[Ischemic heart disease and arterial hypertention as risk factors of surgical treatment of patients with infrarenal segment of aortic aneurysm].
A retrospective analysis of the data of 188 patients with the infrarenal segment of the aortic aneurysm (ISAA) showed, that ischemic heart disease and arterial hypertension were diagnosed practically in all patients--175 (93.0%) and 177 (94.1%) patients respectively. A decreased retractor function of the myocardium was noted in 88 (46.8%) of patients. According to the findings of echocardiography 134 (71.3%) patients had the arterial hypertension of third degree. For the assessment of the influence of the accompanying cardiac pathology on the results of planned surgical treatment and systematization of postoperative cardiac complications the classification, which was proposed by R. B. Rutherford et al. and modified by A. V. Pokrovsky et al. was used. The obtained data point at a direct proportional relationship between the degree of the initial cardiac status, frequency and severity of postoperative cardiac complications in patients after resection of ISAA in 1.6-2.3 times.


How should preoperative examinations be chosen for infants with a ventricular septal defect: transthoracic echocardiography, cardiac CTA, or a combination of these two technologies?
To evaluate the accuracy of transthoracic echocardiography (TTE) and cardiac computed tomography angiography (CTA) in detecting the size and location of ventricular septal defects (VSD) in infants. Data from 258 infants diagnosed with VSD between January 2020 and December 2022 were retrospectively analyzed. All infants underwent both TTE and cardiac CTA. The accuracy of these imaging modalities was assessed by comparing their findings with intraoperative observations of VSD size and location. Intraoperatively, the average VSD size was 6.1 ± 2.5 mm. The defects were classified as committed VSD (Type 1) in 45 patients, noncommitted VSD (Type 2) in 198 patients, inlet VSD (Type 3) in 12 patients, and muscular VSD (Type 4) in 3 patients. Echocardiography estimated the average VSD size at 5.6 ± 2.7 mm, with 42 patients identified as Type 1, 203 as Type 2, 10 as Type 3, and 3 as Type 4. Cardiac CTA estimated the average size at 5.9 ± 3.2 mm, with 48 patients identified as Type 1, 196 as Type 2, 11 as Type 3, and 3 as Type 4. The accuracy rates of TTE and cardiac CTA in diagnosing VSD location were 98.1% and 98.8%, respectively. A survey of surgeons indicated that 80% believe both TTE and cardiac CTA are essential preoperative evaluations. TTE accurately diagnoses the size and location of VSD, while cardiac CTA serves as a valuable complementary method to TTE. Most surgeons advocate for the combined use of these examinations for preoperative assessment.


Novel QTLs for photoperiodic flowering revealed by using reciprocal backcross inbred lines from crosses between japonica rice cultivars.
The rice japonica cultivars Nipponbare and Koshihikari differ in heading date and response of heading to photoperiod (photoperiod sensitivity). Using simple sequence repeat (SSR) and single nucleotide polymorphism (SNP) markers, we conducted quantitative trait locus (QTL) analyses for heading date in a set of reciprocal backcross inbred lines (BILs) from crosses between Nipponbare and Koshihikari. Under natural-day conditions, transgressive segregation in days to heading (DTH) toward both early and late heading was observed in both BIL populations. QTL analyses revealed that two QTLs--on chromosomes 3 and 6--were involved in the difference in heading date between the parental cultivars. The Nipponbare allele at the QTLs on chromosomes 3 and 6 showed, respectively, increasing and decreasing effects on DTH in both BIL populations. The transgressive segregation observed in the BILs could be accounted for mainly by the complementary action of a set of alleles with opposing effects. Both QTLs were finely mapped as single Mendelian factors in secondary mapping populations (BC2F2 plants/BC2F3 lines). The QTL on chromosome 3 was mapped in the 1,140-kb interval between 94O03-4 (SSR) and OJ21G19-4 (SNP) and was designated Hd16. The QTL on chromosome 6 was mapped in the 328-kb interval between P548D347 (SSR) and 0007O20 (SSR) and was designated Hd17. Both Hd16 and Hd17 were involved in photoperiod sensitivity, as revealed by observation of the DTH of nearly isogenic lines of Nipponbare under short- and long-day conditions, suggesting that allelic differences in both Hd16 and Hd17 account for most of the difference in photoperiod sensitivity between the parental cultivars.


Consequences of climate-induced vegetation changes exceed those of human disturbance for wild impala in the Serengeti ecosystem.
In East Africa, climate change is predicted to reduce vegetation quality, and pervasive human disturbance has already resulted in significant declines in biodiversity. We studied the combined effects of reduced forage quality and human disturbance on faecal glucocorticoid metabolite (FGM) concentrations. We predicted that decreasing nutritional quality and increasing human disturbance would have an additive positive effect on FGM levels in wild impala (Aepyceros melampus). Employing a space-for-time approach, we used normalized difference vegetation index (NDVI) as a measure of forage quality, combined with spatially explicit proxies of human disturbance across areas of different protection management strategies in the Serengeti ecosystem. We collected 639 faecal samples, spread over 4 years, including both wet and dry seasons. Impala FGM levels increased significantly with declining NDVI and, to a lesser extent, with increasing proxies for human disturbance. However, we found no interaction between the two, such that impala had elevated FGM levels with low NDVI and low FGM levels with high NDVI regardless of human disturbance levels. This implies that impala will have high FGM levels if forage quality is poor, even with significant protection and reduced human disturbance. Understanding how animals respond to and cope with changes in forage quality and human land use across different protected areas is important for conservationists and managers to better protect species at risk and predict population viability.


Revealing the electronic character of the positive electrode/electrolyte interface in lithium-ion batteries.
High voltage operating active materials are among the most promising components for positive electrodes of future high energy lithium-ion batteries. However, the operating potential range of such materials often exceeds anodically the thermodynamic stability window of the electrolyte. A surface layer is therefore formed, which is supposed to be one of the reasons for the high irreversible charge loss of these electrodes. The electronic character of such a surface layer formed at the electrode/electrolyte interface of LiNi0.5Mn1.5O4 (LNM), stoichiometric (x = 0) and overlithiated (x = 0.1) Li1+x(Ni1/3Mn1/3Co1/3)1-xO2 (NMC) based paste electrodes was investigated in situ using feedback-mode scanning electrochemical microscopy (SECM). The role in the formation of an electronically insulating layer of a conductive carbon additive-based electrode and of the Al current collector was explored as well. The surface layers formed on all oxide based paste electrodes and on conductive carbon additive based electrodes showed unexpectedly an electronic conducting behavior, while the Al current collector formed an electronically insulating layer which was found to be influenced by the electrolyte.


Increase of Stroke Incidence in Young Adults in a Middle-Income Country: A 10-Year Population-Based Study.
The incidence of stroke is on the rise in young adults in high-income countries. However, there is a gap of knowledge about trends in stroke incidence in young adults from low- and middle-income countries. We aimed to measure trends in incidence of ischemic stroke (IS) and intracerebral hemorrhage (IH) in young people from 2005 to 2015 in Joinville, Brazil. We retrospectively ascertained all first-ever IS subtypes and IH that occurred in Joinville in the periods of 2005 to 2006, 2010 to 2011, and 2014 to 2015. Poisson regression was used to calculate incidence rate ratios of all strokes, IS, and IH. We also compared the prevalence of risk factors and extension of diagnostic work-up across the 3 periods. For 10 years, we registered 2483 patients (7.5% aged <45 years). From 2005 to 2006 to 2014 to 2015, overall stroke incidence significantly increased by 62% (incidence rate ratios, 1.62; 95% confidence interval, 1.10-2.40) in subjects <45 years and by 29% in those <55 years (incidence rate ratios, 1.29; 95% confidence interval, 1.04-1.60). Incidence of IS increased by 66% (incidence rate ratios, 1.66; 95% confidence interval, 1.09-2.54), but there was no significant change in incidence of IH in subjects <45 years. Smoking rates decreased by 71% (odds ratio, 0.29; 95% confidence interval, 0.12-0.68). Stroke incidence is rising in young adults in Joinville, Brazil, because of increase in rates of ischemic but not hemorrhagic strokes. We urgently need better policies of cardiovascular prevention in the young.


Identification during imposed change: the roles of personal values, type of change, and anxiety.
Using a person-situation perspective, we explain what happens to individuals' identification with a collective in the context of a change. We propose that given the anxiety that often emerges during change, individuals' personal values (conservation and openness to change) interact with type of change (imposed vs. voluntary) in predicting identification following change. In a pilot, longitudinal field study (N = 61, 67% female) of an imposed university campus relocation, we measured employees' values and identification with the university before and several months after the relocation. In two lab experiments (Study 1: N = 104, 91.3% female; Study 2: N = 113, 75.2% female), we manipulated a change to be either imposed or voluntary and compared the relationships between values and identification across types of change. In Study 2, we also measured anxiety from the change. When change was imposed (all three studies), but not when voluntary (Studies 1 and 2), individuals' conservation was positively, and openness negatively, related to individuals' post-change identification. The effects emerged only for individuals who experienced change-related anxiety (Study 2). Our findings demonstrate that individuals' identification with a changing collective depends on the amount of anxiety change elicits and on the particular combination of their values and type of change.


Undecompressed microbial populations from the deep sea.
Metabolic transformations of glutamate and Casamino Acids by natural microbial populations collected from deep waters (1,600 to 3,100 m) were studied in decompressed and undecompressed samples. Pressure-retaining sampling/incubation vessels and appropriate subsampling/incubation vessels and appropriate subsampling techniques permitted time course experiments. In all cases the metabolic activity in undecompressed samples was lower than it was when incubated at 1 atm. Surface water controls showed a reduced activity upon compression. The processes involving substrate incorporation into cell material were more pressure sensitive than was respiration. The low utilization of substrates, previously found by in situ incubations for up to 12 months, was confirmed and demonstrated to consist of an initial phase of activity, in the range of 5 to 60 times lower than the controls, followed by a stationary phase of virtually no substrate utilization. No barophilic growth response (higher rates at elevated pressure than at 1 atm) was recorded; all populations observed exhibition various degrees of barotolerance.


Location of flow-limiting segments via airway catheters near residual volume in humans.
Previous studies have demonstrated sites of flow limitation in the central airways of dogs and humans. At low lung volumes, however, during a forced expiration, it is not clear whether flow-limiting segments (FLS) move into the lung periphery. Using intrabronchial lateral pressure catheters, we located FLS in human subjects at all lung volumes between functional residual capacity (FRC) and residual volume (RV). Three individuals with severe intracranial hemorrhage maintained on ventilators were studied. Partial maximal flow-volume curves were generated from 1 liter above FRC to RV by lowering downstream pressure and using the interrupter technique. Sites of FLS were defined as the most downstream points where lateral pressure did not change with driving pressure. FLS were found in all subjects in the central airways. In one subject, FLS moved from segmental bronchi to the first subsegmental bronchus as RV was approached but not beyond. In the other two subjects, FLS remained fixed in location at all measured lung volumes. At constant volume, multiple FLS were located, all in parallel, e.g., fixed in left upper, left lower, and right middle lobar bronchi. In conclusion, sites of flow limitation remain in the central airways as lung volume approaches RV. FLS may move peripherally within the central airways but not beyond proximal subsegmental bronchi.


Influence of schooling and age on cognitive performance in healthy older adults.
Few studies have examined the influence of a low level of schooling on age-related cognitive decline in countries with wide social and economic inequalities by using the Cambridge Automated Neuropsychological Test Battery (CANTAB). The aim of the present study was to assess the influence of schooling on age-related cognitive decline using unbiased cognitive tests. CANTAB allows cognitive assessment across cultures and education levels with reduced interference of the examiner during data acquisition. Using two-way ANOVA, we assessed the influences of age and education on test scores of old adults (61-84 years of age). CANTAB tests included: Visual Sustained Attention, Reaction Time, Spatial Working Memory, Learning and Episodic Memory. All subjects had a minimum visual acuity of 20/30 (Snellen Test), no previous or current history of traumatic brain/head trauma, stroke, language impairment, chronic alcoholism, neurological diseases, memory problems or depressive symptoms, and normal scores on the Mini Mental State Examination (MMSE). Subjects were grouped according to education level (1 to 7 and ≥8 years of schooling) and age (60-69 and ≥70 years). Low schooling level was associated with significantly lower performance on visual sustained attention, learning and episodic memory, reaction time, and spatial working memory. Although reaction time was influenced by age, no significant results on post hoc analysis were detected. Our findings showed a significantly worse cognitive performance in volunteers with lower levels of schooling and suggested that formal education in early life must be included in the preventive public health agenda. In addition, we suggest that CANTAB may be useful to detect subtle cognitive changes in healthy aging.


The healthcare cyberpandemic: It's time for an intervention.
The healthcare sector is in crisis as Internet-based actors attack the digital infrastructure necessary for operations. The growing complexity of systems and events on the world stage have given rise to a dynamic threat landscape that includes nation-states affiliates. Challenging even private industry, healthcare systems and budgets already strained by COVID-19 are struggling to cope. A pandemic style response with new investment and legislation is needed.


Surfactant-Free Synthesis of Crystalline Mesoporous Metal Oxides by a Seeds/ NaCl-Mediated Growth Strategy.
Transitional metal oxides (TMOs) with ultra-high specific surface areas (SSAs), large pore volume, and tailored exposed facets appeal to significant interests in heterogeneous catalysis. Nevertheless, synthesizing the metal oxides with all the above features is challenging. Herein, the so-called seeds/NaCl-mediated growth method is successfully developed based on a bottom-up route. First, the (Brunauer-Emmett-Teller) BET SSAs of TMOs prepared with this method are significantly higher, where the BET SSAs of CeO2 , SnO2 , Nb2 O5 , Fe3 O4 , Mn3 O4 , Mg(OH)2 , and ZrO2 reached 187, 275, 518, 212, 147, 186, and 332 m2 g-1 , respectively. Second, these TMOs exhibit unique mesoporous structures, generated mainly by the aggregation of rod-like or other aspherical primary nanoparticles. More importantly, no environmental-unfriendly organic surfactants or expensive metal alkoxides are involved in this method. Therefore, the entire synthesis protocol fully fitted the "green synthesis" definition, and the corresponding TMOs prepares displayed excellent catalytic performance.


Patient involvement in diabetes care: experiences in nine diabetes care groups.
Despite the expected beneficial effects on quality of care, patient involvement in diabetes care groups, which deliver a bundled paid integrated care programme for diabetes type 2, seems to be limited. The aim of this study was to gain insight into levels and methods of patient involvement, into facilitators and barriers, and into the future preferences of care groups and patient representatives. Semi-structured interviews were held with 10 representatives of care groups and 11 representatives of patient advocacy groups. An adapted version of Arnstein's ladder of citizen participation was used to define five levels of patient involvement. Patient involvement in care groups was mostly limited to informing and consulting patients. Higher levels, i.e., advising, co-producing and decision-making, were less frequently observed. Care groups and patient representatives perceived largely the same barriers and facilitators and had similar preferences regarding future themes and design of patient involvement. Constructive collaboration between diabetes care groups and patient representatives to enhance patient involvement in the future seems viable. Several issues such as the lack of evidence for effectiveness of patient involvement, differences in viewpoints on the role and responsibilities of care groups and perceived barriers need to be addressed.


Access to Psychosocial Services Prior to Starting Antipsychotic Treatment Among Medicaid-Insured Youth.
To examine rates and predictors of receiving a psychosocial service before initiating antipsychotic treatment among young people in the Medicaid program. A retrospective new-user cohort study of 8 state Medicaid programs focused on children and adolescents 0 to 20 years, initiating antipsychotic treatment (N = 24,372). The proportion receiving a psychosocial service in the 3 months before initiating antipsychotic treatment was calculated and stratified by socio-demographic and diagnostic characteristics arranged in 9 hierarchical groups, as follows: developmental, psychotic/bipolar, disruptive, attention-deficit/hyperactivity, obsessive-compulsive, stress, major depressive, anxiety, and other disorders. Less than one-half of youth received a psychosocial service before initiating antipsychotic treatment (48.8%). Compared to younger adolescents (12-17 years) initiating antipsychotic treatment (51.5%), corresponding younger children (0-5 years; 39.2%) and older adolescents (18-20 years; 40.1%), but not older children (6-11 years; 51.5%), were significantly less likely to have received a psychosocial service. In relation to youth diagnosed with psychotic or bipolar disorder (52.7%), those diagnosed with attention-deficit/hyperactivity (43.3%), developmental (41.4%), depressive (46.5%), or anxiety (35.6%) disorder were significantly less likely to have received a psychosocial service during the 3 months before antipsychotic initiation. By contrast, youth diagnosed with stress disorders (61.2%) were significantly more likely than those diagnosed with psychotic or bipolar disorders (52.7%) to have received a psychosocial service before starting an antipsychotic. A majority of Medicaid-insured youth initiating antipsychotic treatment have not received a psychosocial service in the preceding 3 months. This service pattern highlights a critical gap in access to psychosocial services.


CircularLogo: A lightweight web application to visualize intra-motif dependencies.
The sequence logo has been widely used to represent DNA or RNA motifs for more than three decades. Despite its intelligibility and intuitiveness, the traditional sequence logo is unable to display the intra-motif dependencies and therefore is insufficient to fully characterize nucleotide motifs. Many methods have been developed to quantify the intra-motif dependencies, but fewer tools are available for visualization. We developed CircularLogo, a web-based interactive application, which is able to not only visualize the position-specific nucleotide consensus and diversity but also display the intra-motif dependencies. Applying CircularLogo to HNF6 binding sites and tRNA sequences demonstrated its ability to show intra-motif dependencies and intuitively reveal biomolecular structure. CircularLogo is implemented in JavaScript and Python based on the Django web framework. The program's source code and user's manual are freely available at http://circularlogo.sourceforge.net . CircularLogo web server can be accessed from http://bioinformaticstools.mayo.edu/circularlogo/index.html . CircularLogo is an innovative web application that is specifically designed to visualize and interactively explore intra-motif dependencies.


Clonal nature of mink cell focus-inducing virus-induced AKR leukemia: studies with X-chromosome inactivation cellular mosaicism.
The number of cells from which murine thymic leukemias (thymomas) develop after neonatal injection with a mink cell focus-inducing recombinant virus was studied in AKR mice heterozygous at the X-linked phosphoglycerate kinase (PGK) locus. Because only one of the two X-chromosomes is active in XX somatic cells, thymic leukemias that are clonal should display either type A or type B PGK but not both, whereas those with a multicellular origin may exhibit both enzymes. In 23 of 25 animals studied, thymomas expressed exclusively (11 animals) or predominantly (12 animals) a single enzyme in contrast to normal tissue which expressed both enzyme types in approximately equal ratios. In the 12 thymomas expressing a minor enzyme component, the predominant enzyme in the original tumor always predominated in the thymomas arising in animals transplanted with the original tumors, indicating that this minor PGK component was not contributed by malignant cells. The results indicate that the great majority of recombinant virus-induced AKR leukemias are clonal.


End-stage kidney disease in patients with clinically manifest vascular disease; incidence and risk factors: results from the UCC-SMART cohort study.
Patients with cardiovascular disease (CVD) are at increased risk of end-stage kidney disease (ESKD). Insights into the incidence and role of modifiable risk factors for end-stage kidney disease may provide means for prevention in patients with cardiovascular disease. We included 8402 patients with stable cardiovascular disease. Incidence rates (IRs) for end-stage kidney disease were determined stratified according to vascular disease location. Cox proportional hazard models were used to assess the risk of end-stage kidney disease for the different determinants. Sixty-five events were observed with a median follow-up of 8.6 years. The overall incidence rate of end-stage kidney disease was 0.9/1000 person-years. Patients with polyvascular disease had the highest incidence rate (1.8/1000 person-years). Smoking (Hazard ratio (HR) 1.87; 95% CI 1.10-3.19), type 2 diabetes (HR 1.81; 95% CI 1.05-3.14), higher systolic blood pressure (HR 1.37; 95% CI 1.24-1.52/10 mmHg), lower estimated glomerular filtration rate (eGFR) (HR 2.86; 95% CI 2.44-3.23/10 mL/min/1.73 m2) and higher urine albumin/creatinine ratio (uACR) (HR 1.19; 95% CI 1.15-1.23/10 mg/mmol) were independently associated with elevated risk of end-stage kidney disease. Body mass index (BMI), waist circumference, non-HDL-cholesterol and exercise were not independently associated with risk of end-stage kidney disease. Incidence of end-stage kidney disease in patients with cardiovascular disease varies according to vascular disease location. Several modifiable risk factors for end-stage kidney disease were identified in patients with cardiovascular disease. These findings highlight the potential of risk factor management in patients with manifest cardiovascular disease.


Suboptimal foraging behavior: a new perspective on gambling.
Why do people gamble? Conventional views hold that gambling may be motivated by irrational beliefs, risk-seeking, impulsive temperament, or dysfunction within the same reward circuitry affected by drugs of abuse. An alternate, unexplored perspective is that gambling is an extension of natural foraging behavior to a financial environment. However, when these foraging algorithms are applied to stochastic gambling outcomes, undesirable results may occur. To test this hypothesis, we recruited participants based on their frequency of gambling-yearly (or less), monthly, and weekly-and investigated how gambling frequency related to irrational beliefs, risk-taking/impulsivity, and foraging behavior. We found that increased gambling frequency corresponded to greater gambling-related beliefs, more exploratory choices on an explore/exploit foraging task, and fewer points earned on a Patchy Foraging Task. Gambling-related beliefs negatively related to performance on the Patchy Foraging Task, indicating that individuals with more gambling-related cognitions tended to leave a patch too quickly. This indicates that frequent gamblers have reduced foraging ability to maximize rewards; however, gambling frequency -and by extension, poor foraging ability- was not related to risk-taking or impulsive behavior. These results suggest that gambling reflects the application of a dysfunctional foraging process to financial outcomes.


Cola intake and serum lipids in the Oslo Health Study.
Soft drinks can be a major source of sucrose, which may influence serum lipid concentration. We have examined the association between intake frequency of various types of soft drinks and the concentration of serum triglycerides (TG) and high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol in the cross-sectional Oslo Health Study. A total of 14 188 subjects of the altogether 18,770 participants of the study had data on intake frequency of colas and non-colas, with or without sugar. The population sample consisted of both sexes and 3 age groups: group 1 (30 years of age), group 2 (40 and 45 years of age), and group 3 (59-60 years of age). In both sexes, HDL decreased and TG increased significantly (p < 0.001) with increasing intake frequency of colas. In contrast, no consistent associations were found between the reported intake of non-cola soft drinks and the serum lipids. We found no significant differences related to the reported presence or absence of sugar in the soft drinks. In multiple linear regression analyses, the colas vs. serum lipid associations prevailed (p < 0.001) after including 13 possible confounders: sex; age group; time since last meal; physical activity; intake of alcohol, coffee, cheese, fruit and (or) berries, and fatty fish; smoking; length of education; use of cholesterol-lowering drugs; and intake of non-colas. Thus, the self-reported intake frequency of colas, but not other soft drinks, was negatively associated with serum HDL, and positively associated with TG and LDL.


Mechanical integrity of subchondral bone in osteochondral autografts and allografts.
To assess the influence of osteochondral graft preservation techniques on post-transplant biomechanics of graft and host subchondral bone in the knee joint. An experimental animal model (sheep), specifically the weight-bearing articular surface of the medial femoral condyle of the knee joints. Each sheep received, in the ipsilateral knee, an allograft that was (a) frozen without dimethyl sulfoxide (DMSO), (b) snap-frozen in liquid nitrogen or (c) frozen with DMSO. The contralateral knee received an autograft that was (a) snap-frozen, (b) treated with DMSO or (c) left untreated (fresh). Mechanical and material properties of bone, including maximal compression stress, modulus of elasticity and bone cores (from the graft centre and surrounding host bone). No significant differences were found in the mechanical properties of the subchondral bone under the graft, but there were significant changes in surrounding bone. Bone surrounding the grafts that were snap-frozen or frozen without DMSO was significantly stronger than the normal control bone. However, bone surrounding fresh autografts and cryoprotected allografts was not significantly different from normal control bone. CONCLUSIONS; The changes in the mechanical behaviour of the host bone may be associated with graft cell viability. The great stiffness of the subchondral host bone may have consequences for long-term graft integrity and for the development of degenerative osteoarthritis.


Processing of Laser-Evoked Potentials in Patients with Chronic Whiplash-Associated Disorders, Chronic Fatigue Syndrome, and Healthy Controls: A Case-Control Study.
Laser-evoked potentials (LEPs) are among the reliable neurophysiological tools to investigate patients with neuropathic pain, as they can provide an objective account of the functional status of thermo-nociceptive pathways. The goal of this study was to explore the functioning of the nociceptive afferent pathways by examining LEPs in patients with chronic whiplash-associated disorders (cWAD), patients with chronic fatigue syndrome (CFS), and healthy controls (HCs). Case-control study. A single medical center in Belgium. The LEPs of 21 patients with cWAD, 19 patients with CFS, and 18 HCs were analyzed in this study. All participants received brief nociceptive CO2 laser stimuli applied to the dorsum of the left hand and left foot while brain activity was recorded with a 32-channel electroencephalogram (EEG). LEP signals and transient power modulations were compared between patient groups and HCs. No between-group differences were found for stimulus intensity, which was supraliminal for Aδ fibers. The amplitudes and latencies of LEP wave components N1, N2, and P2 in patients with cWAD and CFS were statistically similar to those of HCs. There were no significant differences between the time-frequency maps of EEG oscillation amplitude between HCs and both patient populations. EEG responses of heat-sensitive Aδ fibers in patients with cWAD and CFS revealed no significant differences from the responses of HCs. These findings thus do not support a state of generalized central nervous system hyperexcitability in those patients.


Innate Lymphoid Cells in Tumor Immunity.
Innate lymphoid cells (ILCs) are a group of immune cells of the lymphoid lineage that do not possess antigen specificity. The group includes natural killer (NK) cells, lymphoid tissue inducer (LTi) cells and the recently identified ILC1s, ILC2s and ILC3s. Although the role of NK cells in the context of cancer has been well established, the involvement of other ILC subsets in cancer progression and resistance is just emerging. Here, we review the literature on the role of the different ILC subsets in tumor immunity and discuss its implications for cancer treatment and monitoring.


Cognitive computer-based video analysis: its application in assessing the usability of medical systems.
This paper describes a methodology, based on cognitive research, for assessing the usability of medical computing systems. The issue of developing appropriate evaluation tools, both for use in the design process and for analysis of end products, is beginning to be recognized as being of great importance. In this paper, the use of video recording for collecting empirical data on system usability is detailed. The techniques described allow for the collection of an integrated data set consisting of the transcripts of physicians as they "think aloud" in interacting with a medical system, along with video records of user-computer interaction. The use of coding methodologies and a computer-based annotation system for the analysis of video data are described. Our preliminary experience indicates that this methodology offers a powerful way for assessing physicians' informational needs. Implications for the development and evaluation of medical information systems are discussed.


A tale of two cytokines: IL-17 and IL-22 in asthma and infection.
The Th17 pathway has recently been shown to play a critical role in host defense, allergic responses and autoimmune inflammation. Th17 cells predominantly produce IL-17 and IL-22, which are two cytokines with broad effects in the lung and other tissues. This review summarizes not only what is currently known about the molecular regulation of this pathway and Th17-related cytokine signaling, but also the roles of these cytokines in pathogen immunity and asthma. In the last 5 years, the Th17 field has rapidly grown and research has revealed that the Th17 pathway is essential in lung pathogenesis in response to exogenous stimuli. As work in the field continues, it is expected that many exciting therapeutic advances will be made for a broad range of diseases.


[Hereditary hemocromatosis].
Hereditary hemochromatosis is a disorder of iron metabolism characterized by a progressive tissue iron overload which leads to an irreversible organ damage if it is not treated timely. The recent developments in the field of molecular medicine have radically changed the physiopathology and the diagnosis of this disease. However, transferrin saturation and serum ferritin are still the most reliable tests for the detection of subjects with hereditary hemochromatosis. Therapeutic phlebotomy is the mainstay of the treatment of hereditary hemochromatosis. If phlebotomy is started before the onset of irreversible organ damages, the life expectancy of these patients is similar to that of normal population.


Superficial oesophageal mucosal innervation may contribute to severity of symptoms in oesophageal motility disorders.
Mechanisms underlying perception of dysphagia and chest pain have not been completely elucidated, although oesophageal mucosal afferent nerves might play an important role. To evaluate the relationship between oesophageal mucosal afferent nerves and the severity of dysphagia and chest pain in oesophageal motility disorders. We prospectively recruited patients with oesophageal motility disorders having dysphagia and/or chest pain from whom oesophageal biopsies were obtained. High-resolution manometry classified patients into disorders of oesophagogastric junction (OGJ) outflow and disorders of peristalsis. Symptom severity was assessed using validated questionnaires including Brief Oesophageal Dysphagia Questionnaire (BEDQ). Immunohistochemistry was performed on oesophageal biopsies to evaluate the location of calcitonin gene-related peptide (CGRP)-immunoreactive mucosal afferent nerves. Findings were compared to existing data from 10 asymptomatic healthy volunteers. Of 79 patients, 61 patients had disorders of OGJ outflow and 18 had disorders of peristalsis. CGRP-immunoreactive mucosal nerves were more superficially located in the mucosa of patients with oesophageal motility disorders compared to healthy volunteers. Within disorders of OGJ outflow, the location of CGRP-immunoreactive nerves negatively correlated with BEDQ score both in the proximal (ρ = -0.567, p < 0.001) and distal oesophagus (ρ = -0.396, p = 0.003). In the proximal oesophagus, strong chest pain was associated with more superficially located mucosal nerves than weak chest pain (p = 0.04). Multivariate analysis showed superficial nerves in the proximal oesophagus was independently associated with severe dysphagia in disorders of OGJ outflow (p = 0.008). Superficial location of mucosal nerves in the proximal oesophagus might contribute to symptoms, especially severe dysphagia, in disorders of OGJ outflow.


Magnetic resonance contrast media sensing in vivo molecular imaging agents: an overview.
Metabolic imaging is commonly performed by nuclear medicine facilities such as PET or SPECT, etc. The production and biomedical applications of bio-molecular sensing in vivo MRI metabolic contrast agents has recently become of great universal research interest, which follows its great success as a potential cost effective, less radioactive, nuclear medicine alternative. Temperature, redox potential, enzyme activity, free radial/metal ion responsive and/or pH sensitive molecular metabolic MR contrast agents are among the famous instances exemplified, which basically promote MR image contrast enhancement ability to distinguish molecular metabolic/gene expression features. Overall, these MRI contrast agents provide a framework to achieve a greater degree of accuracy from MRI as a low cost, more available facility, non radioactive radiation producing and highly sensitive biomedical tool to propound as a new suggesting opponent for PET nuclear medicine imaging. In the present review, the design, development, examination and future of the above agents will be discussed in detail.


Acute myeloid leukemia is characterized by Wnt pathway inhibitor promoter hypermethylation.
Nuclear localization of non-phosphorylated, active beta-catenin is a measure of Wnt pathway activation and is associated with adverse outcome in patients with acute myeloid leukemia (AML). While genetic alterations of the Wnt pathway are infrequent in AML, inhibitors of this pathway are silenced by promoter methylation in other malignanices. Leukemia cell lines were examined for Wnt pathway inhibitor methylation and total beta-catenin levels, and had frequent methylation of Wnt inhibitors and upregulated beta-catenin by Western blot and immunofluorescence. One hundred sixty-nine AML samples were examined for methylation of Wnt inhibitor genes. Diagnostic samples from 72 patients with normal cytogenetics who received standard high-dose induction chemotherapy were evaluated for associations between methylation and event-free or overall survival. Extensive methylation of Wnt pathway inhibitor genes was observed in cell lines, and 89% of primary AML samples had at least one methylated gene: DKK1 (16%), DKK3 (8%), RUNX3 (27%), sFRP1 (34%), sFRP2 (66%), sFRP4 (9%), sFRP5 (54%), SOX17 (29%), and WIF1 (32%). In contrast to epithelial tumors, methylation of APC (2%) and RASSF1A (0%) was rare. In patients with AML with normal cytogenetics, sFRP2 and sFRP5 methylation at the time of diagnosis was associated with an increased risk of relapse, and sFRP2 methylation was associated with an increased risk for death. In patients with AML: (a) there is a high frequency of Wnt pathway inhibitor methylation; (b) Wnt pathway inhibitor methylation is distinct from that observed in epithelial malignancies; and (c) methylation of sFRP2 and sFRP5 may predict adverse clinical outcome in patients with normal karyotype AML.


Robotic Spleen-Preserving Distal Pancreatectomy with Preservation of Splenic Vessels Using the Gastrohepatic Ligament Approach: The Superior Window Approach in the Kimura Technique.
Minimally invasive spleen-preserving distal pancreatectomy (SPDP) is technically challenging, and only a few reports have described surgical approaches for minimally invasive SPDP. This report demonstrates our novel gastrohepatic ligament approach in robotic SPDP with preservation of the splenic vessels (the superior window approach in the Kimura technique). Our gastrohepatic ligament approach for robotic SPDP included four steps. First, the gastrohepatic ligament was divided extensively, and the pancreas was confirmed (step 1). In this step, we did not lift the stomach, nor did we divide the gastrocolic ligament. Next, the superior and inferior borders of the pancreas were dissected, and the tunneling of the pancreas on the superior mesenteric vein was performed (step 2). Following the division of the pancreas (step 3), the pancreatic body and tail were dissected from the medial to the lateral side with preservation of the splenic vessels (step 4). Using this approach, the pancreas can be directly accessed via the gastrohepatic ligament route and dissected without division of the gastrocolic ligament or retraction of the stomach. The present approach for robotic SPDP preserves splenic vessels, facilitating easy access to the pancreas with minimal dissection, and may be optional in selected patients, including those with low body mass index.


Neutralization map of the hemagglutinin-neuraminidase glycoprotein of Newcastle disease virus: domains recognized by monoclonal antibodies that prevent receptor recognition.
Monoclonal antibodies (MAbs) to the hemagglutinin-neuraminidase (HN) glycoprotein of Newcastle disease virus delineate seven overlapping antigenic sites which form a continuum on the surface of the molecule. Antibodies to five of these sites neutralize viral infectivity principally by preventing attachment of the virion to cellular receptors. Through the identification of single amino acid substitutions in variants which escape neutralization by MAbs to these five antigenic sites, a neutralization map of HN was constructed, identifying several residues that contribute to the epitopes recognized by MAbs which block the attachment function of the molecule. These epitopes are defined, at least in part, by three domains on HN: residues 193 to 201; 345 to 353 (which include the only linear epitope we have identified in HN); and a C-terminal domain composed of residues 494, 513 to 521, and 569. To identify HN residues directly involved in receptor recognition, each of the variants was tested for its ability to agglutinate periodate-modified chicken erythrocytes. One variant with a single amino acid substitution at residue 193 was 2.5- to 3-fold more resistant to periodate treatment of erythrocytes than the wild-type virus, suggesting that this residue influences the binding of virus to a sialic acid-containing receptor(s) on the cell surface.


Potassium-induced aldosterone secretion involves a Cl(-)-dependent mechanism.
Stimulation of aldosterone secretion by increases in extracellular potassium concentration is associated with increases in the volume of the adrenal glomerulosa cell. Because increases in cell volume have been associated with increases in aldosterone secretion, the effect of preventing the potassium-induced increase in cell volume by removal of chloride from the medium on the response of dispersed bovine glomerulosa cells grown in primary culture was determined. Totally replacing the chloride ion with the methylsulfate ion prevented the increase in cell volume and significantly suppressed the increase in aldosterone secretion normally associated with increasing [K] to 10 mM. In the absence of Cl-, the increase in cytosolic calcium concentration ([Ca2+]c) normally induced by increasing the [K] to 10 mM was also significantly suppressed. The replacement of 10 mM methylsulfate by Cl- restored the potassium-induced increase in both cell volume and aldosterone secretion to values not different from those found in the presence of 108 mM Cl-. The potassium-induced increase in cell volume was dependent also on the presence of extracellular calcium. Thus a component of the glomerulosa cell response to an increase in [K] may be caused by a chloride-dependent increase in cell volume that is triggered by the initial depolarization-induced increase in [Ca2+]c. The increase in cell volume enhances the increase in [Ca2+]c and amplifies the increase in aldosterone secretion.


Duchenne muscular dystrophy gene therapy in the canine model.
Duchenne muscular dystrophy (DMD) is an X-linked lethal muscle disease caused by dystrophin deficiency. Gene therapy has significantly improved the outcome of dystrophin-deficient mice. Yet, clinical translation has not resulted in the expected benefits in human patients. This translational gap is largely because of the insufficient modeling of DMD in mice. Specifically, mice lacking dystrophin show minimum dystrophic symptoms, and they do not respond to the gene therapy vector in the same way as human patients do. Further, the size of a mouse is hundredfolds smaller than a boy, making it impossible to scale-up gene therapy in a mouse model. None of these limitations exist in the canine DMD (cDMD) model. For this reason, cDMD dogs have been considered a highly valuable platform to test experimental DMD gene therapy. Over the last three decades, a variety of gene therapy approaches have been evaluated in cDMD dogs using a number of nonviral and viral vectors. These studies have provided critical insight for the development of an effective gene therapy protocol in human patients. This review discusses the history, current status, and future directions of the DMD gene therapy in the canine model.


Combination therapy for treatment of Pseudomonas aeruginosa bloodstream infections.
Management of bloodstream infections ("BSIs") caused by Pseudomonas aeruginosa remains controversial as data supporting the use of definite combination treatment for severe P. aeruginosa infections remain conflicting. We aimed to determine differences in mortality between patients treated with definite combination therapy and monotherapy in a large 11-year cohort. All consecutive patients with P. aeruginosa BSI hospitalized at the University Hospital Basel, Switzerland, a tertiary academic care center, from January 2003 to December 2013 were included. Pertinent clinical data was assessed. Patients with and without definite combination therapy were compared and hazard ratios for death were calculated. During the study period, 187 patients with P. aeruginosa BSI were identified. Definite combination therapy was administered in 42.8% (80/187) of all patients, of which 76% (61/80) received a combination of a betalactam with an aminoglycoside and 24% (19/80) received a combination of a betalactam with a quinolone. The remaining 57.2% (107/187) were treated with betalactam monotherapy. Median treatment duration was 15 days (interquartile range 12-20 days). Mortality was lower in patients receiving definite combination therapy in univariable and multivariable cox regression analyses (HR 0.26, 95% CI 0.11-0.60, p = 0.002 and HR 0.30, 95% CI 0.13-0.71, p = 0.006, respectively), the latter adjusting for age, neutropenia at diagnosis, PITT bacteremia score, and inadequate empirical treatment. Combination therapy (i.e. betalactam-aminoglycoside or betalactam-quinolone combinations) may improve survival of P. aeruginosa BSI, independent of potential confounders such as age, neutropenia, PITT bacteremia score, and inadequate empirical treatment.


Evaluation of Resistance of Banana Genotypes with AAB Genome to Fusarium Wilt Tropical Race 4 in China.
Banana cultivars with the AAB genome group comprise diverse subgroups, such as Plantain, Silk, Iholena, and Pisang Raja, among others, which play an important role in food security in many developing countries. Some of these cultivars are susceptible to Fusarium oxysporum f. sp. cubense tropical race 4 (Foc TR4), the most destructive pathogen threatening banana production worldwide, and some of them are still largely unknown. We evaluated the resistance of 37 banana genotypes, including Plantain, Silk, Iholena, Maia Maoli/Popoulu, Pisang Raja, Pome, and Mysore, to Foc TR4 under both greenhouse and field conditions. Genotypes from the Silk and Iholena subgroups were highly susceptible to Foc TR4. Pome and Mysore showed resistance and intermediate resistance, respectively. However, Pisang Raja ranged from susceptible to intermediate resistance. One cultivar from the Maia Maoli/Popoulu subgroup was highly susceptible, while the other displayed significant resistance. Most Plantain cultivars exhibited high resistance to Foc TR4, except two French types of cultivar, 'Uganda Plantain' and 'Njombe N°2', which were susceptible. The susceptibility to Foc TR4 of some of the AAB genotypes evaluated, especially Plantain and other cooking bananas, indicates that growers dependent on these varieties need to be included as part of the prevention and integrated Foc TR4 management strategies, as these genotypes play a crucial role in food security and livelihoods.


Onset of breast and pubic hair development in 1231 preadolescent Lithuanian schoolgirls.
Correct staging of puberty is essential in order to differentiate different pathologies, as various components of the endocrine system influence breast, pubic, and axillary hair development. To determine the current timing of adrenarche and breast development in Lithuanian preadolescent schoolgirls. Cross-sectional study of 1231 schoolgirls aged 7.0-11.6 years. Puberty was staged according to the method of Tanner. Mean age at entry into each pubertal stage was calculated by probit analysis. Of the 255 girls aged 7 years, two had premature adrenarche (0.8%) and one premature thelarche (0.4%). Mean age of onset of pubic/axillary hair development was 11.0 years, and for breast development (Stage 2) 10.2 years. Breast Stage 3 development was attained at 11.3 years and Stage 4 at 13.9 years. Mean BMI, height, weight, and systolic blood pressure SD scores were higher in pubertal than in prepubertal girls. Skinfold thickness was also significantly higher in girls with isolated adrenarche than in prepubertal girls. The increase in BMI and weight resulted from an increase in body fat as evidenced by measures of subscapular and triceps skinfold thickness. Girls with only signs of adrenarche or thelarche did not differ from each other from the anthropometric standpoint. Premature thelarche and premature adrenarche were relatively uncommon in this population. Pubertal onset was slightly earlier than the UK Tanner standards and tended to occur in girls with a higher BMI.


GRAIL: an E3 ubiquitin ligase that inhibits cytokine gene transcription is expressed in anergic CD4+ T cells.
T cell anergy may serve to limit autoreactive T cell responses. We examined early changes in gene expression after antigen-TCR signaling in the presence (activation) or absence (anergy) of B7 costimulation. Induced expression of GRAIL (gene related to anergy in lymphocytes) was observed in anergic CD4(+) T cells. GRAIL is a type I transmembrane protein that localizes to the endocytic pathway and bears homology to RING zinc-finger proteins. Ubiquitination studies in vitro support GRAIL function as an E3 ubiquitin ligase. Expression of GRAIL in retrovirally transduced T cell hybridomas dramatically limits activation-induced IL-2 and IL-4 production. Additional studies suggest that GRAIL E3 ubiquitin ligase activity and intact endocytic trafficking are critical for cytokine transcriptional regulation. Expression of GRAIL after an anergizing stimulus may result in ubiquitin-mediated regulation of proteins essential for mitogenic cytokine expression, thus positioning GRAIL as a key player in the induction of the anergic phenotype.


Screen Time and Bone Status in Children and Adolescents: A Systematic Review.
Introduction: Technological advances over the last 2 decades have led to an increase in the time spent by children and youth engaged in screen-based activities, and growing recognition of deleterious effects on health. In this systematic review of cohort and cross-sectional studies, we assess current data on the relationship between screen time and bone status in children and teenagers. Methods: We searched PUBMED and SCOPUS databases for studies of children and adolescents that assessed screen time and bone status, determined by measuring bone mineral content or density, bone stiffness index, bone speed of sound, bone broadband ultrasound attenuation, or frame index. Searches were limited to studies published between 1900 and 2020, and performed in accordance with Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines. The studies included were evaluated using the Newcastle-Ottawa quality assessment scale. Results: Ten cohort and cross-sectional studies including pediatric population were selected. The combined study population was 20,420 children/adolescents, of whom 18,444 participated in cross-sectional studies. Four studies assessed the effects of total screen time, seven the consequences of TV viewing time, and six the effects of recreational computer use on bone health. Our findings indicate an inverse association between total and weekly screen time and bone health in children and adolescents. In 57% of the studies included also a negative correlation between television viewing time and bone status was observed, while recreational computer time did not have a significant impact on bone health. According to the only four studies that included dietetic factors, no relevant differences were found between calcium intake and screen time or bone broadband ultrasound attenuation and bone speed of sound. Conclusions: Review of the literature of the past three decades provides strong support for comprehensive education of screen time on bone status. The findings of this systematic review support a negative association between screen time and bone status in children and adolescents, with a different impact when considering the different technological devices. As peak bone mass in adolescents is the strongest predictor of osteoporosis risk, strategies aimed at improving bone health should incorporate conscious use of digital technology.


Development of an indolicidin-derived peptide by reducing membrane perturbation to decrease cytotoxicity and maintain gene delivery ability.
Indolicidin (IL) is a cationic antimicrobial peptide and our previous study has demonstrated its potential as a cell penetrating peptide (CPP) to promote gene delivery. However, the cytotoxicity of IL arisen from its membrane perturbation capacity may restrict its clinical application. To promote gene delivery safety and efficiency, an almost mirror-symmetric IL derivative, SAP10 (RRWKFFPWRR-CONH2), was designed in this study. All-atom molecular dynamics (MD) simulations were performed to understand the association between SAP10 and model lipid bilayers. By comparison with IL, SAP10 with high positively charged density resisted its deep insertion into lipid bilayers, which thus reduced its perturbation to lipid bilayers and improved biocompatibility. Consequently, we further mixed SAP10, polyethylenimine (PEI) and DNA to form the ternary nanocomplexes for gene delivery investigation. Both IL and SAP10 weakened the interaction between to DNA and PEI, which may be beneficial to promote the dissociation of internalized DNA from the carrier molecules. In vitro experiments demonstrated that the SAP10-associated ternary nanocomplexes highly promoted the transfection efficiency to various cells with low cytotoxicity. The effect of the SAP10 on promoting gene delivery was mainly contributed by the adsorbed peptides on the nanoparticles rather than the free ones. In particular, the dose of SAP10 could be increased to broaden the administration window, which ensured its safety on transfection. Therefore, our results suggested the argument that the designed SAP10 is a safe and an efficient peptide to promote PEI-mediated gene delivery.


Validity, discriminative ability, and reliability of the hearing-related quality of life questionnaire for adolescents.
The prevalence of hearing loss (HL) in adolescents has grown over the past decade, but hearing-related quality of life (QOL) has not been well-measured. We sought to develop a reliable, valid measure of hearing-related QOL for adolescents and the Hearing Environments And Reflection on Quality of Life (HEAR-QL). Multisite observational study. Adolescents with HL and siblings without HL were recruited from five centers. Participants completed the HEAR-QL and validated questionnaires measuring generic pediatric QOL (PedsQL), depression and anxiety (RCADS-25), and hearing-related QOL for adults (HHIA) to determine construct and discriminant validity. Participants completed the HEAR-QL 2 weeks later for test-retest reliability. We used exploratory principal components analysis to determine the HEAR-QL factor structure and measured reliability. Sensitivity and specificity of the HEAR-QL, PedsQL, HHIA, and RCADS-25 were assessed. We compared scores on all surveys between those with normal hearing, unilateral, and bilateral HL. A total of 233 adolescents (13-18 years old) participated: 179 with HL, 54 without HL. The original 45-item HEAR-QL was shortened to 28 items after determining factor structure. The resulting HEAR-QL-28 demonstrated excellent reliability (Cronbach's alpha = 0.95) and construct validity (HHIA: r = .845, PedsQL: r = .587; RCADS-25: r = .433). The HEAR-QL-28 displayed excellent discriminant validity, with higher area under the curve (0.932) than the PedsQL (0.597) or RCADS-25 (0.529). Teens with bilateral HL using hearing devices reported worse QOL on the HEAR-QL and HHIA than peers with HL not using devices. The HEAR-QL is a sensitive, reliable, and valid measure of hearing-related QOL for adolescents. 2b.


Hierarchical multi-scale simulations of adhesion at polymer-metal interfaces: dry and wet conditions.
We performed hierarchical multi-scale simulations to study the adhesion properties of various epoxy-aluminium interfaces in the absence and presence of water. The epoxies studied differ from each other in their hexagonal ring structures where one contains aromatic and the other aliphatic rings. As aluminium is unavoidably covered with alumina, a cross-linked epoxy structure near an alumina substrate is created and relaxed by performing coarse-grained simulations. To that purpose, we employ a recently developed parameterization method for variable bead sizes. For polymer-metal interactions, a multi-scale parameterization scheme is applied where the relative adsorption of each bead type is quantified. At the mesoscopic scale, the adhesion properties of different epoxy systems are discussed in terms of their interfacial structure and adsorption behavior. To further perform all-atom simulations, the mesoscopic structures are transformed into atomistic coordinates by applying a reverse-mapping procedure. Interface internal energies are quantified and the simulation results observed at different scales are compared with each other as well as with the available experimental data. The good agreement between observations from simulations and experiments shows the usefulness of such an approach to better understand polymer-metal oxide adhesion.


Respirable stone particles differ in their ability to induce cytotoxicity and pro-inflammatory responses in cell models of the human airways.
Respirable stone- and mineral particles may be a major constituent in occupational and ambient air pollution and represent a possible health hazard. However, with exception of quartz and asbestos, little is known about the toxic properties of mineral particles. In the present study, the pro-inflammatory and cytotoxic responses to six stone particle samples of different composition and with diameter below 10 μm were assessed in human bronchial epithelial cells (HBEC3-KT), THP-1 macrophages and a HBEC3-KT/THP-1 co-culture. Moreover, particle-induced lysis of human erythrocytes was assessed to determine the ability of the particles to lyse biological membranes. Finally, the role of the NLRP3 inflammasome was assessed using a NLRP3-specific inhibitor and detection of ASC oligomers and cleaved caspase-1 and IL-1β. A reference sample of pure α-quartz was included for comparison. Several stone particle samples induced a concentration-dependent increase in cytotoxicity and secretion of the pro-inflammatory cytokines CXCL8, IL-1α, IL-1β and TNFα. In HBEC3-KT, quartzite and anorthosite were the most cytotoxic stone particle samples and induced the highest levels of cytokines. Quartzite and anorthosite were also the most cytotoxic samples in THP-1 macrophages, while anorthosite and hornfels induced the highest cytokine responses. In comparison, few significant differences between particle samples were detected in the co-culture. Adjusting responses for differences in surface area concentrations did not fully account for the differences between particle samples. Moreover, the stone particles had low hemolytic potential, indicating that the effects were not driven by membrane lysis. Pre-incubation with a NLRP3-specific inhibitor reduced stone particle-induced cytokine responses in THP-1 macrophages, but not in HBEC3-KT cells, suggesting that the effects are mediated through different mechanisms in epithelial cells and macrophages. Particle exposure also induced an increase in ASC oligomers and cleaved caspase-1 and IL-1β in THP-1 macrophages, confirming the involvement of the NLRP3 inflammasome. The present study indicates that stone particles induce cytotoxicity and pro-inflammatory responses in human bronchial epithelial cells and macrophages, acting through NLRP3-independent and -dependent mechanisms, respectively. Moreover, some particle samples induced cytotoxicity and cytokine release to a similar or greater extent than α-quartz. Thus, these minerals warrant further attention in future research.


Purification of rat liver plasma membranes by wheat-germ-agglutinin affinity partitioning.
Rat liver plasma membranes were separated from other cellular membranes by affinity partitioning in an aqueous polymer two-phase system by using the lectin wheat-germ agglutinin covalently bound to dextran as the affinity ligand. In borate buffer the bulk of membranes partitioned in the poly(ethylene glycol)-rich top phase, whereas plasma membranes were pulled selectively into the dextran-rich bottom phase in the presence of ligand. The purity and yield of plasma membranes prepared by lectin affinity partitioning and by conventional sucrose-density-gradient centrifugation was similar, as judged from marker-enzyme activities. The affinity procedure, not dependent on lengthy centrifugations, is fast and gentle and will be advantageous when studying labile components.


The flowering of Arabidopsis flower development.
Flowers come in a variety of colors, shapes and sizes. Despite this variety, flowers have a very stereotypical architecture, consisting of a series of sterile organs surrounding the reproductive structures. Arabidopsis, as the premier model system for molecular and genetic analyses of plant development, has provided a wealth of insights into how this architecture is specified. With the advent of the completion of the Arabidopsis genome sequence a decade ago, in combination with a rich variety of forward and reverse genetic strategies, many of the genes and regulatory pathways controlling flower initiation, patterning, growth and differentiation have been characterized. A central theme that has emerged from these studies is the complexity and abundance of both positive and negative feedback loops that operate to regulate different aspects of flower formation. Presumably, this considerable degree of feedback regulation serves to promote a robust and stable transition to flowering, even in the face of genetic or environmental perturbations. This review will summarize recent advances in defining the genes, the regulatory pathways, and their interactions, that underpin how the Arabidopsis flower is formed.


Using Synchrotron-Based Approaches To Examine the Foliar Application of ZnSO4 and ZnO Nanoparticles for Field-Grown Winter Wheat.
The effects of foliar-applied ZnO nanoparticles (ZnO NPs) and ZnSO4 on the winter wheat ( Triticum aestivum L.) grain yield and grain quality were studied under field conditions, with the distribution and speciation of Zn within the grain examined using synchrotron-based X-ray fluorescence microscopy and X-ray absorption spectroscopy. Although neither of the two Zn compounds improved the grain yield or quality, both increased the grain Zn concentration (average increments were 5 and 10 mg/kg for ZnSO4 and ZnO NP treatments, respectively). Across all treatments, this Zn was mainly located within the aleurone layer and crease of the grain, although the application of ZnO NPs also slightly increased Zn within the endosperm. This Zn within the grain was found to be present as Zn phosphate, regardless of the form in which Zn was applied. These results indicate that the foliar application of ZnO NPs appears to be a promising approach for Zn biofortification, as required to improve human health.


Intensity-modulated radiation therapy (IMRT) reduces the dose to the contralateral breast when compared to conventional tangential fields for primary breast irradiation: initial report.
This study was designed to compare the dose received by the contralateral breast during primary breast irradiation using intensity-modulated radiotherapy with the dose received via conventional tangential field techniques. Between March 2003 and March 2004, 44 patients with breast carcinoma were treated using 6-, 10-, or mixed 6/18-MV photons(36 with tangential intensity-modulated radiotherapy technique and eight with three-dimensional technique using tangential fields with wedges) for primary breast irradiation after breast-conserving surgery. Paired thermoluminescent dosimeters were placed on each patient's contralateral breast, 4 cm from the center of the medial border of the tangential field. The thermoluminescent dosimeters were left on the patient during a single fraction and then measured 24 hours later. The mean dose delivered with photons to the primary breast for all patients was 4998 cGy [SD = 52], and the mean single fraction dose was 200 cGy [SD = 9]. The mean percent of the prescribed dose to the contralateral breast was 7.74% (SD = 2.35) for patients treated with intensity-modulated radiotherapy, compared with 9.74% [SD = 2.04] for the patients treated with conventional tangential field techniques. This represented a 20% reduction in the mean dose to the contralateral breast with the use of intensity-modulated radiotherapy when compared with the dose received via the three-dimensional technique, a result that was statistically significant. Primary breast irradiation with tangential intensity-modulated radiotherapy technique significantly reduces the dose to the contralateral breast when compared with conventional tangential techniques.


Changes in attachment and metabolic activity of rat neonatal cardiomyocytes and nonmyocytes caused by Macrovipera lebetina obtusa venom.
The Caucasian viper Macrovipera lebetina obtusa (MLO) is one of the most prevalent and venomous snakes in the Caucasus and the surrounding regions, yet the effects of MLO venom on cardiac function remain largely unknown. We examined the influence of MLO venom (crude and with inhibited metalloproteinases and phospholipase A2) on attachment and metabolic activity of rat neonatal cardiomyocytes (CM) and nonmyocytes (nCM), assessed at 1 and 24 h. After exposing both CM and nCM to varying concentrations of MLO venom, we observed immediate cytotoxic effects at a concentration of 100 μg/ml, causing detachment from the culture substrate. At lower MLO venom concentrations both cell types detached in a dose-dependent manner. Inhibition of MLO venom metalloproteinases significantly improved CM and nCM attachment after 1-hour exposure. At 24-hour exposure to metalloproteinases inhibited venom statistically significant enhancement was observed only in nCM attachment. However, metabolic activity of CM and nCM did not decrease upon exposure to the lower dose of the venom. Moreover, we demonstrated that metalloproteinases and phospholipases A2 are not the components of the MLO venom that change metabolic activity of both CM and nCM. These results provide a valuable platform to study the impact of MLO venom on prey cardiac function. They also call for further exploration of individual venom components for pharmaceutical purposes.


Calpain activation and Na+/Ca2+ exchanger degradation occur downstream of calcium deregulation in hippocampal neurons exposed to excitotoxic glutamate.
Delayed calcium deregulation (DCD) plays an essential role in glutamate excitotoxicity, a major detrimental factor in stroke, traumatic brain injury, and various neurodegenerations. In the present study, we examined the role of calpain activation and Na(+)/Ca(2+) exchanger (NCX) degradation in DCD and excitotoxic cell death in cultured hippocampal neurons. Exposure of neurons to glutamate caused DCD accompanied by secondary mitochondrial depolarization. Activation of calpain was evidenced by detecting NCX isoform 3 (NCX3) degradation products. Degradation of NCX isoform 1 (NCX1) was below the detection limit of Western blotting. Degradation of NCX3 was detected only after 1 hr of incubation with glutamate, whereas DCD occurred on average within 15 min after glutamate application. Calpeptin, an inhibitor of calpain, significantly attenuated NCX3 degradation but failed to inhibit DCD and excitotoxic neuronal death. Calpain inhibitors I, III, and VI also failed to influence DCD and glutamate-induced neuronal death. On the other hand, MK801, an inhibitor of the NMDA subtype of glutamate receptors, added shortly after the initial glutamate-induced jump in cytosolic Ca(2+), completely prevented DCD and activation of calpain and strongly protected neurons against excitotoxicity. Taken together, our results suggest that, in glutamate-treated hippocampal neurons, the initial increase in cytosolic Ca(2+) that precedes DCD is insufficient for sustained calpain activation, which most likely occurs downstream of DCD.


Human Fc receptor-like 5 distinguishes IgG2 disulfide isoforms and deamidated charge variants.
Human Fc receptor-like 5 (FCRL5) is a novel IgG receptor. We reported that IgG2 samples display a thousand-fold range affinity for FCRL5, indicating that attributes beyond the isotype affect binding. We hypothesized that the complex interaction could be exploited to identify distinct changes in the IgG2 molecule. We investigated using surface plasmon resonance two factors that might affect the interaction between IgG2 and FCRL5; heterogeneity related to disulfide isoforms and charge variants. We found that panitumumab and denosumab samples enriched for the more flexible A disulfide isoform bound FCRL5 with two-fold and 82-fold higher apparent affinity, respectively, than the B isoform. We next assessed whether FCRL5 binding can distinguish panitumumab charge variants which increase during storage, using two approaches. First, samples were stored at 40°C to promote acidic variants. Heat stressed panitumumab had up to four-fold higher apparent affinity for FCRL5. Next, we used conditions that promoted deamidation, a common cause of acidic variants. We found that deamidated panitumumab had up to 14-fold higher apparent affinity for FCRL5, indicating that deamidation promotes the interaction. Statistical analyses of kinetic parameters and similarity scores obtained from sensogram comparisons indicated that IgG2 disulfide isoforms, heat stressed and deamidated samples each bind FCRL5 differently. We conclude that based on FCRL5 binding, we can discern distinct changes in the IgG2 molecule, including the disulfide isoform structure and charge variants related to deamidation. Since both IgG2 deamidation and conversion of disulfide isoforms occur in vivo, these findings elucidate the biological FCRL5 ligand.


Soil disturbance alters plant community composition and decreases mycorrhizal carbon allocation in a sandy grassland.
We have studied how disturbance by ploughing and rotavation affects the carbon (C) flow to arbuscular mycorrhizal (AM) fungi in a dry, semi-natural grassland. AM fungal biomass was estimated using the indicator neutral lipid fatty acid (NLFA) 16:1ω5, and saprotrophic fungal biomass using NLFA 18:2ω6,9. We labeled vegetation plots with (13)CO(2) and studied the C flow to the signature fatty acids as well as uptake and allocation in plants. We found that AM fungal biomass in roots and soil decreased with disturbance, while saprotrophic fungal biomass in soil was not influenced by disturbance. Rotavation decreased the (13)C enrichment in NLFA 16:1ω5 in soil, but (13)C enrichment in the AM fungal indicator NLFA 16:1ω5 in roots or soil was not influenced by any other disturbance. In roots, (13)C enrichment was consistently higher in NLFA 16:1ω5 than in crude root material. Grasses (mainly Festuca brevipila) decreased as a result of disturbance, while non-mycorrhizal annual forbs increased. This decreases the potential for mycorrhizal C sequestration and may have been the main reason for the reduced mycorrhizal C allocation found in disturbed plots. Disturbance decreased the soil ammonium content but did not change the pH, nitrate or phosphate availability. The overall effect of disturbance on C allocation was that more of the C in AM fungal mycelium was directed to the external phase. Furthermore, the functional identity of the plants seemed to play a minor role in the C cycle as no differences were seen between different groups, although annuals contained less AM fungi than the other groups.


Development of small-molecule inhibitors that target PI3Kβ.
Phosphatidylinositol-3 kinase (PI3K) β, a subtype of class I PI3Ks, has an essential role in PTEN-deficient tumors and links to thrombosis, male fertility, and Fragile X syndrome. PI3Kβ-specific targeting therapy could be an efficacious treatment for diseases highly dependent on PI3Kβ, while mitigating the severe toxicity of pan-PI3K inhibitors. Achieving selectivity can be accomplished through three primary strategies, namely, binding to the induced lipophilic pocket, targeting the unique amino acid residue of PI3Kβ, or using atropisomerism to lock conformation. In this review, we focus on advances in the development of these β-isoform-selective PI3K inhibitors, providing potential guidance for the further development of novel clinical candidates.


The Bruton tyrosine kinase inhibitor ibrutinib improves anti-MAG antibody polyneuropathy.
To assess whether neuropathy with anti-myelin-associated glycoprotein (MAG) antibody may improve after treatment with ibrutinib, an oral inhibitor of Bruton tyrosine kinase, we prospectively treated with ibrutinib a cohort of 3 patients with anti-MAG neuropathy and Waldenström macroglobulinemia (WM). All 3 patients underwent bone marrow biopsy showing WM, with MYD88 L265P mutated and CXCR4S338X wild type, and were started on ibrutinib 420 mg/die. Patients were assessed at baseline, at 3-6-9 months, and at 12 months in 2 patients with a longer follow-up, using Inflammatory Neuropathy Cause and Treatment (INCAT) Disability Score, INCAT sensory sum score, and Medical Research Council sum score. The modified International Cooperative Ataxia Rating Scale was performed in 2 patients, whereas it was not used in the patient with Parkinson disease as a major comorbidity. Responders were considered the patients improving by at least one point in 2 clinical scales. All the patients reported an early and subjective benefit, consistent with the objective improvement, especially of the sensory symptoms as shown by clinical scales. Treatment was well tolerated. These preliminary data point to a possible efficacy of ibrutinib in anti-MAG antibody neuropathy, which is the most common disabling paraproteinemic neuropathy, where active treatment is eagerly needed. This study provides Class IV evidence that for patients with anti-MAG antibody neuropathy, ibrutinib improves neuropathy symptoms.


Attention bias modification treatment for pediatric anxiety disorders: a randomized controlled trial.
While attention bias modification (ABM) is a promising novel treatment for anxiety disorders, clinical trial data remain restricted to adults. The authors examined whether ABM induces greater reductions in pediatric anxiety symptoms and symptom severity than multiple control training interventions. From a target sample of 186 treatment-seeking children at a hospital-based child anxiety clinic, 40 patients with an ongoing anxiety disorder who met all inclusion criteria were enrolled in the study. Children were randomly assigned to one of three conditions: ABM designed to shift attention away from threat; placebo attention training using stimuli identical to those in the ABM condition; and placebo attention training using only neutral stimuli. All participants completed four weekly 480-trial sessions (1,920 total trials). Before and after the attention training sessions, children's clinical status was determined via semistructured interviews and questionnaires. Reduction in the number of anxiety symptoms and their severity was compared across the three groups. Change in the number of anxiety symptoms and their severity differed across the three conditions. This reflected significant reductions in the number of anxiety symptoms and symptom severity in the ABM condition but not in the placebo attention training or placebo-neutral condition. ABM, compared with two control conditions, reduces pediatric anxiety symptoms and severity. Further study of efficacy and underlying mechanisms is warranted.


Tryptophan-tryptophan energy migration as a tool to follow apoflavodoxin folding.
Submolecular details of Azotobacter vinelandii apoflavodoxin (apoFD) (un)folding are revealed by time-resolved fluorescence anisotropy using wild-type protein and variants lacking one or two of apoFD's three tryptophans. ApoFD equilibrium (un)folding by guanidine hydrochloride follows a three-state model: native <--> unfolded <--> intermediate. In native protein, W128 is a sink for Förster resonance energy transfer (FRET). Consequently, unidirectional FRET with a 50-ps transfer correlation time occurs from W167 to W128. FRET from W74 to W167 is much slower (6.9 ns). In the intermediate, W128 and W167 have native-like geometry because the 50-ps transfer time is observed. However, non-native structure exists between W74 and W167 because instead of 6.9 ns the transfer correlation time is 2.0 ns. In unfolded apoFD this 2.0-ns transfer correlation time is also detected. This decrease in transfer correlation time is a result of W74 and W167 becoming solvent accessible and randomly oriented toward one another. Apparently W74 and W167 are near-natively separated in the folding intermediate and in unfolded apoFD. Both tryptophans may actually be slightly closer in space than in the native state, even though apoFD's radius increases substantially upon unfolding. In unfolded apoFD the 50-ps transfer time observed for native and intermediate folding states becomes 200 ps as W128 and W167 are marginally further separated than in the native state. Apparently, apoFD's unfolded state is not a featureless statistical coil but contains well-defined substructures. The approach presented is a powerful tool to study protein folding.


Well-being and menopause: an investigation of purpose in life, self-acceptance and social role in premenopausal, perimenopausal and postmenopausal women.
Many studies have investigated anxiety and depression during the menopausal transition. However, there is little understanding of positive aspects of well-being among menopausal women. This paper reports on two studies which investigated how menopausal stage and age accounted for how women felt about their purpose in life, self-acceptance and social role. In Study One, 304 women from a community sample completed structured questionnaires which included questions relating to demographic background and two subscales of the Psychological Well-being Inventory: purpose in life and self-acceptance. In Study Two, 203 participants from Study One returned a follow-up structured questionnaire related to purpose in life and social role. Study One found that the effects of age group and menopausal group could not be separated: All women felt they would be more positive about these well-being measures in the future than they had been in the past and at present. Study Two found that women who were perimenopausal and postmenopausal did not feel as positive about their role/s in life as premenopausal women, regardless of their age. The results suggest that the menopause may indicate to women that their role/purpose in life is changing. It is important that any understanding of the menopause incorporate psychosocial aspects of women's lives. Further longitudinal studies are needed to explore well-being factors and the menopause.


Effect of a Rauscher leukemia virus vaccine upon chemical oncogenesis in the mouse.
The concept that type-C RNA viruses serve as determinants of chemically induced cancer would be supported if immunization against such viruses reduced the incidence of methylcholanthrene-induced sarcomas. A formalin vaccine was employed which was able to protect mice against the development of virus-induced Rauscher leukemia: 8/12 vaccinated mice survived versus 1/12 controls. When mice so immunized were challenged with near-threshold doses of chemical carcinogen, sarcoma incidence and death latency did not differ between vaccinated and control groups: within 10 months, a 320 mug dose of methylcholanthrene induced 100% sarcomas in both groups, while a 64 mug dose induced 62% and 65% tumors in vaccinated and control mice respectively. Thus, a relevant postulate of the oncogene hypothesis could not be supported by these studies. Formalin treatment neutralizes the oncogenic effect of mouse leukemia viruses yiwlding preparations that are immunogenic and can be successfully used as vaccines to protect against virus-induced leukemia (5). The finding of murine leukemia viruses in chemically induced tumors (1, 2) poses the question of whether these viruses are present in the tumors as passengers, or whether they are etiologically involved in the process of tumor induction. An approach to answering this question would be to challenge with chemical carcinogens mice which have been vaccinated with leukemia virus. If the virus were somehow involved in tumor induction, antiviral immunization might conceivably interfere with chemical carcinogenesis. Whitmire and Huebner (9) have reported that mice immunized with formalin-treated leukemia viruses, become resistant to sarcomagenesis by methylcholanthrene. Repetition of this experiment by Gericke and Chandra (6) gave non-significant differences between experimental and control groups. The present paper deals with the effect of immunization against Rauscher leukemia virus upon tumor induction by near-threshold doses of methylcholanthrene.


Recall of morphologically complex forms is affected by memory task but not dyslexia.
The authors studied the effect of morphological complexity on working memory in list recall tasks with base words (boy), inflected words (boy + 's) and derived words (boy + hood) in a morphologically rich language: Finnish. Simple serial recall was compared to complex working memory tasks, combining word recall with sentence verification in 8-year-old normally reading participants, dyslexic children, and adults. The normally reading children performed better than dyslexic children on both memory tasks and a test of morphology. Base words were better recalled than morphologically complex words. Memory was better for derived than inflected words in simple but not complex span tasks. There was no interaction between word type and reading group and thus no suggestion of dyslexia being associated with specific problems to represent complex morphology in working memory. Morphological processing in working memory appeared to depend on the task.


T- and B-cell clonality and frequency of human herpes viruses-6, -8 and Epstein Barr virus in angioimmunoblastic T-cell lymphoma.
Angioimmunoblastic T-cell lymphoma (T-AIL) is a peripheral T-cell lymphoma of unknown etiology. Previous clonality studies have shown a heterogeneous composition of this disease with varying restrictions of B- and T-cell populations in the tumour. For the first time in a single study and in the same pathological materials, we have analysed, lymphoid cell clonality and occurrence of human herpes viruses and Epstein Barr virus. Of 18 cases 12 (66.6%) had clonal T- and three (16.6%) had clonal B-cells. Presence of the lymphotropic viral genome of HHV6 was detected in four of 18 lymph node biopsies from T-AIL patients (22%), all were TCRgamma clonal. No HHV8 were found. Epstein Barr genome was found in 40% of cases. There was no significant association between T-cell clonality and HHV-6 or EBV infection, or between B-cell clonality and any virus infection. We conclude that T-AIL is a biologically and clinically heterogeneous entity whose true nature remains to be clarified.


HBA1C AS AN INDIRECT MARKER OF HYPERTRIGLYCERIDEMIA IN TYPE-2 DIABETES MELLITUS.
Diabetes is usually accompanied by dyslipidaemia, and among these triglyceride levels are related to the insulin resistance in type 2 diabetes. HbAlc which is an indicator of diabetes control can depict the severity of hypertriglyceridemia. The objective of this study was to determine the correlation between HbAlc and Triglyceride levels in type 2 Diabetes mellitus. A sample of 150 diabetic patients fulfilling the inclusion and exclusion criteria were selected for this cross-sectional study. Patient included were type 2 Diabetes Mellitus with HbAlc >7. Patients with history of cardiovascular disease, taking lipid lowering medications, smoker and history of cerebral stroke were excluded. HbAlc and triglyceride levels were noted .Study patients were further stratified on the basis of severity of HbAlc and Triglyceride values. The correlation between HbAlc and Triglyceride levels were established with Pearson Correlation. Among total number of 150 patients 44% (n=70) were male and 50.3% (n=80) were female. The correlation of HbAlc with Triglyceride as estimated by Pearson Correlation was positive (p=0.033, r=0.033) and statistically significant. In type 2 diabetes mellitus there is a predictable relationship between Triglycerides and HbAlc.


Understanding Shield Laws.
In anticipation of extraterritorial application of antiabortion laws, many states have enacted laws that attempt to shield abortion providers, helpers, and patients from civil, professional, or criminal liability associated with legal abortion care. This essay analyzes and compares the statutory schemes of the seven early adopting shield states: California, Connecticut, Delaware, Illinois, Massachusetts, New Jersey, and New York. After describing what the laws do and how they operate, we offer reflections on coming disputes, areas of legal uncertainty, and ways to improve future shield laws.


Acoustic rhinometry findings in patients with mild sleep apnea.
Nasal obstruction may contribute to the development of obstructive sleep apnea (OSA). Acoustic rhinometry (AR) measures nasal patency and congestion, which are useful parameters in objectively evaluating nasal obstruction. The nasal obstruction produced by allergic rhinitis may contribute to the development of OSA and can be easily assessed with AR. This study was undertaken to assess the degree of nasal obstruction seen in allergic patients with and without OSA. This study was a retrospective data analysis from a tertiary referral center. The AR data from 10 patients with and 40 patients without mild OSA were compared. The mean congestion factors at the first cross-sectional area (CSA1) on the AR graph were found to be significantly higher in the OSA group than in the non-OSA group (P = 0.03). The classification of change in congestion factors demonstrated significant differences at CSA1, CSA2, and CSA3 and in volume (t distributions <0.001, 0.0312, <0.001, and <0.001, respectively). The non-OSA patients noted a significant subjective improvement in nasal congestion after topical nasal decongestion, whereas the OSA patients did not (P <or= 0.0001 and 0.064, respectively). Although the role of nasal obstruction in OSA is controversial, our study lends evidence to the thought that the nasal obstruction associated with allergic rhinitis is associated with the presence of mild OSA. Whether allergic rhinitis is a direct cause of OSA is debatable, but we have shown that greater nasal congestion is related to the presence of OSA in a population of patients with allergic rhinitis.


Encoding wide-field motion and direction in the central complex of the cockroach Blaberus discoidalis.
In the arthropod brain, the central complex (CX) receives various forms of sensory signals and is associated with motor functions, but its precise role in behavior is controversial. The optomotor response is a highly conserved turning behavior directed by visual motion. In tethered cockroaches, 20% procaine injected into the CX reversibly blocked this behavior. We then used multichannel extracellular recording to sample unit activity in the CX in response to wide-field visual motion stimuli, moving either horizontally or vertically at various temporal frequencies. For the 401 units we sampled, we identified five stereotyped response patterns: tonically inhibited or excited responses during motion, phasically inhibited or excited responses at the initiation of motion, and phasically excited responses at the termination of motion. Sixty-seven percent of the units responded to horizontal motion, while only 19% responded to vertical motion. Thirty-eight percent of responding units were directionally selective to horizontal motion. Response type and directional selectivity were sometimes conditional with other stimulus parameters, such as temporal frequency. For instance, 16% of the units that responded tonically to low temporal frequencies responded phasically to high temporal frequencies. In addition, we found that 26% of wide-field motion responding units showed a periodic response that was entrained to the temporal frequency of the stimulus. Our results show a diverse population of neurons within the CX that are variably tuned to wide-field motion parameters. Our behavioral data further suggest that such CX activity is required for effective optomotor responses.


Ultra-Endurance Participation and Acute Kidney Injury: A Narrative Review.
Increasingly popular, ultra-endurance participation exposes athletes to extremely high levels of functional and structural damage. Ultra-endurance athletes commonly develop acute kidney injury (AKI) and other pathologies harmful to kidney health. There is strong evidence that non-steroidal anti-inflammatory drugs, common amongst ultra-athletes, is linked to increased risk and severity of AKI and potentially ischaemic renal injury, i.e., acute tubular necrosis. Ultra-endurance participation also increases the risk of exertional rhabdomyolysis, exercise-associated hyponatremia, and gastrointestinal symptoms, interlinked pathologies all with potential to increase the risk of AKI. Hydration and fuelling both also play a role with the development of multiple pathologies and ultimately AKI, highlighting the need for individualised nutritional and hydration plans to promote athlete health. Faster athletes, supplementing nitrates, and being female also increase the risk of developing AKI in this setting. Serum creatinine criteria do not provide the best indicator for AKI for ultra-athletes therefore further investigations are needed to assess the practicality and accuracy of new renal biomarkers such as neutrophil gelatinase-associated lipocalin (NGAL). The potential of recurring episodes of AKI provide need for further research to assess the longitudinal renal health impact of ultra-participation to provide appropriate advice to athletes, coaches, medical staff, and event organisers.


Models of Intrauterine growth restriction and fetal programming in rabbits.
Intrauterine growth restriction (IUGR) affects approximately 10% of human pregnancies globally and has immediate and life-long consequences for offspring health. However, the mechanisms underlying the pathogenesis of IUGR and its association with later health and disease outcomes are poorly understood. To address these knowledge gaps, the use of experimental animals is critically important. Since the 50's different environmental, pharmacological, and surgical manipulations have been performed in the rabbit to improve our knowledge of the control of fetal growth, fetal responses to IUGR, and mechanisms by which offspring may be programmed by an adverse gestational environment. The purpose of this review is therefore to summarize the utility of the rabbit as a model for IUGR research. It first summarizes the knowledge of prenatal and postnatal development in the rabbit and how these events relate to developmental milestones in humans. It then describes the methods used to induce IUGR in rabbits and the knowledge gained about the mechanisms determining prenatal and postnatal outcomes of the offspring. Finally, it discusses the application of state of the art approaches in the rabbit, including high-resolution ultrasound, magnetic resonance imaging, and gene targeting, to gain a deeper integrative understanding of the physiological and molecular events governing the development of IUGR. Overall, we hope to engage and inspire investigators to employ the rabbit as a model organism when studying pregnancy physiology so that we may advance our understanding of mechanisms underlying IUGR and its consequences in humans and other mammalian species.


[Development of hepatocyte cultures in toxicity testing]
The liver plays a key role in drug and xenobiotic metabolism. The probability of detecting the toxicity of unknown chemicals in vitro is therefore highest in liver cell cultures. In culture however, enzymes involved in xenobiotic metabolism are preferentially degraded within one to two days. In order to improve this situation, investigations were focused on the maintenance of a tissue-like oxygen tension and the maintenance of xenobiotic metabolism by means of heterotypic cell cultures. In conventional culture dishes, as a function of cell density, the oxygen diffusion is delayed and depleted. Using teflon membrane culture dishes, a stable, incubator-controlled, tissue like oxygen tension of 4% and 13% O2 respectively, was achieved. In co-cultures of hepatocytes, the auxiliary cells selected from livers of 10 day old rats maintained the liver cell-specific cytochrome P-450 dependent aldrin epoxidase up to one week, to 40% of the original value. The analysis of cellular DNA and protein content in hepatocytes by flow cytometry revealed specific ploidy shifts inducible by low oxygen tension, by fetal calf serum, by phenobarbital and dimethylsulfoxide. Chemically induced alterations in ploidy might be an indicator to detect compounds which interfere with growth and differentiation of hepatocytes in culture.


Cross-sectional analysis of the association between fragility fractures and bone microarchitecture in older men: the STRAMBO study.
Areal bone mineral density (aBMD) measured by dual-energy X-ray absorptiometry (DXA) identifies 20% of men who will sustain fragility fractures. Thus we need better fracture predictors in men. We assessed the association between the low-trauma prevalent fractures and bone microarchitecture assessed at the distal radius and tibia by high-resolution peripheral quantitative computed tomography (HR-pQCT) in 920 men aged 50 years of older. Ninety-eight men had vertebral fractures identified on the vertebral fracture assessment software of the Hologic Discovery A device using the semiquantitative criteria, whereas 100 men reported low-trauma peripheral fractures. Men with vertebral fractures had poor bone microarchitecture. However, in the men with vertebral fractures, only cortical volumetric density (D.cort) and cortical thickness (C.Th) remained significantly lower at both the radius and tibia after adjustment for aBMD of ultradistal radius and hip, respectively. Low D.cort and C.Th were associated with higher prevalence of vertebral fractures regardless of aBMD. Severe vertebral fractures also were associated with poor trabecular microarchitecture regardless of aBMD. Men with peripheral fractures had poor bone microarchitecture. However, after adjustment for aBMD, all microarchitectural parameters became nonsignificant. In 15 men with multiple peripheral fractures, trabecular spacing and distribution remained increased after adjustment for aBMD. Thus, in men, vertebral fractures and their severity are associated with impaired cortical bone, even after adjustment for aBMD. The association between peripheral fractures and bone microarchitecture was weaker and nonsignificant after adjustment for aBMD. Thus bone microarchitecture may be a determinant of bone fragility in men, which should be investigated in prospective studies.


Urinary excretion of acetylcarnitine during human diabetic and fasting ketosis.
The urinary excretion of acetylcarnitine was studied in patients with diabetic ketosis before and during insulin therapy and in normal-weight and obese subjects during fasting. In the diabetic ketotic patients, acetylcarnitine represented 61% of the total acylcarnitine excretion. During the first 24 h of insulin treatment, acetylcarnitine excretion decreased and on the 5th day of treatment was 18% of the acylcarnitines excreted. The urinary excretion of the other acylcarnitines fell slowly. In normal-weight subjects fasted for 3 days, the urinary excretion of acetylcarnitine increased on the 2nd day of fasting, and on the 3rd day acetylcarnitine accounted for 78% of the excreted acylcarnitine. In obese subjects there was a progressive increase in urinary acetylcarnitine excretion, but on day 6 it represented only 55% of the total acylcarnitine excreted. The urinary excretion of acetylcarnitine correlated with blood beta-hydroxybutyrate concentration in the normal-weight subjects during fasting and in the diabetic ketotic patients. Acetylcarnitine accounts for a major fraction of the acylcarnitines excreted in the three ketotic conditions studied. The contribution of acetylcarnitine to the change in acylcarnitines as ketosis appears or disappears is significantly less in the obese subjects than in the normal-weight subjects or in the diabetic patients. This difference may reflect an alteration in the production or disposition of acetyl-CoA and acetylcarnitine in obesity.