cohort and a combined North American cohort. Case inclusion required evidence of large-vessel involvement, defined as stenosis, occlusion, or aneurysm by angiography/ultrasonography, or increased 18 F-fluorodeoxyglucose (FDG) uptake by positron emission tomography (PET) in at least 1 of 11 specified arterial territories. K-means cluster analysis identified groups of patients based on the pattern of arterial involvement. Cluster groups were identified in the DCVAS cohort and independently validated in the North American cohort. A total of 1,068 patients were included (DCVAS cohort: TAK = 461, GCA = 217; North American cohort: TAK = 225, GCA = 165). Six distinct clusters of patients were identified in DCVAS and validated in the North American cohort. Patients with TAK were more likely to have disease in the abdominal vasculature, bilateral disease of the subclavian and carotid arteries, or focal disease limited to the left subclavian artery than GCA (P < 0.01). Patients with GCA were more likely to have diffuse disease, involvement of bilateral axillary/subclavian arteries, or minimal disease without a definable pattern than TAK (P < 0.01). Patients with TAK were more likely to have damage by angiography, and patients with GCA were more likely to have arterial FDG uptake by PET without associated vascular damage. Arterial patterns of disease highlight both shared and divergent vascular patterns between TAK and GCA and should be incorporated into classification criteria for large-vessel vasculitis.


Local gene silencing of monocyte chemoattractant protein-1 prevents vulnerable plaque disruption in apolipoprotein E-knockout mice.
Monocyte chemoattractant protein-1 (MCP-1), a CC chemokine (CCL2), has been demonstrated to play important roles in atherosclerosis and becoming an important therapeutic target for atherosclerosis. The present study was undertaken to test the hypothesis that local RNAi of MCP-1 by site-specific delivery of adenovirus-mediated small hairpin RNA (shRNA) may enhance plaque stability and prevent plaque disruption in ApoE-/- mice. We designed an adenovirus-mediated shRNA against mouse MCP-1 (rAd5-MCP-1-shRNA). Male apolipoprotein E-knockout (ApoE-/-) mice (n = 120) were fed a high-fat diet and vulnerable plaques were induced by perivascular placement of constrictive collars around the carotid artery, intraperitoneal injection of lipopolysaccharide and stress stimulation. Mice were randomly divided into RNA interference (Ad-MCP-1i) group receiving local treatment of rAd5-MCP-1-shRNA suspension, Ad-EGFP group receiving treatment of rAd5-mediated negative shRNA and mock group receiving treatment of saline. Two weeks after treatment, plaque disruption rates were significantly lower in the Ad-MCP-1i group than in the Ad-EGFP group (13.3% vs. 60.0%, P = 0.01), and local MCP-1 expression was significantly inhibited in the Ad-MCP-1i group confirmed by immunostaining, qRT-PCR and western blot (P<0.001). Compared with the Ad-EGFP group, carotid plaques in the Ad-MCP-1i group showed increased levels of collagen and smooth muscle cells, and decreased levels of lipid and macrophages. The expression of inflammatory cytokines and activities of matrix metalloproteinases (MMPs) were lower in the Ad-MCP-1i group than in the Ad-EGFP group. In conclusion, site-specific delivery of adenoviral-mediated shRNA targeting mouse MCP-1 downregulated MCP-1 expression, turned a vulnerable plaque into a more stable plaque phenotype and prevented plaque disruption. A marked suppression of the local inflammatory cytokine expression may be the central mechanism involved.


HSA-Coated Magnetic Nanoparticles for MRI-Guided Photodynamic Cancer Therapy.
Photodynamic therapy (PDT) is a promising technique for cancer treatment; however, low tissue permeability for irradiating light and insufficient photosensitizer (PS) accumulation in tumors limit its clinical potential. Nanoparticles are engineered to improve selective drug delivery to tumor sites, but its accumulation is highly variable between tumors and patients. Identifying PS accumulation peak in a personalized manner is crucial for therapeutic outcome. Magnetic nanoparticles (MNPs) provide opportunity for tracking drug accumulation in dynamics using non-invasive magnetic resonance imaging (MRI). The purpose of the study was to evaluate MNP loaded with PS as a theranostic tool for treating cancer in mice xenograft colon cancer models. MNPs coated with human serum albumin (HSA) were loaded with bacteriochlorine a. MRI, atomic emission spectroscopy (AES) and fluorescent imaging were used to study MNP and drug accumulation rates and dynamics in CT26 tumors. Tumor growth curves were evaluated in animals that received PDT at different time points upon MNP systemic injection. Peak MNP accumulation in tumors was detected by MRI 60 min post injection (pi) and the data were verified by AES and fluorescent imaging. Up to 17% of injected dose/g of tissue was delivered to malignant tissues 24 h after injection. Consistent with MRI predicted drug accumulation peak PDT performed 60 min after intravenous injection was more efficient in inhibiting tumor growth than treatment scheduled 30 min and 240 min pi. PS loading on HAS-coated MNPs is a perspective approach to increase drug delivery to tumor site. Tracking for MNP accumulation by MRI can be used to predict drug concentration peak in tumors and to adjust PDT time scheduling for improved antitumor response.


Ferritin is independently associated with the presence of coronary artery calcium in 12,033 men.
Ferritin concentrations are often increased in patients with metabolic syndrome and type 2 diabetes mellitus, but few reports have examined the associations between ferritin and atherosclerosis. We investigated whether any relationship between ferritin and coronary artery calcium score (CACS) >0 (as a marker of atherosclerosis) was independent of potential confounders, such as iron-binding capacity (transferrin), low-grade inflammation, and cardiovascular risk factors. Data were analyzed from a South Korean occupational cohort of 12 033 men who underwent a cardiac computed tomography estimation of CACS and measurements of multiple cardiovascular risk factors. One-thousand three- hundred-fifteen of 12 033 (11.2%) subjects had a CACS >0. For people with a CACS >0, median (interquartile range) ferritin concentration was 196.8 (136.3-291.9) compared with 182.2 (128.1-253.6) in people with a CACS=0; P<0.001. In the highest ferritin quartile, 14.7% (442/3008) of subjects had a CACS >0 compared with 9.7% (292/3010) in the lowest quartile (P<0.0001). With increasing ferritin quartiles, there were also higher proportions of people with diabetes mellitus (P<0.0001), hypertension (P<0.0001), coronary heart disease (P=0.003), and a Framingham Risk Score >10% (P<0.0001). In logistic regression modeling with CACS >0 as the outcome, ferritin but not transferrin was independently associated with CACS >0 (odds ratio for highest quartile versus lowest quartile, 1.66 [95% CI, 1.3-1.98]; P=0.0001). Increased ferritin concentrations are associated with the presence of a marker of early coronary artery atherosclerosis, independently of traditional cardiovascular risk factors including Framingham risk score, transferrin, preexisting vascular disease, diabetes mellitus, metabolic syndrome factors, and low-grade inflammation.


Executive functions in sarcoidosis: a neurocognitive assessment study.
Background: Sarcoidosis is a multisystem, inflammatory disease characterized by non-caseating granulomas in multiple organs. Neuropsychological impairment has been told to be present in about 10% of sarcoidosis patients with diagnosed central nervous system (CNS) involvement. Both anatomical lesions and changes in immunological parameters in sarcoidosis may cause cognitive impairment. Based on the information that soluble interleukin-2 receptors (sIL-2R) and tumour necrosis factor alpha (TNF-‱) which plays a role in the pathogenesis of sarcoidosis accumulate in the basal ganglia and prefrontal structures, impairment in executive functioning is most likely to be expected in sarcoidosis. In this study we aimed to evaluate executive functions in sarcoidosis patients. Method: This study included 21 sarcoidosis patients (14 females, 7 males) and 21 healthy controls (12 females, 9 males). All participants were given Beck Depression Inventory-Second Edition, Stroop Test, Verbal Fluency Tests, Digitspan Forward Test, Digitspan Backwards Test and Trail Making Test Part-B. Test results of sarcoidosis patients were compared with healthy controls. Results: No significant difference was detected between sarcoidosis patients and healthy controls by means of neuropsychological assessment tests (p>0.05). Conclusion: Our study showed that sarcoidosis patients did not have impairment in executive functions. This result may be commented in two different outcomes. One of them, would be the probable necessity of additional electrophysiological or radiological tests including detailed paradigmas for evaluation of executive functions. Secondly the effect of therapeutics used in sarcoidosis (steroids and/or immunosuppressants) on cognition should be questioned regarding the controversial previous data which released cognitive decline in sarcoidosis. (Sarcoidosis Vasc Diffuse Lung Dis 2018; 35: 26-34).


Delayed-onset complications of facial soft tissue augmentation with permanent fillers in 85 patients.
To evaluate factors influencing the onset and type of adverse events in patients injected with permanent fillers in the face and to propose a therapeutic strategy for these complications. A prospectively attained series of 85 patients with delayed-onset complications after facial injection with permanent fillers underwent clinical follow-up and treatment of the complications. Lag times until onset and type of delayed-onset complication varied according to filler material. In 28% (n = 24) of the cases, patients reported the onset of complications after dental procedures, additional injections with fillers, or other invasive treatments in the facial area. Forty-eight (57%) patients required invasive treatment. Abscess formation was significantly more frequent in patients with human immunodeficiency virus infection and facial lipoatrophy (p = .001). The intrinsic characteristics of the injected filler and the immune status of the patient play important roles in the diversity of time of onset and type of delayed-onset adverse events observed. It seems that invasive facial or oral procedures in the vicinity of filler depots can provoke such complications. We propose a strategy for treating these complications and advise great caution when using permanent filling agents.


Brainstem brain-derived neurotrophic factor signaling is required for histone deacetylase inhibitor-induced pain relief.
Our previous study demonstrated that persistent pain can epigenetically suppress the transcription of Gad2 [encoding glutamic acid decarboxylase 65 (GAD65)] and consequently impair the inhibitory function of GABAergic synapses in central pain-modulating neurons. This contributes to the development of persistent pain sensitization. Histone deacetylase (HDAC) inhibitors increased GAD65 activity considerably, restored GABA synaptic function, and rendered sensitized pain behavior less pronounced. However, the molecular mechanisms by which HDAC regulates GABAergic transmission through GAD65 under pain conditions are unknown. This work showed that HDAC inhibitor-induced increases in colocalization of GAD65 and synaptic protein synapsin I on the presynaptic axon terminals of the nucleus raphe magnus (NRM) were blocked by a TrkB receptor antagonist K252a [(9S,10R,12R)-2,3,9,10,11,12-hexahydro-10-hydroxy-9-methyl-1-oxo-9,12-epoxy-1H-diindolo[1,2,3-fg:3',2',1'-kl]pyrrolo[3,4-i][1,6]benzodiazocine-10-carboxylic acid methyl ester], indicating that BDNF-TrkB signaling may be required in GAD65 modulation of GABA synaptic function. At the brain-derived neurotrophic factor (BDNF) promoter, HDAC inhibitors induced significant increases in H3 hyperacetylation, consistent with the increase in BDNF mRNA and total proteins. Although exogenous BDNF facilitated GABA miniature inhibitory postsynaptic currents and GAD65 accumulation in NRM neuronal synapses in normal rats, it failed to do so in animals subjected to persistent inflammation. In addition, blockade of the TrkB receptor with K252a has no effect on miniature inhibitory postsynaptic currents and synaptic GAD65 accumulation under normal conditions. In addition, the analgesic effects of HDAC inhibitors on behavior were blocked by NRM infusion of K252a. These findings suggest that BDNF-TrkB signaling is required for drugs that reverse the epigenetic effects of chronic pain at the gene level, such as HDAC inhibitors.


The combination of methylsulfonylmethane and tamoxifen inhibits the Jak2/STAT5b pathway and synergistically inhibits tumor growth and metastasis in ER-positive breast cancer xenografts.
Combination therapy, which reduces the dosage intensity of the individual drugs while increasing their efficacy, is not a novel approach for the treatment of cancer. Methylsulfonylmethane (MSM) is an organic sulfur compound shown to act against tumor cells. Tamoxifen is a commercially available therapeutic agent for breast malignancies. In the current study, we analyzed the combinatorial effect of MSM and tamoxifen on the suppression of ER-positive breast cancer xenograft growth and metastasis. Additionally, we also validated the molecular targets by which the drug combination regulated tumor growth and metastasis. We observed that the combination of MSM and tamoxifen regulated cell viability and migration in vitro. The intragastric administration of MSM and subcutaneous implantation of tamoxifen tablets led to tumor growth suppression and inhibition of the Janus kinase 2 (Jak2)/signal transducer and activator of transcription 5b (STAT5b) pathway. Our study also assessed the regulation of signaling molecules implicated in the growth, progression, differentiation, and migration of cancer cells, such as Jak2, STAT5b, insulin-like growth factor-1Rβ, and their phosphorylation status. Study results indicated that this combination therapy inhibited tumor growth and metastasis. Therefore, this drug combination may have a synergistic and powerful anticancer effect against breast cancer.


The role of the coordination defect (CD) in the structures of anion-deficient, fluorite-related compounds.
The various superstructure phases that occur with the anion-deficient compositions of binary oxides MO(2-x) with the fluorite structure as parent are explored here in terms of the original 'coordination defect' (or CD) concept in which each vacant oxygen site, □, is 'coordinated' by six O atoms thereby creating the octahedral 'structure-determining' entity [M(3.5)□O(6)]. It emerges that the structure and composition of each anion-deficient (polymorph) phase can be described in terms of crystallographic `motifs' which comprise sets of parallel coplanar polygons based on ½<210>(F) and ½<111>(F) CD linkages.


Canadian Contraception Consensus (Part 3 of 4): Chapter 8 - Progestin-Only Contraception.
To provide guidelines for health care providers on the use of contraceptive methods to prevent pregnancy and on the promotion of healthy sexuality. Overall efficacy of cited contraceptive methods, assessing reduction in pregnancy rate, safety, ease of use, and side effects; the effect of cited contraceptive methods on sexual health and general well-being; and the relative cost and availability of cited contraceptive methods in Canada. Published literature was retrieved through searches of Medline and The Cochrane Database from January 1994 to January 2015 using appropriate controlled vocabulary (e.g., contraception, sexuality, sexual health) and key words (e.g., contraception, family planning, hormonal contraception, emergency contraception). Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies published in English from January 1994 to January 2015. Searches were updated on a regular basis in incorporated in the guideline to June 2015. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies. The quality of the evidence in this document was rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care (Table 1). CHAPTER 8: PROGESTIN-ONLY CONTRACEPTION: Summary Statements Recommendations.


Upregulation of autophagy by Ginsenoside Rg2 in MCF-7 cells.
Autophagy is a major intracellular degradation process that plays an important role in cell survival, stress responses, nutrient sensing and development. Our previous studies have shown that Rg2, a triterpenoid saponin contained in ginseng, protects cells against UVB-induced genotoxicity by increasing DNA repair, in possible association with modulation of protein levels involved in p53 pathway. In this study, we determined an upregulation of autophagy by Rg2. Rg2 treatment for 24 h in MCF-7, a breast cancer cell, did not show cytotoxicity up to 200 μM. Rg2 also upregulated the level of p-p53, p-AMPK, p-ACC, Atg-7 and LC3-II and decreased the level of p62 in concentration-dependent manners. We also determined the level of p53, AMPK, p62, Atg-7 and LC3 after UVB exposure and subsequent incubation in growth medium for 24 h. UVB increased the level of p-p53, p-AMPK, p-ACC and decreased the levels of p62, Atg-7 and LC3-II. Interestingly, Rg2 treatment for 24 h after UVB exposure increased the levels of p-p53, p-AMPK, p-ACC, Atg-7 and LC3-II and decreased the level of cyclobutane pyrimidine dimer, a UVB-induced DNA damage in concentration-dependent manners. All these results suggest that Rg2 increased autophagy and decreased UVB-induced DNA damage, in possible association with the modulation of protein levels in p53- and autophagic pathways.


Epidemiology and Perioperative Mortality of Exploratory Laparotomy in Rural Ghana.
Perioperative mortality rate (POMR) has been identified as an important measure of access to safe surgical and anesthesia care in global surgery. There has been limited study on this measure in rural Ghana. In order to identify areas for future quality improvement efforts, we aimed to assess the epidemiology of exploratory laparotomy and to investigate POMR as a benchmark quality measure. Surgical records were reviewed at a regional referral hospital in Eastern Region, Ghana to identify cases of exploratory laparotomy from July 2017 through June 2018. Patient demographics, health information, and outcomes data were collected. Logistic regression was used to identify predictors of perioperative mortality. The study included operations for 286 adult and 60 pediatric patients. Only 60% of patients were covered by National Health Insurance (NHI). The overall POMR was 11.5% (12.6% adults; 6.7% pediatric). Sixty percent of mortalities were referrals from outside hospitals and the mortality rate for referrals was 13.5%. Odds of mortality was 13 times greater with perforated peptic ulcer disease (OR = 13.1, p = 0.025) and 12 times greater with trauma (OR = 11.7, p = 0.042) when compared to the most common operation. Female sex (OR = 0.3, p = 0.016) and NHI (OR = 0.4, p = 0.031) were protective variables. Individuals 60 years and older (OR = 3.3, p = 0.016) had higher mortality. POMR can be an important outcome and quality indicator for rural populations. Interventions aimed at decreasing emergent hernia repair, preventing perforation of peptic ulcer disease, improving rural infrastructure for response to major trauma, and increasing NHI coverage may improve POMR in rural Ghana.


Radio-frequency-transparent, electrically conductive graphene nanoribbon thin films as deicing heating layers.
Deicing heating layers are frequently used in covers of large radio-frequency (RF) equipment, such as radar, to remove ice that could damage the structures or make them unstable. Typically, the deicers are made using a metal framework and inorganic insulator; commercial resistive heating materials are often nontransparent to RF waves. The preparation of a sub-skin-depth thin film, whose thickness is very small relative to the RF skin (or penetration) depth, is the key to minimizing the RF absorption. The skin depth of typical metals is on the order of a micrometer at the gigahertz frequency range. As a result, it is very difficult for conventional conductive materials (such as metals) to form large-area sub-skin-depth films. In this report, we disclose a new deicing heating layer composite made using graphene nanoribbons (GNRs). We demonstrate that the GNR film is thin enough to permit RF transmission. This metal-free, ultralight, robust, and scalable graphene-based RF-transparent conductive coating could significantly reduce the size and cost of deicing coatings for RF equipment covers. This is important in many aviation and marine applications. This is a demonstration of the efficacy and applicability of GNRs to afford performances unattainable by conventional materials.


Telemedicine in oncology: European perspective.
Telemedicine in oncology or teleoncology integrates many so far well-known telemedicine elements such as teleconsultation, telesupport, telesurgery and telerobotics, teleeducation, and many others and is integral part of many disciplines such as internal medicine, surgery, dermatology, but also dentistry and psychooncology/psychiatry. Changes in ICT, new developments in oncology, the need to think and work interdisciplinarily, geographic and economic challenges as well as the transgression of sectoral boundaries as elements of modern teleoncology. Whereas the northern parts of Europe show a well-developed telemedicine infrastructure with a growing tendency to incorporate teleoncology for documentation, data analysis and quality assurance, in more southern countries this process is still underway and often marked by project status. Modern technology using xDSL and other terrestrial network lines but also satellite connectivity is at hand to cover a wide variety of telemedicine applications and services from which teleoncology benefits. More and more specifically designed software applications can be used to assess the medical workflow of an oncological patient and determine a life-long oncological electronic patient record. The trend, however, goes to the systemic integration of single applications and services into clinical information systems with a telemedicine approach. Although past evaluations of telemedicine applications and services have shown very positive results, only the right financial funding determines their survival and wide-spread usability in daily routine medical use. Formerly identifiable barriers for this use nowadays can be overcome more easily.


Mobile applications for client use: Ethical and legal considerations.
Mobile applications (apps) to support behavioral health are increasing in number and are recommended frequently by medical providers in a variety of settings. As with the use of any adjunct tool in therapy, psychologists adopting new technologies in clinical practice must comply with relevant professional ethics codes and legal standards. However, emerging technologies can outpace regulations regarding their use, presenting novel ethical considerations. Therefore, it is incumbent upon providers to extrapolate current ethical standards and laws to new technologies before they recommend them as adjuncts to face-to-face treatment. This article identifies best practices for incorporating apps into treatment, including competence in the use of smartphones in general and familiarity with the specific apps recommended. Psychologists must conduct informed consent procedures in accordance with existing evidence, as well as privacy and security concerns relating to a particular app, in order to mitigate potential liability regarding the collection of client-generated data. Psychologists also should be prepared to educate clients about how best to safeguard their data, such as through encryption, password protection, or remote deletion of data. By doing so, psychologists can balance potentially competing demands of leveraging emerging technology to improve care while simultaneously ensuring ethical and legal compliance in these new areas. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Potential role of Clara cell protein, an endogenous phospholipase A2 inhibitor, in acute lung injury.
It is now recognized that epithelial cells lining airways and alveoli are capable of releasing various mediators, which have the potential to modulate local inflammatory reactions. The amount of the 16 kDa Clara cell protein (CC16), an inhibitor of phospholipase A2 activity produced by pulmonary epithelial cells, was measured by means of a sensitive immunoassay in the unconcentrated bronchoalveolar lavage fluid (BALF) of 13 control subjects, and in patients with acute lung injury (14 with the full-blown adult respiratory distress syndrome (ARDS); 21 after standard cardiopulmonary bypass surgery, a known risk factor for ARDS). The level of CC16 was compared with other markers of inflammation with a wide range of molecular weights: albumin (nephelometry); total protein (spectrophotometry); beta 2-microglobulin (latex immunoassay); cystatin C (latex immunoassay); alpha 1-antitrypsin (immunoradiometry), and lipocortin-1 (enzyme-linked immunosorbent assay (ELISA)). The Clara cell protein (CC16) was detectable in all BALF, and significantly higher levels of this protein were observed in BALF from patients with acute lung injury. Changes in BALF Clara cell protein levels differed from those of alpha 2-macroglobulin and the natural phospholipase inhibitor lipocortin-1. Alpha 2-macroglobulin levels were not significantly enhanced in patients at risk for ARDS, but were increased in patients with ARDS; whereas, lipocortin 1 levels were not elevated in either group. Pretreatment of patients at risk for ARDS with high dose methylprednisolone did not alter the amount of Clara cell protein recovered in BALF. The mean CC16 level in BALF from patients with ARDS who died was significantly lower than from those who survived. The data presented in this study suggest that pulmonary epithelial cells secrete a natural anti-inflammatory protein during acute lung injury, which might have a protective and immunosuppressive role.


Investigation of the effects of estrogen on skeletal gene expression during zebrafish larval head development.
The development of craniofacial skeletal structures requires well-orchestrated tissue interactions controlled by distinct molecular signals. Disruptions in normal function of these molecular signals have been associated with a wide range of craniofacial malformations. A pathway mediated by estrogens is one of those molecular signals that plays role in formation of bone and cartilage including craniofacial skeletogenesis. Studies in zebrafish have shown that while higher concentrations of 17-β estradiol (E 2) cause severe craniofacial defects, treatment with lower concentrations result in subtle changes in head morphology characterized with shorter snouts and flatter faces. The molecular basis for these morphological changes, particularly the subtle skeletal effects mediated by lower E 2 concentrations, remains unexplored. In the present study we address these effects at a molecular level by quantitative expression analysis of sets of candidate genes in developing heads of zebrafish larvae treated with two different E 2 concentrations. To this end, we first validated three suitable reference genes, ppia2, rpl8 and tbp, to permit sensitive quantitative real-time PCR analysis. Next, we profiled the expression of 28 skeletogenesis-associated genes that potentially respond to estrogen signals and play role in craniofacial development. We found E 2 mediated differential expression of genes involved in extracellular matrix (ECM) remodelling, mmp2/9/13, sparc and timp2a, as well as components of skeletogenic pathways, bmp2a, erf, ptch1/2, rankl, rarab and sfrp1a. Furthermore, we identified a co-expressed network of genes, including cpn1, dnajc3, esr1, lman1, rrbp1a, ssr1 and tram1 with a stronger inductive response to a lower dose of E 2 during larval head development.


Impaired Systolic and Diastolic Left Ventricular Function in Children with Chronic Kidney Disease - Results from the 4C Study.
Children with chronic kidney disease suffer from excessive cardiovascular mortality and early alterations of the cardiovascular system. Tissue doppler imaging is a validated echocardiographic tool to assess early systolic and diastolic cardiac dysfunction. We hypothesized that tissue Doppler velocities would reveal reduced cardiac function in children with chronic kidney disease compared to healthy children. A standardized echocardiographic exam was performed in 128 patients of the Cardiovascular Comorbidity in Children with Chronic Kidney Disease (4C) Study aged 6-17 years with an estimated glomerular filtration rate (eGFR) below 60 ml/min/1.73 m2. Tissue Doppler measurements included early (E') and late (A') diastolic and systolic (S') velocity at the mitral and septal annulus of the left ventricle. Measured values were normalized to z-scores using published reference data. Predictors of E'/A', E/E', S' and left ventricular mass index (LVMI) were assessed by multiple linear regression analyses. Tissue Doppler E' was reduced and tissue Doppler A' increased, resulting in a reduced tissue Doppler E'/A' ratio (z-score -0.14, p < 0.0001) indicating reduced diastolic function compared to healthy children. Reduced tissue Doppler E'/A' Z-Scores were independently associated with lower eGFR (p = 0.002) and increased systolic blood pressure (p = 0.02). While E/E' Z-Scores were increased (Z-score 0.57, p < 0.0001), patients treated with pharmacological RAS blockade but not with other antihypertensive treatments had significantly lower E/E' and higher E'/A' Z-Scores. Systolic tissue Doppler velocities were significantly decreased (Z-score -0.24, p = 0.001) and inversely correlated with E/E' Z-Scores (r = -0.41, p < 0.0001). LVMI was not associated with systolic or diastolic tissue Doppler velocities. Concentric left ventricular hypertrophy showed a tendency to lower S' in multivariate analysis (p = 0.13) but no association to diastolic function. Concentric left ventricular geometry was significantly associated with lower midwall fractional shortening. In summary, systolic and diastolic function assessed by tissue Doppler is impaired. eGFR, systolic blood pressure and the type of antihypertensive medications are significant predictors of diastolic function in children with CKD. Left ventricular morphology is largely independent of tissue Doppler velocities. Tissue Doppler velocities provide sensitive information about early left ventricular dysfunction in this population.


Naturally occurring sites within the Shigella dysenteriae tryptophan operon severely limit tryptophan biosynthesis.
We investigated the structural, functional, and regulatory properties of the Shigella dysenteriae tryptophan (trp.) operon in transduction hybrids in which the cysB-trp-region of Escherichia coli is replaced by the corresponding region from S. dysenteriae. Tryptophan biosynthesis was largely blocked in the hybrids, although the order of the structural genes was identical with that of E. coli. Nutritional tests and enzyme assays revealed that the hybrids produced a defective anthranilate synthetase (ASase). Deletion mapping identified two distinct sites in trpE, each of which was partially responsible for the instability and low activity of ASase. We also discovered a pleiotropic site trpP (S) that maps outside the structural gene region and is closely linked to the S. dysenteriae trp operator. trpP (S) reduced the rate of trp messenger ribonucleic acid synthesis, and consequently trp enzyme levels, 10-fold relative to wild-type E. coli. In recombinants in which the structural genes of E coli were under the control of the S. dysenteriae promoter, enzyme levels were also reduced 10-fold. In some fast-growing revertants of the original hybrids, the rates of trp messenger ribonucleic acid synthesis and levels of tryptophan synthetase were restored to values characteristic of wild-type E.coli. Thus, the Trp auxotrophy associated with the S dysenteriae trp operon derives from the combination of a defective ASase and decreased expression of the entire operon imposed by trpP (S).


Integrating Mathematical Modeling into the Roadmap for Personalized Adaptive Radiation Therapy.
In current radiation oncology practice, treatment protocols are prescribed based on the average outcomes of large clinical trials, with limited personalization and without adaptations of dose or dose fractionation to individual patients based on their individual clinical responses. Predicting tumor responses to radiation and comparing predictions against observed responses offers an opportunity for novel treatment evaluation. These analyses can lead to protocol adaptation aimed at the improvement of patient outcomes with better therapeutic ratios. We foresee the integration of mathematical models into radiation oncology to simulate individual patient tumor growth and predict treatment response as dynamic biomarkers for personalized adaptive radiation therapy (RT).


Vascular Disease and Risk Stratification for Ischemic Stroke and All-Cause Death in Heart Failure Patients without Diagnosed Atrial Fibrillation: A Nationwide Cohort Study.
Stroke and mortality risk among heart failure patients previously diagnosed with different manifestations of vascular disease is poorly described. We conducted an observational study to evaluate the stroke and mortality risk among heart failure patients without diagnosed atrial fibrillation and with peripheral artery disease (PAD) or prior myocardial infarction (MI). Population-based cohort study of patients diagnosed with incident heart failure during 2000-2012 and without atrial fibrillation, identified by record linkage between nationwide registries in Denmark. Hazard rate ratios of ischemic stroke and all-cause death after 1 year of follow-up were used to compare patients with either: a PAD diagnosis; a prior MI diagnosis; or no vascular disease. 39,357 heart failure patients were included. When compared to heart failure patients with no vascular disease, PAD was associated with a higher 1-year rate of ischemic stroke (adjusted hazard rate ratio [HR]: 1.34, 95% confidence interval [CI]: 1.08-1.65) and all-cause death (adjusted HR: 1.47, 95% CI: 1.35-1.59), whereas prior MI was not (adjusted HR: 1.00, 95% CI: 0.86-1.15 and 0.94, 95% CI: 0.89-1.00, for ischemic stroke and all-cause death, respectively). When comparing patients with PAD to patients with prior MI, PAD was associated with a higher rate of both outcomes. Among incident heart failure patients without diagnosed atrial fibrillation, a previous diagnosis of PAD was associated with a significantly higher rate of the ischemic stroke and all-cause death compared to patients with no vascular disease or prior MI. Prevention strategies may be particularly relevant among HF patients with PAD.


Image analysis of the human inner ear.
The KS 300 is a multifunctional software image analysis system using an object-oriented programming environment. The possibility of its application for the inner ear was studied by using specimens from humans and squirrel monkeys, immunostained for the brain-derived calcium-binding protein, S-100 protein. Grey images were used for measurements. The cell borders were outlined by hand, using a digitizer. The absolute grey values of the pixels changed when the brightness of the images or other conditions changed. By contrast, the relative grey values, i.e. the absolute grey values correlated to the mean grey values of the histoimage, remained constant. By utilizing these relative grey values, it was possible to compare cells both between different specimens and between different areas within the same specimen. The different grey values of spiral ganglion cells stained for S-100 protein are objective quantitative measurements and are believed to reflect differences in their function. In some regions of both human and squirrel monkey specimens, relatively intensely stained cells predominated, whereas in other regions, relatively weakly stained cells were mainly observed. Thus, our image analysis system using the relative grey values has proved suitable for quantitative analysis of immunostained specimens in order to compare them and to assess cell function.


Cystectomy and orthotopic ileal neobladder in a male patient 12 years after kidney transplantation; good preservation of the renal function.
In case of cystectomy, some forms of urinary diversion can impair the graft function of renal transplant patients. Here we present the case of a 70-year-old male with carcinoma of the bladder 12 years after renal transplantation. Immunosuppression was achieved with Cyclosporin A (200 mg/day) and Prednisone (5 mg/day). The patient's serum creatinine level was 1.4 mg/dl. Following cystectomy, an orthotopic ileal neobladder was constructed by means of Studer technique, and the afferent ileal loop was anastomosed to the graft ureter. Pathology revealed pT1 G3 N+ transitional cell carcinoma. Ten months later, periaortic nodal recurrences necessitated four cycles of chemotherapy with Epidoxorubicyn and Gemcytabine. To date, 20 months after cystectomy, the patient is stable, with day and night-time urinary continence. His serum creatinine level is 1.3 mg/dl, and there is no evidence of hydronephrosis or acidosis. We conclude that the orthotopic ileal neobladder is an effective form of urinary diversion in renal transplant patients requiring cystectomy, allowing good preservation of the renal function.


Ginger extract consumption reduces plasma cholesterol, inhibits LDL oxidation and attenuates development of atherosclerosis in atherosclerotic, apolipoprotein E-deficient mice.
Oxidative modification of LDL is thought to play a key role in the pathogenesis of atherosclerosis. Consumption of nutrients rich in phenolic antioxidants has been shown to be associated with attenuation of development of atherosclerosis. This study was undertaken to investigate the ex vivo effect of standardized ginger extract on the development of atherosclerosis in apolipoprotein E-deficient (E(0)) mice, in relation to plasma cholesterol levels and the resistance of their LDL to oxidation and aggregation. E(0) mice (n = 60; 6-wk-old) were divided into three groups of 20 and fed for 10 wk via their drinking water with the following: group i) placebo (control group), 1.1% alcohol and water (11 mL of alcohol in 1 L of water); group ii) 25 microg of ginger extract/d in 1.1% alcohol and water and group iii) 250 microg of ginger extract/day in 1.1% alcohol and water. Aortic atherosclerotic lesion areas were reduced 44% (P<0.01) in mice that consumed 250 microg of ginger extract/day. Consumption of 250 microg of ginger extract/day resulted in reductions (P<0.01) in plasma triglycerides and cholesterol (by 27 and 29%, respectively), in VLDL (by 36 and 53%, respectively) and in LDL (by 58 and 33%, respectively). These results were associated with a 76% reduction in cellular cholesterol biosynthesis rate in peritoneal macrophages derived from the E(0) mice that consumed the high dose of ginger extract for 10 wk (P<0.01). Furthermore, peritoneal macrophages harvested from E(0) mice after consumption of 25 or 250 microg of ginger extract/day had a lower (P<0.01) capacity to oxidize LDL (by 45 and by 60%, respectively), and to take up and degrade oxidized LDL (by 43 and 47%, respectively). Consumption of 250 microg of ginger extract/day also reduced (P<0.01) the basal level of LDL-associated lipid peroxides by 62%. In parallel, a 33% inhibition (P<0.01) in LDL aggregation (induced by vortexing) was obtained in mice fed ginger extract. We conclude that dietary consumption of ginger extract by E(0) mice significantly attenuates the development of atherosclerotic lesions. This antiatherogenic effect is associated with a significant reduction in plasma and LDL cholesterol levels and a significant reduction in the LDL basal oxidative state, as well as their susceptibility to oxidation and aggregation.


Korean status of alcoholics and alcohol-related health problems.
Recent changes in the socioeconomic status of Korea have caused big differences in alcohol-related social and health problems. The traditional trait of drinking mild fermented beverages with nutritional side dishes and meals has shifted to drinking strongly distilled liquors without any side dishes. Moreover, the alcohol consumption per adult capita of Korea is now 8.1 liters, which parallels the level of other developed countries; it used to be 1.0 liter in 1960 and 7.0 liters in 1980, respectively. But the alcohol consumption per capita of adult males is now 18.4 liters. Consequently, the national incidence of alcohol-related diseases and accidents has rapidly increased. Korean adult males have the highest risk of the incidence of hepatoma. The rate of car accidents caused by drunken driving is about 10-fold higher than in any other developed country.


The universality of two routines for reading: evidence from Chinese dyslexia.
A study of 11 Chinese neurological patients with reading disorders indicates that reading aloud a non-alphabetic script, like reading alphabetic scripts, can be accomplished using two distinct routines: one that associates a whole written word with its complete pronunciation, and one that utilizes parts of the written word. Each routine can be selectively impaired by brain damage, resulting in different patterns of reading disability. These data are consistent with the independent neural organization of each routine, and the generality of the two-routine model for reading alphabetic and non-alphabetic scripts.


Trichloroacetylation of some cyclic enamines.
The pyrrolidine and morpholine enamines of cyclic ketones such as cyclohexanone and cyclopentanone were successfully diacetylated at alpha- and alpha'-positions with trichloroacetyl chloride using zinc catalyst. Morpholine enamines of the cyclic ketones gave acetylated morpholine in good yields besides the corresponding diacetylated cyclic enamines. When the same reactions were performed by using triethylamine without using zinc, monoacetylation products of the same enamines were synthesized.


[Changes in segmental reflexes upon stimulation of the locus coeruleus of the brain stem and potentiation of catecholamine action].
Rhythmic stimulation of locus coeruleus was accompanied by a depressed inhibitory action of flexor reflex afferents and recurrent inhibition on extensor motoneurons in anaesthetized and decerebellized cats. Such stimulation had no essential effect on the direct inhibition of extensor and flexor motoneurons, on the excitatory action of flexor reflex afferents and recurrent inhibition on the flexor motoneurons. The injection of pyrogallol caused similar effect but it was greatly diminished by cold blockage or transsection of the spinal cord. The experiments with partial cuts of the spinal cord to consider the effects as a result of activation of coerulo-spinal pathway which descend in the ventral quadrant of the spinal cord.


Psychologic factors involved in the decision to undergo reconstructive surgery after burn injury.
Burn injuries often result in permanent changes in physical appearance and function. Although reconstructive surgery is often considered to improve function or physical appearance, or a combination, variables that may predict use of surgery are relatively unknown. Burn survivors (N = 46; 48% male) were assessed at an evaluation for potential reconstructive surgery. Measures of adjustment, distress, and personality were administered. Several psychologic and demographic variables differed among those who did versus those who did not subsequently undergo surgery. Social, sexual, and family relationships were poorer among those who later used surgery, and surgery patients had higher scores on somatization. Subjects who had not returned to work, and individuals with private insurance or managed care, were significantly less likely to follow-up with reconstructive surgery. Contrary to hypothesized results, indexes of burn severity and the injury location were not significantly different between the two groups. Results suggest that interventions designed to aid adjustment after injury may result in the best surgical candidates completing reconstruction.


Impact of racism and discrimination on the physical and mental health among Aboriginal and Torres Strait Islander peoples living in Australia: a protocol for a scoping review.
Racism is increasingly recognised internationally as a key factor contributing to health disparities. A comprehensive body of strong research from international authors has reported negative associations between racism and health outcomes. In Australia, although the literature is more limited, available findings follow global trends. Australia has an identified health gap between Aboriginal and Torres Strait Islander peoples and non-indigenous Australians, and despite efforts to bridge this gap, health inequities continue to exist. This scoping review aims to assess, analyse and synthesise the relationship between racism and discrimination on the physical and mental health of Aboriginal and Torres Strait Islander peoples living in Australia. This is the study protocol for a scoping review. A systematic search will be conducted using five electronic databases: PubMed, CINAHL, Embase, Web of Science and the Australia's National Institute for Aboriginal and Torres Strait Islander Health Research. The database search will include studies published between 2000 and 2020. Reference lists of the included articles will be searched. Outcome measures will include physical and mental health components including chronic conditions, depression and anxiety, psychological distress, social and emotional difficulties, suicide and health-related outcomes such as wellbeing and life satisfaction. Duplications will be removed, and titles and abstracts will be reviewed to select studies. Full-text screening of preselected studies will be performed by four reviewers independently, to select studies according to inclusion criteria. Included studies will be appraised for quality using appropriate tools tailored for each study design. Data will be extracted, and study findings and characteristics synthesised in a narrative summary. Our scoping review will synthesise the evidence on the impacts of racism and discrimination in relation to the physical and mental health of Aboriginal and Torres Strait Islander peoples living in Australia. These findings could guide future health interventions by addressing the exposure of racism and racial discrimination in order to reduce health disparity. It is anticipated the findings to be of interest to policymakers, researchers, Aboriginal and Torres Strait Islander communities and community health organisations and other stakeholders interested in optimising public health interventions for and in partnership with Aboriginal and Strait Torres Islander communities of Australia. The protocol for this review has been registered on the international prospective register of systematic reviews (PROSPERO). The registration ID is CRD42020186193 .


Enhancement in speed and responsivity of uni-traveling carrier photodiodes with GaAs0.5Sb0.5/In0.53Ga0.47As type-II hybrid absorbers.
We demonstrate a top-illuminated high-speed uni-traveling carrier photodiode (UTC-PD) with a novel design in the p-type absorber, which can effectively shorten the photon absorption depth at telecommunication wavelengths (1.31~1.55 μm) and further enhance the bandwidth-efficiency product of UTC-PD. In our proposed new UTC-PD structure, the p-type In0.53Ga0.47As absorption layer is replaced by the type-II GaAs0.5Sb0.5 (p)/In0.53Ga0.47As (i) hybrid absorber. Due to the narrowing of the bandgap and enhancement of the photo-absorption process at the type-II interface between the GaAs0.5Sb0.5 and In0.53Ga0.47As layers, our device shows an over 16.7% improvement in the responsivity compared with that of UTC-PD with the same thickness of pure In0.53Ga0.47As absorber (0.7 μm) and a zero optical coupling loss. Our demonstrated device with a simple top-illuminated structure offers a large active mesa (25 μm), a wide optical-to-electrical (O-E) bandwidth (33 GHz), a high responsivity (0.7 A/W), and a high saturation current (>5 mA) under 1.31 µm optical wavelength. These promising results suggest that our proposed PD structure can fundamentally overcome the trade-off among bandwidth, efficiency, and device active diameter of high-speed PDs.


Ultrasonic guided waves in bone.
Recent progress in quantitative ultrasound (QUS) has shown increasing interest toward measuring long bones by ultrasonic guided waves. This technology is widely used in the field of nondestructive testing and evaluation of different waveguide structures. Cortical bone provides such an elastic waveguide and its ability to sustain loading and resist fractures is known to be related to its mechanical properties at different length scales. Because guided waves could yield diverse characterizations of the bone's mechanical properties at the macroscopic level, the method of guided waves has a strong potential over the standardized bone densitometry as a tool for bone assessment. Despite this, development of guided wave methods is challenging, e.g., due to interferences and multiparametric inversion problems. This paper discusses the promises and challenges related to bone characterization by ultrasonic guided waves.


Risk of major hemorrhage after kidney transplantation.
Major hemorrhagic events are associated with significant morbidity and mortality. We examined the three-year cumulative incidence of hospitalization with major nontraumatic hemorrhage after kidney transplantation. We performed a retrospective cohort study using healthcare administrative data of all adult-incident kidney-only transplantation recipients in Ontario, Canada from 1994 to 2009. We calculated the three-year cumulative incidence, event rate, and incident rate ratio of hospitalization with major hemorrhage, its subtypes and those undergoing a hemorrhage-related procedure. RESULTS were stratified by patient age and donor type and compared to a random and propensity-score matched sample from the general population. Among 4,958 kidney transplant recipients, the three-year cumulative incidence of hospitalization with nontraumatic major hemorrhage was 3.5% (95% confidence interval [CI] 3.0-4.1%, 12.7 events per 1,000 patient-years) compared to 0.4% (95% CI 0.4-0.5%) in the general population (RR = 8.2, 95% CI 6.9-9.7). The crude risk of hemorrhage was 3-9-fold higher in all subtypes (upper/lower gastrointestinal, intra-cranial) and 15-fold higher for gastrointestinal endoscopic procedures compared to the random sample from the general population. After propensity score matching, the relative risk for major hemorrhage and its subtypes attenuated but remained elevated. The cumulative incidence of hemorrhage was higher for older individuals and those with a deceased donor kidney. Kidney transplantation recipients have a higher risk of hospitalization with hemorrhage compared to the general population, with about 1 in 30 recipients experiencing a major hemorrhage in the three years following transplant.


[The safety problem and a physiological strategy for using glucocorticoid hormones].
Principal problems of glucocorticoid hormone application in non-endocrine diseases are discussed proceeding from the mechanism of their action and the role in organism's life. It appeared that the hazard of glucocorticoid therapy is mainly due to the absence of a test for sufficiency and real needs in these hormones. It was shown that the test has to be introduced reflecting on the whole body level the glucocorticoid activity in the cell, that is similar to blood glucose in relation to insulin. The introduction of free blood tyrosine as such test appears to allow the development of safe individual strategy for the usage of glucocorticoids.


[Ecology of Soldado virus: apparent lack of a viral inhibitor in th tissues of the vector tick Ornithodoros (Alectorobius) maritimus Vermeil and Marguet 1967].
It was previously postulated by others that suspensions of ticks O. (A.) maritmus may contain virucidal material (viral inhibitor) for Soldado virus leading to observe different infection rates according as the ticks were tested individually or in pools. In order to test this hypothesis, suspensions of nymphs of this species originating from a laboratory breeding stock, were mixed with Soldado virus before inoculation to suckling mice. No difference in mortality was observed between the mice receiving the virus exposed to tick suspensions and the controls. So, it seems unlike a viral inhibitor was responsible for the phenomenon. Other factors involved in Soldado virus ecology and possibly influencing the virus isolation efficiency are briefly discussed.


Mass Cytometry as a Tool for Investigating Senescence in Multiple Model Systems.
Cellular senescence is a durable cell cycle arrest as a result of the finite proliferative capacity of cells. Senescence responds to both intrinsic and extrinsic cellular stresses, such as aging, mitochondrial dysfunction, irradiation, and chemotherapy. Here, we report on the use of mass cytometry (MC) to analyze multiple model systems and demonstrate MC as a platform for senescence analysis at the single-cell level. We demonstrate changes to p16 expression, cell cycling fraction, and histone tail modifications in several established senescent model systems and using isolated human T cells. In bone marrow mesenchymal stromal cells (BMSCs), we show increased p16 expression with subsequent passage as well as a reduction in cycling cells and open chromatin marks. In WI-38 cells, we demonstrate increased p16 expression with both culture-induced senescence and oxidative stress-induced senescence (OSIS). We also use Wanderlust, a trajectory analysis tool, to demonstrate how p16 expression changes with histone tail modifications and cell cycle proteins. Finally, we demonstrate that repetitive stimulation of human T cells with CD3/CD28 beads induces an exhausted phenotype with increased p16 expression. This p16-expressing population exhibited higher expression of exhaustion markers such as EOMES and TOX. This work demonstrates that MC is a useful platform for studying senescence at a single-cell protein level, and is capable of measuring multiple markers of senescence at once with high confidence, thereby improving our understanding of senescent pathways.


Electrochemical performance of annealed cobalt-benzotriazole/CNTs catalysts towards the oxygen reduction reaction.
One of the major limitations yet to the global implementation of polymer electrolyte membrane fuel cells (PEMFCs) is the cathode catalyst. The development of efficient platinum-free catalysts is the key issue to solve the problem of slow kinetics of the oxygen reduction reaction (ORR) and high cost. We report a promising catalyst for ORR prepared through the annealing treatment under inert conditions of the cobalt-benzotriazole (Co-BTA) complex supported on carbon nanotubes (CNTs). The N-rich benzotriazole precursor was chosen based on its ability to complex Co(II) ions and generate under annealing highly reactive radicals able to tune the physicochemical properties of CNTs. X-Ray photoelectron spectroscopy (XPS) was used to follow the surface structure changes and highlight the active electrocatalytic sites towards the ORR. To achieve further evaluation of the catalysts in acidic medium, voltamperometry, rotating disk electrode (RDE), rotating ring-disk electrode (RRDE) and half-cell measurements were performed. The resulting catalysts (Co/N/CNTs) all show catalytic activity towards the ORR, the most active one resulting from annealing at 700 °C. The overall electron transfer number for the catalyzed ORR was determined to be ∼3.7 with no change upon the catalyst loading, suggesting that the ORR was dominated by a 4e(-) transfer process. The results indicate a promising alternative cathode catalyst for ORR in fuel cells, although its performance is still lower (overpotential around 110 mV evaluated by RDE and RRDE) than the reference Pt/C catalyst.


Strategies for optimizing pathologic staging of sentinel lymph nodes in breast cancer patients.
Due to the extensive pathologic evaluation of the sentinel lymph node (SLN), micrometastases are frequently observed. If micrometastases are clinically relevant, the histopathologic examination of SLNs should be sensitive enough to detect them. The probability of detecting micrometastases was calculated when examining the SLN according to the current Dutch pathology protocol and strategies evaluated to optimize the chance of detection. The dimensions of 20 consecutive axillary SLNs in patients with cT1-2N0 breast cancer were measured. In a mathematical model, the probability of detecting micrometastases in a SLN was calculated. Similarly, strategies to optimize the probability of detecting micrometastases were explored. When applying the pathology guidelines, the calculated probability to detect a micrometastasis was 18% for a 200-microm micrometastasis and 69% for a 2.0-mm metastasis in a median sized SLN. To detect the smallest micrometastasis in a median-sized SLN with a 95% probability, the interval between the sections must be decreased to 200 microm, and 20 levels from both halves must be examined. Given a prognostic significance of micrometastases, our current pathology guidelines are not sensitive enough. The number of sections should be increased, while the interval between cuts should be no more than 200 microm.


Pathological personality, relationship satisfaction, and intimate partner aggression: Analyses using the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, alternative model of personality disorder traits.
Personality disorders (PDs) have been linked to lower levels of marital satisfaction and the perpetration of intimate partner aggression (IPA). Much of this work has used self-reports of PD symptoms conceptualized via the Diagnostic and Statistical Manual of Mental Disorder's (DSM) categorical approach. The current study adds to the literature by examining how marital satisfaction and IPA are associated with a dimensional assessment of PDs, specifically by conceptualizing PDs using the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Section III alternative model of personality disorder. By collecting data from both partners in a sample of newlywed couples, we also leverage PD trait agreement between (a) both partner's own self-reports (similarity), (b) self- and spouse report (accuracy), and (c) self and ratings of partner (perceptual similarity), to examine couple-level predictors of relationship well-being (i.e., satisfaction and psychological/physical IPA). Data were drawn from a sample of 101 newly married couples who participated in baseline and follow-up data collection over a period of 12 months. Actor-partner interdependence analyses revealed significant self-report actor and partner effects on marital satisfaction and psychological and physical IPA; for spouse report, actor effects were more consistent than partner reports. Agreement was moderate for both similarity and accuracy, but greater agreement was related to greater relationship satisfaction, particularly at later time points. Thus, although reports of elevated personality pathology are detrimental to marital functioning, spousal agreement may protect against these effects. (PsycInfo Database Record (c) 2020 APA, all rights reserved).


Regulation of cyclin D2 expression and degradation by follicle-stimulating hormone during rat granulosa cell proliferation in vitro.
Cyclin D2 (CCND2, encoded by Ccnd2) plays an important role in the induction of early-to-mid G1 phase transition and is required for granulosa cell proliferation during ovarian folliculogenesis. In the present study, we investigated the role of follicle-stimulating hormone (FSH) in the regulation of cyclin D2 expression and degradation during rat granulosa cell proliferation in vitro. FSH acutely increased granulosa cell Ccnd2 mRNA abundance and CCND2 protein content as well as proliferation. FSH-induced granulosa cell CCND2 protein content and proliferation were mimicked by forskolin and attenuated by inhibitors of protein kinase A (PKA; H89) and phosphatidylinositol 3-kinase (PI3K; LY294002) as well as PKA catalytic subunit (PRKACA) small interfering RNA (siRNA) and dominant-negative Akt (dn-Akt) but were not affected by mitogen-activated protein kinase kinase 1/2 (MEK1/2; U0126). Interestingly, FSH also enhanced CCND2 protein degradation in granulosa cells, a process involving a PKA-mediated ubiquitin-proteasome degradation pathway. Taken together, these results demonstrate that FSH acutely regulated CCND2 expression through both PKA and PI3K signaling pathways during granulosa cell proliferation and also accelerated its ubiquitination-proteasomal degradation, which may prevent overstimulation of granulosa cell proliferation and follicular growth.


Stress induced ACTH release in capsaicin treated rats.
The plasma concentrations of adrenocorticotropic hormone (ACTH) in rats pretreated with capsaicin as neonates were compared with those of control rats pretreated with the capsaicin vehicle. Capsaicin pretreatment has been shown earlier to abolish the increase in plasma ACTH concentration induced by cold stress while not affecting that induced by restraint stress. In the present experiments rats pretreated with capsaicin showed the same increase in plasma ACTH concentration in response to an i.v. infusion of ovine-corticotropin releasing factor as control rats pretreated with the capsaicin vehicle. Intraperitoneal injection of formalin, surgical stress and intravenous infusion of (-)-isoprenaline increased plasma ACTH concentrations in control rats. In capsaicin pretreated rats the increase in plasma ACTH was significantly attenuated. It is concluded that capsaicin-sensitive sensory neurones mediate the activation of pituitary ACTH secretion in response to somatosensory stimuli. The function of the corticotroph cells of the anterior pituitary is not impaired by capsaicin treatment.