Artificial Intelligence Classification of Central Visual Field Patterns in Glaucoma.
To quantify the central visual field (VF) loss patterns in glaucoma using artificial intelligence. Retrospective study. VFs of 8712 patients with 13 951 Humphrey 10-2 test results from 13 951 eyes for cross-sectional analyses, and 824 patients with at least 5 reliable 10-2 test results at 6-month intervals or more from 1191 eyes for longitudinal analyses. Total deviation values were used to determine the central VF patterns using the most recent 10-2 test results. A 24-2 VF within a 3-month window of the 10-2 tests was used to stage eyes into mild, moderate, or severe functional loss using the Hodapp-Anderson-Parrish scale at baseline. Archetypal analysis was applied to determine the central VF patterns. Cross-validation was performed to determine the optimal number of patterns. Stepwise regression was applied to select the optimal feature combination of global indices, average baseline decomposition coefficients from central VFs archetypes, and other factors to predict central VF mean deviation (MD) slope based on the Bayesian information criterion (BIC). The central VF patterns stratified by severity stage based on 24-2 test results and a model to predict the central VF MD change over time using baseline test results. From cross-sectional analysis, 17 distinct central VF patterns were determined for the 13 951 eyes across the spectrum of disease severity. These central VF patterns could be divided into isolated superior loss, isolated inferior loss, diffuse loss, and other loss patterns. Notably, 4 of the 5 patterns of diffuse VF loss preserved the less vulnerable inferotemporal zone, whereas they lost most of the remaining more vulnerable zone described by the Hood model. Inclusion of coefficients from central VF archetypical patterns strongly improved the prediction of central VF MD slope (BIC decrease, 35; BIC decrease of >6 indicating strong prediction improvement) than using only the global indices of 2 baseline VF results. Eyes with baseline VF results with more superonasal and inferonasal loss were more likely to show worsening MD over time. We quantified central VF patterns in glaucoma, which were used to improve the prediction of central VF worsening compared with using only global indices.


Nursing students' reasoning about two fictitious elderly patient cases.
The aim of this study was to examine and describe how nursing students developed their reasoning and knowledge about the state of health of, and their possible actions regarding, two fictitious elderly patient case histories during their three-year education. The descriptions were audiotaped, transcribed verbatim and analysed by content analysis. The findings show a development in the students' reasoning concerning the more acute case, but no development in reasoning regarding the case of a confused person. This could be due either to a lack of education in gerontology and geriatrics, or to the students receiving limited guidance during their education on how to reason about and reflect upon different ways of approaching emerging problems. The findings could also be understood in the light of traditions and history in nursing education.


Investigation of food microstructure and texture using atomic force microscopy: A review.
We review recent applications of atomic force microscopy (AFM) to characterize microstructural and textural properties of food materials. Based on interaction between probe and sample, AFM can image in three dimensions with nanoscale resolution especially in the vertical orientation. When the scanning probe is used as an indenter, mechanical features such as stiffness and elasticity can be analyzed. The linkage between structure and texture can thus be elucidated, providing the basis for many further future applications of AFM. Microstructure of simple systems such as polysaccharides, proteins, or lipids separately, as characterized by AFM, is discussed. Interaction of component mixtures gives rise to novel properties in complex food systems due to development of structure. AFM has been used to explore the morphological characteristics of such complexes and to investigate the effect of such characteristics on properties. Based on insights from such investigations, development of food products and manufacturing can be facilitated. Mechanical analysis is often carried out to evaluate the suitability of natural or artificial materials in food formulations. The textural properties of cellular tissues, food colloids, and biodegradable films can all be explored at nanometer scale, leading to the potential to connect texture to this fine structural level. More profound understanding of natural food materials will enable new classes of fabricated food products to be developed.


Coparalogy: physical and functional clusterings in the human genome.
Two rounds of large-scale duplications are thought to have occurred in early vertebrate ancestry; this is now known as the "2R hypothesis." They have led to the constitution of subfamilies of paralogous genes. Chromosomal regions that contain present-day paralogs (paralogous regions or paralogons) have been identified in mammals. We show that sets of paralogons (PGs) can be assembled in a tentative "human genome paralogy map" that includes all autosomes and X. A total of 14 PGs, containing more than 1600 genes, were assembled in this paralogy map. Genes that belong to the same PG are coparalogs. We show that identification of coparalogy can be used (i) to broaden data on gene mapping, (ii) to identify physical gene clusters that derive from early cis-duplications, and (iii) to speculate on coevolution and coregulation of genes sharing a common structure or function (functional clusters). Thus, coparalogy analyses should parallel phylogenetic analyses and can help draw hypotheses on gene and genome evolution.


Uptake of methylnaltrexone in Australian patients with opioid-induced constipation: a review of the number of prescriptions presented in the first 12 months of subsidisation.
Disturbed bowel habits are very common in palliative care patients, most commonly thought to be due to opioid use. The peripheral opioid-antagonist methylnaltrexone has been subsidised in Australia to ensure that palliative care patients have timely and equitable access to this medication. The aim of this paper is to describe the use of methylnaltrexone in the first year after it was subsidised for palliative care, in particular focusing on the actual use of this medication compared with predicted need. The predicted need for methylnaltrexone was calculated using an epidemiological approach based on data collected by the Australian Institute of Health and Welfare to determine the number of Australian deaths annually. A single source of data was used to determine the number of patients who die while under the care of palliative services in Australia (National Census of Palliative Care Services, 1999). These figures allowed the number of people likely to be receiving opioids to be estimated and therefore the number who could potentially benefit from methylnaltrexone. The number of patients who might benefit was calculated to be 5000, which contrasts with the 261 actual prescriptions written for methylnaltrexone. Even more striking was the disparity between initial prescriptions and the 93 requests for ongoing use. These data highlight much lower use of methylnaltrexone than predicted and raise a number of questions including the fact that the palliative care literature emphasises opioids as the dominant cause of constipation in palliative care patients given little ongoing use of methylnaltrexone.


Archaeal RecA homologues: different response to DNA-damaging agents in mesophilic and thermophilic Archaea.
Two archaeal proteins, RadA and RadB, share similarity with the RecA/Rad51 family of recombinases, with RadA being the functional homologue. We have studied and compared the RadA and RadB proteins of mesophilic and thermophilic Archaea. In growing cells, RadA levels are similar in mesophilic Methanococcus species and the hyperthermophile Methanococcus jannaschii. Treatment of cells with mutagenic agents (methylmethane sulfonate or UV light) increased the expression of RadA (as evidenced by higher levels of both mRNA and protein) in all organisms tested, but the increase was greater in the mesophiles than in the thermophiles M. jannaschii and Sulfolobus solfataricus. Recombinantly expressed RadA proteins from the mesophile M. voltae and the thermophile M. jannaschii were similar in their ATPase- and DNA-binding activities. All the data are consistent with proposals that RadA plays the same role as eukaryotic Rad51. Surprisingly, the data also suggested that the thermophiles do not need more RadA protein or activity than the mesophiles. On the other hand, RadB is not coregulated with RadA, and its role remains unclear. Neither RadA nor RadB from a mesophile or from a thermophile rescued the UV-sensitive phenotype of an Escherichia coli recA- host.


The effects of fasting on metabolism and performance.
An overnight fast of 8-10 h is normal for most people. Fasting is characterised by a coordinated set of metabolic changes designed to spare carbohydrate and increase reliance on fat as a substrate for energy supply. As well as sparing the limited endogenous carbohydrate, and increased rate of gluconeogenesis from amino acids, glycerol and ketone bodies help maintain the supply of carbohydrate. Many individuals undergo periodic fasts for health, religious or cultural reasons. Ramadan fasting, involving 1 month of abstention from food and fluid intake during daylight hours, is practised by a large part of the world population. This period involves a shift in the pattern of intake from daytime to the hours of darkness. There seems to be little effect on overall daily dietary intake and only small metabolic effects, but there may be implications for both physical and cognitive function. The limited evidence suggests that effects of Ramadan-style fasting on exercise performance are generally small. This needs to be balanced, however, against the observation that small differences in performance are critical in determining the outcomes of sporting events. Studies involving challenging sporting events (prolonged sustained or intermittent high-intensity events, hot and humid environments) are needed. Increases in subjective sensations of fatigue may be the result of loss of sleep or disruption of normal sleep patterns. Modifications to the competition timetable may minimise or even eliminate any effect on performance in sport, but there may be negative effects on performance in some events.


Earliest Mexican Turkeys (Meleagris gallopavo) in the Maya Region: implications for pre-Hispanic animal trade and the timing of turkey domestication.
Late Preclassic (300 BC-AD 100) turkey remains identified at the archaeological site of El Mirador (Petén, Guatemala) represent the earliest evidence of the Mexican turkey (Meleagris gallopavo) in the ancient Maya world. Archaeological, zooarchaeological, and ancient DNA evidence combine to confirm the identification and context. The natural pre-Hispanic range of the Mexican turkey does not extend south of central Mexico, making the species non-local to the Maya area where another species, the ocellated turkey (Meleagris ocellata), is indigenous. Prior to this discovery, the earliest evidence of M. gallopavo in the Maya area dated to approximately one thousand years later. The El Mirador specimens therefore represent previously unrecorded Preclassic exchange of animals from northern Mesoamerica to the Maya cultural region. As the earliest evidence of M. gallopavo found outside its natural geographic range, the El Mirador turkeys also represent the earliest indirect evidence for Mesoamerican turkey rearing or domestication. The presence of male, female and sub-adult turkeys, and reduced flight morphology further suggests that the El Mirador turkeys were raised in captivity. This supports an argument for the origins of turkey husbandry or at least captive rearing in the Preclassic.


The Impact of an Interprofessional Pediatric Oral Health Clerkship on Advancing Interprofessional Education Outcomes.
The aim of this study was to evaluate the effectiveness of an innovative pediatric interprofessional education clinical experience using oral-systemic health as the clinical population example for improving the self-reported interprofessional competencies of family nurse practitioner, dental, and medical students. The objectives of the interprofessional experience were for students to apply pediatric oral health assessment, identify the pediatric oral-systemic connection, and practice a team-based approach to improve oral-systemic outcomes. In spring 2015, fall 2015, and spring 2016, a total of 162 family nurse practitioner, dental, and medical students participated in this interprofessional experience at Bellevue Pediatric Outpatient Clinics together with a pediatric dental resident. Team members collaborated in reviewing the patient chart, taking the patient's medical and dental history, performing an oral assessment, applying fluoride varnish, and providing education and anticipatory guidance. The Interprofessional Collaborative Competency Attainment Survey (ICCAS) was used as a pretest and posttest to evaluate the degree to which students perceived changes in their attitudes about interprofessional competencies following the learning experience. In the results, all students had improved mean scores from pretest to posttest after the experience, and these changes were statistically significant for all students: nurse practitioner (p<0.01), dentistry (p<0.01), and medicine (p<0.001). The mean change from pretest to posttest was statistically significant for each of the six interprofessional competency domains (p<0.01). In both pediatric dental and primary care settings, the changes from pre- to posttest were significant (p<0.001). The experience was similarly effective for all groups of students in increasing their attitudes about interprofessional collaboration. These findings suggest that a clinical approach can be an effective strategy for helping health professions students develop interprofessional competence.


Cardiovascular Health Trajectories From Childhood Through Middle Age and Their Association With Subclinical Atherosclerosis.
Cross-sectional measures of cardiovascular health (CVH) have been associated with cardiovascular disease in older age, but little is known about longitudinal trajectories in CVH and their association with subclinical atherosclerosis in middle age. To model long-term patterns in CVH starting in childhood and to assess their association with subclinical atherosclerosis in middle age. This cohort study used data from 5 prospective cardiovascular cohort studies from the United States and Finland from 1973 to 2015. A total of 9388 participants aged 8 to 55 years had at least 3 examinations and were eligible for this study. Statistical analysis was performed from December 1, 2015, to June 1, 2019. Clinical CVH factors (body mass index, total cholesterol level, blood pressure, and glucose level) were classified as ideal, intermediate, or poor, and were summed as a clinical CVH score. Group-based latent class modeling identified trajectories in this score over time. Carotid intima-media thickness (cIMT) was measured for participants in 3 cohorts, and high cIMT was defined as a value at or above the 90th percentile. The association between CVH trajectory and cIMT was modeled using both linear and logistic regression adjusted for demographics, baseline health behaviors, and baseline (or proximal) CVH score. Among 9388 participants (5146 [55%] female; 6228 [66%] white; baseline mean [SD] age, 17.5 [7.5] years), 5 distinct trajectory groups were identified: high-late decline (1518 participants [16%]), high-moderate decline (2403 [26%]), high-early decline (3066 [32%]), intermediate-late decline (1475 [16%]), and intermediate-early decline (926 [10%]). The high-late decline group had significantly lower adjusted cIMT vs other trajectory groups (high-late decline: 0.64 mm [95% CI, 0.63-0.65 mm] vs intermediate-early decline: 0.72 mm [95% CI, 0.69-0.75 mm] when adjusted for demographics and baseline smoking, diet, and physical activity; P < .01). The intermediate-early declining group had higher odds of high cIMT (odds ratio, 2.4; 95% CI, 1.3-4.5) compared with the high-late decline group, even after adjustment for baseline or proximal CVH score. In this study, CVH declined from childhood into adulthood. Promoting and preserving ideal CVH from early life onward may be associated with reduced CVD risk later in life.


Bacteraemia coincides with low citrulline concentrations after high-dose melphalan in autologous HSCT recipients.
Mucosal damage to the intestines induced by myeloablative conditioning for allogeneic PBSC transplant (PBSCT) can be determined by the concentration of citrulline, which is a functional marker of small intestinal enterocytes. Low citrulline concentrations in blood coincide with and are a response to severe mucosal barrier injury. We treated 29 patients with high-dose melphalan 200 mg/m(2) (Mel-200) to prepare for an autologous PBSCT and collected plasma samples from each patient starting before the myeloablative regimen and three times per week thereafter until discharge. The baseline citrulline concentration was 27.6 mM+/-4.0 (mean+/-95% confidence interval; CI), and citrulline concentrations declined rapidly thereafter reaching a nadir averaging 6.7 mM+/-2.7, 12 days after starting Mel-200. Citrulline concentrations, only increased gradually and were still low (12 mM+/-4) at discharge. A total of 20 patients developed fever, which was associated with bacteraemia in 10 cases. Their mean citrulline concentrations were lower at 5.5 mM+/-1.5 than were those of patients without bacteraemia (10.2 mM+/-3.9). Importantly, neither the number of preceding neutropenic days nor the mean C-reactive protein (CRP) concentration at the onset of fever was different between these two groups. In conclusion, citrulline concentrations rapidly decline after Mel-200 reflecting intestinal mucosal barrier injury. Low citrulline, rather than the duration of neutropenia, is associated with bacteraemia indicating the importance of an intact mucosal barrier in neutropenic patients.


Treating nonalcoholic fatty liver disease in patients with type 2 diabetes mellitus: a review of efficacy and safety.
To review current literature for the efficacy and safety of treatment for nonalcoholic fatty liver disease (NAFLD) in patients with type 2 diabetes mellitus (T2DM). A PubMed literature search from January 1990 to June 2017 was conducted using the search terms nonalcoholic fatty liver disease, diabetes mellitus, type 2, therapy, treatment, treat, therapeutics, nonalcoholic fatty liver, nonalcoholic hepatosteatosis, NASH, NAFLD, metformin, and statin. Bibliographies of chosen articles were reviewed. Relevant articles on metformin, thiazolidinediones (TZD), glucagon-like peptide-1 receptor agonists (GLP-1 RA), and statins for the treatment of NAFLD which included patients with T2DM were reviewed. A total of 23 relevant studies were found and included randomized controlled, observational, and open-label designs, as well as three meta-analyses. Metformin combined with weight loss provides a modest improvement in steatosis and no improvement in fibrosis in patients with NAFLD and T2DM. TZDs showed positive results on fibrosis and resolution of NASH but at least half of patients studied were nonresponders. GLP-1 RAs also showed favorable results on reductions in transaminases and steatosis and improvements in insulin sensitivity and weight loss but lack efficacy data for resolution of NASH or improvement in fibrosis scores. Statins showed favorable results on reductions in transaminases but mixed results for improvement in steatosis and fibrosis scores. All reviewed treatment options are safe for management of NAFLD in patients with T2DM but long-term histological improvements are minimal. TZDs are efficacious for resolution of NASH and improvements in fibrosis but long-term use is required to maintain these results.


Regulation of apoptosis by the p8/prothymosin alpha complex.
p8 is a small-stress protein involved in several cellular functions including apoptosis. To identify its putative partners, we screened a HeLa cDNA library by using the two-hybrid technique and found that p8 binds the antiapoptotic protein prothymosin alpha (ProTalpha). Fluorescence spectroscopy, circular dichroism, and NMR spectroscopy showed that p8 and ProTalpha formed a complex. Binding resulted in important changes in the secondary and tertiary structures of the proteins. Because p8 and ProTalpha form a complex, they could act in concert to regulate the apoptotic cascade. We induced apoptosis in HeLa cells by staurosporine treatment and monitored the effects of knocking down p8 and/or ProTalpha or overexpressing p8 and/or ProTalpha on caspase 3/7 and 9 activities and on cell death. Transfecting ProTalpha or p8 small interfering RNAs increased the activities of both caspases and the number of apoptotic nuclei. However, transfecting both small interfering RNAs resulted in no further increase. Overexpressing p8 or ProTalpha did not alter caspase activities, whereas overexpressing both resulted in a significant reduction of caspase activities. These results strongly suggest that the antiapoptotic response of HeLa cells upon staurosporine treatment requires expression of both p8 and ProTalpha.


Exploring the Ovarian Reserve Within Health Parameters: A Latent Class Analysis.
The process of ovarian aging is influenced by a complex and poorly understood interplay of endocrine, metabolic, and environmental factors. The purpose of this study was to explore the feasibility of using latent class analysis to identify subgroups based on cardiometabolic, psychological, and reproductive parameters of health and to describe patterns of anti-Müllerian hormone levels, a biomarker of the ovarian reserve, within these subgroups. Sixty-nine lean (body mass index [BMI] ⩽ 25 kg/m2) and severely obese (BMI ⩾ 40 kg/m2) postpartum women in Edinburgh, Scotland, were included in this exploratory study. The best fitting model included three classes: Class 1, n = 23 (33.5%); Class 2, n = 30 (42.2%); Class 3, n = 16 (24.3%). Postpartum women with lower ovarian reserve had less favorable cardiometabolic and psychological profiles. Examining the ovarian reserve within distinct subgroups based on parameters of health that affect ovarian aging may facilitate risk stratification in the context of ovarian aging.


Short- and long-term outcomes of combined cardiac and renal transplantation with allografts from a single donor.
Coexisting end-stage heart and kidney failure can be treated by combined cardiac and renal transplantation. This study reviews the short- and long-term outcomes after such a procedure over a 16-year period at a single institution. All patients who underwent single-donor simultaneous heart and kidney transplantation during the period of March 1986 to April 2002 (including heart retransplantation) were included (n = 13). They were listed for combined heart and kidney transplantation as they fulfilled our criteria for irreversible end-stage organ failure. Retrospective review of patient data from the transplant database, patient case notes and post-mortem reports were carried out. The mean (SD) recipient age was 45 (12) years and there were 2 females. The mean pre-operative creatinine level was 724 (415) micromol/liter with 9 patients (69.2%) on continuous ambulatory peritoneal dialysis and 2 patients (15.4%) on hemodialysis prior to transplantation. The 30-day mortality rate was 15.4% (2 of 13). For surviving patients the mean creatinine level at hospital discharge was 158 (93) micromol/liter. The mean number of acute cardiac rejection episodes per 100 patient-days was significantly lower (p = 0.01) than that for the heart-only transplant group (n = 760) during the same period. The median (interquartile range) post-operative survival was 1,969 (620 to 3,468) days. The actuarial survival rates (95% confidence interval) at 1 and 10 years were 77% (54% to 100%) and 67% (40% to 94%), respectively, and were not significantly different from the isolated heart transplant population (p = 0.68). Only 1 episode of acute renal rejection was diagnosed on clinical grounds, which was treated accordingly. There was no renal allograft loss in the long-term survivors. Combined cardiac and renal transplantation with allografts from the same donor has acceptable short- and long-term outcomes for patients with coexisting end-stage cardiac and renal failure. This group of patients may also experience fewer acute rejection episodes post-operatively.


Effects of the harvesting technique and external stenting on progression of vein graft disease 2 years after coronary artery bypass.
In a post hoc analysis of the VEST III trial, we investigated the effect of the harvesting technique on saphenous vein graft (SVG) patency and disease progression after coronary artery bypass grafting. Angiographic outcomes were assessed in 183 patients undergoing open (126 patients, 252 SVG) or endoscopic harvesting (57 patients, 114 SVG). Overall SVG patency was assessed by computed tomography angiography at 6 months and by coronary angiography at 2 years. Fitzgibbon patency (FP I, II and III) and intimal hyperplasia (IH) in a patient subset were assessed by coronary angiography and intravascular ultrasound, respectively, at 2 years. Baseline characteristics were similar between patients who underwent open and those who underwent endoscopic harvesting. Open compared with endoscopic harvesting was associated with higher overall SVG patency rates at 6 months (92.9% vs 80.4%, P = 0.04) and 2 years (90.8% vs 73.9%, P = 0.01), improved FP I, II and III rates (65.2% vs 49.2%; 25.3% vs 45.9%, and 9.5% vs 4.9%, respectively; odds ratio 2.81, P = 0.09) and reduced IH area (-31.8%; P = 0.04) and thickness (-28.9%; P = 0.04). External stenting was associated with improved FP I, II and III rates (odds ratio 2.84, P = 0.01), reduced IH area (-19.5%; P < 0.001) and thickness (-25.0%; P < 0.001) in the open-harvest group and reduced IH area (-12.7%; P = 0.01) and thickness (-9.5%; P = 0.21) in the endoscopic-harvest group. A post-hoc analysis of the VEST III trial showed that open harvesting is associated with improved overall SVG patency and reduced IH. External stenting reduces SVG disease progression, particularly with open harvesting.


Applications for approval to market a new drug; complete response letter; amendments to unapproved applications. Final rule.
The Food and Drug Administration (FDA) is amending its regulations on new drug applications (NDAs) and abbreviated new drug applications (ANDAs) for approval to market new drugs and generic drugs (drugs for which approval is sought in an ANDA). The final rule discontinues FDA's use of approvable letters and not approvable letters when taking action on marketing applications. Instead, we will send applicants a complete response letter to indicate that the review cycle for an application is complete and that the application is not ready for approval. We are also revising the regulations on extending the review cycle due to the submission of an amendment to an unapproved application and starting a new review cycle after the resubmission of an application following receipt of a complete response letter. In addition, we are adding to the regulations on biologics license applications (BLAs) provisions on the issuance of complete response letters to BLA applicants. We are taking these actions to implement the user fee performance goals referenced in the Prescription Drug User Fee Amendments of 2002 (PDUFA III) that address procedures and establish target timeframes for reviewing human drug applications.


Analysis of the Yeast Peptidome and Comparison with the Human Peptidome.
Peptides function as signaling molecules in species as diverse as humans and yeast. Mass spectrometry-based peptidomics techniques provide a relatively unbiased method to assess the peptidome of biological samples. In the present study, we used a quantitative peptidomic technique to characterize the peptidome of the yeast Saccharomyces cerevisiae and compare it to the peptidomes of mammalian cell lines and tissues. Altogether, 297 yeast peptides derived from 75 proteins were identified. The yeast peptides are similar to those of the human peptidome in average size and amino acid composition. Inhibition of proteasome activity with either bortezomib or epoxomicin led to decreased levels of some yeast peptides, suggesting that these peptides are generated by the proteasome. Approximately 30% of the yeast peptides correspond to the N- or C-terminus of the protein; the human peptidome is also highly represented in N- or C-terminal protein fragments. Most yeast and humans peptides are derived from a subset of abundant proteins, many with functions involving cellular metabolism or protein synthesis and folding. Of the 75 yeast proteins that give rise to peptides, 24 have orthologs that give rise to human and/or mouse peptides and for some, the same region of the proteins are found in the human, mouse, and yeast peptidomes. Taken together, these results support the hypothesis that intracellular peptides may have specific and conserved biological functions.


Human leukocyte antigen E contributes to protect tumor cells from lysis by natural killer cells.
The nonclassic class I human leukocyte antigen E (HLA-E) molecule engages the inhibitory NKG2A receptor on several cytotoxic effectors, including natural killer (NK) cells. Its tissue distribution was claimed to be wider in normal than in neoplastic tissues, and surface HLA-E was undetectable in most tumor cell lines. Herein, these issues were reinvestigated taking advantage of HLA-E-specific antibodies, immunohistochemistry, and biochemical methods detecting intracellular and surface HLA-E regardless of conformation. Contrary to published evidence, HLA-E was detected in a few normal epithelia and in a large fraction (approximately 1/3) of solid tumors, including those derived from HLA-E-negative/low-normal counterparts. Remarkably, HLA-E was detected in 30 of 30 tumor cell lines representative of major lymphoid and nonlymphoid lineages, and in 11 of 11, it was surface-expressed, although in a conformation poorly reactive with commonly used antibodies. Coexpression of HLA-E and HLA class I ligand donors was not required for surface expression but was associated with NKG2A-mediated protection from lysis by the cytotoxic cell line NKL and polyclonal NK cells from healthy donors, as demonstrated by antibody-mediated relief of protection in 10% to 20% of the tested target-effector combinations. NKG2A-mediated protection of additional targets became evident on NK effector blocking with antibodies to activating receptors (DNAM-1, natural cytotoxicity receptors, and NKG2D). Thus, initial evidence that the long-elusive HLA-E molecule is enhanced by malignant transformation and is functional in tumor cells is presented here, although its importance and precise functional role remain to be addressed in the context of a general understanding of the NK ligand-receptor network.


Obesity and Weight Loss Attempts among Subjects with a Personal History of Cancer.
Obesity is a risk factor for many cancers and obese cancer patients have a poorer prognosis. This study aimed to evaluate the prevalence of obesity and attempts to lose weight among cancer survivors. The effects of cancer treatment and time since cancer treatment were also evaluated. The 2007 Health Information National Trends Survey data were analysed between 2011 and 2013; respondents with (n = 966) and without (n = 6,093) a personal history of cancer were identified. Each respondent's body mass index (BMI) was calculated using self-reported height and weight measurements and categorised as normal (<25 kg/m(2)), overweight (25-29.9 kg/m(2)) or obese (≥30 kg/m(2)). Cancer survivors were older (mean age = 63.4 versus 44.7 years for those with no history of cancer). Overall, there were similar percentages of overweight (37.6% versus 34.1%; relative risk ratio [RRR] = 0.99; 95% confidence interval [CI]: 0.75-1.31) and obese (31.4% versus 27.5%; RRR = 1.04; 95% CI: 0.79 1.39) respondents among both cancer survivors and those without a history of cancer. Among overweight and obese participants, cancer survivors did not demonstrate increased weight loss attempts compared to those without a history of cancer (61.6% versus 66.3%; odds ratio = 0.94; 95% CI: 0.73 1.20). A high prevalence of overweight and obese cancer survivors were identified without any association with cancer treatment. However, cancer survivors did not demonstrate increased attempts to lose weight in comparison to those without a history of cancer despite awareness of their degree of body fatness. Increased efforts to promote the maintenance of a healthy weight among cancer survivors are needed.


Acute methionine loading does not alter arterial stiffness in humans.
Hyperhomocystinemia is a risk factor for cardiovascular disease, and acute elevation of plasma homocysteine after methionine loading impairs endothelial function in healthy subjects. Interestingly, pretreatment with vitamin C can ameliorate this effect. We have already shown that acute oral vitamin C administration reduces arterial stiffness in healthy subjects, and the aim of the present study was to investigate the effect of methionine loading on arterial stiffness with and without concomitant vitamin C using the noninvasive technique of pulse wave analysis. Eight healthy male subjects (mean age, 29 years; range, 20-42 years) were studied on three occasions at weekly intervals. In a double-blind, double-dummy, randomized order they received orally either 100 mg/kg methionine, 100 mg/kg methionine plus 2 g of vitamin C, or matching placebos. Peripheral and central blood pressure, heart rate, cardiac index, arterial stiffness, and plasma homocysteine levels were assessed at baseline and 6 hours after dosing. Compared with placebo, there was no significant change in any of the hemodynamic parameters, including arterial stiffness, after oral methionine, although plasma homocysteine did increase from 11.5 +/- 1.6 to 28.7 +/- 4.4 microM (mean +/- SEM; p < 0.001). Combined methionine and vitamin C led to a similar increase in plasma homocysteine but significantly reduced augmentation index by 10.5 +/- 3.2% (p = 0.02). Acute hyperhomocystinemia does not significantly alter arterial stiffness, as assessed by pulse wave analysis, whereas a combination of methionine and vitamin C leads to a similar reduction in augmentation index to that previously described after vitamin C alone. These data reinforce evidence that vitamin C reduces arterial stiffness but do not indicate any important interaction with oral methionine.


Etidronate for treating and preventing postmenopausal osteoporosis.
To systematically review the efficacy of etidronate on bone density, fractures and toxicity in postmenopausal women. We searched MEDLINE from 1966 to December 1998, examined citations of relevant articles, and the proceedings of international osteoporosis meetings. We contacted osteoporosis investigators to identify additional studies, primary authors, and pharmaceutical industry sources for unpublished data. We included thirteen trials (with 1010 participants) that randomized women to etidronate or an alternative (placebo or calcium and/or vitamin D) and measured bone density for at least one year. For each trial, three independent reviewers assessed the methodological quality and abstracted data. The data suggested a reduction in vertebral fractures with a pooled relative risk of 0.60% (95% CI 0.41 to 0.88). There was no effect on non-vertebral fractures (pooled relative risk 1.00, (95% CI 0.68 to 1.42)). Etidronate, relative to control, increased bone density after three years of treatment in the lumbar spine by 4.27% (95% CI 2.66 to 5.88), in the femoral neck by 2.19% (95% CI 0.43, 3.95) and in the total body by 0.97% (95% CI 0.39, 1.55). Effects were larger at 4 years, though the number of patients followed was much smaller. Etidronate increases bone density in the lumbar spine and femoral neck. The pooled estimates of fracture reduction with etidronate are consistent with a reduction in vertebral fractures, but no effect on non-vertebral fractures.


Static and Dynamic Predictors of Foot Progression Angle in Individuals with and without Diabetes Mellitus and Peripheral Neuropathy.
Foot progression angle (FPA) is a predictor of elevated regional plantar stresses and loads, which are indicators of dermal injury risk in individuals with diabetes mellitus and peripheral neuropathy (DMPN). FPA accounts for 15-45% of the variance in plantar stresses and loads in adults with DMPN. However, the biomechanical factors underlying an "out-toeing" gait pattern in this clinical population have not been examined. The primary purpose of this study was to identify static and dynamic predictors of foot progression angle magnitude in adults with and without DMPN. Thirty-three adults with and 12 adults without diabetes mellitus participated. Hip rotation, ankle dorsiflexion, and resting calcaneal stance position were measured using a standard goniometer. Kinematic and kinetic data were collected during walking. Static predictor variables did not significantly predict foot progression angle magnitude using multiple regression analysis. Of the dynamic predictor variables, thigh and shank lateral rotation accounted for 37% of foot progression angle variance (p<.01). Our results show that dynamic measures of external rotation of proximal segments (thigh, shank) during gait are strong predictors of foot progression angle. Static measures of limited joint mobility and joint position do not predict foot progression angle. These findings suggest that targeting the thigh and shank rotation using verbal or tactile cueing may be a potential strategy when trying to alter walking movement patterns towards decreasing external (lateral) FPA to minimize risk of elevated regional plantar stresses in adults with DMPN at risk for ulceration.


Readiness of critical care physicians and nurses to handle requests for organ donation.
Critical care nurses and physicians usually care for those patients whose condition progresses to brain death and are also often responsible for requesting organ donation from the family of a brain-dead patient. We hypothesized that staff support, knowledge, and training levels would be significantly associated with organ donation rates. To assess the readiness of critical care staff to successfully handle requests for organ donation. A total of 1061 critical care staff from 28 hospitals in four separate regions of the United States completed a questionnaire that assessed (1) factual knowledge about organ donation, (2) understanding of brain death, (3) previous training in procedures for requesting donations, and (4) comfort levels with the donation process. Staff training in effective procedures for requesting organ donations was significantly correlated with hospitals' donation rates. Less than a third of respondents, however, had received training in explaining brain death to and requesting organ donation from a grieving family. In hospitals with high rates of organ donation, 52.9% of staff had received training; in hospitals with low rates of organ donation, 23.5% of staff had received training. Levels of factual knowledge about organ donation and brain death were unexpectedly low but were not significantly related to hospitals' rates of organ donation. Training of critical care nurses and physicians in effective procedures for requesting organ donation is significantly associated with higher rates of organ donation, yet two thirds of critical care staff report no relevant training. Consequently, critical care staff cannot be considered ready to effectively handle requests for organ donation.


Regulations governing veterinary medicinal products containing genetically modified organisms in the European community.
This paper describes particular aspects of the marketing of veterinary medicinal products (VMPs) that contain or consist of genetically modified micro-organisms (GMMs) or genetically modified organisms (GMOs). The regulatory requirements and the procedures applied in the European Union for each phase (pre-marketing, authorisation process, and post-authorisation labelling and monitoring) are explained. In most cases VMPs are subject to both pharmaceutical and GMO regulations. In the early stages of the process, before applications for marketing authorisation are submitted, the assessment of clinical trials and experiments in contained areas is principally the responsibility of national authorities. However, the marketing of all VMPs containing or consisting of GMOs must be authorised at European level, although the national authorities are informed and involved in the assessment process.


Selective phosphorylation of cytosol proteins associated with transformation and restoration of normal phenotype in AKR mouse embryo fibroblasts.
Phosphoproteins from cytosol preparations of methylcholanthrene-transformed AKR mouse (AKR-MCA) cells were compared to those of their untransformed counterparts, AKR-2B cells, by two-dimensional electrophoresis following an in vitro 32P phosphorylation procedure using endogenous kinases and substrates. Five proteins were phosphorylated in the AKR-MCA cells which were not observed in the AKR-2B cells, while six proteins were phosphorylated in the untransformed cells which were not observed in the malignant cells. Treatment of AKR-MCA cells with 1% N,N-dimethylformamide induced the reversion of the malignant cells to a phenotype similar to that of untransformed AKR-2B cells (S. Chakrabarty et al., Cancer Res., 44: 2181, 1984). Treatment of AKR-MCA cells with dimethyl formamide resulted in the restoration of five of the AKR-2B-associated phosphorylations and abolished 2 of the AKR-MCA-associated phosphorylations. AKR-2B cells have been shown to respond to transforming growth factors with reversible phenotypic transformation (R. F. Tucker et al., Cancer Res., 43: 1581, 1983). Transforming growth factor treatment of AKR-2B cells induced all five of the AKR-MCA-associated phosphoproteins and the loss of all six of the AKR-2B phosphoproteins. Epidermal growth factor treatment of AKR-2B cells resulted in the phosphorylation of several proteins which were not observed in either AKR-MCA or untreated AKR-2B cells. Some, but not all, of the AKR-2B-associated phosphorylations were also observed in epidermal growth factor-treated cells. The results of these studies demonstrated qualitative and/or quantitative changes in cytosolic protein kinase-phosphatase activities between transformed and normal AKR-2B cells. Treatment of AKR-MCA cells with dimethylformamide resulted in the restoration of some of the normal AKR-2B cell-associated protein kinase-phosphatase activities.


The key informant method: a novel means of ascertaining blind children in Bangladesh.
Most information on the causes of blindness has come from examining children in special education. To obtain a more representative population-based sample of children, a novel method was developed for ascertaining severe visually impaired (SVI) or blind (BL) children by training local volunteers to act as key informants (KIs). To compare the demography and cause of blindness in children recruited by KIs with other ascertainment methods. Children with SVI/BL were recruited in all 64 districts of Bangladesh. Three sources for case ascertainment were utilised: schools for the blind (SpEdu), community-based rehabilitation (CBR) programmes and KIs. All data were recorded using the standard WHO/PBL Eye Examination Record. 1935 children were recruited. Approximately 800 KIs were trained. The majority of the children were recruited by the KIs (64.3%). Children recruited by KIs were more likely to be female (odds ratio (OR) 1.6, p<0.001), of pre-school age (OR 14.1, p<0.001), from rural areas (OR 5.9, p<0.001), be multiply impaired (OR 3.1, p = 0.005) and be suffering from treatable eye diseases (OR 1.3, p = 0.005) when compared with those in SpEdu. Overall a child with an avoidable causes of SVI/BL had 40% (adjusted CI 1.1 to 1.7, p = 0.015) and 30% (CI 1.0 to 1.7, p = 0.033) higher odds of being ascertained using the KIs compared with SpEdu and CBR methods, respectively. Using this innovative approach has resulted in one of the largest studies of SVI/BL children to date. The findings indicate that KIs can recruit large numbers of children quickly, and that the children they recruit are more likely to be representative of all blind children in the community.


Overcoming the challenges of caring for a child with foetal alcohol spectrum disorder: a Pilbara community perspective.
Introduction Foetal alcohol spectrum disorder (FASD) is a neurodevelopmental impairment that may result in individuals experiencing poor development, cognitive issues and disruptive behaviours. In Australia, the prevalence of FASD is unknown; however, two studies have revealed the prevalence of FASD in high risk populations in Western Australia. Individuals with FASD may experience higher rates of negative outcomes including poor school performance, involvement with the justice system and incarceration, substance use and are at risk of being placed in out-of-home care. Caregivers of children with FASD can experience challenges and high levels of stress due to the disruptive behaviours displayed by many children diagnosed with FASD. Whilst experiences of caregivers raising children with FASD have been documented globally, little is known about the experiences of caregivers in a remote Australian context, particularly from an Australian Aboriginal perspective. This study aimed to investigate the experiences of caregivers in a remote Australian context. The findings will be valuable to inform programs at the family, community and broader policy levels that can help enhance children's development and wellbeing. Participants (n=7) in this qualitative study were recruited through a FASD diagnostic clinic and family support organisation in the Port Hedland region of Western Australia. Eligible participants were previous or current caregivers of children with a FASD diagnosis or risk of FASD and provided informed consent before participating in semi-structured interviews using a phenomenological approach. The interviews were 30-60 minutes in duration and were audio-recorded and transcribed verbatim using NVivo 11 computer software, with all identifying information removed. The caregivers provided rich, descriptive narratives revealing the challenges and stress they experienced when they first started caring for their child with FASD. Caregivers articulated how they developed and adapted strategies through trial and error that enabled them to better manage disruptive behaviours and maintain a stable, calm environment. A thematic analysis revealed four major themes: the importance of routine and structure for the child and family, the importance of family support, the benefits of peer support groups and various social issues impacting children's development. Maintaining routine and structure had helped many caregivers mitigate stress and reduce disruptive behaviours, and family support allowed caregivers some respite whilst ensuring children remained connected to their biological families and culture. The caregivers also shared that peer support groups would be beneficial to share stories and strategies with others experiencing similar circumstances. Broader societal issues requiring attention at the community level were discussed, in addition to caregivers having awareness of the complexities impacting the children's biological families. The caregivers in this study have gained valuable knowledge and wisdom through caring for a child with FASD that can benefit health professionals and the broader community. Whilst the caregivers in this study have overcome challenges through developing and adapting their own strategies, support services providing tailored programs for caregivers when they first start caring for a child with FASD would be beneficial. Furthermore, formal respite was not utilised by the caregivers in this study due to safety issues, inconsistent parenting and interrupted routines, therefore investigation into training respite caregivers in the area of FASD would be beneficial. Furthermore, respite services should consider provisions to include extended families and kinship relationships in a formal context to enable ongoing cultural and family connection, consistent parenting strategies and routines.


Dendritic cells initiate a two-stage mechanism for T lymphocyte proliferation.
T cells oxidized with sodium periodate proliferate polyclonally in response to accessory cells. We confirmed previous work showing that DC are potent stimulators of this response. In addition, the accessory function of unfractionated mouse spleen and spleen adherent cells was markedly reduced after elimination of DC with a specific monoclonal antibody and complement. Therefore oxidative mitogenesis was used as a model to study the mechanism by which DC stimulate T cell proliferative responses. A two-stage mechanism was identified. The first stage occurred during the first 20 h of culture, required live DC, and involved the progressive release of interleukin 2 (IL-2) into the medium and acquisition of responsiveness to this growth factor. The second stage occurred between 20 and 40 h, did not require live DC, and involved DNA synthesis in response to IL-2. Similar events occurred during culture of DC with unmodified T cells (syngeneic MLR) but were quantitatively reduced. The experimental approach was to co-culture DC and T cells for up to 20 h and then kill the DC with specific antibody, or anti-Ia antibody, and complement. Subsequent proliferation was inhibited if the T cells were cultured in fresh medium. However, proliferation was restored when the lymphocytes were cultured in the original DC-T cell medium, or with a crude or a purified preparation of IL-2. IL-2 did not induce the proliferation of T cells that had been cultured in the absence of DC, and did not synergize with viable DC. We conclude that DC induce proliferation by tightly coordinating the release of, and responsiveness to, T cell growth factor or IL-2.


The choice of alternative 5' splice sites in influenza virus M1 mRNA is regulated by the viral polymerase complex.
The influenza virus M1 mRNA has two alternative 5' splice sites: a distal 5' splice site producing mRNA3 that has the coding potential for 9 amino acids and a proximal 5' splice site producing M2 mRNA encoding the essential M2 ion-channel protein. Only mRNA3 was made in uninfected cells transfected with DNA expressing M1 mRNA. Similarly, using nuclear extracts from uninfected cells, in vitro splicing of M1 mRNA yielded only mRNA3. Only when the mRNA3 5' splice site was inactivated by mutation was M2 mRNA made in uninfected cells and in uninfected cell extracts. In influenza virus-infected cells, M2 mRNA was made, but only after a delay, suggesting that newly synthesized viral gene product(s) were needed to activate the M2 5' splice site. We present strong evidence that these gene products are the complex of the three polymerase proteins, the same complex that functions in the transcription and replication of the viral genome. Gel shift experiments showed that the viral polymerase complex bound to the 5' end of the viral M1 mRNA in a sequence-specific and cap-dependent manner. During in vitro splicing catalyzed by uninfected cell extracts, the binding of the viral polymerase complex blocked the mRNA3 5' splice site, resulting in the switch to the M2 mRNA 5' splice site and the production of M2 mRNA.


SU-E-J-35: A Model for the Simulation of EPID Measurements in the BeamNRC Monte Carlo Package.
The intent of this study was to create a virtual model of a simple Electronic Portal Image Device (EPID) in the BeamNRC Monte Carlo package which would simulate EPID measurements taken in vivo. A typical accelerator was created in the BeamNRC software using published 6MV spectra from Mohan, et. al. and the basic head design of a Varian accelerator head. The particle fluence at the level of the mylar window was output into a planar 'phase space' file. The output of this accelerator was delivered to a phantom with a 1 mm thick slab of water acting as the detector array using the DosXYZ package. Additionally, the fluence from the same geometry was computed at the level of the virtualEPID (vEPID). The simulations were run for 2×2, 5×5, 10×10, 20×20, and 25×25 field sizes, as well as a simple IMRT field. The results of the open field simulations were then used for the parameterization of a deconvolution kernel using the form described by Renner, et. al. The simulations were run with sufficient histories to produce a 1% uncertainty in the resulting fluence and dose matrices in the high dose/fluence region of the output. Additional software was created to convert 'phase space' files to fluence in the same grid as the vEPID. A final software package was written to iteratively determine the exponential fitting parameters described in Ritter, et. al. to deconvolve the detector function from the fluence measurements. The system will allow one to simulate both EPID measurements, as well as remove the detector function from vEPIDsimulations for further use in fluence studies using BeamNRC. This will allow one to simulate a system for in vivo patient measurements using an EPID to study without the need for time on a medical accelerator, and without contributing additional radiation fatigue to the EPID device.


Cyclin D1 Restrains Oncogene-Induced Autophagy by Regulating the AMPK-LKB1 Signaling Axis.
Autophagy activated after DNA damage or other stresses mitigates cellular damage by removing damaged proteins, lipids, and organelles. Activation of the master metabolic kinase AMPK enhances autophagy. Here we report that cyclin D1 restrains autophagy by modulating the activation of AMPK. In cell models of human breast cancer or in a cyclin D1-deficient model, we observed a cyclin D1-mediated reduction in AMPK activation. Mechanistic investigations showed that cyclin D1 inhibited mitochondrial function, promoted glycolysis, and reduced activation of AMPK (pT172), possibly through a mechanism that involves cyclin D1-Cdk4/Cdk6 phosphorylation of LKB1. Our findings suggest how AMPK activation by cyclin D1 may couple cell proliferation to energy homeostasis. Cancer Res; 77(13); 3391-405. ©2017 AACR.


Electromyography of the thigh muscles during lifting tasks in kneeling and squatting postures.
Underground coal miners who work in low-seam mines frequently handle materials in kneeling or squatting postures. To assess quadriceps and hamstring muscle demands in these postures, nine participants performed lateral load transfers in kneeling and squatting postures, during which electromyographic (EMG) data were collected. EMG activity was obtained at five points throughout the transfer for three quadriceps muscles and two hamstring muscles from each thigh. ANOVA results indicated that EMG data for nine of 10 thigh muscles were affected by an interaction between posture and angular position of the load lifted (p < 0.001). Muscles of the right thigh were most active during the lifting portion of the task (lifting a block from the participant's right) and activity decreased as the block was transferred to the left. Left thigh muscles showed the opposite pattern. EMG activity for the majority of thigh muscles was affected by the size of the base of support provided by different postures, with lower EMG activity observed with a larger base of support and increased activity in postures where base of support was reduced (p < 0.05). Thigh EMG activity was lowest in postures with fully flexed knees, which may explain worker preference for this posture. However, such postures are also associated with increased risk of meniscal damage. STATEMENT OF RELEVANCE: Kneeling and squatting postures are sometimes used for manual lifting activities, but are associated with increased knee injury risk. This paper examines the EMG responses of knee extensors/flexors to lifting in these postures, discusses the impact of posture and kneepads on muscle recruitment and explores the implications for work in such postures.


Effect of elevated ambient temperature on sleep, EEG spectra, and brain temperature in the rat.
To examine the relationship between sleep and brain temperature in the rat, the vigilance states, spectral power density of the electroencephalogram (EEG), hypothalamic temperature (T(hy)), and cortical temperature (Tcr) were recorded for 3 days. A 1-day rise of ambient temperature from 23 to 30 degrees C did not affect the percentage of waking, non-rapid eye movement sleep (NREMS), and rapid eye movement sleep (REMS), but increased EEG slow-wave activity in NREMS in the 12-h dark period. T(hy) was invariably higher than Tcr, but at 30 degrees C the difference diminished because of a rise in Tcr. In contrast to Tcr, T(hy) was only slightly increased at 30 degrees C and only during sleep and in the dark period. Although the temperatures changed largely in parallel at vigilance state transitions, Tcr rose more rapidly than T(hy) at NREMS-REMS transitions and more slowly at NREMS-waking transitions. T(hy) declined more rapidly than Tcr at waking-NREMS transitions and more slowly at REMS-NREMS transitions. The results are consistent with a central role of the hypothalamus in the activation and deactivation of the waking state.


Cellular basis of steroid neuroprotection in the wobbler mouse, a genetic model of motoneuron disease.
1. The Wobbler mouse suffers an autosomal recessive mutation producing severe motoneuron degeneration and astrogliosis in the spinal cord. It has been considered a suitable model of human motoneuron disease, including the sporadic form of amyotrophic lateral sclerosis (ALS). 2. Evidences exist demonstrating increased oxidative stress in the spinal cord of Wobbler mice, whereas antioxidant therapy delayed neurodegeneration and improved muscle trophism. 21-Aminosteroids are glucocorticoid-derived hydrophobic compounds with antioxidant potency 3 times higher than vitamin E and 100 times higher than methylprednisolone. They do not bind to intracellular receptors, and prevent lipid peroxidation by insertion into membrane lipid bilayers. 3. In common with the spinal cord of ALS patients, Wobbler mice present astrocytosis with hyperexpression of glial fibrillary acidic protein (GFAP), and increased expression of nitric oxide synthase (NOS) and growth-associated protein (GAP-43) in motoneurons. Here, we review our studies on the effects of a 21-aminosteroid on GFAP, NOS, and GAP-43. 4. First, we showed that 21-aminosteroid treatment further increased GFAP-expressing astrocytes in gray matter of the Wobbler spinal cord. This effect may provide neuroprotection if one considers a trophic and beneficial function of astrocytes during the course of degeneration. Other neuroprotectans used in Wobbler mice (T-588) also increased pre-existing astrocytosis. 5. Second, histochemical determination of NADPH-diaphorase, a parameter indicative of neuronal NOS activity, showed that the 21-aminosteroid down-regulated the high activity of this enzyme in ventral horn motoneurons. Therefore, suppression of nitric oxide by decreasing NADPH-diaphorase (NOS) activity may provide neuroprotection considering that excess NO is highly toxic to motoneurons. 6. Finally, 21-aminosteroid treatment significantly attenuated the aberrant expression of both GAP-43 protein and mRNA in Wobbler motoneurons. Hyperexpression of GAP-43 possibly indicated abnormal synaptogenesis, denervation, and muscle atrophy, parameters which may return to normal following antioxidant steroid treatment. 7. Besides 21-aminosteroids, other steroids also behave as neuroprotectans. In this regard, degenerative diseases may constitute potential targets of these hormones, based on the fact that the spinal cord expresses in a regional and cell-specific fashion, receptors for androgens. progesterone, adrenal steroids, and estrogens.


Evolution of transanal total mesorectal excision according to the IDEAL framework.
Tremendous innovations have taken place in surgical procedures, but contrary to drug development, this process has been unregulated in the past. IDEAL promotes a structured framework for the safe implementation and assessment of a new surgical technique or intervention, by describing five stages for evaluating and reporting of innovations: Idea, Development, Exploration, Assessment and Long term. Transanal total mesorectal excision (TaTME) is a relatively new technique in rectal cancer surgery that has attracted huge interest and increasing adoption worldwide. This review article aims to provide an overview of the evolution of TaTME, according to the IDEAL framework, which guides us in the difficult yet exciting process of surgical innovation.


Preliminary observations of genetic susceptibility of elk (Cervus elaphus nelsoni) to chronic wasting disease by experimental oral inoculation.
To compare the genetic susceptibility of elk (Cervus elaphus nelsoni) with various alleles of the PRNP gene, which encodes the normal cellular prion protein, to chronic wasting disease (CWD), eight 8-month-old elk calves of 3 genotypes (2 132MM, 2 132LM, and 4 132LL) were orally dosed with CWD-infected brain material from elk. During postinoculation (PI) month 23, both 132MM elk had lost appetite, developed clinical signs of weight loss and central nervous system (CNS) dysfunction, and were euthanized. Two other elk (both 132LM) developed similar clinical signs of disease and were euthanized during PI month 40. All 4 affected elk had microscopic lesions of spongiform encephalopathy (SE), and PrPres, the disease-associated form of the prion protein, was detected in their CNS and lymphoid tissues by use of immunohistochemical (IHC) and Western blot (WB) techniques. These findings indicate that elk with MM and LM at codon 132 are susceptible to orally inoculated CWD. All 4 LL elk are alive at PI year 4 and are clinically normal, which suggests that 132LL elk may have reduced susceptibility to oral infection with CWD-infected material or may have prolonged incubation time.


All-trans retinoic acid (ATRA) downregulates MMP-9 by modulating its regulatory molecules.
The vitamin A derivative all-trans retinoic acid (ATRA) is considered as a potent chemotherapeutic drug for its capability of regulating cell growth and differentiation. We aimed to study the effect of ATRA on MMP-9 in MDA-MB-231, human breast cancer cells and the probable molecular mechanisms through which ATRA exerts its effect. Our experimental findings demonstrate that ATRA enters into the nucleus and regulates various signaling pathways viz. Integrin, FAK, ERK, PI-3K, NF-κB and also EGFR and down regulates pro-MMP-9 activity as well as its expression. As a result MDA-MB-231 cell migration on fibronectin medium gets retarded in presence of ATRA. ATRA up regulates TIMP-1 expression. Our study may help to understand the role of ATRA as a regulator of MMP-9 and the possible signaling pathways which are involved in this ATRA mediated down regulation of MMP-9.


Cyclometalated Pt(ii) complexes with a bidentate Schiff-base ligand displaying unexpected cis/trans isomerism: synthesis, structures and electronic properties.
Square planar platinum complexes are an important class of compounds used in (nano)technology, optoelectronics, medicinal chemistry and catalysis. The major research interests in cyclometalated Pt(ii) complexes focus on the selective modulation of their electronic properties and the control of the (cis/trans) geometry. For the first time, we unveil and demonstrate that cis-trans isomers of Pt(ii) complexes can be obtained in a derivative carrying the 1-phenyl-pirazolate (Hppz) and 2-hydroxy-1-naphtyl-(N-phenyl)imine ligands. The two isomers display significant differences in both optical and electronic properties. While luminescence is quenched in solution, they are brightly emissive in the PMMA matrix at room temperature and in the 2MeTHF rigid matrix at 77 K. The phosphorescent emission of the cis isomer, blue-shifted compared to that of the trans one, results from the significantly different trans influence of the ppz ligand. Theoretical investigation highlights the almost isoenergetic potential energy of the two isomers therefore explaining their formation and evidences a large geometry distortion of their triplet state, which should be responsible for the observed luminescence efficiency.


Intraguild interactions between two egg parasitoids of a true bug in semi-field and field conditions.
Research on interspecific competitive interactions among insect parasitoids has often been characterized by laboratory studies in which host insects are exposed to female parasitoids of different species in various sequences and combinations. In the last years, an increasing number of studies have investigated interspecific interactions under field and semi-field conditions although just a few number of works focused on egg parasitoids. In this work, we undertook a two-year study to investigate interspecific interactions between Trissolcus basalis (Wollaston) (Hymenoptera: Platygastridae) and Ooencyrtus telenomicida (Vassiliev) (Hymenoptera: Encyrtidae), two egg parasitoids of the pest Nezara viridula (L.) (Heteroptera: Pentatomidae) that co-occur in cultivated crops. Under semi-field (in out-door mesh cages) and field conditions, we investigated: 1) the seasonal occurrence of competing parasitoid species on sentinel egg masses; 2) the impact achieved by competing species on the shared host on naturally laid egg masses; 3) the outcome of intraguild interactions under controlled conditions. Results from sentinel egg masses showed that T. basalis occurs in May and successfully parasitizes hosts until the end of September/beginning of October, whereas O. telenomicida is mainly occurring in July-August. In both years, it was found that T. basalis is predominant. From naturally laid egg masses, results indicated that T. basalis achieves higher impact on the hosts, even in those egg masses which are parasitized by more than one female of different species ( = multiparasitism). Results from manipulating intraguild interactions showed that T. basalis achieves higher impact on N. viridula when released alone, but it suffers from competition with O. telenomicida. The ecological factors that play a role in intraguild interactions in the context of biological control perspective are discussed.


The health of Canada's Aboriginal children: results from the First Nations and Inuit Regional Health Survey.
Reports on child health in Canada often refer to the disproportionate burden of poor health experienced by Aboriginal children and youth, yet little national data are available. This paper describes the health of First Nations and Inuit children and youth based on the First Nations and Inuit Regional Health Survey (FNIRHS). The FNIRHS combines data from 9 regional surveys conducted in 1996-1997 in Aboriginal reserve communities in all provinces. The target population consisted of all on-reserve communities. All households or a random sample of households or adults (depending on province) were selected based on their population representation. One child was randomly selected from each participating household, except in Ontario and Nova Scotia, where children were randomly selected based upon their population representation. Alberta did not include the section on children's health in their regional survey. Approximately 84% of adults, who were proxy respondents for their child, rated their children's health as very good or excellent. The most frequently reported conditions were ear problems (15%), followed by allergies (13%) and asthma (12%). Broken bones or fractures were the most frequently reported injuries (13%). Respondents reported that 17% of children had behavioural or emotional problems. Overall, 76% of children were reported to get along with the family "very well" or "quite well." While most respondents rated their child's health as very good or excellent, injuries, emotional and behavioural problems, respiratory conditions and ear problems were reported among many Aboriginal children. Issues such as substance abuse, exposure to violence and academic performance were not addressed in the 10 core survey questions. Clearly there is a need for more in-depth information about both the physical and emotional health of Aboriginal children and youth.


Oregano demonstrates distinct tumour-suppressive effects in the breast carcinoma model.
There has been a considerable interest in the identification of natural plant foods for developing effective agents against cancer. Thus, the anti-tumour effects of oregano in the in vivo and in vitro breast cancer model were evaluated. Lyophilized oregano (ORE) was administered at two concentrations of 0.3 and 3 % through diet. The experiment was terminated 14 weeks after carcinogen administration. At autopsy, mammary tumours were removed and prepared for histopathological and immunohistochemical analysis. Moreover, in vitro evaluation in MCF-7 cells was carried out. Low-dose ORE suppressed tumour frequency by 55.5 %, tumour incidence by 44 %, and tumour volume by 44.5 % compared to control animals. Analysis of rat tumour cells showed Ki67, VEGFR-2, CD24, and EpCAM expression decrease and caspase-3 expression increase after low-dose ORE treatment. High-dose ORE lengthened tumour latency by 12.5 days; moreover, Bcl-2, VEGFR-2, CD24, and EpCAM expression decrease and caspase-3 expression increase in carcinoma cells were observed. Histopathological analysis revealed a decrease in the ratio of high-/low-grade carcinomas in both treated groups. In vitro studies showed that ORE decreased survival and proliferation of MCF-7 cells. In ORE-treated MCF-7 cells, an increase in cells expressing sub-G 0/G 1 DNA content and an increase in the percentage of annexin V/PI positive MCF-7 cells were observed. In vitro, both caspase-dependent and possible non-caspase-dependent apoptotic pathways were found. The deactivation of anti-apoptotic activity of Bcl-2, a decrease in mitochondrial membrane potential, and the activation of mitochondrial apoptosis pathway were observed in the ORE-treated MCF-7 cells. Our results demonstrate, for the first time, a distinct tumour-suppressive effect of oregano in the breast cancer model.


The development of bactericidal yeast strains by expressing the Pediococcus acidilactici pediocin gene (pedA) in Saccharomyces cerevisiae.
The excessive use of sulphur dioxide and other chemical preservatives in wine, beer and other fermented food and beverage products to prevent the growth of unwanted microbes holds various disadvantages for the quality of the end-products and is confronted by mounting consumer resistance. The objective of this study was to investigate the feasibility of controlling spoilage bacteria during yeast-based fermentations by engineering bactericidal strains of Saccharomyces cerevisiae. To test this novel concept, we have successfully expressed a bacteriocin gene in yeast. The pediocin operon of Pediococcus acidilactici PAC1.0 consists of four clustered genes, namely pedA (encoding a 62 amino acid precursor of the PA-1 pediocin), pedB (encoding an immunity factor), pedC (encoding a PA-1 transport protein) and pedD (encoding a protein involved in the transport and processing of PA-1). The pedA gene was inserted into a yeast expression/secretion cassette and introduced as a multicopy episomal plasmid into a laboratory strain (Y294) of S. cerevisiae. Northern blot analysis confirmed that the pedA structural gene in this construct (ADH1P-MFa1S-pedA-ADH1T, designated PED1), was efficiently expressed under the control of the yeast alcohol dehydrogenase I gene promoter (ADH1P) and terminator (ADH1T). Secretion of the PED1-encoded pediocin PA-1 was directed by the yeast mating pheromone alpha-factor's secretion signal (MFa1S). The presence of biologically active antimicrobial peptides produced by the yeast transformants was indicated by agar diffusion assays against sensitive indicator bacteria (e.g. Listeria monocytogenes B73). Protein analysis indicated the secreted heterologous peptide to be approximately 4.6 kDa, which conforms to the expected size. The heterologous peptide was present at relatively low levels in the yeast supernatant but pediocin activity was readily detected when intact yeast colonies were used in sensitive strain overlays. This study could lead to the development of bactericidal yeast strains where S. cerevisiae starter cultures not only conduct the fermentations in the wine, brewing and baking industries but also act as biological control agents to inhibit the growth of spoilage bacteria.


A Comparison Study of Validity Indices on Swarm-Intelligence-Based Clustering.
Swarm intelligence has emerged as a worthwhile class of clustering methods due to its convenient implementation, parallel capability, ability to avoid local minima, and other advantages. In such applications, clustering validity indices usually operate as fitness functions to evaluate the qualities of the obtained clusters. However, as the validity indices are usually data dependent and are designed to address certain types of data, the selection of different indices as the fitness functions may critically affect cluster quality. Here, we compare the performances of eight well-known and widely used clustering validity indices, namely, the Caliński-Harabasz index, the CS index, the Davies-Bouldin index, the Dunn index with two of its generalized versions, the I index, and the silhouette statistic index, on both synthetic and real data sets in the framework of differential-evolution-particle-swarm-optimization (DEPSO)-based clustering. DEPSO is a hybrid evolutionary algorithm of the stochastic optimization approach (differential evolution) and the swarm intelligence method (particle swarm optimization) that further increases the search capability and achieves higher flexibility in exploring the problem space. According to the experimental results, we find that the silhouette statistic index stands out in most of the data sets that we examined. Meanwhile, we suggest that users reach their conclusions not just based on only one index, but after considering the results of several indices to achieve reliable clustering structures.


Psychiatric comorbidity in patients with chest pain without a cardiac etiology.
Throughout the world and among different cultural groups, physical symptoms are the most common expressions of social problems and distress; chest pain is one of the most widely seen, medically unexplained physical symptoms. Most of the time, chest pain cases in which an organic etiology cannot be determined over time and in those presenting with atypical features should be evaluated as a component or an accompanying symptom of various specific psychiatric disorders, primarily such as panic disorder and depression. The aim of this study was to determine the psychiatric comorbidity rate in patients with chest pain without a cardiac etiology. Seventy patients admitted to the cardiology clinic with a complaint of chest pain but without any detectable cardiac etiology were included in the study. All patients were evaluated using a Sociodemographic Data Collection Form and Structured Clinical Interview for DSM-IV. Panic disorder was diagnosed in 47.1% of the non-cardiac chest pain group, depressive disorders in 21.4%, generalized anxiety disorder in 5.7%, anxiety disorders not otherwise specified in 5.7%, obsessive compulsive disorder in 5.7%, and undifferentiated somatoform disorder in 2.9%. Two psychiatric diagnoses were established in 12.9% of the patients and no psychiatric diagnosis in 24.3%. Psychiatric disorder rates are quite high in patients with chest pain that cannot be explained cardiologically. These results show the importance of psychiatric evaluations in patients with non-cardiac chest pain or unexplained chest pain (UCP). In addition, understanding the psychiatric symptom profile of these patients will make an important contribution to the treatment of non-cardiac chest pain.


Skin cancer in Puerto Rico: a multiannual incidence comparative study.
The incidence of skin cancer continues to increase worldwide. The purpose of this study was to determine the incidence of skin cancer in Puerto Rico in a selected year (2005) and to compare these findings with those previously reported for Puerto Rico in 1974 and 1981 and with other countries. The data was collected from the pathology reports corresponding to the period of January to December 2005 of 21 participating Pathology Laboratories throughout Puerto Rico. The rate and distribution of the main types of skin cancer was calculated based on sex, age, anatomic location and laterality. The incidence of skin cancer in Puerto Rico for 2005 was 6,568 cases, which represent a rate of 167.9 per 100,000 inhabitants. The most common type of skin cancer was basal-cell carcinoma. Skin cancer was more common in males except for melanoma, which was more common in females. The incidence increases with age on all types of skin cancer. The head and neck area was the most frequent location, except for melanoma in women, which was more common on the legs. The incidence rate was 41.5/100,000 in 1974, 52.5/100,000 in 1981 and 167.9/100,000 in 2005, a 305% increase. We found an increasing incidence of skin cancer in Puerto Rico when compared with previous reported data. This analysis provides a comprehensive evaluation of the epidemiology of skin cancer in Puerto Rico.


Insights into the electric double-layer capacitance of two-dimensional electrically conductive metal-organic frameworks.
Two-dimensional electrically conductive metal-organic frameworks (MOFs) have emerged as promising model electrodes for use in electric double-layer capacitors (EDLCs). However, a number of fundamental questions about the behaviour of this class of materials in EDLCs remain unanswered, including the effect of the identity of the metal node and organic linker molecule on capacitive performance, and the limitations of current conductive MOFs in these devices relative to traditional activated carbon electrode materials. Herein, we address both these questions via a detailed study of the capacitive performance of the framework Cu3(HHTP)2 (HHTP = 2,3,6,7,10,11-hexahydroxytriphenylene) with an acetonitrile-based electrolyte, finding a specific capacitance of 110-114 F g-1 at current densities of 0.04-0.05 A g-1 and a modest rate capability. By directly comparing its performance with the previously reported analogue, Ni3(HITP)2 (HITP = 2,3,6,7,10,11-hexaiminotriphenylene), we illustrate that capacitive performance is largely independent of the identity of the metal node and organic linker molecule in these nearly isostructural MOFs. Importantly, this result suggests that EDLC performance in general is uniquely defined by the 3D structure of the electrodes and the electrolyte, a significant finding not demonstrated using traditional electrode materials. Finally, we probe the limitations of Cu3(HHTP)2 in EDLCs, finding a limited stable double-layer voltage window of 1 V and only a modest capacitance retention of 81% over 30 000 cycles, both significantly lower than state-of-the-art porous carbons. These important insights will aid the design of future conductive MOFs with greater EDLC performances.


Generic formulation of Cyclosporine A, Equoral®, in de novo kidney transplant recipients: five-year follow-up.
Equoral(®) is a generic formulation of Cyclosporine A (CsA), which is significantly cheaper than the original medicine. Our center participated in the clinical trial designed to evaluate the efficacy and safety of Equoral(®) in kidney transplant recipients in the first 9 months after a transplant procedure. The aim of our paper is to present the 5-year follow-up of patients who participated in the study and were monitored in our center. We performed intention-to-treat retrospective analysis of 20 de novo kidney transplant recipients who received Equoral®-based immunosuppressive regimen and were monitored in our department for 5 years after transplantation. The 5-year patient and graft survival was 90%, and the frequency of acute rejection was 15%. In 80% of patients, the initial immunosuppressive regimen had to be changed. In our group of kidney transplant recipients, immunosuppression based on generic formulation of CsA had excellent 5-year patient and graft survival and effectively prevented acute rejection episodes. However, most patients needed modification of the initially administered immunosuppressive regimen.


Acute herpes hepatitis in pregnancy.
A 36 year old primigravid woman presented with a "flu-like" illness and premature labour, followed by severe pneumonitis and hepatitis in the late second trimester of pregnancy. Progressive deterioration obliged an elective delivery of twins, stillborn at 25 weeks of gestation. Herpes virus isolated from one placenta, but not from any fetal tissue, was the only indication of a systemic herpes simplex infection in which there were no mucocutaneous lesions seen before or during the illness. There was no history of herpes simplex infection and antibody studies were not helpful initially for a diagnosis that was confirmed in retrospect. Double staining for viral DNA and antigen showed that the virus was present in host monocytes.


Modulation of Nogo receptor 1 expression orchestrates myelin-associated infiltration of glioblastoma.
As the clinical failure of glioblastoma treatment is attributed by multiple components, including myelin-associated infiltration, assessment of the molecular mechanisms underlying such process and identification of the infiltrating cells have been the primary objectives in glioblastoma research. Here, we adopted radiogenomic analysis to screen for functionally relevant genes that orchestrate the process of glioma cell infiltration through myelin and promote glioblastoma aggressiveness. The receptor of the Nogo ligand (NgR1) was selected as the top candidate through Differentially Expressed Genes (DEG) and Gene Ontology (GO) enrichment analysis. Gain and loss of function studies on NgR1 elucidated its underlying molecular importance in suppressing myelin-associated infiltration in vitro and in vivo. The migratory ability of glioblastoma cells on myelin is reversibly modulated by NgR1 during differentiation and dedifferentiation process through deubiquitinating activity of USP1, which inhibits the degradation of ID1 to downregulate NgR1 expression. Furthermore, pimozide, a well-known antipsychotic drug, upregulates NgR1 by post-translational targeting of USP1, which sensitizes glioma stem cells to myelin inhibition and suppresses myelin-associated infiltration in vivo. In primary human glioblastoma, downregulation of NgR1 expression is associated with highly infiltrative characteristics and poor survival. Together, our findings reveal that loss of NgR1 drives myelin-associated infiltration of glioblastoma and suggest that novel therapeutic strategies aimed at reactivating expression of NgR1 will improve the clinical outcome of glioblastoma patients.


The Role of Ames Dwarfism and Calorie Restriction on Gut Microbiota.
The gut microbiome (GM) represents a large and very complex ecosystem of different microorganisms. There is an extensive interest in the potential role of the GM in different diseases including cancer, diabetes, cardiovascular diseases, and aging. The GM changes over the lifespan and is strongly associated with various age-related diseases. Ames dwarf (df/df) mice are characterized by an extended life- and healthspan, and although these mice are protected from many age-related diseases, their microbiome has not been studied. To determine the role of microbiota on longevity animal models, we investigated the changes in the GM of df/df and normal control (N) mice, by comparing parents before mating and littermate mice at three distinct time points during early life. Furthermore, we studied the effects of a 6-month calorie restriction (CR), the most powerful intervention extending the lifespan. Our data revealed significant changes of the GM composition during early life development, and we detected differences in the abundance of some bacteria between df/df and N mice, already in early life. Overall, the variability of the microbiota by genotype, time-point, and breeding pair showed significant differences. In addition, CR caused significant changes in microbiome according to gastrointestinal (GI) location (distal colon, ileum, and cecum), genotype, and diet. However, the overall impact of the genotype was more prominent than that of the CR. In conclusion, our findings suggest that the gut microbiota plays an important role during postnatal development in long-living df/df mice and CR dietary regimen can significantly modulate the GM.


Reliability of Accelerometer Scores for Measuring Sedentary and Physical Activity Behaviors in Persons With Multiple Sclerosis.
This brief research note examined the reliability of scores from an accelerometer as measures of sedentary and physical activity behaviors in persons with multiple sclerosis (MS). The analysis was performed on a combined data set from 2 previous longitudinal investigations of physical activity in MS. We focused on the number of days required to reliably estimate sedentary behavior, based on time spent in sedentary behavior per day and number of sedentary breaks, number of long sedentary bouts, and average length of sedentary bouts per day. We further examined the number of days required to reliably estimate physical activity behavior, based on time spent in light and moderate-to-vigorous physical activity and average length of activity bouts per day. Between 4-6 days of monitoring and 3-7 days of monitoring were necessary for good reliability of scores from all sedentary outcomes and physical activity outcomes, respectively. These results should guide research and practice examining sedentary and physical activity behaviors using accelerometry in persons with MS.


Retrograde ejaculation following single-level anterior lumbar surgery with or without recombinant human bone morphogenetic protein-2 in 5 randomized controlled trials: clinical article.
The aim of this study was to determine the incidence and assess specific risk factors in the postoperative development of retrograde ejaculation (RE) in men treated for degenerative lumbar disc disease at the L4-5 or L5-S1 level with stand-alone anterior interbody implants with or without recombinant human bone morphogenetic protein-2 (rhBMP-2). Patients enrolled in 5 prospective, randomized, multicenter FDA-approved investigational device exemption studies were observed for a minimum of 2 years to assess the rate of RE. Five hundred eight men with symptomatic single-level lumbar degenerative disc disease with up to Grade 1 spondylolisthesis underwent anterior lumbar interbody surgery with stand-alone anterior implants at either L4-5 or L5-S1. All patient self-reported and physician-documented adverse events were recorded over the entire course of follow-up. In the investigational groups, 207 patients were treated with an open surgical procedure using dual paired constructs and rhBMP-2 on an absorbable collagen sponge. The control groups (n = 301) were treated with lumbar fusion cage implants and iliac crest autograft or a metal-on-metal disc arthroplasty device. Multivariate analyses of RE were performed to assess the influence of treatment (rhBMP-2), surgical approach, and treated level. Data were analyzed for each trial individually and for the data pooled from the 5 trials. Retrograde ejaculation occurred at the highest rates in the earliest clinical trial. Of the 146 men, 6 (4.1%) developed RE postoperatively. In subsequent studies, the rates of RE ranged from 0% to 2.1%. Combining the data from the 5 trials, RE was reported in 7 (3.4%) of the 207 patients who received the rhBMP-2 treatment compared with 5 (1.7%) of the 301 patients who received the autograft or lumbar disc treatment (p = 0.242, Fisher exact test). Cases of RE were reported in 7 (1.6%) of 445 patients who underwent a retroperitoneal spinal exposure; 5 RE cases were reported in 58 patients (8.6%) who underwent a transperitoneal approach. The difference in surgical approaches was significant (p = 0.007, Fisher exact test). There was no difference in the rate of RE based on the lumbar level exposed (p = 0.739). Multivariate analyses were consistent with the conclusions from Fisher exact tests. In the initial rhBMP-2 trial, after adjusting for effects of surgical approach and treated level, the difference in RE between the treatment groups (rhBMP-2 vs autograft or disc arthroplasty) was not significant (p = 0.177); however, the difference in RE between the retroperitoneal and transperitoneal approaches was significant (p = 0.029). In these 5 prospective randomized trials involving anterior lumbar interbody surgery, the use of rhBMP-2 was associated with a higher incidence of RE (3.4% vs 1.7%) but did not reach statistical significance. Based on surgical approach, the difference in rates of RE was statistically significant. This study reports on the outcomes of 5 prospective randomized FDA-approved investigational device exemption trials. Registration for studies became law in 2007. Four of these trials were completed before the law went into effect. The registration number for the lumbar disc arthroplasty trial is NCT00635843.


Low-Hysteresis and Ultrasensitive Microcellular Structures for Wearable Electronic Applications.
Wearable technologies offer the opportunity to record human physiological signals in real time, in a noninvasive way, and the data can be used to aid in the early detection of abnormal health conditions. Here, we demonstrate how the interconnected porosity can be used to increase the sensitivity and linearity of capacitive pressure sensors. The finite element analysis supports the experimental observation that the movement of air during the dynamic mechanical loading is responsible for the high sensitivity observed (0.18 ± 0.01 kPa-1) when compared with the solid poly(glycerol sebacate) sensor (0.0042 ± 0.0002 kPa-1). The porous sensors present strain insensitivity and remarkable linearity over the entire range of applied mechanical pressure (0-6 kPa), capable of detecting both static and dynamic mechanical stimuli (17 nm/s), and a response time of 50 ms, without evidence of fatigue or electrical hysteresis over 10,000 mechanical cycles. The outstanding features of the porous sensors can find a broad range of applications in real-time health monitoring, from demanding movements like walking/running, to small deformations resulting from breathing or heart beating. The ultrasensitive microcellular structures synthesized in this study can be applied to other types of sensing transductions to obtain tunable and function-specific sensors with high sensitivity.


A Percutaneous Knotless Technique for Acute Achilles Tendon Ruptures.
Achilles tendon ruptures are a common tendon injury, usually occurring in middle-aged men during recreational sporting activities. Both nonoperative and operative management are employed to treat these injuries. Several operative treatments are described in the literature, including percutaneous Achilles repair, mini-open repair, and open repair. Open Achilles repair is associated with higher rates of impaired wound healing and infection, whereas minimally invasive techniques have been reported to have an increased risk of iatrogenic sural nerve injury. More recently, low complication rates, improved cosmetic appearance, reduced operating times, and improved clinical outcomes have been reported for the percutaneous Achilles repair technique. In this Technical Note, we present our preferred technique using the Percutaneous Achilles Repair System (Arthrex, Naples, FL), which has been reported to have minimal wound and nerve complications, and early return to activity.


After 50 years, a personal reflection on the development of internal thoracic artery (ITA) grafting.
It has been 50 years since the first publications of evidence that internal thoracic artery (ITA) grafts successfully bypassed obstructions of coronary arteries in dogs and in humans. The evidence consisted of in vivo measurements of blood flow through the grafts and selective angiograms of the grafts months following operation. It may be of interest to recount how that success came about.


Linking perceptual learning with identical stimuli to imagery perceptual learning.
Perceptual learning is usually thought to be exclusively driven by the stimuli presented during training (and the underlying synaptic learning rules). In some way, we are slaves of our visual experiences. However, learning can occur even when no stimuli are presented at all. For example, Gabor contrast detection improves when only a blank screen is presented and observers are asked to imagine Gabor patches. Likewise, performance improves when observers are asked to imagine the nonexisting central line of a bisection stimulus to be offset either to the right or left. Hence, performance can improve without stimulus presentation. As shown in the auditory domain, performance can also improve when the very same stimulus is presented in all learning trials and observers were asked to discriminate differences which do not exist (observers were not told about the set up). Classic models of perceptual learning cannot handle these situations since they need proper stimulus presentation, i.e., variance in the stimuli, such as a left versus right offset in the bisection stimulus. Here, we show that perceptual learning with identical stimuli occurs in the visual domain, too. Second, we linked the two paradigms by telling observers that only the very same bisection stimulus was presented in all trials and asked them to imagine the central line to be offset either to the left or right. As in imagery learning, performance improved.


Long non-coding RNA Meg3 deficiency impairs glucose homeostasis and insulin signaling by inducing cellular senescence of hepatic endothelium in obesity.
Obesity-induced insulin resistance is a risk factor for diabetes and cardiovascular disease. However, the mechanisms underlying endothelial senescence in obesity, and how it impacts obesity-induced insulin resistance remain incompletely understood. In this study, transcriptome analysis revealed that the long non-coding RNA (lncRNA) Maternally expressed gene 3 (Meg3) is one of the top differentially expressed lncRNAs in the vascular endothelium in diet-induced obese mice. Meg3 knockdown induces cellular senescence of endothelial cells characterized by increased senescence-associated β-galactosidase activity, increased levels of endogenous superoxide, impaired mitochondrial structure and function, and impaired autophagy. Moreover, Meg3 knockdown causes cellular senescence of hepatic endothelium in diet-induced obese mice. Furthermore, Meg3 expression is elevated in human nonalcoholic fatty livers and nonalcoholic steatohepatitis livers, which positively correlates with the expression of CDKN2A encoding p16, an important hallmark of cellular senescence. Meg3 knockdown potentiates obesity-induced insulin resistance and impairs glucose homeostasis. Insulin signaling is reduced by Meg3 knockdown in the liver and, to a lesser extent, in the skeletal muscle, but not in the visceral fat of obese mice. We found that the attenuation of cellular senescence of hepatic endothelium by ablating p53 expression in vascular endothelium can restore impaired glucose homeostasis and insulin signaling in obesity. In conclusion, our data demonstrate that cellular senescence of hepatic endothelium promotes obesity-induced insulin resistance, which is tightly regulated by the expression of Meg3. Our results suggest that manipulation of Meg3 expression may represent a novel approach to managing obesity-associated hepatic endothelial senescence and insulin resistance.


Chromatin hyperacetylation abrogates vitamin D-mediated transcriptional upregulation of the tissue-specific osteocalcin gene in vivo.
Cells expressing the bone-specific osteocalcin (OC) gene exhibit two DNase I hypersensitive sites within the proximal (nt -170 to -70) and distal (nt -600 to -400) promoter. These sites overlap elements that independently or in combination contribute to basal and vitamin D-stimulated OC gene transcription. Here we address mechanisms that participate in control of chromatin remodelling at these sites. By applying nuclease digestion and indirect end-labeling or by combining intranuclear footprinting and ligation-mediated PCR, we investigated the effects of nuclear protein hyperacetylation on both chromatin organization and transcriptional activation of the OC gene in bone-derived cells. We report that chromatin hyperacetylation blocks vitamin D stimulation of OC transcription and prevents a key transition in the chromatin structure of the OC gene which is required for formation of the distal DNase I hypersensitive site. This transition involves interaction of sequence-specific nuclear factors and may be required for the ligand-dependent binding of the vitamin D receptor complex, which results in transcriptional enhancement.