Reperfusion and readmission of oxygen. Pathophysiological relevance of oxygen-derived free radicals to arrhythmogenesis.
We have examined the pathophysiological role of readmission of oxygen (and hence production of oxygen-derived free radicals) in the initiation of reperfusion-induced arrhythmias by separating, on a temporal basis, readmission flow from readmission of oxygen. Isolated rat hearts (n = 12/group) were subjected to 10 minutes of regional ischemia and 10 minutes of reperfusion. In controls reperfused with oxygenated solution (Po2 greater than 600 mm Hg), 92% of hearts developed ventricular fibrillation (VF) during the first 20 seconds of reperfusion, whereas in hearts reperfused with hypoxic solution (Po2 9.3-12.2 mm Hg), the incidence of VF was only 17% (p less than 0.05). Subsequent readmission of control solution (Po2 greater than 600 mm Hg) to the latter group led, within 20 seconds, to the appearance of VF in seven of the 10 hearts (70%) that had not previously fibrillated. To examine whether hypoxic reperfusion had prevented VF or merely delayed its onset, the studies were repeated in separate groups of hearts with the duration of hypoxic reperfusion extended to 5 minutes. In addition, to examine the partial pressure dependence of the relation, the Po2 in the reperfusion solution was set at one of five different levels: greater than 600, 150-192.7, 69-85.6, 9.2-14.8, or 0.0 mm Hg. It was found that hypoxia merely delayed VF onset by 20-40 seconds and did not significantly reduce the incidence of VF, which was 83%, 92%, 67%, 58%, and 58%, respectively. This indicated that readmission of oxygen is unnecessary for the initiation of VF during reperfusion. The hearts that reverted to sinus rhythm during the ensuing 5 minutes (n = 8, 4, 5, 9, and 8, respectively) were used to assess the arrhythmogenic consequences of readmission of oxygen. When control solution (Po2 greater than 600 mm Hg) was readmitted, new episodes of VF were elicited within 20 seconds in a manner that was inversely proportional to the preceding Po2 (p less than 0.05), the incidence of new episodes of VF being 0%, 0%, 40%, 67%, and 86%, respectively. The arrhythmogenic effect of readmission of oxygen was not the result of a sudden increase in heart rate, because a similar arrhythmogenic effect of readmission of oxygen was seen in separate groups of hearts that were paced (350 beats/min) throughout hypoxia and readmission of oxygen. In conclusion, readmission of flow and readmission of oxygen are independent determinants of reperfusion-induced arrhythmias.(ABSTRACT TRUNCATED AT 400 WORDS)


Dry Needling as a Treatment Modality for Tendinopathy: a Narrative Review.
Tendinopathy describes a combination of pain, swelling, and impaired performance of the tendon and around structures. There are various treatment options for tendinopathy with unclear efficacy. Dry needling involves inserting needles into the affected tendon, and it is thought to disrupt the chronic degenerative process and encourage localized bleeding and fibroblastic proliferation. The purpose of this review is to review the use of dry needling as a treatment modality for tendinopathy. The effectiveness of dry needling for treatment of tendinopathy has been evaluated in 3 systematic reviews, 7 randomized controlled trials, and 6 cohort studies. The following sites were studied: wrist common extensor origin, patellar tendon, rotator cuff, and tendons around the greater trochanter. There is considerable heterogeneity of the needling techniques, and the studies were inconsistent about the therapy used after the procedure. Most systematic reviews and randomized controlled trials support the effectiveness of tendon needling. There was a statistically significant improvement in the patient-reported symptoms in most studies. Some studies reported an objective improvement assessed by ultrasound. Two studies reported complications. Current research provides initial support for the efficacy of dry needling for tendinopathy treatment. It seems that tendon needling is minimally invasive, safe, and inexpensive, carries a low risk, and represents a promising area of future research. In further high-quality studies, tendon dry needling should be used as an active intervention and compared with appropriate sham interventions. Studies that compare the different protocols of tendon dry needling are also needed.


Respiratory responses to progressive hypoxia in the Amazonian oscar, Astronotus ocellatus.
This study determined the respiratory responses to progressive hypoxia in oscar, an extremely hypoxia-tolerant Amazonian cichlid. Oscar depressed oxygen consumption rates (MO2), beginning at a critical O2 tension (Pcrit) of 46Torr, to only 14% of normoxic rates at 10Torr. Total ventilation (Vw) increased up to 4-fold, entirely due to a rise in ventilatory stroke volume (no change in ventilatory frequency), and water convection requirement (Vw/MO2) increased substantially (up to 15-fold). Gill O2 extraction fell steadily, from 60% down to 40%. Although O2 transfer factor (an index of gill O2 diffusion capacity) increased transiently in moderate hypoxia, it decreased at 10Torr, which may have caused the increased expired-arterial PO2 difference. Venous PO2 was always very low (< or =7Torr). Anaerobic metabolism made a significant contribution to ATP supply, indicated by a 3-fold increase in plasma lactate that resulted in an uncompensated metabolic acidosis. Respiration of isolated gill cells was not inhibited until below 5Torr; because gill water PO2 always exceeded this value, hypoxic ion flux arrest in oscars [Wood et al., Am. J. Physiol. Reg. Integr. Comp. Physiol. 292, R2048-R2058, 2007] is probably not caused by O2 limitation in ionocytes. We conclude that metabolic depression and tolerance of anaerobic bi-products, rather than a superior capacity for O2 supply, allow oscar to thrive in extreme hypoxia in the Amazon.


SU-D-BRB-03: Prediction of Tumor Outcomes Through Wavelet Image Fusion and Texture Analysis of PET/MR Imaging.
To investigate the combination of PET/MR image features for the early prediction of tumor metastases to the lungs in soft-tissue sarcoma (STS) cancer. A dataset of 24 patients with histologically proven STS was used in this study. All patients underwent pre-treatment FDG-PET and MR scans, which comprised of T1 and T2-fat suppression weighted (T2FS) sequences. The patients had a median follow-up period of 36 months (range: 6-69 months). Eight patients developed metastases to the lungs.Tumors were contoured on the T2FS scans by an expert physician. Fusion of the co-registered FDG-PET/MR scans was performed using a wavelet transform technique. A SUV feature (SUVmax) from the FDG-PET scans and 6 texture features from the co-occurrence matrix of the fused scans were extracted from the tumor region and correlation with the clinical endpoint of metastases to the lungs was investigated. Statistical analysis was performed using Spearman's rank correlation (rs) and multivariable logistic regression. The highest univariate prediction was found on FDG-PET/T2FS fused scans analyzed using the texture features "Sum-Mean" and "Variance". These two fused scan-texture feature combinations reached rs = -0.6838 (p = 0.0003). In comparison, SUVmax reached rs = -0.6257 (p = 0.0011). The highest multivariate prediction was found with the following 3- parameter model: -3.15*SUVmax - 5.37*FDG-PET/T2FS-Sum-Mean + 0.57*FDG-PET/T1-Variance. This model reached rs = 0.7977 (p = 0.000005). This work indicates the potential of PET/MR texture features of tumors as complementary metrics to existing prognostic factors. Substantial improvement in terms of prediction of metastases to the lungs in STS cancer was found with the combination of texture features from fused FDG-PET/MR scans. Potentially, this could improve patients' outcomes by allowing better adaptation of treatments. Future work will involve evaluation of the robustness of the proposed method and validation on a larger set of patients.


A high-throughput single-cell analysis of human CD8⁺ T cell functions reveals discordance for cytokine secretion and cytolysis.
CD8+ T cells are a key component of the adaptive immune response to viral infection. An inadequate CD8+ T cell response is thought to be partly responsible for the persistent chronic infection that arises following infection with HIV. It is therefore critical to identify ways to define what constitutes an adequate or inadequate response. IFN-γ production has been used as a measure of T cell function, but the relationship between cytokine production and the ability of a cell to lyse virus-infected cells is not clear. Moreover, the ability to assess multiple CD8+ T cell functions with single-cell resolution using freshly isolated blood samples, and subsequently to recover these cells for further functional analyses, has not been achieved. As described here, to address this need, we have developed a high-throughput, automated assay in 125-pl microwells to simultaneously evaluate the ability of thousands of individual CD8+ T cells from HIV-infected patients to mediate lysis and to produce cytokines. This concurrent, direct analysis enabled us to investigate the correlation between immediate cytotoxic activity and short-term cytokine secretion. The majority of in vivo primed, circulating HIV-specific CD8+ T cells were discordant for cytolysis and cytokine secretion, notably IFN-γ, when encountering cognate antigen presented on defined numbers of cells. Our approach should facilitate determination of signatures of functional variance among individual effector CD8+ T cells, including those from mucosal samples and those induced by vaccines.


Haemolysis during sample preparation alters microRNA content of plasma.
The presence of cell-free microRNAs (miRNAs) has been detected in a range of body fluids. The miRNA content of plasma/serum in particular has been proposed as a potential source of novel biomarkers for a number of diseases. Nevertheless, the quantification of miRNAs from plasma or serum is made difficult due to inefficient isolation and lack of consensus regarding the optimal reference miRNA. The effect of haemolysis on the quantification and normalisation of miRNAs in plasma has not been investigated in great detail. We found that levels of miR-16, a commonly used reference gene, showed little variation when measured in plasma samples from healthy volunteers or patients with malignant mesothelioma or coronary artery disease. Including samples with evidence of haemolysis led to variation in miR-16 levels and consequently decreased its ability to serve as a reference. The levels of miR-16 and miR-451, both present in significant levels in red blood cells, were proportional to the degree of haemolysis. Measurements of the level of these miRNAs in whole blood, plasma, red blood cells and peripheral blood mononuclear cells revealed that the miRNA content of red blood cells represents the major source of variation in miR-16 and miR-451 levels measured in plasma. Adding lysed red blood cells to non-haemolysed plasma allowed a cut-off level of free haemoglobin to be determined, below which miR-16 and miR-451 levels displayed little variation between individuals. In conclusion, increases in plasma miR-16 and miR-451 are caused by haemolysis. In the absence of haemolysis the levels of both miR-16 and miR-451 are sufficiently constant to serve as normalisers.


Comparison of 3 Methods for Maintaining Inter-Fragmentary Compression After Fracture Reduction and Fixation.
It is recommended that the intra-articular component of a supracondylar distal femoral fracture be stabilized by a lag screw to create interfragmental compression. Generally, it is thought that lag screw fixation should precede any positional screw or locking screw application. This study compared 3 methods of maintaining interfragmentary compression after fracture reduction with a reduction clamp. Intra-articular vertical split fractures were created in synthetic femora. A force transducer was interposed between the medial and lateral condyles and 20 lbs of compression was applied to the fracture with a reduction clamp. 3.5-mm cortical lag screws (group 1), 3.5-mm cortical position screws (group 2), and 5.4-mm distal locking screws through a distal femur locking plate (group 3) were placed across the fracture (n = 4/group). After screw placement, the clamp was removed and the amount of residual interfragmentary compression was recorded. After 2 minutes, a final steady-state force was measured and compared across groups. Locking screws placed through the plate (group 3) maintained 27% of the initial force applied by the clamp (P = 0.043), whereas positional screws (group 2) maintained 90% of the initial force applied by the clamp (P = 0.431). The steady-state compression force measured with lag screws (group 1) increased by 240% (P = 0.030) relative to the initial clamp force. The steady-state force in the lag screw group was significantly greater than groups 1 and 2 (P = 0.012). When reducing intra-articular fractures and applying interfragmentary compression with reduction clamps, additional lag screws increase the amount of compression across the fracture interface. Compressing a fracture with reduction clamps and relying on locking screws to maintain the compression result in a loss of interfragmentary compression and should be avoided. This study lends biomechanical support that lag screws placed outside of the plate before locking screws for fracture fixation help maintain optimal interfragmentary compression.


Tui Na for Chronic Nonspecific Low Back Pain: Protocol for a Systematic Review and Meta-analysis.
Chronic nonspecific low back pain (CNLBP) is one of the most common complex pain conditions, and it is strongly associated with high rates of disability. Even though several studies on Tui na for CNLBP have been reported, to our knowledge there has been no systematic review of the currently available publications. This study aims to develop a protocol for a systematic review and meta-analysis that will evaluate the effectiveness and safety of Tui na therapy for patients with CNLBP. An electronic literature search of PubMed, Embase, MEDLINE, Cochrane Library, Springer, Scopus, World Health Organization International Clinical Trials Registry Platform, Physiotherapy Evidence Database (PEDro), Clarivate Analytics, and Chinese biomedical databases (the China National Knowledge Infrastructure, Wan-fang database, Chinese Scientific Journals Database, and Chinese Biomedical Literature Databases) will be conducted. Studies will be screened by two reviewers independently based on titles and abstracts, followed by a full-text reading with eligibility criteria. Randomized controlled trials involving Tui na for patients with CNLBP will be reviewed. The primary outcomes of the study are improvement of pain, analgesic medication reduction, improvement of functional disability, and degree of satisfaction with the intervention. A secondary outcome is any adverse event of Tui na intervention. Methodological quality and risk of bias will be assessed with the Cochrane Collaboration Risk of Bias Tool. If studies are sufficient, a meta-analysis of the effectiveness will be performed. If possible, we will evaluate publication bias using funnel plots. If substantial heterogeneity between studies is present, and there are sufficient studies, subgroup analyses will be conducted to explain the study findings. The review database searches will be initiated in December 2020, with findings expected by January 2021. This protocol will establish a framework of a high-quality literature synthesis on the impact of Tui na treatment in patients with CNLBP. The proposed review will determine whether Tui na is effective and safe for CNLBP patients. PROSPERO CRD42020166731; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=166731. PRR1-10.2196/20615.


Genetic diversity and zoonotic potential of rotavirus A strains in the southern Andean highlands, Peru.
Interspecies transmission is an important mechanism of evolution and contributes to rotavirus A (RVA) diversity. In order to evaluate the detection frequency, genetic diversity, epidemiological characteristics and zoonotic potential of RVA strains in faecal specimens from humans and animals cohabiting in the same environment in the department of Cusco, Peru, by molecular analysis, 265 faecal specimens were obtained from alpacas, llamas, sheep and shepherd children, and tested for RVA by RT-PCR. Genotyping was performed by multiplex PCR and sequence analysis. Rotavirus A was detected in 20.3% of alpaca, 47.5% of llama, 100% of sheep and 33.3% of human samples. The most common genetic constellations were G3-P[40]-I8-E3-H6 in alpacas, G1/G3-P[8]-I1-E1-H1 in llamas, G1/G3/G35-P[1]/P[8]-I1-E1-H1 in sheep and G3-P[40]-I1/I8-E3-H1 in humans. The newly described genotypes P[40] and P[50] were identified in all host species, including humans. Genotyping showed that the majority of samples presented coinfection with two or more RVA strains. These data demonstrate the great genetic diversity of RVA in animals and humans in Cusco, Peru. Phylogenetic analysis suggested that the strains represent zoonotic transmission among the species studied. Due to the characteristics of the human and animal populations in this study (cohabitation of different host species in conditions of poor sanitation and hygiene), the occurrence of zoonoses is a real possibility.


Marine sponge Cribrochalina vasculum compounds activate intrinsic apoptotic signaling and inhibit growth factor signaling cascades in non-small cell lung carcinoma.
Marine-derived compounds have been explored and considered as possible antitumor agents. In this study, we analyzed extracts of the sponge Cribrochalina vasculum for their ability to inhibit tumor cell proliferation. Screening identified two acetylenic compounds of similar structure that showed strong tumor-specific toxicity in non-small cell lung carcinoma (NSCLC) cells and small-cell lung carcinoma cells, and less prominent toxicity in ovarian carcinoma, while having no effect on normal cells. These acetylenic compounds were found to cause a time-dependent increase in activation of apoptotic signaling involving cleavage of caspase-9, caspase-3, and PARP, as well as apoptotic cell morphology in NSCLC cells, but not in normal fibroblasts. Further analysis demonstrated that these compounds caused conformational change in Bak and Bax, and resulted in loss of mitochondrial potential and cytochrome c release in NSCLC cells. Moreover, a decreased phosphorylation of the growth factor signaling kinases Akt, mTOR, and ERK was evident and an increased phosphorylation of JNK was observed. Thus, these acetylenic compounds hold potential as novel therapeutic agents that should be further explored for NSCLC and other tumor malignancies.


Impact of cardiovascular risk factors on the outcome of renal transplantation.
Cardiovascular diseases are common in renal transplant recipients and renal insufficiency has been shown to be a risk factor for cardiovascular disease. Some studies have reported that cardiovascular risk factors may contribute to the outcome of renal transplantation. This study was performed to determine the impact of cardiovascular risk factors on the outcome of renal transplantation in Iranian subjects. This is a retrospective, observational study including patients of 20-85 years of age who had undergone renal transplantation. Parameters documented and analyzed included demographics, cardiovascular risk factors, past medical history, date of last transplantation, the outcome of transplant, last measured serum creatinine, cause of graft failure, rejection, and death. A total of 192 patients were analyzed including 152 in the case group (with identifiable cardiovascular risk factors) and 40 controls (transplant recipients without identifiable risk factors). The mean serum creatinine in the case and control groups were 1.33 +/- 0.13 and 1.29 +/- 0.36 mg/dL respectively (P = 0.493). Response to transplantation was categorized based on a report from the World Health Organization. Complete response to grafting occurred in the control group more than the case group (P = 0.009), while frequency of partial response to grafting was higher in the case group (0.008). A history of chronic obstructive pulmonary diseases (COPD) could significantly predict the outcome of grafting (P = 0.008) as could the occurrence of renal failure (P = 0.022). Results were consistently reproduced using multivariate cumulative log it model. Our study indicates that the measured cardiovascular risk factors do not significantly influence the outcome of renal transplantation.


Harnessing lymphoma epigenetics to improve therapies.
Affinity maturation and terminal differentiation of B cells via the germinal center reaction is a complex multistep process controlled by transcription factors that induce or suppress large dynamic transcriptional programs. This occurs via the recruitment of coactivator or corepressor complexes that epigenetically regulate gene expression by post-translationally modifying histones and/or remodeling chromatin structure. B-cell-intrinsic developmental programs both regulate and respond to interactions with other cells in the germinal center that provide survival and differentiation signals, such as T-follicular helper cells and follicular dendritic cells. Epigenetic and transcriptional programs that naturally occur during B-cell development are hijacked in B-cell lymphoma by genetic alterations that directly or indirectly change the function of transcription factors and/or chromatin-modifying genes. These in turn skew differentiation toward the tumor cell of origin and alter interactions between lymphoma B cells and other cells within the microenvironment. Understanding the mechanisms by which genetic alterations perturb epigenetic and transcriptional programs regulating B-cell development and immune interactions may identify opportunities to target these programs using epigenetic-modifying agents. Here, we discuss recently published studies centered on follicular lymphoma and diffuse large B-cell lymphoma within the context of prior knowledge, and we highlight how these insights have informed potential avenues for rational therapeutic interventions.


Instrumented assessment of shoulder function: A study of inertial sensor based methods.
Inertial sensors have the potential to provide objective and practical methods to assess joint and limb function in the clinical setting. The aim of this study is to evaluate the psychometric properties of inertial sensor metrics in the assessment of patients with subacromial shoulder pain. 25 patients with unilateral subacromial shoulder pain and 50 control subjects were recruited. Assessments were carried out on both shoulders for all participants during a short movement procedure. Patients had assessments repeated after receiving three months of physiotherapy. Inertial metrics evaluated included a smoothness measure and speed and power scores derived from the range of angular velocity and acceleration profiles. Individual shoulder scores and asymmetry scores were both evaluated in terms of reliability, known-group validity, convergent validity and responsiveness. Regression analysis identified age to be a significant predictor for all scores, therefore an age matched sub-cohort of control subjects was used for comparative analyses. All scores demonstrated inter-rater reliability (ICC = 0.48-0.82), were able to differentiate pathological from healthy shoulders (AUC = 0.62-0.91) and displayed significant changes following treatment. Scores derived from the range of acceleration and velocity profiles demonstrated the largest effect sizes (Cohens d = 0.8-1.35), and displayed the highest correlation with the Oxford Shoulder Score (r = -0.40 - -0.58). The scores investigated demonstrate good psychometric properties and have potential to complement existing methods of assessment in the clinical or research setting. Further work is required to fully understand their clinical relevance and optimise assessment methods and interpretation.


Mouse papillary lung tumors transplacentally induced by N-nitrosoethylurea: evidence for alveolar type II cell origin by comparative light microscopic, ultrastructural, and immunohistochemical studies.
A histogenetic study was designed to evaluate controversial findings on the cell of origin of tubular/papillary lung tumors in mice, i.e., bronchiolar Clara cell versus alveolar type II cell. N-Nitrosoethylurea (0.5 mmol or 0.74 mmol/kg) was given to pregnant C3H (C3H/HeNCr MTV-) and Swiss Webster [Tac:(SW)fBR] mice as a single i.p. injection on Day 14, 15, 16, or 18 of gestation. The offspring were studied at various ages ranging from 7 days to 52 wk. Serial sections of the whole lung (100 to 200 sections per mouse) showed that solid/alveolar and papillary tumors arose from the pulmonary acinus, invading the bronchioles only as the tumors grew. Furthermore, a mixture of solid and papillary patterns within a single module did not represent a merging of two tumors but a progression from the solid to the papillary form. By use of two rabbit antisera against mouse lung surfactant apoproteins found in normal alveolar type II cells, it was shown by the avidin-biotin peroxidase complex procedure, by the peroxidase-antiperoxidase technique, and by indirect immunofluorescence that both solid and papillary tumors contained these proteins that are specific markers for alveolar type II cells. With a rabbit anti-rat Clara cell antiserum, none of the tumors studied was immunoreactive while normal Clara cells were reactive. The nitroblue tetrazolium formazan stain for dehydrogenase enzymes, found particularly in Clara cells, did not reveal these enzymes in any lung tumors from either strain. Ultrastructurally, no typical features of the mature Clara cell were detected in papillary or other pulmonary neoplasms. However, all tumors showed characteristic alveolar type II cell structures such as various stages of lamellar body formation, although these features were less well differentiated in the papillary tumors. Argentaffin dense bodies, representing lysosomes and immature forms of lamellar bodies, were commonly observed in papillary tumors. Some features of the papillary tumors such as cell shape, high glycogen content, and primary cilia were equivalent to those seen in pulmonary epithelial precursor cells during fetal development. With age, the papillary tumors became invasive, accumulated neutral lipids, and developed bizarre cleaved nuclei and lamellated nuclear pseudoinclusions. In conclusion, the papillary lung tumors of the mouse, at least those induced transplacentally by N-nitrosoethylurea, constitute less well-differentiated or poorly differentiated alveolar type II cell adenomas or carcinomas with fetal morphological and biochemical properties.


Drug and Alcohol Related Patient Presentations to Emergency Departments during Sporting Mass-Gathering Events: An Integrative Review.
Drug and alcohol consumption at sporting mass-gathering events (MGEs) has become part of the spectator culture in some countries. The direct and indirect effects of drug and alcohol intoxication at such MGEs has proven problematic to in-event health services as well as local emergency departments (EDs). With EDs already under significant strain from increasing patient presentations, resulting in access block, it is important to understand the impact of sporting and other MGEs on local health services to better inform future planning and provision of health care delivery. The aim of this review was to explore the impact of sporting MGEs on local health services with a particular focus on drug and alcohol related presentations. A well-established integrative literature review methodology was undertaken. Six electronic databases and the Prehospital and Disaster Medicine (PDM) journal were searched to identify primary articles related to the aim of the review. Articles were included if published in English, from January 2008 through July 2019, and focused on a sporting MGE, mass-gathering health, EDs, as well as drug and alcohol related presentations. Seven papers met the criteria for inclusion with eight individual sporting MGEs reported. The patient presentation rate (PPR) to in-event health services ranged from 0.18/1,000 at a rugby game to 41.9/1,000 at a recreational bicycle ride. The transport to hospital rate (TTHR) ranged from 0.02/1,000 to 19/1,000 at the same events. Drug and alcohol related presentations from sporting MGEs contributed up to 10% of ED presentations. Alcohol was a contributing factor in up to 25% of cases of ambulance transfers. Drug and alcohol intoxication has varying levels of impact on PPR, TTHR, and ED presentation numbers depending on the type of sporting MGE. More research is needed to understand if drug and alcohol intoxication alone influences PPR, TTHR, and ED presentations or if it is multifactorial. Inconsistent data collection and reporting methods make it challenging to compare different sporting MGEs and propose generalizations. It is imperative that future studies adopt more consistent methods and report drug and alcohol data to better inform resource allocation and care provision.


Comet encke: radar detection of nucleus.
The nucleus of the periodic comet Encke was detected in November 1980 with the Arecibo Observatory's radar system (wavelength, 12.6 centimeters). The echoes in the one sense of circular polarization received imply a radar cross section of 1.1 +/- 0.7 square kilometers. The estimated bandwidth of these echoes combined with an estimate of the rotation vector of Encke yields a radius for the nucleus of l.5(+2.3)(-1.0) kilometers. The uncertainties given are dependent primarily on the range of models considered for the comet and for the manner in which its nucleus backscatters radio waves. Should this range prove inadequate, the true value of the radius of the nucleus might lie outside the limits given.


G-protein-independent coupling of MC4R to Kir7.1 in hypothalamic neurons.
The regulated release of anorexigenic α-melanocyte stimulating hormone (α-MSH) and orexigenic Agouti-related protein (AgRP) from discrete hypothalamic arcuate neurons onto common target sites in the central nervous system has a fundamental role in the regulation of energy homeostasis. Both peptides bind with high affinity to the melanocortin-4 receptor (MC4R); existing data show that α-MSH is an agonist that couples the receptor to the Gαs signalling pathway, while AgRP binds competitively to block α-MSH binding and blocks the constitutive activity mediated by the ligand-mimetic amino-terminal domain of the receptor. Here we show that, in mice, regulation of firing activity of neurons from the paraventricular nucleus of the hypothalamus (PVN) by α-MSH and AgRP can be mediated independently of Gαs signalling by ligand-induced coupling of MC4R to closure of inwardly rectifying potassium channel, Kir7.1. Furthermore, AgRP is a biased agonist that hyperpolarizes neurons by binding to MC4R and opening Kir7.1, independently of its inhibition of α-MSH binding. Consequently, Kir7.1 signalling appears to be central to melanocortin-mediated regulation of energy homeostasis within the PVN. Coupling of MC4R to Kir7.1 may explain unusual aspects of the control of energy homeostasis by melanocortin signalling, including the gene dosage effect of MC4R and the sustained effects of AgRP on food intake.


What Makes a Photograph Memorable?
When glancing at a magazine, or browsing the Internet, we are continuously exposed to photographs. Despite this overflow of visual information, humans are extremely good at remembering thousands of pictures along with some of their visual details. But not all images are equal in memory. Some stick in our minds while others are quickly forgotten. In this paper, we focus on the problem of predicting how memorable an image will be. We show that memorability is an intrinsic and stable property of an image that is shared across different viewers, and remains stable across delays. We introduce a database for which we have measured the probability that each picture will be recognized after a single view. We analyze a collection of image features, labels, and attributes that contribute to making an image memorable, and we train a predictor based on global image descriptors. We find that predicting image memorability is a task that can be addressed with current computer vision techniques. While making memorable images is a challenging task in visualization, photography, and education, this work is a first attempt to quantify this useful property of images.


Deposition of C3b and iC3b onto particulate activators of the human complement system. Quantitation with monoclonal antibodies to human C3.
Monoclonal antibodies were used to determine the number and molecular form of C3 bound to particulate activators of the complement (C) system by human serum. Sheep erythrocytes (E) coated with IgM (EIgM) and IgG (EIgG) were used to study activation of the classical pathway (CP). Yeast (Y), rabbit erythrocytes (ER), and five species of bacteria (Escherichia coli, Staphylococcus aureus, Streptococcus pneumoniae type 3, Streptococcus pyogenes, and Hemophilus influenzae type b) were used to study activation of the alternative pathway (AP). The deposition of C3b onto EIgM and EIgG incubated in C7-deficient human serum was dependent on the serum concentration. At all serum concentrations tested, there was complete conversion of C3b to iC3b. Kinetic analysis of C3b deposition and conversion to iC3b indicated that these events occurred almost simultaneously; the reaction was completed by 15 min. The deposition of C3 onto the AP activators ER and Y was also dependent on serum concentration, and ER, but not Y, required the presence of Mg-EGTA and thus the activation of only the AP. C3b deposition and conversion to iC3b on Y was complete in 15 min, with 82% of bound C3 converted to iC3b. For ER, maximum C3 deposition required 30 min in both the presence and absence of Mg-EGTA. However, after 1 h of incubation, 74% of bound C2 was iC3b in the absence of Mg-EGTA, compared with only 52% in the presence of Mg-EGTA. Thus, even on AP activators, a large portion of C3b may be converted to iC3b, and this conversion is probably controlled by elements on the particle's surface. Studies with the five species of bacteria yielded similar results. Approximately 3-5 X 10(4) molecules of C3 were bound per microorganism, with opsonization being completed in 30 min. Remarkably, only 16-28% of bound C3 was in the form of iC3b, even after 2 h of incubation. The presence or absence of Mg-EGTA, or the addition of purified CR1 to the reaction mixture, did not significantly effect the ratio of C3b to iC3b. Finally, SDS-PAGE and autoradiography of particle-bound 125I-C3 fragments confirmed that there was no conversion of iC3b to C3d,g or C3d. The data obtained about the opsonization of bacteria suggest that the predominant form of C3 that is encountered by inflammatory phagocytes may be C3b.


Msx genes are important apoptosis effectors downstream of the Shh/Gli3 pathway in the limb.
In tetrapods, the anteroposterior (AP) patterning of the limb is under the control of the antagonistic activities of the secreted factor Sonic hedgehog (Shh) and Gli3R, the truncated repressor form of the transcription factor Gli3. In this report, we show that Msx1 and Msx2 are targets and downstream effectors of Gli3R. Consequently, in Shh null mutants, Msx genes are overexpressed and, furthermore, partially responsible for the limb phenotype. This is exemplified by the fact that reducing Msx activity in Shh mutants partially restores a normal limb development. Finally, we show that the main action of the Msx genes, in both normal and Shh(-/-) limb development, is to control cell death in the mesenchyme. We propose that, in the limb, Msx genes act downstream of the Shh/Gli3 pathway by transducing BMP signaling and that, in the absence of Shh signaling, their deregulation contributes to the extensive apoptosis that impairs limb development.


Bronchodilatory effect of Portulaca oleracea in airways of asthmatic patients.
Therapeutic effects of Portulaca oleracea for respiratory diseases are indicated in ancient Iranian medical books. The relaxant effect of this plant have also been observed on smooth muscle tissue in previous studies. Therefore, in the present study, the bronchodilatory effect of the boiled extract of Portulaca oleracea in the airway of asthmatic patients was examined. The relaxant effect of the orally administered 0.25 ml/kg of 5% boiled extract in comparison with 3 mg/kg oral theophylline and 200 microg inhaled salbutamol was studied by measuring forced expiratory volume in one second (FEV1), peak expiratory flow (PEF), maximal mid-expiratory flow (MEF(25-75)), and specific airway conductance (sGaw). The FEV1, PEF, MEF(25-75), and sGaw were measured before, administration and repeated 15, 30, 60, 90, and 120 min after administration of the oral extract and theopylline. For inhaled salbutamol measurements were performed 5, 15, 30, and 60 min post-inhalation. Results showed that the boiled extract of Portulaca oleracea caused significant increases in all measured pulmonary function tests (PFTs), (P < 0.05 to P < 0.01). There was no significant difference between the maximum increase in measured PFTs due to the boiled extract and theophylline. However, maximum increase in PEF and MEF(25-75) due to the boiled extract were significantly lower than those of salbutamol (P < 0.05 for both cases). The onset of brochodilatory effect of extract was similar to that of theophylline beginning 60 min, but the effect of extract decline after 120 min after administration. In conclusion, the results of the present study showed that Portulaca oleracea has a relatively potent but transient bronchodilatory effect on asthmatic airways.


Steroidogenic factor 1: an essential mediator of endocrine development.
The orphan nuclear receptor steroidogenic factor 1 (SF-1, also called Ad4BP and officially designated NR5A1) has emerged as an essential regulator of endocrine development and function. Initially identified as a tissue-specific transcriptional regulator of the cytochrome P450 steroid hydroxylases, SF-1 has considerably broader roles, as evidenced from studies in knockout mice lacking SF-1. The SF-1-knockout mice lacked adrenal glands and gonads and therefore died from adrenal insufficiency within the first week after birth. In addition, SF-1 knockout mice exhibited male-to-female sex reversal of their internal and external genitalia, impaired expression of multiple markers of pituitary gonadotropes, and agenesis of the ventromedial hypothalamic nucleus (VMH). These studies delineated essential roles of SF-I in regulating endocrine differentiation and function at multiple levels, particularly with respect to reproduction. This chapter will review the experiments that established SF-1 as a pivotal, global determinant of endocrine differentiation and function. We next discuss recent insights into the mechanisms controlling the expression and function of SF-1 as well as the current status of research aimed at delineating its roles in specific tissues. Finally, we highlight areas where additional studies are needed to expand our understanding of SF-1 action.


Comparison of the efficacy of a demand oxygen delivery system with continuous low flow oxygen in subjects with stable COPD and severe oxygen desaturation on walking.
Provision of ambulatory oxygen using an intermittent pulsed flow regulated by a demand oxygen delivery system (DODS) greatly increases the limited supply time of standard portable gaseous cylinders. The efficacy of such a system has not previously been studied during submaximal exercise in subjects with severe chronic obstructive pulmonary disease (COPD) in whom desaturation is likely to be great and where usage is often most appropriate. Fifteen subjects with severe COPD and oxygen desaturation underwent six minute walk tests performed in random order to compare the efficacy of a demand oxygen delivery system (DODS) with continuous flow oxygen. Walk distance, breathlessness, oxygen saturation, resting time, and recovery time (objective and subjective) were recorded and compared for each walk. Breathing continuous oxygen compared with baseline air breathing improved mean walk distance (295 m versus 271 m) and recovery time (47 seconds versus 112 seconds), whilst the lowest recorded saturation (81% versus 74%) and time desaturated below 90% (201 seconds versus 299 seconds) were reduced. When the DODS was compared with air breathing only the walk distance changed (283 m versus 271 m). A comparison of the DODS with continuous oxygen breathing showed the DODS to be less effective at oxygenating subjects with inferior lowest saturation (78% versus 81%), time spent below 90% (284 seconds versus 201 seconds), time to objective recovery (83 seconds versus 47 seconds), and walk distance (283 m versus 295 m). Neither of the delivery systems was able to prevent desaturation in these subjects. The use of continuous flow oxygen, however, was accompanied by improvements in oxygenation, walk distance, and recovery time compared with air breathing. The DODS produced only a small increase in walk distance without elevation of oxygen saturation, but was inferior to continuous flow oxygen in most of the measured variables when compared directly.


Screening of Chemopreventive Agents in Animal Models: Results on Reproducibility, Agents of a Given Class, and Agents Tested During Tumor Progression.
Because of the importance of testing reproducibility of results, we present our findings regarding screening agents in preclinical chemoprevention studies in rodent models performed by the Chemopreventive Agent Development Research Group (CADRG) of the Division of Cancer Prevention of the NCI. These studies were performed via contracts to various commercial and academic laboratories. Primarily, results with positive agents are reported because positive agents may progress to the clinics. In testing reproducibility, a limited number of direct repeats of our standard screening assays were performed; which entailed initiating treatment shortly after carcinogen administration or in young transgenic mice and continuing treatment until the end of the study. However, three additional protocols were employed relating to reproducibility: (i) testing agents at lower doses to determine efficacy and reduced toxicity; (ii) testing agents later in tumor progression when microscopic lesions existed and, (iii) testing multiple agents of the same mechanistic class. Data with six models that were routinely employed are presented: MNU-induced ER-positive mammary cancer in rats; MMTV-Neu ER-negative mammary cancers in transgenic mice; AOM-induced colon tumors in rats; intestinal adenomas in Min mice; OH-BBN-induced invasive rat urinary bladder cancers in rats; and UV-induced skin squamous carcinomas in mice. It was found that strongly positive results were highly reproducible in the preclinical models evaluated. Cancer Prev Res; 11(10); 595-606. ©2018 AACR.


Outcomes following myxopapillary ependymoma resection: the importance of capsule integrity.
OBJECT While extent of resection has been shown to correlate with outcomes after myxopapillary ependymoma (MPE) resection, the effect of capsular violation has not been well studied. The role of adjuvant radiation also remains controversial. In this paper the authors' goals were to evaluate outcomes following resection of MPE based on intraoperative capsular violation and to explore the role of adjuvant radiotherapy in cases of capsular violation. METHODS A retrospective review of patients undergoing resection of MPE at 2 academic institutions between 1990 and 2013 was performed. Cases with dissemination at presentation, less than 12 months of follow-up, or incomplete records were excluded. Extent of resection was defined as en bloc if all visible tumor was removed without capsular violation, gross-total resection (GTR) if all visible tumor was removed, but with capsular violation, and subtotal resection (STR) if a known residual was left at the time of surgery. Postoperative MR images were reviewed to confirm the extent of resection. Primary outcomes were progression-free survival (PFS) and overall recurrence rates. The effects of extent of resection, capsular violation, and adjuvant radiotherapy on recurrence rates and PFS were analyzed using Kaplan-Meier statistics. Associations between recurrence and preoperative variables were evaluated using Fisher exact methods and t-tests where appropriate. RESULTS Of the 107 patients reviewed, 58 patients (53% were male) met inclusion criteria. The mean age at surgery was 40.8 years (range 7-68 years). The median follow-up was 51.5 months (range 12-243 months). Extent of resection was defined as en bloc in 46.5% (n = 27), GTR in 34.5% (n = 20), and STR in 18.9% (n = 11). No recurrences were noted in the en bloc group, compared with 15% (n = 3) and 45% (n = 5) in the GTR and STR groups. En bloc resection was achieved most frequently in tumors involving the conus. Twelve patients (20%) underwent adjuvant radiotherapy following either STR or GTR. The overall recurrence rate was 13.8% (n = 8), and the 5-year PFS was 81%. Capsular violation was associated with a higher recurrence rate (p = 0.005). Adjuvant radiotherapy showed a nonsignificant trend of lower recurrence rates (16.7% vs 31.6%, p = 0.43) and longer PFS at 5 years (83.3% vs 49.9%, p = 0.16) in cases of capsular violation. CONCLUSIONS A strong correlation between capsular violation and recurrence was found following removal of MPE and should be assessed when defining extent of resection in future studies. Although the use of adjuvant radiotherapy in cases of capsular violation showed a trend toward improved PFS, further investigation is needed to establish its role as salvage therapy also appears to be effective at halting disease progression.


Medical management of benign prostatic hyperplasia: a review.
Benign prostatic hyperplasia (BPH) is a common disease affecting elderly men with 70% of men over 70 years showing microscopic evidence of hyperplasia. Transurethral resection of the prostate is the gold standard treatment. Medical management of BPH has involved the use of plant extracts, amino acids, kampo and animal organ preparations in various countries with unsatisfactory results. The use of alpha adrenergic antagonists dates back twenty years representing a major breakthrough in the treatment by relaxation of the dynamic contraction of smooth muscle component of prostatic obstruction. The evolution of alpha antagonist therapy resulted in clinical trials with selective antagonists such as prazosin, alfuzosin, indoramin, terazosin and doxazosin all of which achieve similar effective relief of obstructive symptoms as phenoxybenzamine, but with fewer side effects related to postural hypotension. 5-alpha reductase inhibitors, finasteride and episteride, recently synthesised act on the static component of obstruction caused by the enlarging prostate. They inhibit conversion of testosterone to the potent intracellular androgen dihydrotestosterone (DHT) resulting in the reduction of prostate volume and improvement of obstructive symptoms. Clinical trials with finasteride for three years indicate that 63% of patients had a reduction of greater than 20% in prostatic volume and 42% had a decrease of greater than 30% with a mean increase peak flow rate of 2.4 mls/s equivalent, to 20 years reversal of disease progression.


Gestalt Breastfeeding: Helping Mothers and Infants Optimize Positional Stability and Intraoral Breast Tissue Volume for Effective, Pain-Free Milk Transfer.
In the past decade, biological nurturing and activation of maternal and infant instincts after birth have constituted a major advance in clinical breastfeeding support. Yet, physiologic breastfeeding initiation is not enough to ensure ongoing pain-free and effective breastfeeding for many pairs. Current interventions, including "hands-off" mammalian approaches, do not improve breastfeeding outcomes, including in randomized controlled trials. Back-arching, difficulty latching or staying on the breast, and fussing at the breast are common signs of infant positional instability during breastfeeding. These cues are, however, often misdiagnosed as signs of medical conditions or oral connective tissue abnormalities, and underlying positional instability is not addressed. New clinical approaches are urgently required. This article offers a clinical approach to fit and hold (or latch and positioning)- gestalt breastfeeding, which aims to optimize positional stability and intraoral breast tissue volumes for pain-free effective breastfeeding. The word gestalt (pronounced "ger-shtolt") means a whole that is more than the sum of its parts. Gestalt breastfeeding builds on the theoretical foundations of complexity science, physiologic breastfeeding initiation, and new understandings of the biomechanics of infant suck elucidated in ultrasound studies. It also integrates simple psychological strategies from applied functional contextualism, popularly known as Acceptance and Commitment Therapy, empowering women to attend mindfully to breast sensations and their infant's cues. Gestalt breastfeeding can be reproduced for research purposes, including in comparison studies with oral surgery, and has the potential to improve breastfeeding outcomes.


A high-resolution linear optical scanner using a traveling-wave acoustic lens.
The focusing properties of traveling acoustic waves can be employed in line-scan systems to convert a low-resolution optical beam into a high-resolution beam, both beams scanning linearly in synchronism with the acoustic wave velocity. Used in conjunction with any low-resolution scanner, for example a simple Bragg deflection cell, the scanning lens can yield at least an order of magnitude improvement in resolution, without the need for mechanical elements such as spinning mirrors. The device is inherently achromatic, and can be used just as effectively with white light as with monochromatic laser light. Experiments with dilational acoustic waves in water, and flexural waves on thin elastic strips, have confirmed the effectiveness of this novel approach, and indicate that systems with resolution capabilities up to a few thousand spots per line can be expected. Thus, immediate applications should be found in the fields of recording and reproduction of photographic images, analog and digital data recording and display, and high-speed printing.


The NLRP3 inflammasome contributes to sarcopenia and lower muscle glycolytic potential in old mice.
The mechanisms underpinning decreased skeletal muscle strength and slowing of movement during aging are ill-defined. "Inflammaging," increased inflammation with advancing age, may contribute to aspects of sarcopenia, but little is known about the participatory immune components. We discovered that aging was associated with increased caspase-1 activity in mouse skeletal muscle. We hypothesized that the caspase-1-containing NLRP3 inflammasome contributes to sarcopenia in mice. Male C57BL/6J wild-type (WT) and NLRP3-/- mice were aged to 10 (adult) and 24 mo (old). NLRP3-/- mice were protected from decreased muscle mass (relative to body mass) and decreased size of type IIB and IIA myofibers, which occurred between 10 and 24 mo of age in WT mice. Old NLRP3-/- mice also had increased relative muscle strength and endurance and were protected from age-related increases in the number of myopathic fibers. We found no evidence of age-related or NLRP3-dependent changes in markers of systemic inflammation. Increased caspase-1 activity was associated with GAPDH proteolysis and reduced GAPDH enzymatic activity in skeletal muscles from old WT mice. Aging did not alter caspase-1 activity, GAPDH proteolysis, or GAPDH activity in skeletal muscles of NLRP3-/- mice. Our results show that the NLRP3 inflammasome participates in age-related loss of muscle glycolytic potential. Deletion of NLRP3 mitigates both the decline in glycolytic myofiber size and the reduced activity of glycolytic enzymes in muscle during aging. We propose that the etiology of sarcopenia involves direct communication between immune responses and metabolic flux in skeletal muscle.


Computer measurement of retinal nerve fiber layer striations.
An image analysis method to measure retinal nerve fiber layer (RNFL) striations from digitized fundus photographs was developed to improve detection and monitoring of progressive diffuse RNFL loss. Striations were measured by comparing the high spatial frequency variability across with the variability along the RNFL. This locally normalized measure of striations compensates for the wide density variations both within individuals and between individuals and RNFL photographs. Five repeated measurements were taken at each of three locations from each retinal image. Measurements from five patients with recorded visual field loss due to optic nerve diseases were compared with five normal subjects and five suspect eyes. Measurements clearly distinguished the three groups when taken at the temporal arcades. Measurements above and below the arcades were also consistent, but did not distinguish normals from suspects. The measure was correlated with graded estimates of RNFL integrity of two trained observers (rho = -0.57, p < 0.001 and rho = -0.61, p < 0.001).


Laparoscopy in the evaluation of women with unexplained ascites: an invaluable diagnostic tool.
To assess whether laparoscopy is a reliable technique for the investigation of women presenting with ascites and in whom the diagnosis remains obscure. Prospective nonrandomized clinical study (Canadian Task Force classification II-2). University Departments of a tertiary referral center. Women presenting in our institution with ascites in whom the diagnosis remained obscure after an extensive nonoperative diagnostic work-up. Undiagnosed cases were submitted to laparoscopy, and selective biopsy specimens were taken for histologic study. Over a 3-year period, 73 patients were admitted to our institution with diffuse ascites. In 9 patients (12.3%), the diagnosis remained obscure, and these patients were further investigated with laparoscopy. Selective biopsy specimens obtained at laparoscopy clarified the specific cause of the ascites in all 9 patients. Peritoneal carcinomatosis was responsible in 5 patients (a metastatic gastrointestinal tumor in 1 patient, a malignant mesothelioma of the peritoneum in 1 patient, and a serous papillary carcinoma of the peritoneum and of the ovary in 2 and 1 patients, respectively). Three patients were found with miliary peritoneal tuberculosis, and the last patient had an unusual peritoneal reaction to methylene blue after laparoscopic adhesiolysis. Laparoscopy is a valuable means of assessing the peritoneal cavity in patients with unexplained ascites, where the primary cause remains unclear. The diagnosis can be accurately made with selective biopsy specimens, and appropriate treatment can be instituted without delay.


Assessing unmodified 70-mer oligonucleotide probe performance on glass-slide microarrays.
Long oligonucleotide microarrays are potentially more cost- and management-efficient than cDNA microarrays, but there is little information on the relative performance of these two probe types. The feasibility of using unmodified oligonucleotides to accurately measure changes in gene expression is also unclear. Unmodified sense and antisense 70-mer oligonucleotides representing 75 known rat genes and 10 Arabidopsis control genes were synthesized, printed and UV cross-linked onto glass slides. Printed alongside were PCR-amplified cDNA clones corresponding to the same genes, enabling us to compare the two probe types simultaneously. Our study was designed to evaluate the mRNA profiles of heart and brain, along with Arabidopsis cRNA spiked into the labeling reaction at different relative copy number. Hybridization signal intensity did not correlate with probe type but depended on the extent of UV irradiation. To determine the effect of oligonucleotide concentration on hybridization signal, 70-mers were serially diluted. No significant change in gene-expression ratio or loss in hybridization signal was detected, even at the lowest concentration tested (6.25 microm). In many instances, signal intensity actually increased with decreasing concentration. The correlation coefficient between oligonucleotide and cDNA probes for identifying differentially expressed genes was 0.80, with an average coefficient of variation of 13.4%. Approximately 8% of the genes showed discordant results with the two probe types, and in each case the cDNA results were more accurate, as determined by real-time PCR. Microarrays of UV cross-linked unmodified oligonucleotides provided sensitive and specific measurements for most of the genes studied.


Phenotypic CD8+ T cell diversification occurs before, during, and after the first T cell division.
Effector T cell responses rely on a phenotypically and functionally heterogeneous population of cells. Whether this diversity is programmed before clonal expansion or in later phases as a result of stochastic events or asymmetric cell division is not fully understood. In this study, we first took advantage of a sensitive in vitro assay to analyze the composition of single CD8(+) T cell progenies. Heterogeneity was predominantly observed between progenies of distinct clones, but could also be detected within individual progenies. Furthermore, by physically isolating daughter cells of the first T cell division, we showed that differences in paired daughter cell progenies contributed to intraclonal diversification. Finally, we developed an in vivo limiting dilution assay to compare individual T cell progenies following immunization. We provided evidence for simultaneous intraclonal and interclonal diversification in vivo. Our results support the idea that T cell diversification is a continuous process, initiated before clonal expansion and amplified during the first and subsequent cell divisions.


Mitochondrial Abnormality Facilitates Cyst Formation in Autosomal Dominant Polycystic Kidney Disease.
Autosomal dominant polycystic kidney disease (ADPKD) constitutes the most inherited kidney disease. Mutations in the PKD1 and PKD2 genes, encoding the polycystin 1 and polycystin 2 Ca2+ ion channels, respectively, result in tubular epithelial cell-derived renal cysts. Recent clinical studies demonstrate oxidative stress to be present early in ADPKD. Mitochondria comprise the primary reactive oxygen species source and also their main effector target; however, the pathophysiological role of mitochondria in ADPKD remains uncharacterized. To clarify this function, we examined the mitochondria of cyst-lining cells in ADPKD model mice (Ksp-Cre PKD1flox/flox) and rats (Han:SPRD Cy/+), demonstrating obvious tubular cell morphological abnormalities. Notably, the mitochondrial DNA copy number and peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) expression were decreased in ADPKD model animal kidneys, with PGC-1α expression inversely correlated with oxidative stress levels. Consistent with these findings, human ADPKD cyst-derived cells with heterozygous and homozygous PKD1 mutation exhibited morphological and functional abnormalities, including increased mitochondrial superoxide. Furthermore, PGC-1α expression was suppressed by decreased intracellular Ca2+ levels via calcineurin, p38 mitogen-activated protein kinase (MAPK), and nitric oxide synthase deactivation. Moreover, the mitochondrion-specific antioxidant MitoQuinone (MitoQ) reduced intracellular superoxide and inhibited cyst epithelial cell proliferation through extracellular signal-related kinase/MAPK inactivation. Collectively, these results indicate that mitochondrial abnormalities facilitate cyst formation in ADPKD.


Dachsous1b cadherin regulates actin and microtubule cytoskeleton during early zebrafish embryogenesis.
Dachsous (Dchs), an atypical cadherin, is an evolutionarily conserved regulator of planar cell polarity, tissue size and cell adhesion. In humans, DCHS1 mutations cause pleiotropic Van Maldergem syndrome. Here, we report that mutations in zebrafish dchs1b and dchs2 disrupt several aspects of embryogenesis, including gastrulation. Unexpectedly, maternal zygotic (MZ) dchs1b mutants show defects in the earliest developmental stage, egg activation, including abnormal cortical granule exocytosis (CGE), cytoplasmic segregation, cleavages and maternal mRNA translocation, in transcriptionally quiescent embryos. Later, MZdchs1b mutants exhibit altered dorsal organizer and mesendodermal gene expression, due to impaired dorsal determinant transport and Nodal signaling. Mechanistically, MZdchs1b phenotypes can be explained in part by defective actin or microtubule networks, which appear bundled in mutants. Accordingly, disruption of actin cytoskeleton in wild-type embryos phenocopied MZdchs1b mutant defects in cytoplasmic segregation and CGE, whereas interfering with microtubules in wild-type embryos impaired dorsal organizer and mesodermal gene expression without perceptible earlier phenotypes. Moreover, the bundled microtubule phenotype was partially rescued by expressing either full-length Dchs1b or its intracellular domain, suggesting that Dchs1b affects microtubules and some developmental processes independent of its known ligand Fat. Our results indicate novel roles for vertebrate Dchs in actin and microtubule cytoskeleton regulation in the unanticipated context of the single-celled embryo.


Mandibular reconstruction with full thickness calvarial bone and temporal muscle flap.
Eleven patients underwent mandibular reconstruction with pedicled temporal muscle flaps combined with vascularised or free full thickness calvarial bone grafts. Six were primary and five secondary reconstructions. The indications were squamous cell carcinoma (n = 6), radio-osteonecrosis (n = 4), and gunshot wound (n = 1). Five patients also had endosseus implants, either simultaneously or delayed. The only major complications were necrosis of the whole calvarial bone (n = 1) and permanent facial nerve palsy (n = 1). The advantages of using full thickness calvarial bone are that it is thick enough to take an endosseous implant, morbidity is low, there is virtually no postoperative pain, the scar is invisible, and there is only one donor area for both hard and soft tissue. Transplantation of full thickness calvarial bone and temporal muscle is a viable alternative to an osseomyocutaneous microvascularised free flap for reconstruction of the mandible when the neck has been previously operated on or irradiated, and anastomosis may be critical.


Excited state non-adiabatic dynamics of the smallest polyene, trans 1,3-butadiene. I. Time-resolved photoelectron-photoion coincidence spectroscopy.
The ultrafast excited state dynamics of the smallest polyene, trans-1,3-butadiene, were studied by femtosecond time-resolved photoelectron-photoion coincidence (TRPEPICO) spectroscopy. The evolution of the excited state wavepacket, created by pumping the bright 1Bu (ππ*) electronic state at its origin of 216 nm, is projected via one- and two-photon ionization at 267 nm onto several ionization continua. The results are interpreted in terms of Koopmans' correlations and Franck-Condon factors for the excited and cationic states involved. The known predissociative character of the cation excited states is utilized to assign photoelectron bands to specific continua using TRPEPICO spectroscopy. This permits us to report the direct observation of the famously elusive S1(21Ag) dark electronic state during the internal conversion of trans 1,3-butadiene. Our phenomenological analysis permits the spectroscopic determination of several important time constants. We report the overall decay lifetimes of the 11Bu and 21Ag states and observe the re-appearance of the hot ground state molecule. We argue that the apparent dephasing time of the S2(11Bu) state, which leads to the extreme breadth of the absorption spectrum, is principally due to large amplitude torsional motion on the 1Bu surface in conjunction with strong non-adiabatic couplings via conical intersections, whereupon nuclear wavepacket revivals to the initial Franck-Condon region become effectively impossible. In Paper II [W. J. Glover et al., J. Chem. Phys. 148, 164303 (2018)], ab initio multiple spawning is used for on-the-fly computations of the excited state non-adiabatic wavepacket dynamics and their associated TRPEPICO observables, allowing for direct comparisons of experiment with theory.


Proximal Tubular Cell-Specific Ablation of Carnitine Acetyltransferase Causes Tubular Disease and Secondary Glomerulosclerosis.
Proximal tubular epithelial cells are highly energy demanding. Their energy need is covered mostly from mitochondrial fatty acid oxidation. Whether derailments in fatty acid metabolism and mitochondrial dysfunction are forerunners of tubular damage has been suggested but is not entirely clear. Here we modeled mitochondrial overload by creating mice lacking the enzyme carnitine acetyltransferase (CrAT) in the proximal tubules, thus limiting a primary mechanism to export carbons under conditions of substrate excess. Mice developed tubular disease and, interestingly, secondary glomerulosclerosis. This was accompanied by increased levels of apoptosis regulator and fibrosis markers, increased oxidative stress, and abnormal profiles of acylcarnitines and organic acids suggesting profound impairments in all major forms of nutrient metabolism. When mice with CrAT deletion were fed a high-fat diet, kidney disease was more severe and developed faster. Primary proximal tubular cells isolated from the knockout mice displayed energy deficit and impaired respiration before the onset of pathology, suggesting mitochondrial respiratory abnormalities as a potential underlying mechanism. Our findings support the hypothesis that derailments of mitochondrial energy metabolism may be causative to chronic kidney disease. Our results also suggest that tubular injury may be a primary event followed by secondary glomerulosclerosis, raising the possibility that focusing on normalizing tubular cell mitochondrial function and energy balance could be an important preventative strategy.


Operational Demands of AAC Mobile Technology Applications on Programming Vocabulary and Engagement During Professional and Child Interactions.
Typically, the vocabulary in augmentative and alternative communication (AAC) technologies is pre-programmed by manufacturers or by parents and professionals outside of daily interactions. Because vocabulary needs are difficult to predict, young children who use aided AAC often do not have access to vocabulary concepts as the need and interest arises in their daily interactions, limiting their vocabulary acquisition and use. Ideally, parents and professionals would be able to add vocabulary to AAC technologies "just-in-time" as required during daily interactions. This study compared the effects of two AAC applications for mobile technologies: GoTalk Now (which required more programming steps) and EasyVSD (which required fewer programming steps) on the number of visual scene displays (VSDs) and hotspots created in 10-min interactions between eight professionals and preschool-aged children with typical development. The results indicated that, although all of the professionals were able to create VSDs and add vocabulary during interactions with the children, they created more VSDs and hotspots with the app with fewer programming steps than with the one with more steps, and child engagement and programming participation levels were high with both apps, but higher levels for both variables were observed with the app with fewer programming steps than with the one with more steps. These results suggest that apps with fewer programming steps may reduce operational demands and better support professionals to (a) respond to the child's input, (b) use just-in-time programming during interactions,


The role of adipocytokines in atherogenesis and atheroprogression.
Research investigations on adipose tissue were focused for several decades on its "storage" function. Emerging evidence unveiled adipose tissue as an endocrine organ releasing a several mediators termed as adipokines. Adipokine-mediated functions include both physiological and pathophysiological roles such as regulation of energy metabolism, immune response and vascular homeostasis, as well as inflammatory and metabolic diseases (i.e. atherogenesis, diabetes and obesity clustered in the concept of metabolic syndrome). A dysregulation of adipokine levels has been also suggested as a potential common mechanism underlying these disorders. For instance, an unbalance between pro- and anti-inflammatory adipokines was positively associated with traditional risk factors (dyslipidaemia, hypertension, insulin resistance) in obesity, diabetes and atherogenesis. Adipokine-mediated activities particularly affected endothelial dysfunction/activation and intraplaque inflammation/vulnerability. The purpose of this narrative review is to provide an overview on the role of adipokines in atherogenesis. Evidence from basic research studies about adipokine-induced regulation of vascular and immune cell subsets will be discussed. Finally, conflicting results from clinical trials we be reported, with an attempt to better understand the reason why promising basic research results did not allow a speedy "into human" translation for clinical management of atherogenesis.


Rational construction of functional molybdenum (tungsten)-copper-sulfur coordination oligomers and polymers from preformed cluster precursors.
The investigation of heterometallic Mo(W)-M'-S clusters (M' = transition metals) has its genesis in the late 1970s with the identification of the nitrogenase iron-molybdenum cofactor (FeMoco) featuring a Mo-Fe-S double-cubane cluster core. This has led to the generation of a library of cluster skeletons subsequently used as building blocks for oligomers (OGs) and polymers, merging this field with the fascinating developments in supramolecular chemistry and coordination polymers (CPs). While resembling the general metal-ligand assembly to form CPs in one-pot, cluster-based OGs or CPs are conventionally prepared from Mo(W)-S synthons and Cu(i) salts in the presence of bridging ligands. This review summarizes the synthesis of Mo(W)-Cu-S cluster-supported OGs and CPs through a two-step strategy involving preformed clusters. This stepwise approach facilitates clean conversion, and is amenable to exquisite design protocols and yields products otherwise inaccessible via a direct one-pot method. We review the synthesis of OGs and CPs by cluster core upgrading, downgrading, ligand substitution, and cluster aggregation reactions, together with the optical and host-guest properties of the products. In doing so, we demonstrate the power and generality of this strategy for assembling these unique materials and offer clues on how to adapt this less practiced method to preparing extended molecular assemblies with potentially intriguing properties.


An Energy Efficient Technique Using Electric Active Shielding for Capacitive Coupling Intra-Body Communication.
Capacitive coupling intra-body communication (CC-IBC) has become one of the candidates for healthcare sensor networks due to its positive prevailing features of energy efficiency, transmission rate and security. Under the CC-IBC scheme, some of the electric field emitted from signal (SIG) electrode of the transmitter will couple directly to the ground (GND) electrode, acting equivalently as an internal impedance of the signal source and inducing considerable energy losses. However, none of the previous works have fully studied the problem. In this paper, the underlying theory of such energy loss is investigated and quantitatively evaluated using conventional parameters. Accordingly, a method of electric active shielding is proposed to reduce the displacement current across the SIG-GND electrodes, leading to less power loss. In addition, the variation of such loss in regard to frequency range and positions on human body was also considered. The theory was validated by finite element method simulation and experimental measurement. The prototype result shows that the receiving power has been improved by approximate 5.5 dBm while the total power consumption is maximally 9 mW less using the proposed technique, providing an energy efficient option in physical layer for wearable and implantable healthcare sensor networks.


Single-trial analysis of the neural correlates of speech quality perception.
Assessing speech quality perception is a challenge typically addressed in behavioral and opinion-seeking experiments. Only recently, neuroimaging methods were introduced, which were used to study the neural processing of quality at group level. However, our electroencephalography (EEG) studies show that the neural correlates of quality perception are highly individual. Therefore, it became necessary to establish dedicated machine learning methods for decoding subject-specific effects. The effectiveness of our methods is shown by the data of an EEG study that investigates how the quality of spoken vowels is processed neurally. Participants were asked to indicate whether they had perceived a degradation of quality (signal-correlated noise) in vowels, presented in an oddball paradigm. We find that the P3 amplitude is attenuated with increasing noise. Single-trial analysis allows one to show that this is partly due to an increasing jitter of the P3 component. A novel classification approach helps to detect trials with presumably non-conscious processing at the threshold of perception. We show that this approach uncovers a non-trivial confounder between neural hits and neural misses. The combined use of EEG signals and machine learning methods results in a significant 'neural' gain in sensitivity (in processing quality loss) when compared to standard behavioral evaluation; averaged over 11 subjects, this amounts to a relative improvement in sensitivity of 35%.


Why Does Disaster Recovery Work Influence Mental Health?: Pathways through Physical Health and Household Income.
Disaster recovery work increases risk for mental health problems, yet the mechanisms underlying this association are unclear. We explored links from recovery work to post-traumatic stress (PTS), major depression (MD), and generalized anxiety disorder (GAD) symptoms through physical health symptoms and household income in the aftermath of the Deepwater Horizon oil spill. As part of the NIEHS GuLF STUDY, participants (N = 10,141) reported on cleanup work activities, spill-related physical health symptoms, and household income at baseline, and mental health symptoms an average of 14.69 weeks (SD = 16.79) thereafter. Cleanup work participation was associated with higher physical health symptoms, which in turn were associated with higher PTS, MD, and GAD symptoms. Similar pattern of results were found in models including workers only and investigating the influence of longer work duration and higher work-related oil exposure on mental health symptoms. In addition, longer worker duration and higher work-related oil exposure were associated with higher household income, which in turn was associated with lower MD and GAD symptoms. These findings suggest that physical health symptoms contribute to workers' risk for mental health symptoms, while higher household income, potentially from more extensive work, might mitigate risk.


Immunoreceptor DAP12 bearing a tyrosine-based activation motif is involved in activating NK cells.
Natural killer (NK) cells express cell-surface receptors of the immunoglobulin and C-type lectin superfamilies that recognize major histocompatibility complex (MHC) class I peptides and inhibit NK-cell-mediated cytotoxicity. These inhibitory receptors possess ITIM sequences (for immunoreceptor tyrosine-based inhibitory motifs) in their cytoplasmic domains that recruit SH2-domain-containing protein tyrosine phosphatases, resulting in inactivation of NK cells. Certain isoforms of these NK-cell receptors lack ITIM sequences and it has been proposed that these 'non-inhibitory' receptors may activate, rather than inhibit, NK cells. Here we show that DAP12, a disulphide-bonded homodimer containing an immunoreceptor tyrosine-based activation motif (ITAM) in its cytoplasmic domain, non-covalently associates with membrane glycoproteins of the killer-cell inhibitory receptor (KIR) family without an ITIM in their cytoplasmic domain. Crosslinking of KIR-DAP12 complexes results in cellular activation, as demonstrated by tyrosine phosphorylation of cellular proteins and upregulation of early-activation antigens. Phosphorylated DAP12 peptides bind ZAP-70 and Syk protein tyrosine kinases, suggesting that the activation pathway is similar to that of the T- and B-cell antigen receptors.


High frequency ultrasound measurement of digital dermal thickness in systemic sclerosis.
Currently, assessment of dermal thickness in systemic sclerosis (SSc) is performed by palpation and assessment using the modified Rodnan skin score (mRSS). To verify whether high frequency ultrasound (US) may be a reliable and a reproducible method to measure digital dermal thickness. In 70 patients with SSc, skin thickness was evaluated with US by 2 observers at 2 different sites on the second digit of the dominant limb to determine the interobserver variability. Patients and controls were examined twice by the first observer for intraobserver variability. Patients were divided into three subgroups according to the phase of the disease (oedematous, fibrotic or atrophic). At both examined areas, US showed a significant dermal thickening (p<0.001) in the whole group of patients with SSc. A low intraobserver and interobserver variability was found. A highly significant correlation between the global mRSS and the local dermal thickness at the two examined sites (p=0.032, p=0.021) was detected. Skin thickness was significantly higher in the oedematous than in the fibrotic group (p<0.001) and significantly higher in the fibrotic and the oedematous group (p<0.001) than in the atrophic group (p<0.002). US is a reliable tool giving reproducible results, and is able to detect digital dermal thickening in SSc.


Adjudin-mediated Sertoli-germ cell junction disassembly affects Sertoli cell barrier function in vitro and in vivo.
Adjudin, an analogue of lonidamine, affects adhesion between Sertoli and most germ cells, resulting in reversible infertility in rats, rabbits and dogs. Previous studies have described the apical ectoplasmic specialization, a hybrid-type of Sertoli cell-elongating/elongated spermatid adhesive junction, as a key target of adjudin. In this study, we ask if the function of the blood-testis barrier which is constituted by co-existing tight junctions, desmosome-gap junctions and basal ectoplasmic specializations can be maintained when the seminiferous epithelium is under assault by adjudin. We report herein that administration of a single oral dose of adjudin to adult rats increased the levels of several tight junction and basal ectoplasmic specialization proteins during germ cell loss from the seminiferous epithelium. These findings were corroborated by a functional in vitro experiment when Sertoli cells were cultured on Matrigel™-coated bicameral units in the presence of adjudin and transepithelial electrical resistance was quantified across the epithelium. Indeed, the Sertoli cell permeability barrier was shown to become tighter after adjudin treatment as evidenced by an increase in transepithelial electrical resistance. Equally important, the blood-testis barrier in adjudin-treated rats was shown to be intact 2 weeks post-treatment when its integrity was monitored following vascular administration of inulin-fluorescein isothiocyanate which failed to permeate past the barrier and enter into the adluminal compartment. These results illustrate that a unique mechanism exists to maintain blood-testis barrier integrity at all costs, irrespective of the presence of germ cells in the seminiferous epithelium of the testis.


The Copenhagen Standardised MRI protocol to assess the pubic symphysis and adductor regions of athletes: outline and intratester and intertester reliability.
There is currently no standardised MRI evaluation protocol for athletes who present with symptoms that may relate to the pubic symphysis, the pubic bones, and the adductor muscle insertions. We outline the protocol and reliability data. Three musculoskeletal radiologists developed an 11-element MRI evaluation protocol defined according to precise criteria and illustrated in a pictorial atlas. Eighty-six male athletes (soccer players and non-soccer players) underwent standardised 3 Tesla MRI of the pelvis. Two external musculoskeletal radiologists were trained to use the protocol and pictorial atlas during two sessions of 2-4 h each. Each radiologist rated all 86 MRI independently. One radiologist evaluated the scans once, the other twice 2 months apart. Cohen κ statistics were used to determine intraobserver and interobserver agreement. The main findings were (1) substantial intraobserver (κ range 0.65-0.67) and moderate interobserver (κ range 0.45-0.52) agreement in rating pubic bone marrow oedema, (2) substantial to moderate intraobserver (κ range 0.49-0.72) and moderate-to-fair interobserver (κ range 0.21-0.52) agreement in rating most other MRI findings, (3) slight intraobserver and interobserver (κ range -0.06-0.05) agreement in rating adductor longus tendinopathy. The Copenhagen Standardised MRI protocol demonstrated moderate-to-substantial reliability in rating bone marrow oedema, and varied from fair-to-substantial agreement for the majority of MRI features, but showed only slight agreement in rating adductor longus tendinopathy. This rigorous investigation also confirms that while MRI evaluation seems to provide reasonable reliability in rating pubic bone marrow oedema, the evaluation of adductor tendinopathy in a clinical and research setting needs further resolution by continued development and testing of MRI acquisition protocols.


Pharmacokinetics of telbivudine following oral administration of escalating single and multiple doses in patients with chronic hepatitis B virus infection: pharmacodynamic implications.
The pharmacokinetics of telbivudine were evaluated in adult patients with chronic hepatitis B virus (HBV) infection following once-daily oral administration at escalating doses of 25, 50, 100, 200, 400, and 800 mg/day for 4 weeks. Telbivudine was rapidly absorbed after oral administration, with the median times T(max) to the maximum plasma concentration (C(max)) ranging from 0.8 to 3.0 h postdosing across cohorts. Single-dose and steady-state maximum C(max)s and the areas under the plasma concentration-time curve from time zero to time t (AUC(0-t)s) increased proportionally with dose. At steady-state, the values of C(max) and AUC(0-t) were higher than those obtained after the administration of a single dose, indicative of a slight accumulation, with the ratios of the steady-state value to the value after the administration of a single dose ranging from 1.14 to 1.49 for C(max) and from 1.40 to 1.70 for AUC(0-t). While the elimination of telbivudine from plasma was apparently monophasic over the 8-h sampling period, the substantial steady-state trough plasma levels observed in the groups receiving doses of 100 to 800 mg were clearly indicative of the presence of a second slower elimination phase, with the mean estimated half-lives ranging from 29.5 to 41.3 h by compartmental modeling analysis. Pharmacokinetic and pharmacodynamic analyses by using maximum-effect modeling established a quantitative relationship between a reduction in serum HBV DNA levels and parameters of drug exposure, in particular, the steady-state C(max) and AUC(0-t). In summary, this study showed that telbivudine exhibits dose-proportional plasma pharmacokinetics with sustained steady-state drug exposure and exposure-related antiviral activity, supporting the need for further clinical studies by use of a once-daily regimen in patients with chronic HBV infection.


Acetylation of poly(ADP-ribose) polymerase-1 by p300/CREB-binding protein regulates coactivation of NF-kappaB-dependent transcription.
Poly(ADP-ribose) polymerase-1 (PARP-1) and nuclear factor kappaB (NF-kappaB) have both been demonstrated to play a pathophysiological role in a number of inflammatory disorders. We recently presented evidence that PARP-1 can act as a promoter-specific coactivator of NF-kappaB in vivo independent of its enzymatic activity. PARP-1 directly interacts with p300 and both subunits of NF-kappaB (p65 and p50) and synergistically coactivates NF-kappaB-dependent transcription. Here we show that PARP-1 is acetylated in vivo at specific lysine residues by p300/CREB-binding protein upon stimulation. Furthermore, acetylation of PARP-1 at these residues is required for the interaction of PARP-1 with p50 and synergistic coactivation of NF-kappaB by p300 and the Mediator complex in response to inflammatory stimuli. PARP-1 physically interacts with the Mediator. Interestingly, PARP-1 interacts in vivo with histone deacetylases (HDACs) 1-3 but not with HDACs 4-6 and might be deacetylated in vivo by HDACs 1-3. Thus, acetylation of PARP-1 by p300/CREB-binding protein plays an important regulatory role in NF-kappaB-dependent gene activation by enhancing its functional interaction with p300 and the Mediator complex.


MiR-222 targeted PUMA to improve sensitization of UM1 cells to cisplatin.
microRNAs have been shown to play critical roles in regulating the chemosensitivity of cancer cells. As a member of the oncogenic miRNAs (oncomiRs), miR-222 has been reported to drive the oncogenesis of many types of malignancies. However, little is known concerning the specific role of miR-222 in human oral squamous cell carcinoma (OSCC). The present study explored the role and mechanism of miR-222 in increasing the expression of p53 up-regulated modulator of apoptosis (PUMA) and enhancing the sensitivity of OSCC to cisplatin (CDDP). Results showed that antisense (As)-miR-222 inhibits the expression of miR-222. In contrast, PUMA was dramaticallyup-regulated. IC50 values were significantly decreased in cells treated with As-miR-222 combined with CDDP, to a greater extent than in cells treated with CDDP alone. Furthermore, As-miR-222 enhanced apoptosis and inhibited the invasiveness of UM1 cells. Analysis of the above data suggested that, in UM1 cells, there might be a regulatory loop between miR-222 and PUMA, and that miR-222 inhibition increased the chemosensitivity to CDDP. These findings demonstrated that down-regulation of miR-222 could enhance the chemosensitivity of human OSCC cells to CDDP, and that the combination of As-miR-222 and CDDP could be an effective therapeutic strategy by boosting the expression of PUMA for controlling the growth of OSCC.


Actigraphy of Wrist and Ankle for Measuring Sleep Duration in Altitude Travelers.
Latshang, Tsogyal Daniela, Daniela Juliana Mueller, Christian Maurizio Lo Cascio, Anne-Christin Stöwhas, Katrin Stadelmann, Noemi Tesler, Peter Achermann, Reto Huber, Malcolm Kohler, and Konrad Ernst Bloch. Actigraphy of wrist and ankle for measuring sleep duration in altitude travelers. High Alt Med Biol. 17:194-202, 2016-Aims: Actigraphy might be convenient to assess sleep disturbances in altitude field studies. Therefore, we evaluated whether actigraphy accurately measures sleep duration in healthy subjects traveling to altitude. Fifty-one healthy men, aged mean ± standard deviation (SD) 27 ± 9 years, were studied during one night at Zurich (490 m), two nights at Davos Wolfgang (1630 m), and two nights at Jakobshorn (2590 m), in randomized order. Sleep duration measured by actigraphy, using a one-axis device at the wrist (n = 51), a three-axis device at the other wrist, and a three-axis device at the ankle (n = 22), was compared with corresponding total sleep time (TST) measured by polysomnography. During 255 polysomnographic overnight studies, 449 paired actigraphic recordings were obtained. The median polysomnographic-derived TST ranged from 397 to 408 minutes. Actigraphic mean TST from wrists with one-axis and three-axis devices, and from ankle agreed well with polysomnographic values with a bias of +1, -7, +6 minutes, respectively. Corresponding limits of agreement (±2 SD of bias) were ±51, ±60, and ±59 minutes. Limits of agreement of mean TST over five nights by actigraphy and polysomnography were similar to the coefficient of repeatability (2 SD of mean) of polysomnographic TST, that is, ±31, ±38, and ±36 minutes versus ±34 minutes. Actigraphy of the wrist or ankle by a one-axis or a three-axis device accurately estimates mean TST in groups of subjects and mean TST over several nights in individuals traveling to altitude. Therefore, actigraphy is valuable for assessing effects of altitude and other environmental influences on sleep duration during field studies over extended periods.


Replicability of Neural and Behavioral Measures of Tinnitus Handicap in Civilian and Military Populations: Preliminary Results.
Purpose In the past decade, resting-state functional connectivity, acquired using functional magnetic resonance imaging (fMRI), has emerged as a popular measure of tinnitus, especially as related to self-reported handicap or psychological reaction. The goal of this study was to assess replicability of neural correlates of tinnitus, namely, resting-state functional connectivity, in the same individuals acquired over 2 sessions. Method Data were collected at 2 different sites (University of Illinois at Urbana-Champaign and Joint Base San Antonio Wilford Hall Ambulatory Surgical Center) using similar 3T magnets and similar data acquisition paradigms. Thirty-six patients (all civilians) were scanned using resting-state fMRI at the University of Illinois at Urbana-Champaign. Ten patients, active-duty Service members and Veterans, were scanned at the Wilford Hall Ambulatory Surgical Center and the Department of Defense Hearing Center of Excellence. Each participant was scanned twice, a week apart, using identical protocols of 10 min resting-state fMRI. Results Tinnitus handicap scores using the Tinnitus Functional Index and the Tinnitus Primary Function Questionnaire ranged between no or mild handicap to moderately severe handicap but did not significantly differ between visits. We examined the default mode, dorsal attention, and auditory resting-state networks and found that the strength of the within-network functional connections across visit was similar for the attention and default mode networks but not for the auditory network. In addition, the functional connection between the attention network and precuneus, a region of the default mode network, was also replicable across visits. Conclusions Our results show that resting-state fMRI measures are replicable and reliable in patients with a subjective condition, although some networks and functional connections may be more stable than others. This paves the way for using resting-state fMRI to measure the efficacy of tinnitus interventions and as a tool to help propose better management options.


Determination of oxidative stress markers and their importance in early diagnosis of uremia-related complications.
The existence of oxidative stress and the higher incidence of cardiovascular diseases in association with uremia is well proved. The uremic status of serum copper, ceruloplasmin (CP), protein thiols, malonyldialdehyde (MDA), and glutathione S-transferase (GST) levels was studied. The study was carried out on 51 chronic renal failure (CRF) patients who were not on hemodialysis therapy and on 42 healthy controls. Serum urea, creatinine, and MDA levels were found to be significantly increased (P < 0.001), and total protein, albumin, protein thiols, and copper levels were found to be significantly decreased in CRF patients compared to normal controls (P < 0.001). Ceruloplasmin levels were decreased significantly (P < 0.05), and there was no significant change in serum GST levels in CRF patients compared to normal controls. In conclusion, the significant increase in levels of MDA, and the decrease in levels of protein thiols, CP, and copper in uremia patients when compared to controls, reconfirms the presence of stress in this patient population. In view of the changes in other markers of oxidative stress, this absence of any significant change in the activity of GST in uremia patients compared to controls, warrants further study.


Adult tree swallow (Tachycineta bicolor) survival on the polychlorinated biphenyl-contaminated Housatonic River, Massachusetts, USA.
Tree swallows (Tachycineta bicolor) were captured and banded at six sites that differed in polychlorinated biphenyl (PCB) contamination levels in the Housatonic River watershed, western Massachusetts, USA, from 2000 through 2004 to test the prediction that apparent survival rates of females in more contaminated areas were lower than those from less contaminated areas. We also tested whether plumage coloration affected over-winter survival and whether concentrations of PCBs in eggs differed between birds that did and that did not return the following year. Apparent survival rates were calculated using mark-recapture methods and compared using Akaike's Information Criterion. Model-adjusted survival rates ranged from 0.365 to 0.467 for PCB-contaminated females and between 0.404 and 0.476 for reference females. Models with either survival or capture probability modeled as functions of treatment (degree of PCB contamination), year, and age received some support. The model-averaged parameter estimate reflecting a treatment effect for high-PCB birds was negative (beta = -0.046, SE(beta) = 0.0939). Fifty-four percent of the total model weights involved models in which survival was a function of PCB treatment. Eggs were collected for contaminant analyses from a random sample of females that did and that did not return the following year. Concentrations of total PCBs were the same or higher in the eggs of females that returned compared to the eggs of those that did not return at both the highly and the moderately contaminated PCB sites. This may have resulted from higher-quality females with higher lipid reserves being more likely than lower-quality females to return the following year. Percentage lipid was positively correlated with total PCBs in eggs. Survival rates were similar among swallows with brown versus blue plumage.


Study of morphological variation of northern Neotropical Ariidae reveals conservatism despite macrohabitat transitions.
Morphological convergence triggered by trophic adaptations is a common pattern in adaptive radiations. The study of shape variation in an evolutionary context is usually restricted to well-studied fish models. We take advantage of the recently revised systematics of New World Ariidae and investigate skull shape evolution in six genera of northern Neotropical Ariidae. They constitute a lineage that diversified in the marine habitat but repeatedly adapted to freshwater habitats. 3D geometric morphometrics was applied for the first time in catfish skulls and phylogenetically informed statistical analyses were performed to test for the impact of habitat on skull diversification after habitat transition in this lineage. We found that skull shape is conserved throughout phylogeny. A morphospace analysis revealed that freshwater and marine species occupy extreme ends of the first principal component axis and that they exhibit similar Procrustes variances. Yet freshwater species occupy the smallest shape space compared to marine and brackish species (based on partial disparity), and marine and freshwater species have the largest Procrustes distance to each other. We observed a single case of shape convergence as derived from 'C-metrics', which cannot be explained by the occupation of the same habitat. Although Ariidae occupy such a broad spectrum of different habitats from sea to freshwater, the morphospace analysis and analyses of shape and co-variation with habitat in a phylogenetic context shows that conservatism dominates skull shape evolution among ariid genera.


Comparison of airway measurements during influenza-induced tachypnea in infant and adult cotton rats.
Increased respiratory rate (tachypnea) is frequently observed as a clinical sign of influenza pneumonia in pediatric patients admitted to the hospital. We previously demonstrated that influenza infection of adult cotton rats (Sigmodon hispidus) also results in tachypnea and wanted to establish whether this clinical sign was observed in infected infant cotton rats. We hypothesized that age-dependent differences in lung mechanics result in differences in ventilatory characteristics following influenza infection. Lung tidal volume, dynamic elastance, resistance, and pleural pressure were measured in a resistance and compliance system on mechanically-ventilated anesthestized young (14-28 day old) and adult (6-12 week old) cotton rats. Animals at the same age were infected with influenza virus, and breathing rates and other respiratory measurements were recorded using a whole body flow plethysmograph. Adult cotton rats had significantly greater tidal volume (TV), and lower resistance and elastance than young animals. To evaluate the impact of this increased lung capacity and stiffening on respiratory disease, young and adult animals were infected intra-nasally with influenza A/Wuhan/359/95. Both age groups had increased respiratory rate and enhanced pause (Penh) during infection, suggesting lower airway obstruction. However, in spite of significant tachypnea, the infant (unlike the adult) cotton rats maintained the same tidal volume, resulting in an increased minute volume. In addition, the parameters that contribute to Penh were different: while relaxation time between breaths and time of expiration was decreased in both age groups, a disproportionate increase in peak inspiratory and expiratory flow contributed to the increase in Penh in infant animals. While respiratory rate is increased in both adult and infant influenza-infected cotton rats, the volume of air exchanged per minute (minute volume) is increased in the infant animals only. This is likely to be a consequence of greater lung elastance in the very young animals. This model replicates many respiratory features of humans and consequently may be a useful tool to investigate new strategies to treat respiratory disease in influenza-infected infants.