A text messaging intervention to improve heart failure self-management after hospital discharge in a largely African-American population: before-after study.
There is increasing interest in finding novel approaches to reduce health disparities in readmissions for acute decompensated heart failure (ADHF). Text messaging is a promising platform for improving chronic disease self-management in low-income populations, yet is largely unexplored in ADHF. The purpose of this pre-post study was to assess the feasibility and acceptability of a text message-based (SMS: short message service) intervention in a largely African American population with ADHF and explore its effects on self-management. Hospitalized patients with ADHF were enrolled in an automated text message-based heart failure program for 30 days following discharge. Messages provided self-care reminders and patient education on diet, symptom recognition, and health care navigation. Demographic and cell phone usage data were collected on enrollment, and an exit survey was administered on completion. The Self-Care of Heart Failure Index (SCHFI) was administered preintervention and postintervention and compared using sample t tests (composite) and Wilcoxon rank sum tests (individual). Clinical data were collected through chart abstraction. Of 51 patients approached for recruitment, 27 agreed to participate and 15 were enrolled (14 African-American, 1 White). Barriers to enrollment included not owning a personal cell phone (n=12), failing the Mini-Mental exam (n=3), needing a proxy (n=2), hard of hearing (n=1), and refusal (n=3). Another 3 participants left the study for health reasons and 3 others had technology issues. A total of 6 patients (5 African-American, 1 White) completed the postintervention surveys. The mean age was 50 years (range 23-69) and over half had Medicaid or were uninsured (60%, 9/15). The mean ejection fraction for those with systolic dysfunction was 22%, and at least two-thirds had a prior hospitalization in the past year. Participants strongly agreed that the program was easy to use (83%), reduced pills missed (66%), and decreased salt intake (66%). Maintenance (mean composite score 49 to 78, P=.003) and management (57 to 86, P=.002) improved at 4 weeks, whereas confidence did not change (57 to 75, P=.11). Of the 6 SCHFI items that showed a statistically significant improvement, 5 were specifically targeted by the texting intervention. Over half of ADHF patients in an urban, largely African American community were eligible and interested in participating in a text messaging program following discharge. Access to mobile phones was a significant barrier that should be addressed in future interventions. Among the participants who completed the study, we observed a high rate of satisfaction and preliminary evidence of improvements in heart failure self-management.


Molecular mechanisms of acquired resistance to tyrosine kinase targeted therapy.
In recent years, tyrosine kinases (TKs) have been recognized as central players and regulators of cancer cell proliferation, apoptosis, and angiogenesis, and are therefore considered suitable potential targets for anti-cancer therapies. Several strategies for targeting TKs have been developed, the most successful being monoclonal antibodies and small molecule tyrosine kinase inhibitors. However, increasing evidence of acquired resistance to these drugs has been documented, and extensive preclinical studies are ongoing to try to understand the molecular mechanisms by which cancer cells are able to bypass their inhibitory activity.This review intends to present the most recently identified molecular mechanisms that mediate acquired resistance to tyrosine kinase inhibitors, identified through the use of in vitro models or the analysis of patient samples. The knowledge obtained from these studies will help to design better therapies that prevent and overcome resistance to treatment in cancer patients.


Joining of Dissimilar Alloys Ti-6Al-4V and Ti-6Al-2Sn-4Zr-2Mo-0.1Si Using Linear Friction Welding.
Dissimilar joints between Ti-6Al-4V (Ti-64) and Ti-6Al-2Sn-4Zr-2Mo-0.1Si (Ti-6242) were manufactured using linear friction welding. The weld quality, in terms of the microstructure and mechanical properties, was investigated after stress relief annealing (SRA) at 750 °C for 2 h and compared with the as-welded (AWed) results. The central weld zone (CWZ) microstructure in the AWed condition consisted of recrystallized prior-β grains with α' martensite, which transformed into an acicular α+β structure after SRA. The hardness in the AWed condition was highest in the CWZ and decreased sharply through the thermomechanically affected zones (TMAZ) to the parent materials (PMs). After SRA, the hardness of the CWZ decreased, mainly due to tempering of the α' martensite microstructure. Static tensile testing of the dissimilar welds in both the AWed and stress relief annealed (SRAed) conditions resulted in ductile fracture occurring exclusively in the Ti-6Al-4V side of the joint. The promising results on joining of Ti-64 to Ti-6242 provide valuable insight for tailoring performance of next-generation aero-engine products.


Analysis of p16 (CDKN2/MTS-1/INK4A) alterations in primary sporadic uveal melanoma.
To define more clearly the role of the tumor suppressor gene p16 in uveal melanoma by determining the relative contribution of all known mechanisms of p16 inactivation in this tumor. A comprehensive genetic analysis of the p16 gene was performed in 33 primary sporadic ciliochoroidal and choroidal melanomas. Fourteen highly polymorphic microsatellite markers surrounding the p16 locus on chromosome 9p21 were used for the microsatellite analysis. Sequence analysis of the p16 gene was performed on those tumors with 9p21 loss of heterozygosity. To investigate methylation as an alternative mechanism of inactivation of p16, methylation-specific polymerase chain reaction was performed on all tumor DNA samples. Loss of heterozygosity (LOH) was found in 8 of 33 (24%) uveal melanomas. No evidence of a second region of LOH that did not include the p16 locus was found. Four cases had hemizygous losses including markers both distal and proximal to p16. Homozygous deletion of the p16 gene was detected in the 4 remaining cases by microsatellite analysis. Sequence analysis revealed no p16 mutations in the tumors with hemizygous loss of p16. Methylation of the 5' CpG island of p16 was found in one tumor with 9p21 LOH and in another without LOH. p16 inactivation by HD or methylation occurs in 27% of uveal melanomas, representing the most common molecular genetic alteration identified thus far in uveal melanoma.


Systematic review and meta-analysis of age-related differences in instructed emotion regulation success.
The process model of emotion regulation (ER) is based on stages in the emotion generative process at which regulation may occur. This meta-analysis examines age-related differences in the subjective, behavioral, and physiological outcomes of instructed ER strategies that may be initiated after an emotional event has occurred; attentional deployment, cognitive change, and response modulation. Within-process strategy, stimulus type, and valence were also tested as potential moderators of the effect of age on ER. A systematic search of the literature identified 156 relevant comparisons from 11 studies. Few age-related differences were found. In our analysis of the subjective outcome of response modulation strategies, young adults used expressive enhancement successfully (g = 0.48), but not expressive suppression (g = 0.04). Response modulation strategies had a small positive effect among older adults, and enhancement vs suppression did not moderate this success (g = 0.31 and g = 0.10, respectively). Young adults effectively used response modulation to regulate subjective emotion in response to pictures (g = 0.41) but not films (g = 0.01). Older adults were able to regulate in response to both pictures (g = 0.26) and films (g = 0.11). Interestingly, both age groups effectively used detached reappraisal, but not positive reappraisal to regulate emotional behavior. We conclude that, in line with well-established theories of socioemotional aging, there is a lack of evidence for age differences in the effects of instructed ER strategies, with some moderators suggesting more consistent effectiveness for older compared to younger adults.


3,3'-Diindolylmethane, but not indole-3-carbinol, inhibits histone deacetylase activity in prostate cancer cells.
Increased consumption of cruciferous vegetables is associated with a reduced risk of developing prostate cancer. Indole-3-carbinol (I3C) and 3,3'-diindolylmethane (DIM) are phytochemicals derived from cruciferous vegetables that have shown promise in inhibiting prostate cancer in experimental models. Histone deacetylase (HDAC) inhibition is an emerging target for cancer prevention and therapy. We sought to examine the effects of I3C and DIM on HDACs in human prostate cancer cell lines: androgen insensitive PC-3 cells and androgen sensitive LNCaP cells. I3C modestly inhibited HDAC activity in LNCaP cells by 25% but no inhibition of HDAC activity was detected in PC-3 cells. In contrast, DIM significantly inhibited HDAC activity in both cell lines by as much as 66%. Decreases in HDAC activity correlated with increased expression of p21, a known target of HDAC inhibitors. DIM treatment caused a significant decrease in the expression of HDAC2 protein in both cancer cell lines but no significant change in the protein levels of HDAC1, HDAC3, HDAC4, HDAC6 or HDAC8 was detected. Taken together, these results show that inhibition of HDAC activity by DIM may contribute to the phytochemicals' anti-proliferative effects in the prostate. The ability of DIM to target aberrant epigenetic patterns, in addition to its effects on detoxification of carcinogens, may make it an effective chemopreventive agent by targeting multiple stages of prostate carcinogenesis.


A Call to Reduce the Use of Bridging Anticoagulation.
Because of the recent publication of several important studies, there has been a major change in how we think about perioperative management of anticoagulation. Because of these changes, existing consensus guidelines are suddenly out of date and can no longer be used as is, particularly the 2012 American College of Chest Physicians Antithrombotic Guidelines, version 9. We estimate that well over 90% of patients receiving warfarin therapy should not receive bridging anticoagulation during periprocedural interruptions of therapy, except under unusual circumstances and with appropriate justification. Accumulating evidence also suggests that bridging is not indicated among patients receiving direct-acting oral anticoagulant therapy. The large number of patients potentially affected represents an important safety concern and requires an immediate change in practice.


Study of cohabitation and interconnection effects on normal and leukaemic stem cells dynamics in acute myeloid leukaemia.
On the basis of recent studies, understanding the intimate relationship between normal and leukaemic stem cells is very important in leukaemia treatment. The authors' aim in this work is to clarify and assess the effect of coexistence and interconnection phenomenon on the healthy and cancerous stem cell dynamics. To this end, they perform the analysis of two time-delayed stem cell models in acute myeloid leukaemia. The first model is based on decoupled healthy and cancerous stem cell populations (i.e. there is no interaction between cell dynamics) and the second model includes interconnection between both population's dynamics. By using the positivity of both systems, they build new linear functions that permit to derive global stability conditions for each model. Moreover, knowing that most common types of haematological diseases are characterised by the existence of oscillations, they give conditions for the existence of a limit cycle (oscillations) in a particularly interesting healthy situation based on Poincare-Bendixson theorem. The obtained results are simulated and interpreted to be significant in understanding the effect of interconnection and would lead to an improvement in leukaemia treatment.


Gender and incidence of dementia in the Framingham Heart Study from mid-adult life.
Gender-specific risks for dementia and Alzheimer's disease (AD) starting in midlife remain largely unknown. Prospectively ascertained dementia/AD and cause-specific mortality in Framingham Heart Study (FHS) participants was used to generate 10- to 50-year risk estimates of dementia/AD on the basis of the Kaplan-Meier method (cumulative incidence) or accounting for competing risk of death (lifetime risk [LTR]). Overall, 777 cases of incident dementia (601 AD) occurred in 7901 participants (4333 women) over 136,266 person-years. Whereas cumulative incidences were similar in women and men, LTRs were higher in women older than 85 years of age. LTR of dementia/AD at age 45 was 1 in 5 in women and 1 in 10 in men. Cardiovascular mortality was higher in men with rate ratios decreasing from approximately 6 at 45 to 54 years of age to less than 2 after age 65. Selective survival of men with a healthier cardiovascular risk profile and hence lower propensity to dementia might partly explain the higher LTR of dementia/AD in women.


Current status and trends in the treatment of acute pulmonary thromboembolism.
Untreated acute pulmonary thromboembolism (APTE) is associated with high mortality, which is reduced by prompt treatment. Anticoagulation is fundamental in the treatment of APTE and should be initiated from suspicion. The efficacy and safety of novel anticoagulant drugs, such as oral anti-Xa and anti-IIa inhibitors, are topics in the treatment of APTE and are now under investigation. Thrombolytic therapy is a widely accepted treatment strategy for massive APTE, but its use for submassive APTE is controversial. Catheter intervention, percutaneous cardiopulmonary support and surgical embolectomy are also necessary and effective for some patients with APTE. A retrievable inferior vena cava filter is preferred for transient protection against APTE. Some studies have demonstrated the feasibility of outpatient treatment in patients with APTE after risk stratification.


Effect of high-hydrostatic pressure and moderate-intensity pulsed electric field on plum.
Moderate intensity pulse electric fields were applied in plum with the aim to increase bioactive compounds content of the fruit, while high-hydrostatic pressure was applied to preserve the purées. High-hydrostatic pressure treatment was compared with an equivalent thermal treatment. The addition of ascorbic acid during purée manufacture was also evaluated. The main objective of this study was to assess the effects on microorganisms, polyphenoloxidase, color and bioactive compounds of high-hydrostatic pressure, or thermal-processed plum purées made of moderate intensity pulse electric field-treated or no-moderate intensity pulse electric field-treated plums, after processing during storage. The application of moderate intensity pulse electric field to plums slightly increased the levels of anthocyanins and the antioxidant activity of purées. The application of Hydrostatic-high pressure (HHP) increased the levels of bioactive compounds in purées, while the thermal treatment preserved better the color during storage. The addition of ascorbic acid during the manufacture of plum purée was an important factor for the final quality of purées. The color and the bioactive compounds content were better preserved in purées with ascorbic acid. The no inactivation of polyphenoloxidase enzyme with treatments applied in this study affected the stability purées. Probably more intense treatments conditions (high-hydrostatic pressure and thermal treatment) would be necessary to reach better quality and shelf life during storage.


[Comparison between Phoenix system and agar-based methods for antimicrobial susceptibility testing of Streptococcus spp].
Introduction. Antibiotic resistance is an emerging problem among streptococcal species, especially for severe infections. Automated diagnostic systems for antimicrobial susceptibility testing, such as BD Phoenix, is a recently available instruments that makes it possible to obtain results within 12 h. Methods. Antimicrobial susceptibility testing results of the BD Phoenix system were compared to those obtained from Clinical Laboratory Standards Institute (CLSI) disk-diffusion method. Two-hundred different clinical isolates of streptococci were assayed: beta-hemolytic (n=65), viridans (n=87), S. penumoniae (n=48). Results. Overall, there was categorical agreement greater than 96.7% (94.8% for beta-hemolytic and 97.9% for viridans group) in relationship to the disk-diffusion method. The minor error rates were less than 10% for all the antibiotics. The greatest percentage of serious errors corresponded to erythromycin and clindamycin within the beta-hemolytic group (14.7%). Overall percentage of very serious errors was less 0.5%. The results for penicillin in viridans streptococci and S. pneumoniae results showed 89.7% and 91.7% of categorical agreement, respectively, using the Etest as reference. Conclusions. The automated BD Phoenix system is a very useful and effective diagnostic tool for quantitative testing of sensitivity to antibiotics in the streptococci group.


The use of an active learning approach to teach metabolism to students of nutrition and dietetics.
This article describes the transition from a traditional instructor-centered course, based on lectures, to a student-centered course based on active learning methodologies as part of the reform of the Spanish higher education system within the European Higher Education Area (EHEA). Specifically, we describe the use of active learning methodologies to teach metabolism to students of nutrition and dietetics during the first year of their professional training in a 4-year undergraduate degree (Bachelor of Human Nutrition and Dietetics). In the new course design, the number of didactic lectures was largely reduced and complemented with a series of activities (problems/case studies, discussion workshops, self-assessment quizzes) aimed to get students actively engaged, to encourage self-learning, and to promote sustained work throughout the length of the course. The article presents quantitative data demonstrating a clear and significant improvement in students' performance when an active approach was implemented. Importantly, the improved performance was achieved without work overload. Finally, students' responses to this new teaching methodology have been very positive and overall satisfaction high. In summary, our results strongly argue in favor of the teaching model described herein.


Influence of Organ Culture on the Characteristics of the Human Limbal Stem Cell Niche.
Organ culture storage techniques for corneoscleral limbal (CSL) tissue have improved the quality of corneas for transplantation and allow for longer storage times. Cultured limbal tissue has been used for stem cell transplantation to treat limbal stem cell deficiency (LSCD) as well as for research purposes to assess homeostasis mechanisms in the limbal stem cell niche. However, the effects of organ culture storage conditions on the quality of limbal niche components are less well described. Therefore, in this study, the morphological and immunohistochemical characteristics of organ-cultured limbal tissue are investigated and compared to fresh limbal tissues by means of light and electron microscopy. Organ-cultured limbal tissues showed signs of deterioration, such as edema, less pronounced basement membranes, and loss of the most superficial layers of the epithelium. In comparison to the fresh limbal epithelium, organ-cultured limbal epithelium showed signs of ongoing proliferative activity (more Ki-67+ cells) and exhibited an altered limbal epithelial phenotype with a loss of N-cadherin and desmoglein expression as well as a lack of precise staining patterns for cytokeratin ((CK)14, CK17/19, CK15). The analyzed extracellular matrix composition was mainly intact (collagen IV, fibronectin, laminin chains) except for Tenascin-C, whose expression was increased in organ-cultured limbal tissue. Nonetheless, the expression patterns of cell-matrix adhesion proteins varied in organ-cultured limbal tissue compared to fresh limbal tissue. A decrease in the number of melanocytes (Melan-A+ cells) and Langerhans cells (HLA-DR+, CD1a+, CD18+) was observed in the organ-cultured limbal tissue. The organ culture-induced alterations of the limbal epithelial stem cell niche might hamper its use in the treatment of LSCD as well as in research studies. In contrast, reduced numbers of donor-derived Langerhans cells seem associated with better clinical outcomes. However, there is a need to consider the preferential use of fresh CSL for limbal transplants and to look at ways of improving the limbal stem cell properties of stored CSL tissue.


Isolation and characterization of antibody fragments selective for specific protein morphologies from nanogram antigen samples.
We developed atomic force microscope (AFM)-based protocols that enable isolation and characterization of antibody-based reagents that selectively bind target protein variants using low nanogram amounts or less of unpurified starting material. We isolated single-chain antibody fragments (scFvs) that specifically recognize an oligomeric beta-amyloid (Aβ) species correlated with Alzheimer's disease (AD) using only a few nanograms of an enriched but not purified sample obtained from human AD brain tissue. We used several subtractive panning steps to remove all phage binding nondesired antigens and then used a single positive panning step using minimal antigen. We also used AFM to characterize the specificity of the isolated clones, again using minimal material, selecting the C6 scFv based on expression levels. We show that C6 selectively binds cell and brain-derived oligomeric Aβ. The protocols described are readily adapted to isolating antibody-based reagents against other antigenic targets with limited availability.


Optical technologies for the detection of viruses like COVID-19: Progress and prospects.
The outbreak of life-threatening pandemic like COVID-19 necessitated the development of novel, rapid and cost-effective techniques that facilitate detection of viruses like SARS-CoV-2. The presently popular approach of a collection of samples using the nasopharyngeal swab method and subsequent detection of RNA using the real-time polymerase chain reaction suffers from false-positive results and a longer diagnostic time scale. Alternatively, various optical techniques namely optical sensing, spectroscopy, and imaging shows a great promise in virus detection. Herein, a comprehensive review of the various photonics technologies employed for virus detection, particularly the SARS-CoV family, is discussed. The state-of-art research activities in utilizing the photonics tools such as near-infrared spectroscopy, Fourier transform infrared spectroscopy, Raman spectroscopy, fluorescence-based techniques, super-resolution microscopy, surface plasmon resonance-based detection, for virus detection accounted extensively with an emphasis on coronavirus detection. Further, an account of emerging photonics technologies of SARS-CoV-2 detection and future possibilities is also explained. The progress in the field of optical techniques for virus detection unambiguously show a great promise in the development of rapid photonics-based devices for COVID-19 detection.


Lasers in Spine Surgery.
Laser spine surgery has been a focus of intense interest in the lay press and among patients. On the Internet, a host of purported benefits to laser surgery exists. Lasers have long been used in pain management procedures such as percutaneous diskectomy. However, a few published articles are available on lasers in conventional spine surgery. From our review of the literature, the purported advantages of lasers, such as reduced inflammation and degeneration, are not been supported by preclinical research. The available clinical studies do not show a notable advantage for laser surgery. Moreover, the low enrollment, nonblinded, retrospective studies that are available are heavily subject to bias. The documented advantages of laser spine surgery described in the research studies are not consistent with the public's impression of its purported benefits. Furthermore, laser-specific complications are present about which patients should be informed. On the basis of the current research, we conclude that lasers add distinct potential complications without any corresponding clinical benefit. Because of the public interest, we feel that this is an important topic for the general orthopaedic community.


Estimating time and travel costs incurred in clinic based screening: flexible sigmoidoscopy screening for colorectal cancer.
To identify the characteristics of mode of travel to screening clinics; to estimate the time and travel costs incurred in attending; to investigate whether such costs are likely to bias screening compliance. Twelve centres in the trial of flexible sigmoidoscopy screening for colorectal cancer, drawn from across Great Britain. Analysis of 3525 questionnaires completed by screening subjects while attending clinics. Information supplied included sociodemographic characteristics, modes of travel, expenses, activities foregone owing to attendance, and details of companions. More than 80% of subjects arrived at the clinics by car, and about two thirds were accompanied. On average, the clinic visit involved a 14.4 mile (22.8 km) round trip, requiring 130 minutes. Mean travel costs amounted to 6.10 Pounds per subject. The mean gross direct non-medical and indirect cost per subject amounted to 16.90 Pounds, and the mean overall gross cost per attendance was 22.40 Pounds. Compared with the Great Britain population as a whole, non-manual classes were more strongly represented, and the self employed less strongly represented, among the attendees. In relation to direct medical costs, the time and travel costs of clinic based screening can be substantial, may influence the overall cost effectiveness of a screening programme, and may deter potential subjects from attending.


Time Course of Upper Limb Function in Children with Unilateral Cerebral Palsy: A Five-Year Follow-Up Study.
Knowledge on long-term evolution of upper limb function in children with unilateral cerebral palsy (CP) is scarce. The objective was to report the five-year evolution in upper limb function and identify factors influencing time trends. Eighty-one children (mean age 9 y and 11 mo, SD 3 y and 3 mo) were assessed at baseline with follow-up after 6 months, 1, and 5 years. Passive range of motion (PROM), tone, muscle, and grip strength were assessed. Activity measurements included Melbourne Assessment, Jebsen-Taylor test, Assisting Hand Assessment (AHA), and ABILHAND-Kids. At 5-year follow-up, PROM (p < 0.001) and AHA scores (p < 0.001) decreased, whereas an improvement was seen for grip strength (p < 0.001), Melbourne Assessment (p = 0.003), Jebsen-Taylor test (p < 0.001), and ABILHAND-Kids (p < 0.001). Age influenced the evolution of AHA scores (p = 0.003), with younger children being stable over time, but from 9 years onward, children experienced a decrease in bimanual performance. Manual Ability Classification System (MACS) levels also affected the evolution of AHA scores (p = 0.02), with stable scores in MACS I and deterioration in MACS II and III. In conclusion, over 5 years, children with unilateral CP develop more limitations in PROM, and although capacity measures improve, the spontaneous use of the impaired limb in bimanual tasks becomes less effective after the age of 9 years.


Progressing Ultragreen, Energy-Efficient Biobased Depolymerization of Poly(ethylene terephthalate) via Microwave-Assisted Green Deep Eutectic Solvent and Enzymatic Treatment.
Effective interfacing of energy-efficient and biobased technologies presents an all-green route to achieving continuous circular production, utilization, and reproduction of plastics. Here, we show combined ultragreen chemical and biocatalytic depolymerization of polyethylene terephthalate (PET) using deep eutectic solvent (DES)-based low-energy microwave (MW) treatment followed by enzymatic hydrolysis. DESs are emerging as attractive sustainable catalysts due to their low toxicity, biodegradability, and unique biological compatibility. A green DES with triplet composition of choline chloride, glycerol, and urea was selected for PET depolymerization under MW irradiation without the use of additional depolymerization agents. Treatment conditions were studied using Box-Behnken design (BBD) with respect to MW irradiation time, MW power, and volume of DES. Under the optimized conditions of 20 mL DES volume, 260 W MW power, and 3 min MW time, a significant increase in the carbonyl index and PET percentage weight loss was observed. The combined MW-assisted DES depolymerization and enzymatic hydrolysis of the treated PET residue using LCC variant ICCG resulted in a total monomer conversion of ≈16% (w/w) in the form of terephthalic acid, mono-(2-hydroxyethyl) terephthalate, and bis-(2-hydroxyethyl) terephthalate. Such high monomer conversion in comparison to enzymatically hydrolyzed virgin PET (1.56% (w/w)) could be attributed to the recognized depolymerization effect of the selected DES MW treatment process. Hence, MW-assisted DES technology proved itself as an efficient process for boosting the biodepolymerization of PET in an ultrafast and eco-friendly manner.


Effects of interrupted photoperiods on the induction of ovulation in anestrous mares.
The ability of interrupted photoperiods to induce early estrus and ovulation was examined. Horse mares were exposed to long (16 h light) or short (10 h light), noninterrupted photoperiods, ambient light, or various interrupted photoperiod treatments from December 1 to April 15 (135 d). Follicular development was assessed by rectal palpation and estrous behavior was determined by teasing with a stallion. Serum concentrations of progesterone were used as an indicator of corpus luteum function. Differences among the light treatment groups were compared for the following behavioral and ovarian characteristics: days to first detectable 3-cm follicle, days to first estrous behavior, days to first ovulation, the number of mares ovulating within the treatment period, and the number of ovulations within the treatment period per mare. Compared with the ambient and 10L:14D (L = h of light and D = h of darkness) photoperiod treatments, ovulation was advanced to the greatest extent by a photoperiod of 16L:8D and the interrupted photoperiod 10L:8D:2L:4D. These two stimulatory photoperiod treatments were characterized by the presence of light 8 to 10 h after dusk. Therefore, the present data are consistent with an external coincidence model for the induction of seasonal breeding in horses, with the photoinducible phase occurring within the period 8 to 10 h after dusk.


The changing landscape of aortic valve replacement in the USA.
The aim of this study was to analyse the real-world national data on parallel utilisation of transcatheter (TAVR) and surgical (SAVR) aortic valve replacement. We queried an all-payer, administrative United States in-patient database to identify all AVR hospitalisations in patients aged ≥18 years from January 2012 to December 2016 and examined the temporal changes in the number of AVR procedures and in-hospital mortality. A total of 463,675 AVRs were performed - 363,275 (78.4%) SAVR and 100,400 (21.6%) TAVR. AVR linearly increased (from 78,985 in 2012 to 103,415 in 2016; +30.9%; ptrend<0.001) largely due to a marked increase in TAVR (from 7,655 to 33,545; +338%; ptrend<0.001), whereas the absolute number of SAVRs remained relatively stable (from 71,330 to 69,870; -1%; ptrend<0.001). The number of TAVRs increased in all pre-specified age groups (<75, 75-79, 80-85, and ≥85 years; ptrend<0.001 for all). In contrast, the number of SAVRs increased modestly in patients aged <75 years (ptrend<0.001) and declined in those aged 75-79 years, 80-84 years, or ≥85 years (ptrend<0.001 for all). Age- and sex-adjusted in-hospital mortality after isolated (aOR 1.00 [0.95-1.05]; ptrend=0.96) or combined SAVR (aOR 1.01 [0.97-1.05]; ptrend=0.66) remained unchanged during the study period, whereas in-hospital mortality after TAVR declined (aOR 0.75 [0.70-0.79]; ptrend<0.001). Similar trends in in-hospital mortality were seen in the age subgroups. The number of AVRs markedly increased in the USA from 2012 to 2016, mainly due to the widespread adoption of TAVR, whereas the number of SAVRs remained relatively stable. In-hospital mortality after TAVR declined, whereas that after SAVR has remained unchanged.


Genetic engineering of an H-2Dd/Q10b chimeric histocompatibility antigen: purification of soluble protein from transformant cell supernatants.
We have constructed a recombinant class I gene in which 5' sequences of H-2Dd are linked to the 3' half of a Qa subregion gene, Q10b. This hybrid gene would be expected to direct the synthesis of a protein containing the N and C1 domains of H-2Dd covalently linked to the C2 domain of the secreted, nonpolymorphic, Q10b antigen. Following DNA-mediated gene transfer into mouse L cells, transformants were analyzed by radiolabeling and immunoprecipitation. These cells secreted a molecule reactive with anti-H-2Dd monoclonal antibodies that identify epitopes on the N and C1 domains as well as with an anti-Q10 carboxyl-terminal peptide antiserum. The H-2Dd-derived antigen is associated with beta 2-microglobulin and is readily purified in milligram amounts from culture supernatants by immunoaffinity chromatography.


A Comprehensive Study of the Radical Scavenging Activity of Rosmarinic Acid.
Rosmarinic acid (RA) is reported in separate studies to be either an inducer or reliever of oxidative stress, and this contradiction has not been resolved. In this study, we present a comprehensive examination of the radical scavenging activity of RA using density functional theory calculations in comparison with experimental data. In model physiological media, RA exhibited strong HO• radical scavenging activity with overall rate constant values of 2.89 × 1010 and 3.86 × 109 M-1 s-1. RA is anticipated to exhibit excellent scavenging properties for HOO• in an aqueous environment (koverall = 3.18 × 108 M-1 s-1, ≈2446 times of Trolox) following the hydrogen transfer and single electron transfer pathways of the dianion state. The neutral form of the activity is equally noteworthy in a lipid environment (koverall = 3.16 × 104 M-1 s-1) by the formal hydrogen transfer mechanism of the O6(7,15,16)-H bonds. Chelation with RA may prevent Cu(II) from reduction by the ascorbic acid anion (AA-), hence blocking the OIL-1 pathway, suggesting that RA in an aqueous environment also serves as an OIL-1 antioxidant. The computational findings exhibit strong concurrence with the experimental observations, indicating that RA possesses a significant efficacy as a radical scavenger in physiological environments.


Intermediate-term outcomes associated with kidney transplantation in recipients 80 years and older: an analysis of the OPTN/UNOS database.
An increasing number of patients 80 years and older have received a kidney transplant in the United States, but their outcomes are not well described. Using Organ Procurement and Transplantation Network/United Network of Organ Sharing data, outcomes of recipients 80 years and older were evaluated. Thirty-one thousand one hundred seventy-nine elderly recipients defined by age 60 years and older receiving kidney transplants from 2000 to 2008 were stratified: ages 60 to 69 years (n=24,877), 70 to 79 years (n=6,103), and 80 years and older (n=199). Cox regression models were used to compare patient, graft, and death-censored graft survival. The majority of recipients 80 years and older was male (82.9%), white (87.9%), and less likely to have diabetes or coronary artery disease. More expanded criteria donor (ECD) but fewer living donor transplants were performed among 80 years and older compared with those younger than 80 years. Perioperative mortality, defined as death within 30 days posttransplant, was rare (60-69 years: 1.4%; 70-79 years: 1.5%; and ≥80 years: 2.5%) but tended to be higher among those 80 years and older compared with recipients 60 to 69 years (hazard ratio [HR] 1.67; 95% confidence interval [CI] 0.69-4.05). At 2 years, survival was lower for 80 years and older (73%; HR 2.42; 95% CI 1.91-3.06) and 70 to 79 years (86%; HR: 1.42; 95% CI: 1.34-1.51) compared with recipients 60 to 69 years (89%). There was a greater risk of graft loss among recipients 80 years and older compared with those 60 to 69 years (HR 1.78; 95% CI 1.42-2.23); however, no difference in death-censored graft survival was observed (0.89; 0.57-1.39). Among recipients 80 years and older, no difference in survival was observed between standard criteria donor and ECD recipients. Although perioperative mortality was uncommon among elderly recipients (1.5%), a trend toward higher perioperative mortality was observed in recipients 80 years and older. There was no difference in survival among standard criteria donor and ECD recipients.


Mumps virus infection of dissociated rodent spinal ganglia in vitro. Expression and disappearance of viral structural proteins from neurons.
Cultured spinal ganglia and cord from mice and hamsters were infected with mumps virus or Sendai virus. Expression of five structural proteins, the haemagglutinin-neuraminidase, fusion, nucleocapsid (NP), phospho (P) and matrix proteins was examined with monoclonal antibodies to each protein. In Sendai virus-infected mouse neurons all five viral proteins were detected. In hamster neurons infected with mumps virus all viral proteins were also expressed, but in mouse neurons only the NP and P proteins were seen. This suggests a species-specific cellular restriction of viral protein synthesis in mumps virus-infected mouse neurons. There was no, or only a slight, reduction in the number of neurons between days 4 and 20 after infection of mouse cultures with mumps virus, but the proportion of infected neurons diminished from 68% to 15% during this time.


Assessing the Effectiveness of Complex Interventions to Meet the Needs of VA Stakeholders: Experience of the Department of Veterans Affairs Evidence Synthesis Program.
Complex health care interventions involve multiple distinct elements that contribute to their functioning. Conducting systematic reviews of complex interventions has substantial challenges. Although methodological guidance exists, less is known about the practical strategies and approaches undertaken by systematic review groups to navigate common challenges and enhance impacts of systematic review findings. Describe pragmatic approaches taken by Department of Veterans Affairs Evidence Synthesis Programs (VA ESP) in conducting systematic reviews of effectiveness and implementation barriers and facilitators for complex interventions to provide VA stakeholders with evidence to guide national health care practice and policy. We describe 3 systematic reviews conducted by VA ESP teams to evaluate the evidence for complex health care interventions. We summarize key findings, implications for future research needs and policy, dissemination of findings, and approaches taken to address common challenges. The VA ESP experience adds to existing systematic review methods and provides a perspective on generating rigorous and relevant reviews of complex interventions. Reviews of complex interventions often encounter challenges related to sources of variability in many dimensions, and lack of clarity and information in reporting of intervention elements, local context, and implementation factors. Evidence synthesis teams should work closely with stakeholders to understand their needs, synthesize and interpret results in meaningful ways, and explore implications that are most relevant for day-to-day clinical practice and operational decisions of learning health care systems. More evaluation of the impact of systematic reviews may improve uptake of findings from future reviews and enhance translation of evidence into practice and policy.


Definition of human rotavirus serotypes by plaque reduction assay.
Twenty different human rotavirus reassortants were characterized serologically by a plaque reduction assay as belonging to one of three distinct serotypes. Fourteen were similar if not identical to our prototype Wa strain; two were like the prototype DS-1 strain, and four belonged to a third serotype for which a prototype has not yet been selected. Hyperimmune sera raised against the three serotypes were required to distinguish among them, since postinfection sera had lower titers and were more cross-reactive than hyperimmune sera. These results confirmed the ability of a qualitative cytopathic neutralization test to predict correctly the Wa or DS-1 serotype. A strain of rhesus rotavirus (MMU 18006) was identified as belonging to the newly defined third serotype. Finally, an attempt was made to correlate previously published serotype analysis by neutralization of fluorescent cell-forming units with the results determined by the plaque reduction neutralization assay.


Vestibular Schwannoma Stereotactic Radiosurgery in Octogenarians: Case Series.
The management of octogenarians with vestibular schwannomas (VS) has received little attention. However, with the increase in octogenarian population, more effort is needed to clarify the value of stereotactic radiosurgery (SRS) in this population. The aim of this study was to evaluate the safety and efficacy of SRS in this patient age group. A retrospective study of 62 patients aged 80 years or older who underwent single-session SRS for symptomatic VS during a 35-year interval was performed. The median patient age was 82 years, and 61.3% were male. SRS was performed as planned adjuvant management or for delayed progression after prior partial resection in 5 patients. SRS resulted in a 5-year tumor control rate of 95.6% with a 4.8% risk of adverse radiation effects (ARE). Tumor control was unrelated to patient age, tumor volume, Koos grade, sex, SRS margin dose, or prior surgical management. Four patients underwent additional management including 1 patient with symptomatic progression requiring surgical resection, 2 patients with symptomatic hydrocephalus requiring cerebrospinal fluid diversion, and 1 patient whose tumor-related cyst required delayed cyst aspiration. Three patients developed ARE, including 1 patient with permanent facial weakness (House-Brackmann grade II), 1 who developed trigeminal neuropathy, and 1 who had worsening gait disorder. Six patients had serviceable hearing preservation before SRS, and 2 maintained serviceable hearing preservation after 4 years. A total of 44 (71%) patients died at an interval ranging from 6 to 244 months after SRS. SRS resulted in tumor and symptom control in most octogenarian patients with VS.


Social security benefits for mental and behavioral disorders among workers in Piaui, Brazil, in 2014.
The characteristics of social security benefits changed over time as a function of modifications in the patterns of work organization. This process gave rise to new social vulnerabilities which include aspects visibly related to occupational health, as is the case of mental and behavioral disorders. To describe temporary social security benefits granted by the National Social Security Institute (INSS) to workers with mental and behavioral disorders in Piaui, Brazil, in 2014. Cross-sectional, descriptive and retrospective study based on INSS data collected in November 2015 relative to 2014. 1,473 benefits were granted along the analyzed period, 50.4% of which corresponded to male workers. Most beneficiaries resided in the state capital and had urban jobs. Mood disorders accounted for 47.7% of sick leaves. The mean duration of benefits was 112.6 days. There was significant difference in the duration of benefits according to their type (p<0.012), urban versus rural jobs (p<0.015) and sex (p=0.010). Mood disorders were the most frequent reason for sick leaves due to mental and behavioral disorders and the affected workers were granted social security benefits. The duration of leaves significantly differed as a function of the type of benefits, urban versus rural jobs and sex.


One-pot fabrication of yolk-shell nanospheres with ultra-small Au nanoparticles for catalysis.
We report a "one-pot" method for the direct synthesis of an organosilica shell/silica core nanoreactor confined with ultra-small metal (Au, Pd, and Ru) nanoparticles. The nano-reactor confined with Au nanoparticles showed high activity towards styrene oxidation using O2 as the oxidant under 1 atm pressure and could be stably recycled without deterioration of both conversion and selectivity. The strategy could be adapted onto other nanostructures with little modification to obtain yolk-shell nanoreactors for catalysis application.


Canine small bowel motor patterns and contractions are not neurally regulated during enteric nutrient infusion.
The aims of this study were to determine the effects of duodenal and jejunoileal nutrient infusions on small intestinal motor patterns and intestinal contractions in neurally intact and neurally isolated small bowel. Fifteen dogs were prepared with duodenal and jejunal infusion and manometry catheters and a diverting jejunal cannula. Ten of the dogs underwent in situ neural isolation of the jejunoileum. A mixed nutrient meal (0.5 kcal/ml) was infused into the duodenum or jejunum at 3 ml/min for 5 h. Control experiments involved infusion of a balanced salt solution. Manometric data collected on-line to a microcomputer were analyzed for direction, distance, and velocity of spread of single pressure waves (SPW) and clustered contractions. Isolated duodenal and jejunoileal nutrient infusions inhibited the fasting motor pattern in neurally intact and neurally isolated small bowel. Motor activity (motility index) increased slightly during nutrient infusion within groups, but there were few differences between groups. Neither neural isolation nor nutrient infusion had a consistent effect on spread of SPW or migration of clustered contractions. Isolated duodenal and jejunoileal nutrient infusions in the dog inhibit fasting motor patterns and increase motor activity slightly but have little effect on characteristics of individual and clustered contractions. Extrinsic innervation to the jejunoileum or intrinsic neural continuity of the jejunum with the duodenum had little effect on single or grouped contractions. Although the changes in motor activity demonstrated in this study appear small, alterations in intestinal transit and absorption may still occur and may be of importance physiologically.


Automatic tracking of cells for video microscopy in patch clamp experiments.
Visualisation of neurons labeled with fluorescent proteins or compounds generally require exposure to intense light for a relatively long period of time, often leading to bleaching of the fluorescent probe and photodamage of the tissue. Here we created a technique to drastically shorten light exposure and improve the targeting of fluorescent labeled cells that is specially useful for patch-clamp recordings. We applied image tracking and mask overlay to reduce the time of fluorescence exposure and minimise mistakes when identifying neurons. Neurons are first identified according to visual criteria (e.g. fluorescence protein expression, shape, viability etc.) and a transmission microscopy image Differential Interference Contrast (DIC) or Dodt contrast containing the cell used as a reference for the tracking algorithm. A fluorescence image can also be acquired later to be used as a mask (that can be overlaid on the target during live transmission video). As patch-clamp experiments require translating the microscope stage, we used pattern matching to track reference neurons in order to move the fluorescence mask to match the new position of the objective in relation to the sample. For the image processing we used the Open Source Computer Vision (OpenCV) library, including the Speeded-Up Robust Features (SURF) for tracking cells. The dataset of images (n = 720) was analyzed under normal conditions of acquisition and with influence of noise (defocusing and brightness). We validated the method in dissociated neuronal cultures and fresh brain slices expressing Enhanced Yellow Fluorescent Protein (eYFP) or Tandem Dimer Tomato (tdTomato) proteins, which considerably decreased the exposure to fluorescence excitation, thereby minimising photodamage. We also show that the neuron tracking can be used in differential interference contrast or Dodt contrast microscopy. The techniques of digital image processing used in this work are an important addition to the set of microscopy tools used in modern electrophysiology, specially in experiments with neuron cultures and brain slices.


Feasibility of allogeneic stem-cell transplantation after azacitidine bridge in higher-risk myelodysplastic syndromes and low blast count acute myeloid leukemia: results of the BMT-AZA prospective study.
Allogeneic stem-cell transplantation (HSCT) is the only curative treatment in myelodysplastic syndromes (MDS). Azacitidine (AZA) is increasingly used prior to HSCT, however in Europe it is only approved for patients who are not eligible for HSCT. We conducted a phase II multicenter study to prospectively evaluate the feasibility of HSCT after treatment with AZA in 70 patients with a myelodysplastic syndrome (MDS), 19 with acute myeloid leukemia (AML), and 8 with chronic myelomonocytic leukemia (CMML). After a median of four cycles (range 1-11): 24% of patients achieved complete remission, 14% partial remission, 8% hematologic improvement, 32% had stable and 22% progressive disease. Ten patients discontinued treatment before the planned four cycles, due to an adverse event in nine cases. A HSC donor was identified in 73 patients, and HSCT was performed in 54 patients (74% of patients with a donor). Main reasons for turning down HSCT were lack of a donor, an adverse event, or progressive disease (9, 12, and 16 patients, respectively). At a median follow-up of 20.5 months from enrolment, response to AZA was the only independent prognostic factor for survival. Compared to baseline assessment, AZA treatment did not affect patients' comorbidities at HSCT: the HCT-CI remained stable in 62% patients, and worsened or improved in 23% and 15% of patients, respectively. Our study shows that HSCT is feasible in the majority of patients with HR-MDS/AML/CMML-2 after AZA treatment. As matched unrelated donor was the most frequent source of donor cells, the time between diagnosis and HSCT needed for donor search could be 'bridged' using azacitidine. These data show that AZA prior to HSCT could be a better option than intensive chemotherapy in higher-risk MDS. The trial has been registered with the EudraCT number 2010-019673-1.


Neuroimaging of rodent and primate models of alcoholism: initial reports from the integrative neuroscience initiative on alcoholism.
Neuroimaging of animal models of alcoholism offers a unique path for translational research to the human condition. Animal models permit manipulation of variables that are uncontrollable in clinical, human investigation. This symposium, which took place at the annual meeting of the Research Society on Alcoholism in Vancouver, British Columbia, Canada, on June 29th, 2004, presented initial findings based on neuroimaging studies from the two centers of the Integrative Neuroscience Initiative on Alcoholism funded by the National Institute on Alcohol Abuse and Alcoholism. Effects of alcohol exposure were assessed with in vitro glucose metabolic imaging of rat brain, in vitro receptor imaging of monkey brain, in vivo magnetic resonance imaging of monkey brain, and in vivo magnetic resonance spectroscopic quantification of alcohol metabolism kinetics in rat brain.


Veterans' reports of pain and associations with ratings of health, health-risk behaviors, affective distress, and use of the healthcare system.
The improved management of pain among veterans seeking care in Veterans Health Administration (VHA) facilities has been established as a priority. This study documents the high prevalence of reports of pain among a convenience sample of 685 veterans seeking care in a VHA primary care setting. Also reported are associations of pain complaints with self-rated health, an index of emotional distress, health-risk behaviors such as tobacco and alcohol use, health-related concerns about diet and weight, and perceptions of the availability of social support. The relationship between the presence of pain and use of outpatient and inpatient medical and mental health services is also examined. Nearly 50% of the sample reported that they experience pain regularly and that they were concerned about this problem at the time of the index visit to their primary care provider. Persons acknowledging the presence of pain, relative to those not reporting pain, were younger, reported worsening health over the past year, had greater emotional distress, used tobacco, had diet and/or weight concerns, and were found to use more outpatient medical, but not inpatient medical or mental health services. Results support the goals of the VHA National Pain Management Strategy designed to reduce unnecessary pain and suffering among veterans receiving care in VHA facilities.


The association of initiation factor 4F with poly(A)-binding protein is enhanced in serum-stimulated Xenopus kidney cells.
Serum stimulation of cultured Xenopus kidney cells results in enhanced phosphorylation of the translational initiation factor (eIF) 4E and promotes a 2.8-fold increase in the binding of the adapter protein eIF4G to eIF4E, to form the functional initiation factor complex eIF4F. Here we demonstrate the serum-stimulated co-isolation of the poly(A)-binding protein (PABP) with the eIF4F complex. This apparent interaction of PABP with eIF4F suggests that a mechanism shown to be important in the control of translation in the yeast Saccharomyces cerevisiae also operates in vertebrate cells. We also present evidence that the signaling pathways modulating eIF4E phosphorylation and function in Xenopus kidney cells differ from those in several mammalian cell types studied previously. Experiments with the immunosuppressant rapamycin suggest that the mTOR signaling pathway is involved in serum-promoted eIF4E phosphorylation and association with eIF4G. Moreover, we could find little evidence for regulation of eIF4E function via interaction with the specific binding proteins 4E-BP1 or 4E-BP2 in these cells. Although rapamycin abrogated serum-enhanced rates of protein synthesis and the interaction of eIF4G with eIF4E, it did not prevent the increase in association of eIF4G with PABP. This suggests that serum stimulates the interaction between eIF4G and PABP by a distinct mechanism that is independent of both the mTOR pathway and the enhanced association of eIF4G with eIF4E.


Proteome analysis of coinfection of epithelial cells with Filifactor alocis and Porphyromonas gingivalis shows modulation of pathogen and host regulatory pathways.
Changes in periodontal status are associated with shifts in the composition of the bacterial community in the periodontal pocket. The relative abundances of several newly recognized microbial species, including Filifactor alocis, as-yet-unculturable organisms, and other fastidious organisms have raised questions on their impact on disease development. We have previously reported that the virulence attributes of F. alocis are enhanced in coculture with Porphyromonas gingivalis. We have evaluated the proteome of host cells and F. alocis during a polymicrobial infection. Coinfection of epithelial cells with F. alocis and P. gingivalis strains showed approximately 20% to 30% more proteins than a monoinfection. Unlike F. alocis ATCC 35896, the D-62D strain expressed more proteins during coculture with P. gingivalis W83 than with P. gingivalis 33277. Proteins designated microbial surface component-recognizing adhesion matrix molecules (MSCRAMMs) and cell wall anchor proteins were highly upregulated during the polymicrobial infection. Ultrastructural analysis of the epithelial cells showed formation of membrane microdomains only during coinfection. The proteome profile of epithelial cells showed proteins related to cytoskeletal organization and gene expression and epigenetic modification to be in high abundance. Modulation of proteins involved in apoptotic and cell signaling pathways was noted during coinfection. The enhanced virulence potential of F. alocis may be related to the differential expression levels of several putative virulence factors and their effects on specific host cell pathways.


1D nanocrystals with precisely controlled dimensions, compositions, and architectures.
The ability to synthesize a diverse spectrum of one-dimensional (1D) nanocrystals presents an enticing prospect for exploring nanoscale size- and shape-dependent properties. Here we report a general strategy to craft a variety of plain nanorods, core-shell nanorods, and nanotubes with precisely controlled dimensions and compositions by capitalizing on functional bottlebrush-like block copolymers with well-defined structures and narrow molecular weight distributions as nanoreactors. These cylindrical unimolecular nanoreactors enable a high degree of control over the size, shape, architecture, surface chemistry, and properties of 1D nanocrystals. We demonstrate the synthesis of metallic, ferroelectric, upconversion, semiconducting, and thermoelectric 1D nanocrystals, among others, as well as combinations thereof.


The effect of entrapment in liposomes on the in vivo distribution of [3H]methotrexate in a primate.
Entrapment of methotrexate (MTX) plus [3',5', 9(n)-3H]methotrexate into positively charged liposomes greatly alters the subsequent distribution of [3H]MTX in a cynomologous monkey (Macaca irus) after a single i.v. injection ([3H]MTX; refers to total radioactivity derived from purified [3H]MTX). When [3H]MTX is incorporated into small, sonically disrupted liposomes, the level of the entrapped [3H]MTX in the total plasma volume was still 50% of the total injected dose after 4 hr, which is 100 times greater than the level found when the same amount of free MTX (1 to 4 mg) plus [3H]MTX was injected. When entrapped in larger mechanicanically disperesed liposomes, however, the plasma levels of liposome-entrapped [3H]MTX at 4 hr was only 6-fold greater than free [3H]MT. The liposome-entrapped MTX (refers to MTX measured by dihydrofolate reductase assay) did not show detectable breakdown in the plasma whereas free MTX showed up to 97% breakdown. Increased clearance of [3H]MTX entrapped in mechanically dispersed liposomes was complemented by its much greater uptake into tissues, especially spleen, compared with sonically disrupted liposomes. There was over a 160-fold increased uptake by the spleen of liposome-entrapped [3H] MTX relative to free [3H]MTX, whereas for sonically disrupted liposomes the comparable ratio was 20. Although this liposome-entrapped MTX showed significant breakdown, it was less than that found after injection of free MTX. In certain tissues, especially the small intestine, a reduced uptake of liposome-entrapped [3H]MTX WAS FOUND. Uptake of liposome-entrapped [3H]MTX into liposomes led to a much lower renal clearance of [3H]MTX, especially in the case of sonically disrupted liposomes. Possible reasons for these effects and the relationship of our findings to those of others are discussed.


Age-adjusted International Prognostic Index predicts autologous stem cell transplantation outcome for patients with relapsed or primary refractory diffuse large B-cell lymphoma.
Second-line chemotherapy followed by high-dose therapy (HDT) with autologous stem cell transplantation (ASCT) cures less than half of the patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). Prognostic models capable of predicting outcome are essential. In 3 sequential clinical trials, conducted from January 1993 to August 2000, we treated 150 patients with relapsed or primary refractory DLBCL with ifosfamide, carboplatin, and etoposide (ICE) chemotherapy followed by HDT/ASCT for patients with chemosensitive disease. We evaluated the age-adjusted International Prognostic Index at the initiation of second-line therapy (sAAIPI) as a predictor of progression-free survival (PFS) and overall survival (OS). At a median follow-up of 4 years, the PFS and OS are 28% and 34% by intention to treat and 39% and 45% for only those patients with chemosensitive disease. Three risk groups with different PFS and OS were identified by the sAAIPI: low risk (0 factors), 70% and 74%; intermediate risk (1 factor), 39% and 49%; and high risk (2 or 3 factors), 16% and 18% (P <.001 for both PFS and OS). The sAAIPI also predicts the PFS and OS for patients with ICEchemosensitive disease: low risk, 69% and 83%; intermediate risk, 46% and 55%; and high risk, 25% and 26% (P <.001 PFS and OS). The sAAIPI predicts outcome for patients with relapsed or primary refractory DLBCL in both intent-to-treat and chemosensitive populations. This powerful prognostic instrument should be used to evaluate new treatment approaches and to compare results of different regimens.


Activating transcription factor 4 is translationally regulated by hypoxic stress.
Hypoxic stress results in a rapid and sustained inhibition of protein synthesis that is at least partially mediated by eukaryotic initiation factor 2alpha (eIF2alpha) phosphorylation by the endoplasmic reticulum (ER) kinase PERK. Here we show through microarray analysis of polysome-bound RNA in aerobic and hypoxic HeLa cells that a subset of transcripts are preferentially translated during hypoxia, including activating transcription factor 4 (ATF4), an important mediator of the unfolded protein response. Changes in mRNA translation during the unfolded protein response are mediated by PERK phosphorylation of the translation initiation factor eIF2alpha at Ser-51. Similarly, PERK is activated and is responsible for translational regulation under hypoxic conditions, while inducing the translation of ATF4. The overexpression of a C-terminal fragment of GADD34 that constitutively dephosphorylates eIF2alpha was able to attenuate the phosphorylation of eIF2alpha and severely inhibit the induction of ATF4 in response to hypoxic stress. These studies demonstrate the essential role of ATF4 in the response to hypoxic stress, define the pathway for its induction, and reveal that GADD34, a target of ATF4 activation, negatively regulates the eIF2alpha-mediated inhibition of translation. Taken with the concomitant induction of additional ER-resident proteins identified by our microarray analysis, this study suggests an important integrated response between ER signaling and the cellular adaptation to hypoxic stress.


Obesity and bronchodilator response in black and Hispanic children and adolescents with asthma.
Obesity is associated with poor asthma control, increased asthma morbidity, and decreased response to inhaled corticosteroids. We hypothesized that obesity would be associated with decreased bronchodilator responsiveness in children and adolescents with asthma. In addition, we hypothesized that subjects who were obese and unresponsive to bronchodilator would have worse asthma control and would require more asthma controller medications. In the Study of African Americans, Asthma, Genes, and Environments (SAGE II) and the Genes-environments and Admixture in Latino Americans (GALA II) study, two identical, parallel, case-control studies of asthma, we examined the association between obesity and bronchodilator response in 2,963 black and Latino subjects enrolled from 2008 to 2013 using multivariable logistic regression. Using bronchodilator responsiveness, we compared asthma symptoms, controller medication usage, and asthma exacerbations between nonobese (< 95th% BMI) and obese (≥ 95th% BMI) subjects. The odds of being bronchodilator unresponsive were 24% (OR, 1.24; 95% CI, 1.03-1.49) higher among obese children and adolescents compared with their not obese counterparts after adjustment for age, race/ethnicity, sex, recruitment site, baseline lung function (FEV1/FVC), and controller medication. Bronchodilator-unresponsive obese subjects were more likely to report wheezing (OR, 1.38; 95% CI, 1.13-1.70), being awakened at night (OR, 1.34; 95% CI, 1.09-1.65), using leukotriene receptor inhibitors (OR, 1.33; 95% CI, 1.05-1.70), and using inhaled corticosteroid with long-acting β2-agonist (OR, 1.37; 95% CI, 1.05-1.78) than were their nonobese counterpart. These associations were not seen in the bronchodilator-responsive group. Obesity is associated with bronchodilator unresponsiveness among black and Latino children and adolescents with asthma. The findings on obesity and bronchodilator unresponsiveness represent a unique opportunity to identify factors affecting asthma control in blacks and Latinos.


SURVIVAL AND PERIOPERATIVE MORBIDITY OF TOTALLY LAPAROSCOPIC VERSUS OPEN GASTRECTOMY FOR EARLY GASTRIC CANCER: ANALYSIS FROM A SINGLE LATIN AMERICAN CENTRE.
Laparoscopic gastrectomy has numerous perioperative advantages, but the long-term survival of patients after this procedure has been less studied. To compare survival, oncologic and perioperative outcomes between completely laparoscopic vs. open gastrectomy for early gastric cancer. This study was retrospective, and our main outcomes were the overall and disease-specific 5-year survival, lymph node count and R0 resection rate. Our secondary outcome was postoperative morbidity. Were included 116 patients (59% men, age 68 years, comorbidities 73%, BMI 25) who underwent 50 laparoscopic gastrectomies and 66 open gastrectomies. The demographic characteristics, tumour location, type of surgery, extent of lymph node dissection and stage did not significantly differ between groups. The overall complication rate was similar in both groups (40% vs. 28%, p=ns), and complications graded at least Clavien 2 (36% vs. 18%, p=0.03), respiratory (9% vs. 0%, p=0.03) and wound-abdominal wall complications (12% vs. 0%, p=0.009) were significantly lower after laparoscopic gastrectomy. The lymph node count (21 vs. 23 nodes; p=ns) and R0 resection rate (100% vs. 96%; p=ns) did not significantly differ between groups. The 5-year overall survival (84% vs. 87%, p=0.31) and disease-specific survival (93% vs. 98%, p=0.20) did not significantly differ between the laparoscopic and open gastrectomy groups. The results of this study support similar oncologic outcome and long-term survival for patients with early gastric cancer after laparoscopic gastrectomy and open gastrectomy. In addition, the laparoscopic approach is associated with less severe morbidity and a lower occurrence of respiratory and wound-abdominal wall complications.


Animal models to assess the therapeutic efficacy of human serum and serum-converted platelet lysates for dry eye syndrome: Seeing is believing.
There is much interest in the clinical use of serum-converted human blood or platelet concentrates in regenerative medicine, most specifically for wound healing and tissue repair of soft and hard tissues. The scientific rationale supporting the clinical efficacy of these preparations is based on the expectation that their physiological mixture of natural growth factors can orchestrate cell expansion and differentiation in vivo. However, a lack of standardization and regulatory oversight of these blood materials maintain a perception of uncertainty in the scientific and medical community on the value of these preparations for some clinical indications. More studies are needed to understand the mechanism of action underlying their expected efficacy and standardize their use, and benefit from their biological versatility. One application of serum is as eye drop for treating dry eye syndrome (DES), a multifactorial disease of the ocular surface, which has a prevalence of 15% of more in the population. DES can lead to chronic inflammation of the ocular surface, surface impairment in the cornea and conjunctiva, and, in patients with Sjogren syndrome, result in a disruption of the ocular surface epithelium. Objective experimental assessment of safety and efficacy of serum eye drops can help establish scientific rationale in optimal product composition and use. This can be achieved, first, through cell cultures with relevant cell models, before considering, then, animal studies using DES animal models. Several models have been evaluated and are reported in this concise review. The model we have developed encompasses the use of rabbits, where their eyes are treated with 0.1% benzalkonium chloride (BAC), a common preservative in ophthalmic agents, 3 times daily for 4 weeks. This relatively mild treatment results in moderate DES pathology, with a stable shortage of tear secretion throughout a 7-week study period, which we found suitable for assessing efficacy of serum eye drops.


mRNA localization to P-bodies in yeast is bi-phasic with many mRNAs captured in a late Bfr1p-dependent wave.
The relocalization of translationally repressed mRNAs to mRNA processing bodies Pbodies is a key consequence of cellular stress across many systems. Pbodies harbor mRNA degradation components and are implicated in mRNA decay, but the relative timing and control of mRNA relocalization to Pbodies is poorly understood. We used the MS2GFP system to follow the movement of specific endogenous mRNAs in live Saccharomyces cerevisiae cells after nutritional stress. It appears that the relocalization of mRNA to Pbodies after stress is biphasic some mRNAs are present early, whereas others are recruited much later concomitant with recruitment of translation initiation factors, such as eIF4E. We also find that Bfr1p is a latephaselocalizing Pbody protein that is important for the delayed entry of certain mRNAS to Pbodies. Therefore, for the mRNAs tested, relocalization to Pbodies varies both in terms of the kinetics and factor requirements. This work highlights a potential new regulatory juncture in gene expression that would facilitate the overall rationalization of protein content required for adaptation to stress.


High-precision structural analysis of subnuclear complexes in fixed and live cells via spatially modulated illumination (SMI) microscopy.
Spatially modulated illumination (SMI) microscopy is a method of wide field fluorescence microscopy featuring interferometric illumination, which delivers structural information about nanoscale architecture in fluorescently labelled cells. The first prototype of the SMI microscope proved its applicability to a wide range of biological questions. For the SMI live cell imaging this system was enhanced in terms of the development of a completely new upright configuration. This so called Vertico-SMI transfers the advantages of SMI nanoscaling to vital biological systems, and is shown to work consistently at different temperatures using both oil- and water-immersion objective lenses. Furthermore, we increased the speed of data acquisition to minimize errors in the detection signal resulting from cellular or object movement. By performing accurate characterization, the present Vertico-SMI now offers a fully-fledged microscope enabling a complete three-dimensional (3D) SMI data stack to be acquired in less than 2 seconds. We have performed live cell measurements of a tet-operator repeat insert in U2OS cells, which provided the first in vivo signatures of subnuclear complexes. Furthermore, we have successfully implemented an optional optical configuration allowing the generation of high-resolution localization microscopy images of a nuclear pore complex distribution.


Neurovascular Coupling Remains Intact During Incremental Ascent to High Altitude (4240 m) in Acclimatized Healthy Volunteers.
Neurovascular coupling (NVC) is the temporal link between neuronal metabolic activity and regional cerebral blood flow (CBF), supporting adequate delivery of nutrients. Exposure to high altitude (HA) imposes several stressors, including hypoxia and hypocapnia, which modulate cerebrovascular tone in an antagonistic fashion. Whether these contrasting stressors and subsequent adaptations affect NVC during incremental ascent to HA is unclear. The aim of this study was to assess whether incremental ascent to HA influences the NVC response. Given that CBF is sensitive to changes in arterial blood gasses, in particular PaCO2, we hypothesized that the vasoconstrictive effect of hypocapnia during ascent would decrease the NVC response. 10 healthy study participants (21.7 ± 1.3 years, 23.57 ± 2.00 kg/m2, mean ± SD) were recruited as part of a research expedition to HA in the Nepal Himalaya. Resting posterior cerebral artery velocity (PCAv), arterial blood gasses (PaO2, SaO2, PaCO2, [HCO3 -], base excess and arterial blood pH) and NVC response of the PCA were measured at four pre-determined locations: Calgary/Kathmandu (1045/1400 m, control), Namche (3440 m), Deboche (3820 m) and Pheriche (4240 m). PCAv was measured using transcranial Doppler ultrasound. Arterial blood draws were taken from the radial artery and analyzed using a portable blood gas/electrolyte analyzer. NVC was determined in response to visual stimulation (VS; Strobe light; 6 Hz; 30 s on/off × 3 trials). The NVC response was averaged across three VS trials at each location. PaO2, SaO2, and PaCO2 were each significantly decreased at 3440, 3820, and 4240 m. No significant differences were found for pH at HA (P > 0.05) due to significant reductions in [HCO3 -] (P < 0.043). As expected, incremental ascent to HA induced a state of hypoxic hypocapnia, whereas normal arterial pH was maintained due to renal compensation. NVC was quantified as the delta (Δ) PCAv from baseline for mean PCAv, peak PCAv and total area under the curve (ΔPCAv tAUC) during VS. No significant differences were found for Δmean, Δpeak or ΔPCAv tAUC between locations (P > 0.05). NVC remains remarkably intact during incremental ascent to HA in healthy acclimatized individuals. Despite the array of superimposed stressors associated with ascent to HA, CBF and NVC regulation may be preserved coincident with arterial pH maintenance during acclimatization.


Application of the semi-analytical Fourier transform to electromagnetic modeling.
The Fast Fourier Transform (FFT) algorithm makes up the backbone of fast physical optics modeling. Its numerical effort, approximately linear on the sample number of the function to be transformed, already constitutes a huge improvement on the original Discrete Fourier Transform. However, even this orders-of-magnitude improvement in the number of operations required can fall short in optics, where the tendency is to work with field components that present strong wavefront phases: this translates, as per the Nyquist-Shannon sampling theorem, into a huge sample number. So much so, in fact, that even with the reduced effort of the FFT, the operation becomes impracticable. Finding a workaround that allows us to evade, at least in part, these stringent sampling requirements is then fundamental for the practical feasibility of the Fourier transform in optics. In this work we propose, precisely, a way to tackle the Fourier transform that eschews the sampling of second-order polynomial phase terms, handling them analytically instead: it is for this reason that we refer to this method as the "semi-analytical Fourier transform". We present here the theory behind this concept and show the algorithm in action at several examples which serve to illustrate the vast potential of this approach.


A comparison of actual to estimated weights in Australian children attending a tertiary children's' hospital, using the original and updated APLS, Luscombe and Owens, Best Guess formulae and the Broselow tape.
During paediatric resuscitation it is essential to be able to estimate the child's weight as it determines drug doses and equipment sizes. Age and length-based estimations exist, with age-based estimations being especially useful in the preparation phase and the length-based Broselow tape having weight-based drug doses and equipment already assigned via a colour code system. The aim of this study was to compare the actual recorded weights of Australian children to the predicted weights using the original and updated APLS, Luscombe and Owens and Best Guess formulae and the Broselow tape. A retrospective observational study of children attending an Australian tertiary children's hospital. From 49,565 patients extracted from the database, 37,114 children with age and weight and 37,091 children with age and height recorded were included in the analysis. Best Guess was the most accurate, with the smallest overall mean difference 0.86 kg. For <1 year old, Broselow tape was the most accurate (mean difference -0.43 kg), Best Guess was the most accurate for ages 1-5 years and 11-14 years (mean difference 0.27 and 0.20 kg respectively), and the updated APLS formula was the most accurate for 6-10 year-old (mean difference 0.42 kg). The Broselow tape was able to only classify 48.9% of children into the correct weight colour band. For an age-based weight estimation, in infants less than one year the new APLS formula is the most accurate and over one year the Best Guess formulae should be used.


Assessment and computational bioevaluation of heavy metals from selected cosmetic products.
Heavy metal toxicity in environment has been an increasing issue for last decades, though now the attention has diverted to presence of heavy metals in cosmetic products. The aim of this study was to determine the concentration of selected heavy metals in cosmetic products (lipsticks and foundations) using ICP-OES. Health risk assessment was done by using hazard quotient (HQ) and hazard index (HI). HQ for lipsticks was below the safe limit (HQ = < 1) while for foundations it exceeded the safe limit (HQ = >1). Mostly, mercury (Hg) and iron (Fe) were found to be exceeding the permissible limit, the allowed limits are Hg, 1 ppm; Fe, 10 ppm; Cd, 0.3 ppm; and Cr, 1 ppm. Iron was found to be highest in lipsticks (123.86 ± 1.05 ppm) as well as in foundations (34.52 ± 0.08 ppm). Health risk assessment was done by using hazard quotient (HQ) and hazard index (HI). HQ for lipsticks was below the safe limit (HQ = < 1) while for foundations it exceeded the safe limit (HQ = >1). To understand the binding pattern of heavy metals to skin targets, molecular docking studies were carried out. This revealed the potentially harmful behavior of these heavy metals on the skin. This will provide new direction for the structural changes of consistence and activity of macromolecules in our body. Research proved that prolonged use of cosmetic products containing heavy metals can be harmful and sometimes fatal to human life as these heavy metals can penetrate through the skin and target the skin enzymes, disrupting their normal function leading to various skin related issues such as dermatitis (itching, redness, burning) hence the monitoring of cosmetic products is necessary for safety of human being.


Investigation of a Common Clinical Approach to Poor Growth in Preterm Infants.
This study aimed to determine the effect of elevated energy intake with medium-chain triglyceride (MCT) oil or formula powder on growth velocity and weight z-score in very low birth weight infants receiving human milk and human milk fortifier. This was a cohort study of infants exposed to MCT oil or formula powder for at least 7 days. Mean 7-day change in growth velocity and weight z-scores were compared pre- and postintervention. Forty-three infants received increased energy with either MCT oil or formula powder. Infants receiving MCT oil were more preterm and had a lower birth weight. When evaluating 7-day changes pre- and postintervention, growth velocity increased from 10.0 g/kg/day to 19.8 g/kg/day, and change in weight Z-score increased from -0.24 to 0.05. This clinical approach using MCT oil or formula powder for additional energy was associated with improved, at least short-term, growth velocity and weight z-score trajectory.


Complete groin lymphadenectomy with preservation of the fascia lata in the treatment of vulvar carcinoma.
The goal of this study was to assess the local groin recurrence of vulvar carcinoma in patients treated by complete groin node dissection with preservation of the fascia lata (GNDPFL). This study is a retrospective chart review of 60 patients with Stage I-IV vulvar carcinoma who underwent radical vulvectomy and GNDPFL between 1990 and 1998. All superficial inguinal nodes and the deep femoral nodes on the anterior and medial surfaces of the femoral vein within the fossa ovalis were removed en bloc while sparing the fascia lata and the cribriform fascia over the femoral artery. Of the 60 study patients, 14 patients had Stage I disease, 20 Stage II, 21 Stage III, and 5 Stage IV. The mean number of nodes removed was 10 per groin. Thirty-nine patients had benign nodes on groin dissection. None of these 39 patients developed cancer recurrence in the dissected groins. Twenty-one of the sixty study patients (34%) had malignant nodes on groin dissection. Of these 21 patients, 2 experienced cancer recurrence in the groins. Our study describes a groin recurrence rate of 7.6% in patients with fewer than three malignant unilateral groin nodes. Postoperatively, 13% of patients developed lymphedema and 15% formed lymphoceles. The zero groin recurrence rate in patients with negative nodes and the low rate of recurrence in patients with positive nodes indicate that groin lymphadenectomy with preservation of fascia lata is complete, therapeutic, and comparable to radical techniques of lymphadenectomy involving skeletonization of femoral vessels, resection of fascia lata, and muscle transposition.


A photo-electroactive surface strategy for immobilizing ligands in patterns and gradients for studies of cell polarization.
We report a combined photochemical and electrochemical method to pattern ligands and cells in complex geometries and gradients on inert surfaces. This work demonstrates: (1) the control of density of immobilized ligands within overlapping photopatterns, and (2) the attached cell culture patterned onto ligand defined gradients for studies of directional cell polarity. Our approach is based on the photochemical activation of benzoquinonealkanethiols. Immobilization of aminooxy terminated ligands in selected region of the quinone monolayer resulted in patterns on the surface. This approach is unique in that the extent of photochemical deprotection, as well as ligand immobilization can be monitored and quantified by cyclic voltammetry in situ. Furthermore, complex photochemical patterns of single or multiple ligands can be routinely generated using photolithographic masks. Finally, this methodology is completely compatible with attached cell culture and we show how the subtle interplay between cell-cell interactions and underlying peptide gradient influences cell polarization. The combined use of photochemistry, electrochemistry and well defined surface chemistry provides molecular level control of patterned ligands and gradients on surfaces.


Conformational Properties of Aβ Peptide Oligomers in Aqueous Ionic Liquid Solution: Insights from Molecular Simulation Studies.
Alzheimer's disease is a progressive irreversible neurological disorder with abnormal extracellular deposition of amyloid β (Aβ) peptides in the brain. We have carried out atomistic molecular dynamics simulations to investigate the size-dependent conformational properties of aggregated Aβ oligomers of different orders, namely, pentamer [O(5)], decamer [O(10)], and hexadecamer [O(16)] in aqueous solutions containing the ionic liquid (IL) 1-butyl-3-methylimidazolium tetrafluoroborate ([BMIM][BF4]). The calculations revealed reduced peptide conformational fluctuations in O(5) and O(10) in the presence of the IL. In contrast, the higher order oligomer [O(16)] has been found to exhibit greater structural distortion due to enhanced flexibilities of its peptide units in the presence of the IL. Based on the distributions of the solvent (water) and the cosolvent (IL) components, it is demonstrated that exchange of water by the IL ion pairs at the exterior surface of the oligomers primarily occurs beyond the first layer of surface-bound water molecules. Importantly, a reduced number of relatively weaker peptide salt bridges have been found in O(16) in binary water-IL solution as compared to the other two smaller-sized oligomers [O(5) and O(10)]. Such differential influence of the IL on peptide salt bridges results in less favorable binding free energies of peptide monomers to O(16), which leads to its greater structural distortion and reduced stability compared to those of O(5) and O(10).


Dermal uptake of nicotine from air and clothing: Experimental verification.
This study aims to elucidate in greater detail the dermal uptake of nicotine from air or from nicotine-exposed clothes, which was demonstrated recently in a preliminary study. Six non-smoking participants were exposed to gaseous nicotine (between 236 and 304 μg/m3 ) over 5 hours while breathing clean air through a hood. Four of the participants wore only shorts and 2 wore a set of clean clothes. One week later, 2 of the bare-skinned participants were again exposed in the chamber, but they showered immediately after exposure instead of the following morning. The 2 participants who wore clean clothes on week 1 were now exposed wearing a set of clothes that had been exposed to nicotine. All urine was collected for 84 hours after exposure and analyzed for nicotine and its metabolites, cotinine and 3OH-cotinine. All participants except those wearing fresh clothes excreted substantial amounts of biomarkers, comparable to levels expected from inhalation intake. Uptake for 1 participant wearing exposed clothes exceeded estimated intake via inhalation by >50%. Biomarker excretion continued during the entire urine collection period, indicating that nicotine accumulates in the skin and is released over several days. Absorbed nicotine was significantly lower after showering in 1 subject but not the other. Differences in the normalized uptakes and in the excretion patterns were observed among the participants. The observed cotinine half-lives suggest that non-smokers exposed to airborne nicotine may receive a substantial fraction through the dermal pathway. Washing skin and clothes exposed to nicotine may meaningfully decrease exposure.


Implementation and Evaluation of an Intervention for Children in Afghanistan at Risk for Substance Use or Actively Using Psychoactive Substances.
The present study examined the impact of a novel intervention for children at risk for substance use or actively using substances that was provided to 783 children between 4 and 18 years of age in Afghanistan. They received the Child Intervention for Living Drug-free (CHILD) protocol while in outpatient or residential treatment. CHILD included age-appropriate literacy and numeracy, drug education, basic living safety, and communication and trauma coping skills. A battery of measures examined multiple child health domains at treatment's start and end and 12 weeks later. For younger children, there were no significant Gender or Gender X Time effects (all p's > .16 and .35, resp.). The time main effect was significant for all outcomes (all p's < .00192, the prespecified per-comparison error rate). Post hoc testing showed significant improvements from residential treatment entry to completion for all scales. For older children, a time main effect was significant for (all p's < .00192, the prespecified per-comparison error rate) all but one outcome. Community follow-up means were significantly lower than residential treatment entry means. CHILD had a positive impact on children, and treatment impact endured from posttreatment to follow-up assessment.


[Nuclear structures in the late oogenesis of the common frog. I. Light microscopic observations].
The dynamics of the Rana temporaria karyosphere formation throughout different seasons was studied in addition to morphological changes in the karyosphere components with and without hormonal stimulation of oocyte maturation in vitro. Towards the end of summer, the nuclear structure (lampbrush chromosomes and multiple nucleoli) were shown to assemble in the centre of the nucleus forming a karyosphere. The completely formed karyosphere (up to 150--200 mu in diameter) is observed during autumn and winter to consist of the central chromosome part and a surrounding capsule. The capsule consists of numerous nucleoli and a distinct fibrous component. Filaments penetrating the whole nucleolar zone of the capsule are tightly packed around the chromosomes, thus forming the inner fibrous zone of the capsule, separating the chromosomes from the nucleoli. On the periphery of the karyosphere, threads attached to the nucleoli are clearly seen. This pattern of the karyosphere construction is conserved through winter till spring. In winter, spherical nucleoli change into rings and necklaces. In spring, nucleoli become spherical again and lose their threads. In the period of oocyte maturation and disappearance of nuclear envelopes, numerous nucleoli fuse into a single conglomeration which later disappears. Only the inner fibrous zone is conserved which separates the chromosomes from the cytoplasm and yolk platelets. In this state, the karyosphere persists up to the first meiotic metaphase. The nature of the fibrous component of the karyosphere capsule, its origin and function are discussed.


Perceived Severity of Cyberbullying: Differences and Similarities across Four Countries.
Cyberbullying is a ubiquitous topic when considering young people and internet and communication technologies (ICTs). For interventional purposes, it is essential to take into account the perspective of adolescents. This is the reason why our main focus is (1) investigating the role of different criteria in the perceived severity of cyberbullying incidents, and (2) examining the differences between countries in the perceived severity of cyberbullying. The sample consisted of 1,964 adolescents (48.2% girls) from middle and high schools of four different countries, i.e., Estonia, Italy, Germany, and Turkey. The participants' age ranged from 12 to 20 years old with a mean age of 14.49 (SD = 1.66) years. To assess perceived severity, participants rated a set of 128 scenarios, which systematically included one or more of five criteria (intentionality, repetition, imbalance of power, public vs. private, and anonymity) and represented four types of cyberbullying behaviors (Written-Verbal, Visual, Exclusion, Impersonation). The role of different criteria was analyzed using the Exploratory Structural Equation Modeling (ESEM). Results showed a similar structure across the four countries (invariant except for the latent factors' means). Further, criteria of imbalance of power and, to a lesser extent, intentionality, anonymity, and repetition always in combination, were found to be the most important criteria to define the severity of cyberbullying. Differences between countries highlighted specific features of Turkish students, who perceived all scenarios as more severe than adolescents from other countries and were more sensitive to imbalance of power. German and Italian students showed an opposite perception of anonymity combined with intentionality. For Italian participants, an anonymous attack was less threatening than for participants of other countries, whereas for German students anonymity caused more insecurity and fear. In addition, Italian adolescents were more perceptive of the criterion of intentionality. Finally, Estonian adolescents did not show strong differences in their factor scores compared to adolescents from the other countries.


Proximal Interphalangeal Joint Fractures.
Multiple fracture patterns can occur around the proximal interphalangeal joint and require surgeons to have a thorough understanding of the anatomy, clinical and radiographic examination, common fracture patterns, surgical and nonsurgical treatment options, and potential complications. Proximal phalangeal condylar fractures are typically managed surgically, because even nondisplaced fractures have a propensity for displacement. Middle phalangeal base fractures most commonly present as a volar lip fracture with or without dorsal subluxation or dislocation. Treatment options include extension block splinting or pinning, transarticular pinning, open reduction and internal fixation, external fixation, volar plate arthroplasty, and hemihamate arthroplasty. Less common fractures include dorsal lip fractures with or without volar subluxation or dislocation (the central slip fracture), lateral plateau impaction or avulsion injuries, and pilon fractures. The main goals in the management of middle phalangeal base fractures are to restore articular congruency and initial early range of motion, which are more important than obtaining an anatomic reduction.


Analysis of the effect of inapparent bovine paratuberculosis.
Inapparent paratuberculosis was studied in a Guernsey herd with a history of paratuberculosis (Johne's disease); the herd was maintained at between 900 and 950 cattle. Fecal specimens and intestinal tissue specimens from any of these that were slaughtered were examined culturally for the presence of Mycobacterium paratuberculosis. The reasons given for culling and slaughtering of cows from this herd were compared with infection status determined by culturing. Less than one-third of the culturally confirmed paratuberculous cattle were culled because of clinically apparent paratuberculosis. Mastitis was the reason for culling 3.6% of the non-infected cattle and 22.6% of the cattle with inapparent paratuberculosis. Infertility was also significantly higher in cows with inapparent paratuberculosis than in noninfected cows in the same herd. Separation of parturient dams and calves from the rest of the herd was shown to materially reduce the level of infection and incidence of clinical paratuberculosis.


Identification of stoichiometric and microstructural parameters of a lithium-ion cell with blend electrode.
The measurement of the active material volume fraction in composite electrodes of lithium-ion battery cells is difficult due to the small (sub-micrometer) and irregular structure and multi-component composition of the electrodes, particularly in the case of blend electrodes. State-of-the-art experimental methods such as focused ion beam/scanning electron microscopy (FIB/SEM) and subsequent image analysis require expensive equipment and significant expertise. We present here a simple method for identifying active material volume fractions in single-material and blend electrodes, based on the comparison of experimental equilibrium cell voltage curve (open-circuit voltage as function of charge throughput) with active material half-cell potential curves (half-cell potential as function of lithium stoichiometry). The method requires only (i) low-current cycling data of full cells, (ii) cell opening for measurement of electrode thickness and active electrode area, and (iii) literature half-cell potentials of the active materials. Mathematical optimization is used to identify volume fractions and lithium stoichiometry ranges in which the active materials are cycled. The method is particularly useful for model parameterization of either physicochemical (e.g., pseudo-two-dimensional) models or equivalent circuit models, as it yields a self-consistent set of stoichiometric and structural parameters. The method is demonstrated using a commercial LCO-NCA/graphite pouch cell with blend cathode, but can also be applied to other blends (e.g., graphite-silicon anode).


Factors Associated with Vaginal Lactobacillus Predominance Among African American Women Early in Pregnancy.
Background: Vaginal Lactobacillus is considered protective of some adverse reproductive health outcomes, including preterm birth. However, factors that increase or decrease the likelihood of harboring Lactobacillus in the vaginal microbiome remain largely unknown. In this study, we sought to identify risk and protective factors associated with vaginal Lactobacillus predominance within a cohort of pregnant African American women. Materials and Methods: Vaginal microbiome samples were self-collected by African American women (N = 436) during their 8-14th week of pregnancy. Sociodemographic information and measures of health behaviors, including substance use, antibiotic exposure, sexual practices, frequency of vaginal intercourse, and the use of vaginal products, were collected through participant self-report. The V3-V4 region of the 16S rRNA gene was targeted for amplification and sequencing using Illumina HiSeq, with bacterial taxonomy assigned using the PECAN classifier. Univariate and a series of multivariate logistic regression models identified factors predictive of diverse vaginal microbiota or Lactobacillus predominance. Results: Participants who used marijuana in the past 30 days (aOR 1.80, 95% CI 1.08-2.98) were more likely to have diverse non-Lactobacillus-predominant vaginal microbiota, as were women not living with their partners (aOR 1.90, 95% CI 1.20-3.01). Cohabitating or marijuana usage were not associated with type of Lactobacillus (non-iners Lactobacillus vs. Lactobacillus iners) predominance (aOR 1.11, 95% CI 0.52-2.38 and aOR 0.56, 95% CI 0.21-1.47, respectively). Conclusions: Living with a partner is conducive to vaginal Lactobacillus predominance. As such, cohabitation may be in important covariate to consider in vaginal microbiome studies.