Diuretic strategies in patients with acute decompensated heart failure.
Loop diuretics are an essential component of therapy for patients with acute decompensated heart failure, but there are few prospective data to guide their use. In a prospective, double-blind, randomized trial, we assigned 308 patients with acute decompensated heart failure to receive furosemide administered intravenously by means of either a bolus every 12 hours or continuous infusion and at either a low dose (equivalent to the patient's previous oral dose) or a high dose (2.5 times the previous oral dose). The protocol allowed specified dose adjustments after 48 hours. The coprimary end points were patients' global assessment of symptoms, quantified as the area under the curve (AUC) of the score on a visual-analogue scale over the course of 72 hours, and the change in the serum creatinine level from baseline to 72 hours. In the comparison of bolus with continuous infusion, there was no significant difference in patients' global assessment of symptoms (mean AUC, 4236±1440 and 4373±1404, respectively; P=0.47) or in the mean change in the creatinine level (0.05±0.3 mg per deciliter [4.4±26.5 μmol per liter] and 0.07±0.3 mg per deciliter [6.2±26.5 μmol per liter], respectively; P=0.45). In the comparison of the high-dose strategy with the low-dose strategy, there was a nonsignificant trend toward greater improvement in patients' global assessment of symptoms in the high-dose group (mean AUC, 4430±1401 vs. 4171±1436; P=0.06). There was no significant difference between these groups in the mean change in the creatinine level (0.08±0.3 mg per deciliter [7.1±26.5 μmol per liter] with the high-dose strategy and 0.04±0.3 mg per deciliter [3.5±26.5 μmol per liter] with the low-dose strategy, P=0.21). The high-dose strategy was associated with greater diuresis and more favorable outcomes in some secondary measures but also with transient worsening of renal function. Among patients with acute decompensated heart failure, there were no significant differences in patients' global assessment of symptoms or in the change in renal function when diuretic therapy was administered by bolus as compared with continuous infusion or at a high dose as compared with a low dose. (Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov number, NCT00577135.).


Differentiation of meat-related microorganisms using paper-based surface-enhanced Raman spectroscopy combined with multivariate statistical analysis.
Surface-enhanced Raman spectroscopy (SERS) with subsequent chemometric evaluation was performed for the rapid and non-destructive differentiation of seven important meat-associated microorganisms, namely Brochothrix thermosphacta DSM 20171T, Pseudomonas fluorescens DSM 4358, Salmonella enterica subsp. enterica sv. Enteritidis DSM 14221, Listeria monocytogenes DSM 19094, Micrococcus luteus DSM 20030T, Escherichia coli HB101 and Bacillus thuringiensis sv. israelensis DSM 5724. A simple method for collecting spectra from commercial paper-based SERS substrates without any laborious pre-treatments was used. In order to prepare the spectroscopic data for classification at genera level with a subsequent chemometric evaluation consisting of principal component analysis and discriminant analysis, a data pre-processing method with spike correction and sum normalisation was performed. Because of the spike correction rather than exclusion, and therefore the use of a balanced data set, the multivariate analysis of the data is significantly resilient and meaningful. The analysis showed that the differentiation of meat-associated microorganisms and thereby the detection of important meat-related pathogenic bacteria was successful on genera level and a cross-validation as well as a classification of ungrouped data showed promising results, with 99.5% and 97.5%, respectively.


MHC heterozygosity and survival in red junglefowl.
Genes of the major histocompatibility complex (MHC) form a vital part of the vertebrate immune system and play a major role in pathogen resistance. The extremely high levels of polymorphism observed at the MHC are hypothesised to be driven by pathogen-mediated selection. Although the exact nature of selection remains unclear, three main hypotheses have been put forward; heterozygote advantage, negative frequency-dependence and fluctuating selection. Here, we report the effects of MHC genotype on survival in a cohort of semi-natural red junglefowl (Gallus gallus) that suffered severe mortality as a result of an outbreak of the disease coccidiosis. The cohort was followed from hatching until 250 days of age, approximately the age of sexual maturity in this species, during which time over 80% of the birds died. We show that on average birds with MHC heterozygote genotypes survived infection longer than homozygotes and that this effect was independent of genome-wide heterozygosity, estimated across microsatellite loci. This MHC effect appeared to be caused by a single susceptible haplotype (CD_c) the effect of which was masked in all heterozygote genotypes by other dominant haplotypes. The CD_c homozygous genotype had lower survival than all other genotypes, but CD_c heterozygous genotypes had survival probabilities equal to the most resistant homozygote genotype. Importantly, no heterozygotes conferred greater resistance than the most resistant homozygote genotype, indicating that the observed survival advantage of MHC heterozygotes was the product of dominant, rather than overdominant processes. This pattern and effect of MHC diversity in our population could reflect the processes ongoing in similarly small, fragmented natural populations.


Google search histories of patients presenting to an emergency department: an observational study.
To test patients' willingness to share and link their prior Google search histories with data from their electronic medical record (EMR), and to explore associations between search histories and clinical conditions. Cross-sectional study of emergency department (ED) patients from 2016 to 2017. Academic medical centre ED. A total of 703 patients were approached; 334 of a volunteer sample of 411 (81%) reported having a Google account; 165 of those (49%) consented to share their Google search histories and EMR data; 119 (72%) were able to do so. 16 (13%) of those 119 patients had no data and were not included in the final count. Patients under the age of 18 or with a triage level of 1 were considered ineligible and were not approached. Health relatedness of searches in the remote past and within 7 days of the ED visit, and associations between patients' clinical and demographic characteristics and their internet search volume and search content. The 103 participants yielded 591 421 unique search queries; 37 469 (6%) were health related. In the 7 days prior to an ED visit, the percentage of health-related searches was 15%. During that time, 56% of patients searched for symptoms, 53% for information about a hospital and 23% about the treatment or management of a disease. 53% of participants who used Google in the week leading up to their ED visit searched for content directly related to their chief complaint. Patients were willing to allow researchers simultaneous access to their Google search histories and their EMR data. The change in volume and content of search activity prior to an ED visit suggests opportunities to anticipate and improve health care utilisation in advance of ED visits.


InterAxis: Steering Scatterplot Axes via Observation-Level Interaction.
Scatterplots are effective visualization techniques for multidimensional data that use two (or three) axes to visualize data items as a point at its corresponding x and y Cartesian coordinates. Typically, each axis is bound to a single data attribute. Interactive exploration occurs by changing the data attributes bound to each of these axes. In the case of using scatterplots to visualize the outputs of dimension reduction techniques, the x and y axes are combinations of the true, high-dimensional data. For these spatializations, the axes present usability challenges in terms of interpretability and interactivity. That is, understanding the axes and interacting with them to make adjustments can be challenging. In this paper, we present InterAxis, a visual analytics technique to properly interpret, define, and change an axis in a user-driven manner. Users are given the ability to define and modify axes by dragging data items to either side of the x or y axes. from which the system computes a linear combination of data attributes and binds it to the axis. Further, users can directly tune the positive and negative contribution to these complex axes by using the visualization of data attributes that correspond to each axis. We describe the details of our technique and demonstrate the intended usage through two scenarios.


Expression of a Serratia marcescens chitinase gene in Sinorhizobium fredii USDA191 and Sinorhizobium meliloti RCR2011 impedes soybean and alfalfa nodulation.
A gene encoding chitinase from Serratia marcescens BJL200 was cloned into a broad-host-range vector (pRK415) and mobilized into Sinorhizobium fredii USDA191. Chitinolytic activity was detected in S. fredii USDA191 transconjugants that carried the S. marcescens chiB gene. Chitinase-producing S. fredii USDA191 formed nodules on soybean cultivar McCall. However, there was a delay in nodule formation and a marked decrease in the total number of nodules formed by the chitinase-producing S. fredii in comparison with the wild-type strain. Expression of chitinase in S. meliloti RCR2011 also impeded alfalfa nodulation. Thin-layer chromatography of 14C-labeled Nod factors from chitinase-producing S. fredii USDA191 revealed hydrolysis of lipochitooligosaccharides.


Forebrain pain mechanisms.
Emotional-affective and cognitive dimensions of pain are less well understood than nociceptive and nocifensive components, but the forebrain is believed to play an important role. Recent evidence suggests that subcortical and cortical brain areas outside the traditional pain processing network contribute critically to emotional-affective responses and cognitive deficits related to pain. These brain areas include different nuclei of the amygdala and certain prefrontal cortical areas. Their roles in various aspects of pain will be discussed. Biomarkers of cortical dysfunction are being identified that may evolve into therapeutic targets to modulate pain experience and improve pain-related cognitive impairment. Supporting data from preclinical studies in neuropathic pain models will be presented. Neuroimaging analysis provides evidence for plastic changes in the pain processing brain network. Results of clinical studies in neuropathic pain patients suggest that neuroimaging may help determine mechanisms of altered brain functions in pain as well as monitor the effects of pharmacologic interventions to optimize treatment in individual patients. Recent progress in the analysis of higher brain functions emphasizes the concept of pain as a multidimensional experience and the need for integrative approaches to determine the full spectrum of harmful or protective neurobiological changes in pain.


Histological subtype of gastric adenocarcinoma: two cases of mixed fundic and pyloric mucosa-type adenocarcinoma.
Adenocarcinomas with differentiation towards fundic or pyloric glands are rare histological subtypes. We herein describe two cases of new histological subtypes: mixed fundic and pyloric mucosa-type adenocarcinoma detected in Helicobacter pylori uninfected patients. The first patient was a woman in her 40s. A glossy, reddish, nodular lesion with a flat elevated whitish area was detected at the gastric fundus. When the nodular lesion was visualised with magnifying narrow-band imaging (M-NBI), an absent microvascular pattern plus an irregular microsurface pattern with a demarcation line was observed. The second patient was a woman in her 60s. A glossy, reddish, elevated lesion was detected at the gastric body. M-NBI finding was a regular microvascular pattern plus a regular microsurface pattern with a demarcation line. Histological examination of the resected specimens from both cases showed a very well- to well-differentiated adenocarcinoma which has differentiation towards the mixed fundic and pyloric mucosa. The histological and serological findings of both cases indicated the absence of H. pylori infection. The present two cases demonstrate further evidence of a new histological subtype of gastric adenocarcinoma: mixed fundic and pyloric mucosa-type adenocarcinoma, which has distinct characteristic endoscopic findings.


Preoperative and intraoperative continuous use of dexmedetomidine on hyperalgesia after patients' remifentanil anesthesia.
Analyze clinical use of dexmedetomidine to relieve prognosis of remifentanil anesthesia recovery and analyze intervention effect. Choose 3600 cases of cerebral functional area operation patients treated in different hospitals during June 2011 and December 2015 for general analysis, group the patients by considering relevant parting of anesthesia recovery by American Society of Anesthesiologists, and divide the patients into dexmedetomidine group and control group according to different use of drugs. The two groups of patients are anesthetized, patients' anesthesia wake-up time and wake-up success rate are recorded, and effect of two types of anesthesia wake-up way are compared. There exists no significant statistical difference in wake-up success rate of the two groups of patients, wake-up time has small difference, but anesthesia recovery quality of dexmedetomidine group is higher, which is conducive to physical rehabilitation of patients and minimize the effects of anesthetics on patients. In clinical surgery, after use of remifentanil anesthesia on patients, use of dexmedetomidine for anesthesia recovery can minimize adverse effects of drugs on patients and thus is worthy to be effectively promoted in clinics.


Involvement of capsaicin-sensitive afferent nerves and cholecystokinin 2/gastrin receptors in gastroprotection and adaptation of gastric mucosa to Helicobacter pylori-lipopolysaccharide.
Lipopolysaccharide (LPS) is one of the virulence factors in the Helicobacter pylori (Hp)-infected stomach, but it remains unknown whether single and prolonged pretreatment with Hp-LPS can affect the course of gastric damage induced by aspirin (ASA). We compared the effects of Hp-LPS with those induced by LPSs isolated from intestinal Bacteroides fragilis, Yersinia enterocolitica, and Campylobacter jejuni applied for 4 days on acute ASA-induced gastric lesions in rats. The area of ASA-induced gastric lesions, gastric blood flow (GBF), expression of mRNA and protein of leptin and plasma leptin, gastrin, interleukin-1beta, and tumor necrosis factor-alpha levels were examined. Single (once) or repeated (five times) i.p. injections of Hp-LPS (1 mg/kg) or intestinal LPSs failed to produce macroscopic gastric damage and did not affect the GBF when compared with vehicle. Hp-LPS injected repeatedly suppressed the gastric acid secretion, up-regulated leptin mRNA and protein, and increased plasma leptin and gastrin levels. Hp-LPS significantly reduced the ASA-induced gastric damage and the accompanying decline in the GBF, and these effects were significantly attenuated by capsaicin denervation and selective antagonism of cholecystokinin-B (CCK2) receptors by RPR-102681 [N-(metoxy-3 phenyl) N-(N-methyl N-phenyl-carbamylmethyl) carbamoylmethyl]-3 ureido]-3 phenyl]-2 propronique] but not by loxiglumide, an antagonist of CCK1 receptors. We conclude that 1) daily application of Hp-LPS enhances gastric mucosal resistance against ASA damage due to the increase of GBF and the expression and release of leptin and gastrin exerting trophic and gastroprotective effects, and 2) this enhanced resistance to ASA damage in Hp-LPS-adapted stomach is mediated by the sensory afferents and specific CCK2/gastrin receptors.


Evolving homogeneous neurocontrollers for a group of heterogeneous robots: coordinated motion, cooperation, and acoustic communication.
This article describes a simulation model in which artificial evolution is used to design homogeneous control structures and adaptive communication protocols for a group of three autonomous simulated robots. The agents are required to cooperate in order to approach a light source while avoiding collisions. The robots are morphologically different: Two of them are equipped with infrared sensors, one with light sensors. Thus, the two morphologically identical robots should take care of obstacle avoidance; the other one should take care of phototaxis. Since all of the agents can emit and perceive sound, the group's coordination of actions is based on acoustic communication. The results of this study are a proof of concept: They show that dynamic artificial neural networks can be successfully synthesized by artificial evolution to design the neural mechanisms required to underpin the behavioral strategies and adaptive communication capabilities demanded by this task. Postevaluation analyses unveil operational aspects of the best evolved behavior. Our results suggest that the building blocks and the evolutionary machinery detailed in the article should be considered in future research work dealing with the design of homogeneous controllers for groups of heterogeneous cooperating and communicating robots.


An alternative to SH2 domains for binding tyrosine-phosphorylated proteins.
Src homology 2 (SH2) domains bind specifically to tyrosine-phosphorylated proteins that participate in signaling by growth factors and oncogenes. A protein domain was identified that bound specifically to the tyrosine-phosphorylated form of its target protein but differs from known SH2 sequences. Phosphotyrosine-binding (PTB) domains were found in two proteins: SHC, a protein implicated in signaling through Ras; and SCK, encoded by a previously uncharacterized gene. The PTB domain of SHC specifically bound to a tyrosine-phosphorylated 145-kilodalton protein. PTB domains are an alternative to SH2 domains for specifically recruiting tyrosine-phosphorylated proteins into signaling complexes and are likely to take part in signaling by many growth factors.


Can an infectious disease genomics project predict and prevent the next pandemic?
The world of genomics is transforming medicine, and is likely to influence the future development of new drugs, diagnostics, and vaccines. To date, the greater focus of genomics and medicine has been on conditions affecting resourcewealthy settings, primarily involving scientists and companies in those settings. However, we believe that it is possible to expand genomics into a more global technology that can also focus on diseases of resource-limited settings. This goal can be achieved if genomics is made a global priority. We feel one way to move in this direction is through a comprehensive approach to infectious diseases-i.e., an Infectious Disease Genomics Project-that would mirror the Human Genome Project. Without an active, unified effort specifically focused on allowing actors at any level to participate in the genomics revolution, infectious diseases that primarily affect the poor will likely not achieve the same level of scientifici advancement as diseases affecting the wealthy.


Treatment of isolated ascending aortic aneurysm by off-pump epiaortic wrapping is safe and durable.
Isolated ascending aortic aneurysm (iAA) is usually treated by open graft repair requiring sternotomy, cardiopulmonary bypass (CPB) and cardioplegia. This approach carries significant mortality in older patients or those presenting with comorbidities. We report an original series of patients presenting with iAA and treated with epiaortic wrapping by using a synthetic mesh. This less invasive aortic repair technique allows reducing the aortic diameter to a predefined value and is performed without CPB. Data from patients presenting with an iAA and treated with the wrapping technique (WT) by polypropylene/polyester mesh from November 2006 to July 2015 were collected. The end-points that were analysed included maximal aortic transverse diameter, perioperative mortality and morbidity, survival, freedom from reinterventions and aortic valve function during follow-up. The maximal aneurysm transverse diameter was analysed based on contrast-enhanced computed tomography (CTA) or magnetic resonance (MR) performed preoperatively, and during the follow-up. The off-pump WT was used in 33 cases with no perioperative mortality. The median radiological follow-up was 33.47 (range: 1-106) months. Overall, the WT achieved a 30% diameter reduction. The mean preoperative and postoperative ascending aortic transverse diameter was 5.5 cm [standard deviation (SD): 0.6] and 3.7 cm (SD: 0.30), respectively (P = 0.001). In addition, CTA or MR follow-up showed stable diameters at the level of the aortic root and the distal ascending aorta. No death occurred during the follow-up. At 5 years, the estimated freedom rate from reinterventions of the aortic root and ascending aorta was 94%. This series shows that the WT with a polypropylene/polyester mesh allows safe off-pump treatment of patients with iAA. Mid- and long-term results are promising. This technique could be an attractive alternative, especially for patients unfit for aortic surgery with CPB and cardioplegia.


LIM domain-binding 1 maintains the terminally differentiated state of pancreatic β cells.
The recognition of β cell dedifferentiation in type 2 diabetes raises the translational relevance of mechanisms that direct and maintain β cell identity. LIM domain-binding protein 1 (LDB1) nucleates multimeric transcriptional complexes and establishes promoter-enhancer looping, thereby directing fate assignment and maturation of progenitor populations. Many terminally differentiated endocrine cell types, however, remain enriched for LDB1, but its role is unknown. Here, we have demonstrated a requirement for LDB1 in maintaining the terminally differentiated status of pancreatic β cells. Inducible ablation of LDB1 in mature β cells impaired insulin secretion and glucose homeostasis. Transcriptomic analysis of LDB1-depleted β cells revealed the collapse of the terminally differentiated gene program, indicated by a loss of β cell identity genes and induction of the endocrine progenitor factor neurogenin 3 (NEUROG3). Lineage tracing confirmed that LDB1-depleted, insulin-negative β cells express NEUROG3 but do not adopt alternate endocrine cell fates. In primary mouse islets, LDB1 and its LIM homeodomain-binding partner islet 1 (ISL1) were coenriched at chromatin sites occupied by pancreatic and duodenal homeobox 1 (PDX1), NK6 homeobox 1 (NKX6.1), forkhead box A2 (FOXA2), and NK2 homeobox 2 (NKX2.2) - factors that co-occupy active enhancers in 3D chromatin domains in human islets. Indeed, LDB1 was enriched at active enhancers in human islets. Thus, LDB1 maintains the terminally differentiated state of β cells and is a component of active enhancers in both murine and human islets.


The effect of a nutritionally-balanced cassava (Manihot esculenta Crantz) diet on endocrine function using the dog as a model. 2. Thyroid.
Growing dogs were divided into three groups and were fed on nutritionally-balanced diets. Control dogs were fed on a rice diet, the cassava (gari) group ate a diet in which gari provided the carbohydrate source, while the rice + cyanide group consumed the rice diet to which hydrocyanic acid (equivalent to that present in gari) was added. Each group consumed its diet for 14 weeks, during which plasma thiocyanate concentration and total serum triiodothyronine (T3) were monitored. At the end of the experiment the concentrations of the plasma free amino acids phenylalanine and tyrosine, the thyroid weights and histology were determined. While plasma thiocyanate remained undetectable in control dogs, animals consuming both gari and rice + cyanide generated significant amounts. In the control dogs and the gari group, total serum T3 increased 40 and 38.8% respectively from the basal level by the end of the period (P less than 0.02). In contrast there was a decrease in T3 by 36% in the dogs fed on rice + cyanide (P less than 0.05). This group also showed significant thyroid enlargement and a histological picture consistent with parenchymatous goitre, whereas the gari group was essentially normal. The relatively low mean thyroid weight, the rise in total serum T3 level and the normal histological appearance of the gland indicate that dogs that consumed the gari diet were essentially normal with respect to their thyroid function, in spite of their high blood thiocyanate content. In contrast, dogs that consumed rice with cyanide suffered from hypothyroidism and goitre.(ABSTRACT TRUNCATED AT 250 WORDS)


Reduced relationship to cortical white matter volume revealed by tractography-based segmentation of the corpus callosum in young children with developmental delay.
The corpus callosum is the primary anatomical substrate for interhemispheric communication, which is important for a range of adaptive and cognitive behaviors in early development. Previous studies that have measured the corpus callosum in developmental populations have been limited by the use of rather arbitrary methods of subdividing the corpus callosum. The purpose of this study was to measure the corpus callosum in a clinical group of developmentally delayed children using a subdivision that more accurately reflected the anatomical properties of the corpus callosum. The authors applied tractography to subdivide the corpus callosum into regions corresponding to the cortical regions to and from which its fibers travel in a clinical group of very young children with developmental delay, a precursor to general mental retardation, in comparison with typically developing children. The data demonstrate that the midsagittal area of the entire corpus callosum is reduced in children presenting with developmental delay, reflected in the smaller area of each of the fiber-based callosal subdivisions. In addition, while the area of each subdivision was strongly and significantly correlated with the corresponding cortical white matter volume in comparison subjects, this correlation was prominently absent in the developmentally delayed group. A fiber-based subdivision successfully separates lobar regions of the corpus callosum, and the areas of these regions distinguish a developmentally delayed clinical group from the comparison group. This distinction was evident both in the area measurements themselves and in their correlation to the white matter volumes of the corresponding cortical lobes.


Quantifying the effect of age on short-term and long-term case fatality in 14,000 patients with incident cases of cardiovascular disease.
Age is a major determinant of case fatality following acute cardiovascular disease (CVD) events. Its impact, however, varies by time after the event, sex and diagnostic category. We were able to quantify these effects with good precision in a large cohort of patients. A national cohort of 14,227 CVD patients representing all the recorded first-CVD events in people aged 35-84 years in New Zealand in 1995 were examined, using electronic linkage of routine health data. Case fatality by age was assessed in three phases: prehospital deaths, fatality after hospitalization up to 28 days and from 28 days up to 5 years after the event. It was assessed in these phases by sex and by the diagnostic categories: acute myocardial infarction (AMI), stroke and other coronary heart diseases. Case fatality in the prehospital phase showed substantial age differences. In particular, a strong positive monotonic age gradient was observed for AMI, but a U-shaped age-case-fatality gradient for stroke. From admission to 28 days, AMI case fatality demonstrated the strongest age gradient. In contrast, there was minimal age effect on 28-day stroke mortality, and case fatality for other coronary heart diseases was low. From 28 days to 5 years, there was a substantial positive monotonic age by case-fatality gradient for all diagnoses. Age has a large impact on case fatality following cardiovascular events, although the effect varies significantly by time elapsed after the event, diagnostic category and sex. As the lifetime benefits of many cardiovascular interventions depend on preintervention risk and case fatality, the role of age needs careful attention while making treatment decisions.


Comparison of different focusing fiber tips for improved oral diode laser surgery.
State of the art for use of the fiber guided diode laser in dental therapy is the application of bare fibers. A novel concept with delivery fiber and exchangeable fiber tips enables the use of tips with special and optimized geometries for various applications. The aim of this study is the comparison of different focusing fiber tips for enhanced cutting efficacy in oral surgery. For this purpose various designs of tip geometry were investigated and optimized by ray tracing simulations. Two applicators, one with a sphere, and another one with a taper, were realized and tested on porcine gingiva (diode laser, 940 nm, 5 W/cw; 7 W/modulated). The cutting depth and quality were determined by light microscope. Histological sections of the cuts were prepared by a cryo-microtome and microscopically analyzed to determine the cut depths and thermal damage zones. The simulations show that, using a sphere as fiber tip, an intensity increase of up to a factor of 16.2 in air, and 13.2 in water compared to a bare 200 µm fiber can be achieved. Although offering high focusing factor in water, the cutting quality of the sphere was rather poor. This is probably caused by a derogation of the focusing quality due to contamination during cutting and light scattering. Much better results were achieved with conically shaped fiber tips. Compared to bare fibers they exhibit improved handling properties with no hooking, more regular and deeper cuts (5 W/cw: 2,393 ± 468 µm, compared to the cleaved bare fiber 5 W/cw: 711 ± 268 µm). The thermal damage zones of the cuts are comparable for the various tips and fibers. In conclusion the results of our study show that cutting quality and efficiency of diode laser on soft tissue can be significantly improved using conically shaped fiber tips.


What is Developmental Dyslexia?
Until the 1950s, developmental dyslexia was defined as a hereditary visual disability, selectively affecting reading without compromising oral or non-verbal reasoning skills. This changed radically after the development of the phonological theory of dyslexia; this not only ruled out any role for visual processing in its aetiology, but it also cast doubt on the use of discrepancy between reading and reasoning skills as a criterion for diagnosing it. Here I argue that this theory is set at too high a cognitive level to be explanatory; we need to understand the pathophysiological visual and auditory mechanisms that cause children's phonological problems. I discuss how the 'magnocellular theory' attempts to do this in terms of slowed and error prone temporal processing which leads to dyslexics' defective visual and auditory sequencing when attempting to read. I attempt to deal with the criticisms of this theory and show how it leads to a number of successful ways of helping dyslexic children to overcome their reading difficulties.


Improved EEG source localization with Bayesian uncertainty modelling of unknown skull conductivity.
Electroencephalography (EEG) source imaging is an ill-posed inverse problem that requires accurate conductivity modelling of the head tissues, especially the skull. Unfortunately, the conductivity values are difficult to determine in vivo. In this paper, we show that the exact knowledge of the skull conductivity is not always necessary when the Bayesian approximation error (BAE) approach is exploited. In BAE, we first postulate a probability distribution for the skull conductivity that describes our (lack of) knowledge on its value, and model the effects of this uncertainty on EEG recordings with the help of an additive error term in the observation model. Before the Bayesian inference, the likelihood is marginalized over this error term. Thus, in the inversion we estimate only our primary unknown, the source distribution. We quantified the improvements in the source localization when the proposed Bayesian modelling was used in the presence of different skull conductivity errors and levels of measurement noise. Based on the results, BAE was able to improve the source localization accuracy, particularly when the unknown (true) skull conductivity was much lower than the expected standard conductivity value. The source locations that gained the highest improvements were shallow and originally exhibited the largest localization errors. In our case study, the benefits of BAE became negligible when the signal-to-noise ratio dropped to 20 dB.


Gradient-index lens optical backplane.
An optical backplane design based on gradient-index lenses is described. This design is based on a tapped bus architecture and offers an affordable and efficient card-to-card communication method. It was found that the use of gradient-index lenses reduced the alignment tolerances by a factor of 10 over an equivalent free-space model. Results from simulation and from the construction of a five-node, proof-of-concept demonstration unit are presented. The excess loss measured for the 25 different combinations varied from a low of 0.7 dB to a high of 4.0 dB.


TRAF6 is essential for maintenance of regulatory T cells that suppress Th2 type autoimmunity.
Regulatory T cells (Tregs) maintain immune homeostasis by limiting inflammatory responses. TRAF6 plays a key role in the regulation of innate and adaptive immunity by mediating signals from various receptors including the T-cell receptor (TCR). T cell-specific deletion of TRAF6 has been shown to induce multiorgan inflammatory disease, but the role of TRAF6 in Tregs remains to be investigated. Here, we generated Treg-specific TRAF6-deficient mice using Foxp3-Cre and TRAF6-flox mice. Treg-specific TRAF6-deficient (cKO) mice developed allergic skin diseases, arthritis, lymphadenopathy and hyper IgE phenotypes. Although TRAF6-deficient Tregs possess similar in vitro suppression activity compared to wild-type Tregs, TRAF6-deficient Tregs did not suppress colitis in lymphopenic mice very efficiently due to reduced number of Foxp3-positive cells. In addition, the fraction of TRAF6-deficient Tregs was reduced compared with wild-type Tregs in female cKO mice without inflammation. Moreover, adoptive transfer of Foxp3 (+) Tregs into Rag2(-/-) mice revealed that TRAF6-deficient Tregs converted into Foxp3(-) cells more rapidly than WT Tregs under lymphopenic conditions. Fate-mapping analysis also revealed that conversion of Tregs from Foxp3(+) to Foxp3(-) (exFoxp3 cells) was accelerated in TRAF6-deficient Tregs. These data indicate that TRAF6 in Tregs plays important roles in the maintenance of Foxp3 in Tregs and in the suppression of pathogenic Th2 type conversion of Tregs.


Identifying reproducible individual differences in childhood functional brain networks: An ABCD study.
The 21-site Adolescent Brain Cognitive Development (ABCD) study provides an unparalleled opportunity to characterize functional brain development via resting-state functional connectivity (RSFC) and to quantify relationships between RSFC and behavior. This multi-site data set includes potentially confounding sources of variance, such as differences between data collection sites and/or scanner manufacturers, in addition to those inherent to RSFC (e.g., head motion). The ABCD project provides a framework for characterizing and reproducing RSFC and RSFC-behavior associations, while quantifying the extent to which sources of variability bias RSFC estimates. We quantified RSFC and functional network architecture in 2,188 9-10-year old children from the ABCD study, segregated into demographically-matched discovery (N = 1,166) and replication datasets (N = 1,022). We found RSFC and network architecture to be highly reproducible across children. We did not observe strong effects of site; however, scanner manufacturer effects were large, reproducible, and followed a "short-to-long" association with distance between regions. Accounting for potential confounding variables, we replicated that RSFC between several higher-order networks was related to general cognition. In sum, we provide a framework for how to characterize RSFC-behavior relationships in a rigorous and reproducible manner using the ABCD dataset and other large multi-site projects.


Role of ATP-dependent K(+) channels in the electrical excitability of early embryonic stem cell-derived cardiomyocytes.
Single, murine embryonic stem cell-derived early stage cardiomyocytes dissociated from embryoid bodies expressed two inward rectifier K(+) channels, I(K1) and the ATP dependent K(+) current. I(K1) exhibited low density in early stage cardiomyocytes, but increased significantly in late stage cells. In contrast, the ATP dependent K(+) current was expressed at similar densities in early and late stage cardiomyocytes. This current was found to be involved in the determination of the membrane potential, since glibenclamide depolarized early cardiomyocytes and exerted a positive chronotropic effect. Some cardiomyocytes displayed a bursting behavior of action potentials, characterized by alternating periods with and without action potentials. During the phases without action potentials, the membrane potential was hyperpolarized, indicating the involvement of K(+) channels in the generation of this bursting behavior. Extracellular recording techniques were applied to spontaneously contracting areas of whole embryoid bodies. In 20% of these bursting behavior similar to that seen in the single cells was observed. In regularly beating embryoid bodies, bursting could be induced by reduction of substrates from the extracellular medium as well as by superfusion with the positive chronotropic agents Bay K 8644 or isoproterenol. Perfusion with substrate-reduced medium induced bursting behavior after a short latency, isoproterenol and Bay K 8644 resulted in a positive chronotropic response followed by bursting behavior with longer latencies. The spontaneous bursting was blocked by glibenclamide. These experimental results suggest that intermittent activation of ATP dependent K(+) channels underlies the bursting behavior observed in single cardiomyocytes and in the whole embryoid body. Conditions of metabolic stress lead to the rhythmic suppression of action potential generation. Our data indicate that ATP dependent K(+) channels play a prominent role in the cellular excitability of early cardiomyocytes.


Response patterning on an avoidance schedule as a function of time-correlated stimuli.
Control of avoidance response patterning by time-correlated stimuli was studied in rhesus monkeys. At several shock-shock = response-shock intervals, the intervals were divided into 8, 4, or 2 time segments by correlating, respectively, 1, 2, or 4 discrete lights of an eight-light display with each successive segment. A further condition examined response patterning when the avoidance interval was not segmented: all eight lights of the display were lit throughout the interval. Reversal of the order in which the lights were lit in sequence was also examined. Generally, increasing the number of lights lit at one time (decreasing the number of signalled time segments) increased response rates and shifted interresponse time distributions to the left. When the lights were lit one at a time, signalling eight discrete time segments of the interval, response rates were consistently low.


Phlebotomine mortality effect of systemic insecticides administered to dogs.
Zoonotic visceral leishmaniasis (ZVL) caused by Leishmania (Leishmania) infantum is an important disease in humans and dogs. Different mammal species are reservoirs but dogs are considered to be the main one. Phlebotomine sand flies are the proven vector. Four systemic insecticides approved for their use in dogs were previously selected based on their potential to be used in endemic countries as part of the control programs of ZVL. These insecticides are proved to be safe and effective against the on-label insects and parasites, but there is no information about their activity against phlebotomine sand flies. The phlebotomine mortality of four systemic insecticides in dogs was evaluated using two randomized clinical trials. For the first trial, thirty dogs were randomly allocated into five groups: four treatments and one control, of equal size. The treatments evaluated were: Guardian®SR, Elanco (moxidectin); Comfortis®, Elanco (spinosad); Bravecto®, Merck Animal Health (fluralaner); and NexGard®, Merial (afoxolaner). Blood from dogs was taken at days 2, 4, 21 and 31 post-treatment (trial 1). The compound that showed the highest efficacy was selected for a second trial (trial 2) with 20 dogs sampled at days 0, 2, 4, 7, 14, 18, 32, 39, 51 and 84 post-treatment. Membrane feeding bioassays with Phlebotomus papatasi were used to evaluate the phlebotomine mortality efficacy of the different treatments. Phlebotomine mortality was observed every 24 h following the membrane feeding during 5 days. A mixed model for a negative binomial logistic regression, and a Cox proportional hazard mixed model were used to estimate phlebotomine mortality due to different treatments. Fluralaner was the only compound that showed significant phlebotomine mortality. Fluralaner maintained the phlebotomine mortality between 60-80% for 30 days after treatment. In trial 1 we found that fluralaner increased the risk of death by 1.9 times (95% CI: 1.02-3.6) and 1.7 times (95% CI: 1.09-2.6) at days 2 and 4 after treatment. The Cox model resulted in an increase of 1.47 (95% CI: 1.1-1.96) times in hazard risk at day 2 and 1.89 (95% CI: 1.35-2.45) at day 4 after treatment. In trial 2 we found that fluralaner increased the risk of death by 1.64 times (95% CI: 1.16-2.54) and 1.97 times (95% CI: 1.23-3.17) at days 14 and 32. The hazard risk was also increased by 1.92 (95% CI: 1.4-2.64) times at day 14 after treatment. Phlebotomine survival including all experimental days was significantly lower in the fluralaner group in both trials. A single oral treatment of fluralaner in dogs induces phlebotomine mortality. Systemic insecticides in dogs should be considered as a potential preventive measure of ZVL.


STITCHER: Dynamic assembly of likely amyloid and prion β-structures from secondary structure predictions.
The supersecondary structure of amyloids and prions, proteins of intense clinical and biological interest, are difficult to determine by standard experimental or computational means. In addition, significant conformational heterogeneity is known or suspected to exist in many amyloid fibrils. Previous work has demonstrated that probability-based prediction of discrete β-strand pairs can offer insight into these structures. Here, we devise a system of energetic rules that can be used to dynamically assemble these discrete β-strand pairs into complete amyloid β-structures. The STITCHER algorithm progressively 'stitches' strand-pairs into full β-sheets based on a novel free-energy model, incorporating experimentally observed amino-acid side-chain stacking contributions, entropic estimates, and steric restrictions for amyloidal parallel β-sheet construction. A dynamic program computes the top 50 structures and returns both the highest scoring structure and a consensus structure taken by polling this list for common discrete elements. Putative structural heterogeneity can be inferred from sequence regions that compose poorly. Predictions show agreement with experimental models of Alzheimer's amyloid beta peptide and the Podospora anserina Het-s prion. Predictions of the HET-s homolog HET-S also reflect experimental observations of poor amyloid formation. We put forward predicted structures for the yeast prion Sup35, suggesting N-terminal structural stability enabled by tyrosine ladders, and C-terminal heterogeneity. Predictions for the Rnq1 prion and alpha-synuclein are also given, identifying a similar mix of homogenous and heterogeneous secondary structure elements. STITCHER provides novel insight into the energetic basis of amyloid structure, provides accurate structure predictions, and can help guide future experimental studies.


Prevalence of complications of male circumcision in Anglophone Africa: a systematic review.
There is growing evidence that male circumcision (MC) prevents heterosexual acquisition of HIV by males in sub-Saharan Africa, the region of the world heavily affected by the HIV pandemic. While there is growing support for wide-spread availability and accessibility of MC in Africa, there is limited discussion about the prevalence of physical complications of male circumcision on the continent. A systematic literature search and review of articles in indexed journals and conference abstracts was conducted to collect and analyze prevalence of complications of MC in Anglophone sub-Saharan Africa. Information extracted included: indications for MC, complications reported, age of patients and category of circumcisers. There were 8 articles and 2 abstracts that were suitable for the analysis. The studies were not strictly comparable as some reported on a wide range of complications while others reported just a limited list of possible complications. Prevalence of reported complications of MC ranged from 0% to 50.1%. Excluding the study with 50.1%, which was on a series of haemophilia patients, the next highest prevalence of complications was 24.1%. Most of the complications were minor. There was no firm evidence to suggest that MCs performed by physician surgeons were associated with lower prevalence of complications when compared with non-physician health professionals. The available data are inadequate to obtain a reasonable assessment of the prevalence of complications of MC in sub-Saharan Africa. Some of the available studies however report potentially significant prevalence of complications, though of minor clinical significance. This should be considered as public health policy makers consider whether to scale-up MC as an HIV preventative measure. Decision for the scale-up will depend on a careful cost-benefit assessment of which physical complications are certainly an important aspect. There is need for standardized reporting of complications of male circumcision.


Sulodexide ameliorates early but not late kidney disease in models of radiation nephropathy and diabetic nephropathy.
Sulodexide is a glycosaminoglycan with anticoagulant and antithrombotic activities. Although sulodexide reduced albuminuria in patients with type 1 and type 2 diabetes, long-term effects on chronic renal injury are not established. We investigated sulodexide effects and mechanisms in a rat radiation nephropathy model and in the db/db mouse model of diabetic kidney disease. Sprague-Dawley rats received kidney radiation and were treated as follows: 15 mg/kg/day sulodexide s.c., 6 day/week (SUL) or no treatment (CONT). Subsets of animals were sacrificed after 8 weeks and 12 weeks. Blood pressure, serum creatinine, creatinine clearance (CrCl) and urinary protein excretion were measured every 4 weeks. Sclerosis and plasminogen activator inhibitor-1 (PAI-1) expression were assessed at 8 and 12 weeks, and collagen I, total collagen content and phospho-smad-2 expressions were determined at 12 weeks. Twelve-week-old db/db mice received sulodexide as above or vehicle. Albuminuria and CrCl were assessed at intervals till sacrifice at week 9 with assessment of urinary transforming growth factor-beta (TGF-beta) and glomerular lesions. Blood pressure, serum creatinine and CrCl were not different in radiation rat CONT vs SUL at any time. Proteinuria was significantly lower in SUL compared to CONT at 4 and 8 weeks but not at 12 weeks. Sclerosis and PAI-1 expression trended lower in SUL vs CONT at 8 weeks. There was no difference between the groups in sclerosis, collagen I mRNA, total collagen content or PAI-1 expression at 12 weeks. Phospho-smad 2 expression was significantly decreased in SUL compared to CONT at 12 weeks. Db/db mice with or without SUL showed no difference in urinary albumin/creatinine ratio, urine TGF-beta or mesangial matrix expansion. Our data show that sulodexide can reduce the early, but not late, proteinuria in radiation nephropathy in rats. In addition, sulodexide did not affect urine TGF-beta established albuminuria or mesangial matrix expansion in a chronic model of diabetic kidney disease in mice. Although sulodexide may affect TGF-beta activation in radiation nephropathy, this effect appeared insufficient in this model to inhibit the expressions of PAI-1 and collagen and reduce accumulation of extracellular matrix. These results may explain in part its lack of efficacy in recent clinical trials of chronic kidney disease.


Drawing the boundaries of nanoscience--rationalizing the concerns?
Nanotechnology as an emerging field is strongly related to visionary prospects which are disposed to reappear as dystopian concerns. As long as nanotechnology does not provide reliable criteria for assessing these worries as rational or as irrational they remain a challenge for ethical reflection. Given this underdetermination, many nanovisions and their corresponding concerns should therefore be considered as "arational." For that reason, a "constructivist" stance is endorsed which does not seek to take part in discussions as to how ethicists should cope with controversial worries, but tries to observe how concerns are managed by different social actors. This perspective allows us to remodel some concerns such as "grey goo" not solely as a societal reaction, but also as challenging and irritating factors. As such they potentially initiate two different processes simultaneously: a differentiation in terms of demarcating science from non-science on the one hand, and a rationalization of concerns on the other. Analyzing these processes empirically allows to reconstruct how "arational" concerns are socially made rational or, on the contrary, irrational.


The effect of GSM-like ELF radiation on the alpha band of the human resting EEG.
Mobile phone handsets such as those operating in the GSM network emit extremely low frequency electromagnetic fields ranging from DC to at least 40 kHz. As a subpart of an extended protocol, the influence of these fields on the human resting EEG has been investigated in a fully counter balanced, double blind, cross-over design study that recruited 72 healthy volunteers. A decrease in the alpha frequency band was observed during the 20 minutes of ELF exposure in the exposed hemisphere only. This result suggests that ELF fields as emitted from GSM handsets during the DTX mode may have an effect on the resting alpha band of the human EEG.


Distinct tumour antigen-specific T-cell immune response profiles at different hepatocellular carcinoma stages.
Cancer-testis antigens (CTAs) and tumour-associated antigens (TAAs) are frequently expressed in hepatocellular carcinoma (HCC); however, the role of tumour-antigen-specific T cell immunity in HCC progression is poorly defined. We characterized CTA- and TAA-specific T cell responses in different HCC stages and investigated their alterations during HCC progression. Fifty-eight HCC patients, 15 liver cirrhosis patients, 15 chronic hepatitis B patients and 10 heathy controls were enrolled in total. IFN-γ ELSPOT using CTAs, including MAGE-A1, MAGE-A3, NY-ESO-1, and SSX2, and two TAAs, SALL4 and AFP, was performed to characterize the T-cell immune response in the enrolled individuals. The functional phenotype of T cells and the responsive T cell populations were analyzed using short-term T-cell culture. T cell responses against CTAs and TAAs were specific to HCC. In early-stage HCC patients, the SALL4-specific response was the strongest, followed by MAGE-A3, NY-ESO-1, MAGE-A1 and SSX2. One-year recurrence-free survival after transcatheter arterial chemoembolization plus radiofrequency ablation treatment suggested the protective role of CTA-specific responses. The four CTA- and SALL4-specific T cell responses decreased with the progression of HCC, while the AFP-specific T cell response increased. A higher proportion of CD4+ T cells specific to CTA/SALL4 was observed than AFP-specific T cell responses. The IFN-γ ELISPOT assay characterized distinct profiles of tumour-antigen-specific T cell responses in HCC patients. CTA- and SALL4-specific T cell responses may be important for controlling HCC in the early stage, whereas AFP-specific T cell responses might be a signature of malignant tumour status in the advanced stage. The application of immunotherapy at an early stage of HCC development should be considered.


Unfavorable prognosis of acute leukemia in infancy.
Pretreatment characteristics of 48 infants (under 2 years of age) with leukemia treated over a period of 18 years at a single institution were studied in relation to response to therapy, extramedullary involvement, and survival. In order to provide a basis of comparison, 45 of the infants were each paired with an older (2-9 years of age) leukemic child, who had the same race, and disease type, who was treated within the same period of time and received similar suportive care and chemotherapy, and when possible, was of the same sex. The overall median survival times of infants and their pairmates were 211 days and 445 days, respectively. Initial status of the spleen was the single significant factor in relation to the length of survival. Median survival time for infants with splenomegaly was 186 days compared to a median survival time of 414 days for infants without splenomegaly. The complete response rate was 75% for infants and 80% for the pairmates. Median duration of remission was 84 days for infants and 280 days for their pairmates. Initial peripheral leucocyte count was significantly related to the duration of remission; patients with very high leucocyte counts had the shortest remissions. The duration of remission increased throughout the period covered by this study, however, prognosis relative to pairmates remained poor. Central nervous system leukemia occurred in 44% of infants and 40% of the pairmates; incidence of CNS leukemia was much higher (70%) in infants under one year of age than in infants one year old (37%). Extramedullary leukemia occurred at other sites in 46% of the infants and 31% of the pairmates. The only pretreatment characteristic of prognostic importance for predicting extramedullary involvement was the patient's age at diagnosis.


Promotion of physical activity in a developing country: the Agita São Paulo experience.
The purpose of this paper is to present key points of an intervention programme (Agita São Paulo Program) to promote physical activity in a developing country. Agita is a multi-level, community-wide intervention designed to increase knowledge about the benefits and the level of physical activity in a mega-population of 34 million inhabitants of São Paulo State, Brazil. The main message was taken from the Centers for Disease Control/American College of Sports Medicine (CDC/ACSM) recommendation that: 'everyone should accumulate at least 30 minutes of physical activity, on most days of the weeks, of moderate intensity, in one single or in multiple sessions'. Activities were encouraged in three settings: home, transport and leisure time. Focus groups were students from elementary schools through to college, white and blue collar workers, and elderly people. Innovative aspects included: (1) a research centre leading the process, (2) scientific and institutional partnerships (over 160 groups), (3) a feasible approach--the 'one-step-ahead' model, (4) empowerment, (5) inclusion, (6) non-paid media, (7) social marketing, and (8) culture-linked. Data were obtained from 645 random, home-based questionnaires over four years--stratified by sex, age, education and socio-economic level. These data show that the Agita message reached 55.7% of the population, and among these, 23.1% knew the main message. Recall of Agita and knowledge of its purpose were well distributed among different socioeconomic levels, being known by 67% of the most educated. The prevalence of people reaching the recommendation was 54.8% (men 48.7%, women 61%); and risk of being sedentary was quite smaller among those who knew the Agita message (7.1%) compared with those who did not know (13.1%). In conclusion, based upon the Agita São Paulo experience, it appears that a multi-level, community-wide intervention to promote physical activity may obtain good results if the model contains the items listed above.


Effects of prolonged load carriage on angular jerk of frontal and sagittal knee motion.
During training, service members routinely walk with heavy body borne loads for long periods of time. These loads alter knee biomechanics and may produce jerky knee motions that reportedly increase joint loading and risk of musculoskeletal injury. Yet, it is unknown if service members use jerky knee motions during prolong walking with body borne load. To quantify the effects of body borne load and duration of walking on the jerkiness of sagittal and frontal plane knee motion. Eighteen participants had angular jerk of knee motion quantified while they walked (1.3 m/s) for 60-min with three body borne loads (0, 15, and 30 kg). Peak and cost of angular jerk for sagittal and frontal plane knee motion was quantified and submitted to a repeated measures linear model to test the main effects and interaction of load (0, 15, and 30 kg) and time (0, 15, 30, 45, and 60 min). Body borne load increased peak and cost of angular jerk for sagittal plane knee motion up to 35 % and 110 %, respectively, and frontal plane knee motion up to 20 % and 51 %, respectively (all p<0.001), while jerk cost of frontal plane knee motion (p=0.001) increased 31 % after walking 45 min. Body borne load produced large (between 20 % and 110 %), incremental increases in angular jerk for both sagittal and frontal plane knee motion; whereas, duration of walking led to a 31 % increase in jerkiness of frontal plane knee motion. Service members who often walking for long periods of time with heavy body borne loads may have greater risk of developing musculoskeletal injury and disease due to large increases in jerky knee motions.


Treatment of adults with growth hormone (GH) deficiency with recombinant human GH.
In a double blind, cross-over placebo-controlled trial, we studied the effects of 26 weeks of replacement therapy with recombinant human GH on body composition, metabolic parameters, and well-being in 10 patients with adult-onset GH deficiency (GHD). All patients received appropriate thyroid, adrenal, and gonadal replacement therapy. The dose of recombinant human GH was 0.25-0.5 U/kg.week (0.013-0.026 mg/kg.day) and was administered sc daily at bedtime. One patient was withdrawn from the study because of edema and atrial fibrillation. Body composition was estimated with three independent methods: computed tomography, bioelectric impedance, and total body potassium combined with total body water assessments. The Comprehensive Psychological Rating Scale and the Symptom Check List-90 were used to assess any change in psychopathology. After 26 weeks of treatment, adipose tissue (AT) mass decreased 4.7 kg (P < 0.001). Subcutaneous AT decreased by an average of 13%, whereas visceral AT was reduced by 30%. Muscle volume increased by 2.5 kg (5%; P < 0.05). According to the four-compartment model derived from assessments of total body potassium and total body water, body cell mass and extracellular fluid volume increased significantly by 1.6 and 3.0 kg, whereas body fat decreased by 6.1 kg. Results obtained by the bioelectric impedance technique were similar. The mean (+/- SD) concentrations of insulin-like growth factor-I increased from 0.26 (0.06) at baseline to 2.56 (1.55) and 2.09 (1.03) kU/L after 6 and 26 weeks of treatment. Calcium and serum phosphate, osteocalcin, and procollagen-III concentrations were significantly higher, and intact PTH concentrations were reduced after 6 and 26 weeks of treatment, respectively. Total and free T3 concentrations were significantly increased after 6 and 26 weeks of treatment, whereas free T4 concentrations were reduced at 6 weeks, but after 26 weeks, free T4 concentrations had returned to pretreatment values. Finally, after 26 weeks of treatment, there was a decrease in the Comprehensive Psychological Rating Scale score (P < 0.05). The results show that GH replacement in GHD adults results in marked alterations in body composition, fat distribution, and bone and mineral metabolism and reduces psychiatric symptoms. Finally, we conclude that the observed beneficial effects of replacement therapy with GH are of sufficient magnitude to consider treatment of GHD adults.


Study 275: Updated Expanded Access Program for Remestemcel-L in Steroid-Refractory Acute Graft-versus-Host Disease in Children.
Clinical outcomes in children with steroid-refractory acute graft-versus-host disease (SR-aGVHD) are generally poor, with a high mortality rate and limited therapeutic options. Here we report our updated investigational experience with mesenchymal stromal cell (MSC) therapy with remestemcel-L in a multicenter expanded access protocol (ClinicalTrials.gov identifier NCT00759018) in 241 children with aGVHD who failed to respond to steroids with or without other secondary and tertiary immunosuppressive therapies. A total of 241 children with grade B-D SR-aGVHD were enrolled at 50 sites in 8 countries and received 8 biweekly i.v. infusions of human MSCs, 2 × 106 per kg for 4 weeks, with an option for an additional 4 weekly infusions after day +28 for subjects who achieved either a partial response (PR) or mixed response. The mean age of the subjects was 9.6 years; 39% were female, and 60% were white. Most of the subjects had grade C (30%) or grade D (50%) disease, and in most cases, the subjects had failed to respond to other immunosuppressive agents after failing steroids. The primary endpoint was overall response (OR; the sum of complete response [CR] and PR) at day +28. Across all subjects, a 28-day OR was observed in 157 patients (65.1%), with 34 (14.1%) achieving CR and 123 (51.3%) achieving PR. Stratified by aGVHD grade at baseline, the OR rate at day +28 was 72.9% for patients with aGVHD grade B, 67.1% for those with aGVHD grade C, and 60.8% for those with aGVHD grade D. Survival through day +100, a secondary endpoint of the study, was 66.9% (n = 160 of 239). Importantly, survival through day +100 was significantly greater in subjects who achieved a day +28 OR compared with nonresponders (82.1% versus 38.6%; P < .001, log-rank test). Remestemcel-L safety was generally well tolerated, with no infusional toxicity and no identified safety concerns. In summary, this update to the remestemcel-L expanded access program confirms the reported clinical and survival benefits of remestemcel-L therapy in children with aGVHD who have exhausted all conventional therapeutic options.


Mercury and autoimmunity: implications for occupational and environmental health.
Mercury (Hg) has long been recognized as a neurotoxicant; however, recent work in animal models has implicated Hg as an immunotoxicant. In particular, Hg has been shown to induce autoimmune disease in susceptible animals with effects including overproduction of specific autoantibodies and pathophysiologic signs of lupus-like disease. However, these effects are only observed at high doses of Hg that are above the levels to which humans would be exposed through contaminated fish consumption. While there is presently no evidence to suggest that Hg induces frank autoimmune disease in humans, a recent epidemiological study has demonstrated a link between occupational Hg exposure and lupus. In our studies, we have tested the hypothesis that Hg does not cause autoimmune disease directly, but rather that it may interact with triggering events, such as genetic predisposition, exposure to antigens, or infection, to exacerbate disease. Treatment of mice that are not susceptible to Hg-induced autoimmune disease with very low doses and short term exposures of inorganic Hg (20-200 microg/kg) exacerbates disease and accelerates mortality in the graft versus host disease model of chronic lupus in C57Bl/6 x DBA/2 mice. Furthermore, low dose Hg exposure increases the severity and prevalence of experimental autoimmune myocarditis (induced by immunization with cardiac myosin peptide in adjuvant) in A/J mice. To test our hypothesis further, we examined sera from Amazonian populations exposed to Hg through small-scale gold mining, with and without current or past malaria infection. We found significantly increased prevalence of antinuclear and antinucleolar antibodies and a positive interaction between Hg and malaria. These results suggest a new model for Hg immunotoxicity, as a co-factor in autoimmune disease, increasing the risks and severity of clinical disease in the presence of other triggering events, either genetic or acquired.


[Management and herd performance of dairy herds with and without chronic wasting disease].
'Chronic wasting' in cattle acquired a special meaning in the Netherlands in 1999. It was used to define animal health problems that were thought to be associated with the use of bovine herpesvirus 1 marker vaccine. Criteria have not been set by which an objectively independent inventory of the problems could be made. The objective of this study was to determine management factors associated with the problem of 'chronic wasting' prior to the use of the BHV1 marker vaccine. Knowledge about these factors could be helpful for generating additional hypotheses about the aetiology of chronic wasting in cattle. A total of 188 farms participated in the study, of which 94 had severe problems with chronic wasting. The other half consisted of control farms matched with the case farms that did not report problems after the use of the BHV1 marker vaccine. Data analyses were performed over the period before (and not at the time of) 'chronic wasting' problems. Data were collected from various sources. A questionnaire was used to collect information on farm management practice. In addition, information on laboratory submissions for 1996 to 1998, animal movements in 1998, roughage analyses of 1997 and 1998, expenses for animal health in 1998, and herd performance in 1995 to 1999 was collected. In the analyses, a distinction was made between information obtained objectively and subjectively. Herds with problems of 'chronic wasting' were larger than herds without wasting problems (animals, surface) but not more intensively managed. 'Wasting' herds had a lower performance in terms of fertility and udder health. In addition, these herds had more contact with other herds through the purchase of animals. There were no differences in farm management practices related to disease control and prevention. Additional studies are required with regard to the patho-physiology of chronic wasting cows. The role of herd size needs more study.


Emergence of Resistance to Macrolides and Rifampin in Clinical Isolates of Rhodococcus equi from Foals in Central Kentucky, 1995 to 2017.
The objective of this study was to determine the prevalence of Rhodococcus equi strains resistant to macrolides and rifampin over time in clinical samples from foals submitted to diagnostic laboratories in central Kentucky. We performed a retrospective observational study of all clinical samples from foals that were submitted to veterinary diagnostic laboratories in Kentucky between January 1995 and December 2017. Samples were included if the R. equi bacterium was cultured and tested for in vitro susceptibility to erythromycin or rifampin. In vitro susceptibility testing to erythromycin was available for 2,169 isolates of R. equi, while susceptibility testing to both erythromycin and rifampin was available for 1,681 isolates. Rifampin resistance was first detected in 2000, and erythromycin resistance was first detected in 2004. Between 1995 and 2006, the proportion of resistant isolates of R. equi was 0.7% for erythromycin and 2.3% for rifampin. There was a significant (P < 0.001) increase in the proportion of resistant R. equi between 2007 and 2017, with 13.6% of isolates being resistant to erythromycin and 16.1% being resistant to rifampin. Between 2007 and 2017, isolates of R. equi resistant to erythromycin or rifampin were significantly less likely to be isolated from feces than from the respiratory tract, other soft tissues, or musculoskeletal infections. The considerable increase in the prevalence of isolates of R. equi resistant to macrolides and rifampin since 2007 is of concern for both human and animal health.


The relationship between pulmonary system impedance and right ventricular function in normal sheep.
Right ventricular (RV) afterload is a key determinant of RV function and is increased in many cardiopulmonary pathologies. Pulmonary circulation input impedance has been used to quantify afterload previously but due to its complexity has not been widely applied. This study examines the effect of a subset of the impedance spectrum, the zeroth and first harmonic impedance moduli (Z (0), Z (1)), on RV performance in large animals. An artificial circuit with adjustable resistance and compliance (C) was implanted into the pulmonary circulation of five sheep. Resistance was varied to increase Z (0) in increments of 2 mmHg/(L/min) until Z (0) was 8 mmHg/(L/min) above baseline. At each Z (0), C was adjusted between 0, 0.5 and 2 mL/mmHg or 0, 1, and 5 mL/mmHg. Fourier transforms of the pulmonary artery pressure and flow in each situation were used to calculate the pulmonary impedance. Results show that the percent change in cardiac output (%DeltaCO) is linearly related to the change in Z (0) (DeltaZ (0)). Increases in Z (1) (DeltaZ (1)) decreased %DeltaCO but to a much smaller degree, with the effect of DeltaZ (1) increasing with DeltaZ (0). Regression of these results produce the equation: %DeltaCO = (-0.0829DeltaZ (1) - 3.65)DeltaZ (0) - 9.02 (R (2) = 0.69). Blood flow and pressure moduli are small at harmonics higher than the first and are unlikely to affect RV function. Therefore, during acute, high afterload states, Z (0) is the primary determinant of CO, while the effect of Z (1) is minor.


Genome-wide classification and expression analysis of MYB transcription factor families in rice and Arabidopsis.
The MYB gene family comprises one of the richest groups of transcription factors in plants. Plant MYB proteins are characterized by a highly conserved MYB DNA-binding domain. MYB proteins are classified into four major groups namely, 1R-MYB, 2R-MYB, 3R-MYB and 4R-MYB based on the number and position of MYB repeats. MYB transcription factors are involved in plant development, secondary metabolism, hormone signal transduction, disease resistance and abiotic stress tolerance. A comparative analysis of MYB family genes in rice and Arabidopsis will help reveal the evolution and function of MYB genes in plants. A genome-wide analysis identified at least 155 and 197 MYB genes in rice and Arabidopsis, respectively. Gene structure analysis revealed that MYB family genes possess relatively more number of introns in the middle as compared with C- and N-terminal regions of the predicted genes. Intronless MYB-genes are highly conserved both in rice and Arabidopsis. MYB genes encoding R2R3 repeat MYB proteins retained conserved gene structure with three exons and two introns, whereas genes encoding R1R2R3 repeat containing proteins consist of six exons and five introns. The splicing pattern is similar among R1R2R3 MYB genes in Arabidopsis. In contrast, variation in splicing pattern was observed among R1R2R3 MYB members of rice. Consensus motif analysis of 1kb upstream region (5' to translation initiation codon) of MYB gene ORFs led to the identification of conserved and over-represented cis-motifs in both rice and Arabidopsis. Real-time quantitative RT-PCR analysis showed that several members of MYBs are up-regulated by various abiotic stresses both in rice and Arabidopsis. A comprehensive genome-wide analysis of chromosomal distribution, tandem repeats and phylogenetic relationship of MYB family genes in rice and Arabidopsis suggested their evolution via duplication. Genome-wide comparative analysis of MYB genes and their expression analysis identified several MYBs with potential role in development and stress response of plants.


Hypoglycemia unawareness in IDDM.
To assess the characteristics of patients with hypoglycemia unawareness (development of neuroglycopenia without appropriate prior autonomic warning symptoms) and its predisposing factors. We studied 43 insulin-dependent diabetes mellitus patients who were objectively categorized as having or not having hypoglycemia using the stepped hypoglycemic clamp technique in which plasma glucose was clamped at plateaus of 4.3, 3.6, 3.0, and 2.3 mmol/l and a statistical criterion (onset of autonomic warning symptoms at a plasma glucose concentration 2 SD below normal) and examined their clinical characteristics and hormonal, symptomatic, and cognitive responses. Eleven (26%) of the patients were classified as having hypoglycemia unawareness. Compared with the other patients, unaware patients had a lower HbA1c level (P < 0.01), a longer duration of diabetes (P < 0.01), and a history of more severe hypoglycemia (P < 0.003). During experimental hypoglycemia, counterregulatory hormone responses, neuroglycopenic symptoms, and cognitive dysfunction all began at lower plasma glucose concentrations in unaware patients (P < 0.01, 0.03, and 0.01, respectively). Moreover, although the magnitudes of their plasma catecholamine responses and autonomic symptoms were reduced (both, P < 0.01), the plasma catecholamine levels at which autonomic symptoms began was not altered. Finally, as seen from glucose infusion rates necessary to maintain identical plasma glucose levels, patients with hypoglycemia unawareness had increased sensitivity to insulin (P < 0.001). Our results confirm an association between hypoglycemia unawareness and duration of diabetes, glycemic control, and occurrence of severe hypoglycemia, and in addition provide evidence that both autonomic and neuroglycopenic symptoms are affected and that insulin sensitivity is increased, but beta-adrenergic sensitivity is not diminished.


Rapid Ketamine Infusion at an Analgesic Dose Resulting in Transient Hypotension and Bradycardia in the Emergency Department.
Ketamine's favorable hemodynamic and safety profile is motivating increasing use in the prehospital environment. Despite these advantages, certain side effects require advanced planning and training. We present a case of rapid intravenous administration of ketamine causing bradycardia and hypotension. A 46-year-old man presented to the emergency department for an exacerbation of chronic shoulder pain. Given the chronicity of the pain and multiple failed treatment attempts, ketamine at an analgesic dose was used. Despite the local protocol directing administration over several minutes, it was pushed rapidly, resulting in malaise, nausea, pallor, bradycardia, and hypotension. The patient returned to his baseline without intervention. This and other known side effects of ketamine, such as behavioral disturbances, altered sense of reality, and elevated heart rate and blood pressure, are well documented in the literature. With this report, the authors aim to raise awareness of transient bradycardia and hypotension associated with the rapid administration of ketamine at an analgesic dose.


Duloxetine is both an inhibitor and a substrate of cytochrome P4502D6 in healthy volunteers.
Duloxetine, a potent dual reuptake inhibitor of serotonin and norepinephrine currently undergoing clinical investigation for treatment of depression and stress urinary incontinence, has the potential to act as both a substrate and an inhibitor of cytochrome P4502D6 (CYP2D6). Our objectives were to determine the effect of duloxetine on the pharmacokinetics of desipramine, a tricyclic antidepressant metabolized by CYP2D6 (study 1), and the effect of paroxetine, a potent CYP2D6 inhibitor, on duloxetine pharmacokinetics (study 2). Subjects were healthy men and women between 21 and 63 years old. All subjects were genotypically CYP2D6 extensive metabolizers. In study 1, 50 mg of desipramine was administered as a single dose alone and in the presence of steady-state duloxetine 60 mg twice daily. In study 2, steady-state pharmacokinetics of duloxetine 40 mg once daily were determined in the presence and absence of steady-state paroxetine 20 mg once daily. Duloxetine increased the maximum plasma concentration of desipramine 1.7-fold and the area under the concentration-time curve 2.9-fold. Paroxetine increased the maximum plasma concentration of duloxetine and the area under the concentration-time curve at steady state 1.6-fold. Reports of adverse events were similar whether duloxetine was administered alone or in combination with desipramine or paroxetine. Duloxetine 60 mg twice daily is a moderately potent CYP2D6 inhibitor, intermediate between paroxetine and sertraline. The potent CYP2D6 inhibitor paroxetine has a moderate effect on duloxetine concentrations. The results of these 2 studies suggest that caution should be used when CYP2D6 substrates and inhibitors are coadministered with duloxetine.


From bench to bed: bridging from informatics theory to practice. An exploratory analysis.
In 2009, the journal Applied Clinical Informatics (ACI) commenced publication. Focused on applications in clinical informatics, ACI was intended to be a companion journal to METHODS of Information in Medicine (MIM). Both journals are official journals of IMIA, the International Medical Informatics Association. To explore, after five years, which congruencies and interdependencies exist in publications of these journals and to determine if gaps exist. To achieve this goal, major topics discussed in ACI and in MIM had to be analysed. Finally, we wanted to explore, whether the intention of publishing these companion journals to provide an information bridge from informatics theory to informatics practice and from practice to theory could be supported by this model. In this manuscript we will report on congruencies and interdependencies from practise to theory and on major topis in ACI. Further results will be reported in a second paper. Retrospective, prolective observational study on recent publications of ACI and MIM. All publications of the years 2012 and 2013 from these journals were indexed and analysed. Hundred and ninety-six publications have been analysed (87 ACI, 109 MIM). In ACI publications addressed care coordination, shared decision support, and provider communication in its importance for complex patient care and safety and quality. Other major themes included improving clinical documentation quality and efficiency, effectiveness of clinical decision support and alerts, implementation of health information technology systems including discussion of failures and succeses. An emerging topic in the years analyzed was a focus on health information technology to predict and prevent hospital admissions and managing population health including the application of mobile health technology. Congruencies between journals could be found in themes, but with different focus in its contents. Interdependencies from practise to theory found in these publications, were only limited. Bridging from informatics theory to practise and vice versa remains a major component of successful research and practise as well as a major challenge.


Theoretical study of dihydrogen bonds between (XH)2, X = Li, Na, BeH, and MgH, and weak hydrogen bond donors (HCN, HNC, and HCCH).
The dihydrogen-bonded (DHB) complexes formed by (XH)2, with X = Li, Na, BeH, and MgH, with one, two, and four protonic molecules (HCN, HNC, and HCCH) have been studied. These complexes have been compared to those of the XH monomers with the same hydrogen bond donor molecules. The energetic results have been rationalized based on the electrostatic potential of the isolated hydridic systems. The electron density properties have been analyzed within the AIM methodology, both at the bond critical points and the integrated values at the atomic basins. Exponential relationships between several properties calculated at the bond critical points (rho,nabla2rho, lambdai, G, and V) and variation of integrated properties (energy, charge, and volume) vs the DHB distance have been obtained.


Induction of plasminogen activator inhibitor I by the PPARalpha ligand, Wy-14,643, is dependent on ERK1/2 signaling pathway.
Impairment of the fibrinolytic system, mostly due to elevated plasma levels of plasminogen activator inhibitor 1 (PAI-1), is often associated with metabolic disorders such as diabetes mellitus and insulin-resistance syndrome. Moreover, insulin, as we have previously shown, directly stimulates PAI-1 production with a mechanism underlying a complex signaling network which ultimately leads to ERK activation. In this study we have analyzed the effects of agonists of the peroxisome proliferator-activated receptor (PPAR) alpha and gamma on PAI-1 biosynthesis in HepG2 cells in the presence or absence of insulin. The high affinity PPARalpha agonist, Wy-14,643, increased basal and insulin-stimulated PAI-1 antigen release with a mechanism involving gene transcription. We then investigated whether the MAP kinase pathway also plays a role in the stimulatory properties of Wy-L4,643. Wy-L4,643 increases phosphorylation of ERK and p38 in a time-dependent manner without affecting that of SAPK/JNK or ERK5. Moreover, the MEK (ERK kinase) inhibitors, PD98059 and UO126, completely prevented PAI-1 induction by Wy-14,643 without inhibiting the activation of a reporter gene carrying the PPRE element. Interestingly, the addition of p38 inhibitor followed by insulin and Wy-14,643 resulted in a greater than additive stimulation of PAI-1 secretion acting through ERK1/2 phosphorylation. In contrast, the synthetic PPARgamma agonist, rosiglitazone, did not change PAI-1 level, although this compound induced transcription from the PPRE-driven luciferase reporter construct. In conclusion, Wy-14,643 induces PAI-1 gene expression, in the presence or absence of insulin, with a mechanism which is independent on PPARalpha activation and requires signaling through the ERK1/2 signaling pathway.


Autoimmune Peripheral Neuropathies and Contribution of Antiganglioside/Sulphatide Autoantibody Testing.
Peripheral immune-mediated polyneuropathies (IMPN) are a diverse group of rare neurological illnesses characterized by nerve damage. Leading morphological features are mostly nerve fibre demyelination or combination of axonal damage and demyelination. There has been remarkable progress in the clinical and electrophysiological categorization of acute (fulminant, life-threatening) and chronic (progressive/remitting-relapsing) immune-mediated neuropathies recently. Besides electrophysiological and morphological makers, autoantibodies against glycolipids or paranodal/nodal molecules have been recommended as candidate markers for IMPN. The progress in testing for autoantibodies (autoAbs) to glycolipids such as gangliosides and sulfatide may have significant implications on the stratification of patients and their treatment response. Thus, this topic was reviewed in a presentation held during the 1st Panhellenic Congress of Autoimmune Diseases, Rheumatology and Clinical Immunology in Portaria, Pelion, Greece. For acute IMPN, often referred to as Guillain-Barré syndrome and its variants, several serological markers including autoAbs to gangliosides and sulphatide have been employed successfully in clinical routine. However, the evolution of serological diagnosis of chronic variants, such as chronic inflammatory demyelinating polyneuropathy or multifocal motor neuropathy, is less satisfactory. Serological diagnostic markers could, therefore, help in the differential diagnosis due to their assumed pathogenic role. Additionally, stratification of patients to improve their response to treatment may be possible. In general, a majority of patients respond well to causal therapy that includes intravenous immunoglobulins and plasmapheresis. As second line therapy options, biologicals (e.g., rituximab) and immunosuppressant or immunomodulatory drugs may be considered when patients do not respond adequately.


Bacterial flagellin promotes viral entry via an NF-kB and Toll Like Receptor 5 dependent pathway.
Viruses and bacteria colonize hosts by invading epithelial barriers. Recent studies have shown that interactions between the microbiota, pathogens and the host can potentiate infection through poorly understood mechanisms. Here, we investigated whether diverse bacterial species could modulate virus internalization into host cells, often a rate-limiting step in establishing infections. Lentiviral pseudoviruses expressing influenza, measles, Ebola, Lassa or vesicular stomatitis virus envelope glycoproteins enabled us to study entry of viruses that exploit diverse internalization pathways. Salmonella Typhimurium, Escherichia coli and Pseudomonas aeruginosa significantly increased viral uptake, even at low bacterial frequencies. This did not require bacterial contact with or invasion of host cells. Studies determined that the bacterial antigen responsible for this pro-viral activity was the Toll-Like Receptor 5 (TLR5) agonist flagellin. Exposure to flagellin increased virus attachment to epithelial cells in a temperature-dependent manner via TLR5-dependent activation of NF-ΚB. Importantly, this phenotype was both long lasting and detectable at low multiplicities of infection. Flagellin is shed from bacteria and our studies uncover a new bystander role for this protein in regulating virus entry. This highlights a new aspect of viral-bacterial interplay with significant implications for our understanding of polymicrobial-associated pathogenesis.


Oxytocin: behavioral associations and potential as a salivary biomarker.
Oxytocin (OT) is a neuropeptide that is produced primarily in the hypothalamus and is best known for its role in mammalian birth and lactation. Recent evidence also implicates OT in social behaviors, including parental behavior, the formation of social bonds, and the management of stressful experiences. OT is reactive to stressors, and plays a role in the regulation of both the central and autonomic nervous system, including effects on immune and cardiovascular function. Knowledge of patterns of OT release would be of value in many fields of science and medicine. However, measurements of OT concentration in blood are infrequently performed, and previous attempts to measure OT in saliva have been unsuccessful. Using a sensitive enzyme immunoassay (EIA) and concentrated samples we were able to detect reproducible changes in salivary OT as a function of lactation and massage. These results indicate that measurements of biologically relevant changes in salivary OT are possible. These results confirm the biological relevance of changes in salivary OT with stressors and support saliva as a noninvasive source to monitor central neuroendocrine function.


Optimization of packetization masks for image coding based on an objective cost function for desired packet spreading.
In image communication over lossy packet networks (e.g., cell phone communication), packet loss errors lead to damaged images. Damaged images can be repaired with passive error concealment methods, which use neighboring coefficient or pixel values to estimate the missing ones. Neighboring image data should, thus, be spread over different packets. This paper presents a novel robust packetization method for the transmission of image content in lossy packet networks. We first define novel criteria for a good packetization. Based on these properties, we propose a cost function for packetization masks. We then use stochastic optimization to calculate optimal packetization masks. We test our packetization technique on both wavelet coding and DCT coding. Compared to other packetization techniques, we are able to achieve the same or better mean quality of the reconstructed images but with less fluctuation in quality, which is important for the viewer experience. In this way, we significantly increase the worst case quality, especially for high packet loss rates. This leads to visually more pleasing images in case of a passive reconstruction.


Detection and kinetic characterization of a highly reactive heme-thiolate peroxygenase compound I.
The extracellular heme-thiolate peroxygenase from Agrocybe aegerita (AaeAPO) has been shown to hydroxylate alkanes and numerous other substrates using hydrogen peroxide as the terminal oxidant. We describe the kinetics of formation and decomposition of AaeAPO compound I upon its reaction with mCPBA. The UV-vis spectral features of AaeAPO-I (361, 694 nm) are similar to those of chloroperoxidase-I and the recently described cytochrome P450-I. The second-order rate constant for AaeAPO-I formation was 1.0 (±0.4) × 10(7) M(-1) s(-1) at pH 5.0, 4 °C. The relatively slow decomposition rate, 1.4 (±0.03) s(-1), allowed the measurement of its reactivity toward a panel of substrates. The observed rate constants, k2', spanned 5 orders of magnitude and correlated linearly with bond dissociation enthalpies (BDEs) of strong C-H bond substrates with a log k2' vs BDE slope of ∼0.4. However, the hydroxylation rate was insensitive to a C-H BDE below 90 kcal/mol, similar to the behavior of the tert-butoxyl radical. The shape and slope of the Brønsted-Evans-Polanyi plot indicate a symmetrical transition state for the stronger C-H bonds and suggest entropy control of the rate in an early transition state for weaker C-H bonds. The AaeAPO-II Fe(IV)O-H BDE was estimated to be ∼103 kcal/mol. All results support the formation of a highly reactive AaeAPO oxoiron(IV) porphyrin radical cation intermediate that is the active oxygen species in these hydroxylation reactions.


Dynamic cytoplasmic projections connect mammalian spermatogonia in vivo.
Throughout the male reproductive lifespan, spermatogonial stem cells (SSCs) produce committed progenitors that proliferate and then remain physically connected in growing clones via short cylindrical intercellular bridges (ICBs). These ICBs, which enlarge in meiotic spermatocytes, have been demonstrated to provide a conduit for postmeiotic haploid spermatids to share sex chromosome-derived gene products. In addition to ICBs, spermatogonia exhibit multiple thin cytoplasmic projections. Here, we have explored the nature of these projections in mice and find that they are dynamic, span considerable distances from their cell body (≥25 μm), either terminate or physically connect multiple adjacent spermatogonia, and allow for sharing of macromolecules. Our results extend the current model that subsets of spermatogonia exist as isolated cells or clones, and support a model in which spermatogonia of similar developmental fates are functionally connected through a shared dynamic cytoplasm mediated by thin cytoplasmic projections.


Enhanced production and activation of progelatinase A mediated by membrane-type 1 matrix metalloproteinase in human papillary thyroid carcinomas.
Matrix metalloproteinases (MMPs) are believed to be involved in the invasion and metastasis of various human carcinomas. In the present study, the production levels of seven different MMPs (MMP-1, -2, -3, -7, -8, -9, and -13), the activation of the zymogen of MMP-2 (proMMP-2), the expression of membrane-type MMPs (MT1-, MT2-, and MT3-MMPs), and the tissue localization of the activated enzyme were examined in human invasive papillary thyroid carcinomas. Sandwich enzyme immunoassays revealed that among the MMPs examined, only the MMP-2 production level is significantly enhanced in the carcinoma tissues compared with the follicular adenoma and normal control thyroid tissues. Gelatin zymography indicated that the proMMP-2 activation ratio is considerably higher in carcinomas with lymph node metastasis than it is in those without metastasis, follicular adenomas, or normal controls (P < 0.01). Northern blot analysis of the expression of MT1-, MT2-, and MT3-MMPs, which are known to activate proMMP-2 in vitro, demonstrated the predominant expression of MT1-MMP mRNA in the carcinoma tissues (15 of 15 cases), whereas MT2-MMP expression was confined to 26% of the cases (4 of 15 cases), and no consistent expression of MT3-MMP was observed. MTI-MMP mRNA expression levels correlated with the proMMP-2 activation ratio (r = 0.692; P < 0.01), but such a correlation was not obtained with MT2-MMP. There was also a direct correlation between MT1-MMP expression and lymph node metastasis (P < 0.05). In situ hybridization indicated that both carcinoma and stromal cells express MT1-MMP transcripts (five of six cases). MT1-MMP was also immunolocalized to carcinoma and stromal cells in all of the carcinoma samples (26 of 26 cases), which were positive for MMP-2. In situ zymography indicated definite gelatinolytic activity in the carcinoma cell nests, which was abolished by incubation of the carcinoma samples with a synthetic MMP inhibitor before the reaction. These results suggest for the first time that among seven different MMPs, the production of proMMP-2 and its MT1-MMP-mediated activation in the carcinoma cell nests play an important role in the lymph node metastasis of human invasive papillary thyroid carcinomas.


Very fast wave-front measurements at the human eye with a custom CMOS-based Hartmann-Shack sensor.
We describe what we believe to be the first wave-front measurements of the human eye at a sampling rate of 300 Hz with a custom Hartmann-Shack wave-front sensor that uses complementary metal-oxide semiconductor (CMOS) technology. This sensor has been developed to replace standard charge-coupled device (CCD) cameras and the slow software image processing that is normally used to reconstruct the wave front from the focal-plane image of a lenslet array. We describe the sensor's principle of operation and introduce the performance with static wave fronts. The system has been used to measure human-eye wave-front aberrations with a bandwidth of 300 Hz, which is approximately an order of magnitude faster than with standard software-based solutions. Finally, we discuss the measured data and consider further improvements to the system.


Examining the prevalence, correlates and inequalities of undiagnosed hypertension in Nepal: a population-based cross-sectional study.
To examine the prevalence, correlates and sociodemographic inequalities of undiagnosed hypertension in Nepal. This study used cross-sectional 2016 Nepal Demographic and Health Survey (NDHS) data. Undiagnosed patients with hypertension were defined as an NDHS respondent who was diagnosed as hypertensive (systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg) during the survey, but never took any prescribed anti-hypertensive medicine to lower/control blood pressure and was never identified as having hypertension by a health professional prior the survey. Multiple binary logistic regression analysis was performed, and Concentration Index was measured. Nepal. Adult patients with hypertension. Among 3334 patients with hypertension, 50.4% remained undiagnosed during the survey in Nepal. Adjusted model reveals that patients who were male, belonged to households other than the highest wealth quintile, and lived in province 4 and province 5 were at higher risk of remaining undiagnosed for hypertension. Patients who were ≥65 years of age and were overweight/obese were at lower risk of remaining undiagnosed for hypertension. The poor-rich gap was 24.6 percentage points (Q1=64.1% vs Q5=39.6%) and poor:rich ratio was 1.6 (Q1/Q5=1.6) in the prevalence of undiagnosed hypertension. Undiagnosed hypertension was disproportionately higher among lower socioeconomic status groups (Concentration Index, C=-0.18). Inequalities in the prevalence of undiagnosed hypertension further varied across other geographic locations, including place of residence, ecological zones and administrative provinces. Undiagnosed hypertension was highly prevalent in Nepal and there were substantial inequalities by sociodemographics and subnational levels. Increasing awareness, strengthening routine screening to diagnose hypertension at primary health service facilities and enactment of social health insurance policy may help Nepal to prevent and control this burden.


Age and sex correlate with bony changes and anatomic variations of the lumbosacroiliac region of the vertebral column in a mixed population of horses.
To provide a postmortem description of anatomic variations and changes of the lumbosacroiliac region in horses. The authors hypothesized that lesion severity would increase with age and body weight and correlate to anatomic variations. Lumbosacroiliac vertebral specimens from 38 horses (mean age, 16 years; range, 5 to 30 years) that died or were euthanized for reasons unrelated to the study between November 2019 and October 2021. The lumbosacroiliac region of the vertebral column was removed from each cadaver. After dissection, disarticulation, and boiling, the anatomic specimens were examined for anatomic variations and osseous changes of the articular process joints (APJs), intertransverse joints (ITJs), and sacroiliac joints (SIJs). The lengths of L6-S1 intertransverse articular surfaces were measured and their ratios calculated. Descriptive statistics were obtained, and the χ2 test was used to assess differences in anatomic variations and abnormal changes of the APJs, ITJs, and SIJs. The most common anatomic variation was a sacrum-like shape of the transverse processes of L6 (29/38 [76%]) and converging orientation of dorsal spinous process of L6 (33/38 [87%]). The highest prevalence of bony changes was detected at L5-L6 (right, 34/38 [89%]; left, 33/38 [87%]) and L6-S1 APJs (right, 38/38 [100%]; left, 37/38 [97%]) and at SIJs (right, 32/38 [86%]; left, 31/38 [82%]). The shape of L6 transverse processes differed between breed (P = .01) and was associated with presence of L4-L5 ITJs (P < .01). Age and sex were associated with changes of the sacral dorsal spinous processes, ITJs, and APJs. The clinical significance of these findings could not be confirmed based on the study limitations.