Effects of esophageal stimulation in patients with functional disorders of the gastrointestinal tract.
We studied the effects of esophageal electrical stimulation on cortical-evoked potentials (EPs) and power spectrum of heart rate variability (PS/HRV) in patients with diabetes and non-cardiac chest pain (NCCP). We also recorded cognitive-evoked potentials (P300 EPs) in response to an odd-ball stimulation in patients with NCCP. Diabetic patients did not yield reproducible cortical EPs. Their power spectra of heart rate variability (PS/HRV) showed an increased vagal modulation during stimulation. In patients with NCCP the P300 EPs were of greater amplitude (17 +/- 3 microV vs. 12 +/- 1 microV in controls, p < 0.04), while peak latencies were slightly elongated in patients (382 +/- 22 ms vs. 354 +/- 12 ms in controls). The PS/HRV in these patients also showed an increased vagal modulation of the sinus node activity. Our results suggest the following: (1) in patients with diabetes, afferent pathways and processing of sensory signals are likely to be impaired; (2) an increased perception of esophageal stimulation reflects an exaggerated brainstem response and altered cortical processing of visceral sensation in patients with NCCP.


Global Initiative for Children's Surgery: A Model of Global Collaboration to Advance the Surgical Care of Children.
Recommendations by the Lancet Commission on Global Surgery regarding surgical care in low- and middle-income countries (LMICs) require development to address the needs of children. The Global Initiative for Children's Surgery (GICS) was founded in 2016 to identify solutions to problems in children's surgery by utilizing the expertise of practitioners from around the world. This report details this unique process and underlying principles. Three global meetings convened providers of surgical services for children. Through working group meetings, participants reviewed the status of global children's surgery to develop priorities and identify necessary resources for implementation. Working groups were formed under LMIC leadership to address specific priorities. By creating networking opportunities, GICS has promoted the development of LMIC-LMIC and HIC-LMIC partnerships. GICS members identified priorities for children's surgical care within four pillars: infrastructure, service delivery, training and research. Guidelines for provision of care at every healthcare level based on these pillars were created. Seventeen subspecialty, LMIC chaired working groups developed the Optimal Resources for Children's Surgery (OReCS) document. The guidelines are stratified by subspecialty and level of health care: primary health center, first-, second- and third-level hospitals, and the national children's hospital. The OReCS document delineates the personnel, equipment, facilities, procedures, training, research and quality improvement components at all levels of care. Worldwide collaboration with leadership by providers from LMICs holds the promise of improving children's surgical care. GICS will continue to evolve in order to achieve the vision of safe, affordable, timely surgical care for all children.


Electrodes and multiple electrode systems for radio frequency ablation: a proposal for updated terminology.
Research on technology for soft tissue radio frequency (RF) ablation is ever advancing. A recent proposal to standardize terminology of RF electrodes only deals with the most frequently used commercial electrodes. The aim of this study was to develop a logical, versatile, and unequivocal terminology to describe present and future RF electrodes and multiple electrode systems. We have carried out a PubMed search for the period from January 1st 1990 to July 1st 2004 in seven languages and contacted the six major companies that produce commercial RF electrodes for use in the liver. In a first step, names have been defined for the five existing basic designs of single-shaft electrode. These names had to be unequivocal, descriptive of the electrode's main working principle and as short as possible. In a second step, these basic names have been used as building blocks to describe the single-shaft electrodes in combination designs. In a third step, using the same principles, a logical terminology has been developed for multiple electrode systems, defined as the combined use of more than one single-shaft RF electrode. Five basic electrode designs were identified and defined: plain, cooled, expandable, wet, and bipolar electrodes. Combination designs included cooled-wet, expandable-wet, bipolar-wet, bipolar-cooled, bipolar-expandable, and bipolar-cooled-wet electrodes. Multiple electrode systems could be characterized by describing several features: the number of electrodes that were used (dual, triple, etc.), the electric mode (monopolar or bipolar), the activation mode (consecutive, simultaneous or switching), the site of the inserted electrodes (monofocal or multifocal), and the type of single-shaft electrodes that were used. In this terminology, the naming ofthe basic electrode designs has been based on objective criteria. The short and unequivocal names of the basic designs can easily be combined to describe current and future combination electrodes. This terminology provides an exact and complete description of the versatile novel multiple electrode systems.


Combined impact of exercise and temperature in learning and memory performance of fluoride toxicated rats.
In previous studies, we investigated a link between high fluoride exposure and functional IQ deficits in rats. This study is an extension conducted to explore the combined influence of physical exercise and temperature stress on the learning ability and memory in rats and to assess whether any positive modulation could be attenuated due to exercise regimen subjected to F-toxicated animals at different temperatures. Accumulation of ingested fluoride resulted significant inhibition in acetylcholinesterase activity (P < 0.05), plasma cortisol levels (P < 0.05), and impaired the acquisition, performance, latency time, and retention in fluoride-exposed animals. Fluoride-toxicated rats took more number of sessions during the learning phase [F (5, 35) = 19.065; P < 0.05] and post hoc analysis on the number of correct choices revealed that there was a significant effect of treatments [F (5, 30) = 15.763; P < 0.05]; sessions [F (8, 240) = 58.698; P < 0.05]; and also significant difference in the interactions [F (40, 240) = 1.583; P < 0.05]. The latency data also revealed a significant difference between groups [F (5, 30) = 28.085; P < 0.05]; time = [F (8, 240) = 136.314; P < 0.05]; and there was a significant difference in the interactions [F (40, 240) = 2.090; P < 0.05]. In order to ascertain if interdependence between fluoride concentrations and the foregoing free radical parameters, respective correlation coefficients were calculated and results clearly emphasize the positive role of exercise in the promotion of cognitive functions by decreasing fluoride levels in rat hippocampus. A significant recovery in cognitive function was noticed in all the exercised animals due to reduced burden of brain oxidative stress. In comparison to exercise regimens performed at different temperatures, high (35 °C) and low temperatures (20 °C) led to a slower acquisition and poor retention of the task when compared to thermo neutral temperatures (25 and 30 °C). Thus exercise up-regulate antioxidant defenses and promote learning abilities in fluorotic population.


Flow-based local optimization for image-to-geometry projection.
The projection of a photographic data set on a 3D model is a robust and widely applicable way to acquire appearance information of an object. The first step of this procedure is the alignment of the images on the 3D model. While any reconstruction pipeline aims at avoiding misregistration by improving camera calibrations and geometry, in practice a perfect alignment cannot always be reached. Depending on the way multiple camera images are fused on the object surface, remaining misregistrations show up either as ghosting or as discontinuities at transitions from one camera view to another. In this paper we propose a method, based on the computation of Optical Flow between overlapping images, to correct the local misalignment by determining the necessary displacement. The goal is to correct the symptoms of misregistration, instead of searching for a globally consistent mapping, which might not exist. The method scales up well with the size of the data set (both photographic and geometric) and is quite independent of the characteristics of the 3D model (topology cleanliness, parametrization, density). The method is robust and can handle real world cases that have different characteristics: low level geometric details and images that lack enough features for global optimization or manual methods. It can be applied to different mapping strategies, such as texture or per-vertex attribute encoding.


Effects of serotonin in the hippocampus: how SSRIs and multimodal antidepressants might regulate pyramidal cell function.
The hippocampus plays an important role in emotional and cognitive processing, and both of these domains are affected in patients with major depressive disorder (MDD). Extensive preclinical research and the notion that modulation of serotonin (5-HT) neurotransmission plays a key role in the therapeutic efficacy of selective serotonin reuptake inhibitors (SSRIs) support the view that 5-HT is important for hippocampal function in normal and disease-like conditions. The hippocampus is densely innervated by serotonergic fibers, and the majority of 5-HT receptor subtypes are expressed there. Furthermore, hippocampal cells often co-express multiple 5-HT receptor subtypes that can have either complementary or opposing effects on cell function, adding to the complexity of 5-HT neurotransmission. Here we review the current knowledge of how 5-HT, through its various receptor subtypes, modulates hippocampal output and the activity of hippocampal pyramidal cells in rodents. In addition, we discuss the relevance of 5-HT modulation for cognitive processing in rodents and possible clinical implications of these results in patients with MDD. Finally, we review the data on how SSRIs and vortioxetine, an antidepressant with multimodal activity, affect hippocampal function, including cognitive processing, from both a preclinical and clinical perspective.


ZIKA virus elicits P53 activation and genotoxic stress in human neural progenitors similar to mutations involved in severe forms of genetic microcephaly.
Epidemiological evidence from the current outbreak of Zika virus (ZIKV) and recent studies in animal models indicate a strong causal link between ZIKV and microcephaly. ZIKV infection induces cell-cycle arrest and apoptosis in proliferating neural progenitors. However, the mechanisms leading to these phenotypes are still largely obscure. In this report, we explored the possible similarities between transcriptional responses induced by ZIKV in human neural progenitors and those elicited by three different genetic mutations leading to severe forms of microcephaly in mice. We found that the strongest similarity between all these conditions is the activation of common P53 downstream genes. In agreement with these observations, we report that ZIKV infection increases total P53 levels and nuclear accumulation, as well as P53 Ser15 phosphorylation, correlated with genotoxic stress and apoptosis induction. Interestingly, increased P53 activation and apoptosis are induced not only in cells expressing high levels of viral antigens but also in cells showing low or undetectable levels of the same proteins. These results indicate that P53 activation is an early and specific event in ZIKV-infected cells, which could result from cell-autonomous and/or non-cell-autonomous mechanisms. Moreover, we highlight a small group of P53 effector proteins that could act as critical mediators, not only in ZIKV-induced microcephaly but also in many genetic microcephaly syndromes.


Steady-state and dynamic properties of cardiac sodium-calcium exchange. Secondary modulation by cytoplasmic calcium and ATP.
Dynamic responses of cardiac sodium-calcium exchange current to changes of cytoplasmic calcium and MgATP were monitored and analyzed in giant membrane patches excised from guinea pig myocytes. Secondary dependencies of exchange current on cytoplasmic calcium are accounted for in terms of two mechanisms: (a) The sodium-dependent inactivation process, termed I1 modulation, is itself strongly modulated by cytoplasmic calcium. Recovery from the I1 inactivated state is accelerated by increasing cytoplasmic calcium, and the calculated rate of entrance into I1 inactivation is slowed. (b) A second modulation process, termed I2 modulation, is not sodium dependent. As with I1 modulation, the entrance into I2 inactivation takes place over seconds in the absence of cytoplasmic calcium. The recovery from I2 inactivation is a calcium-dependent transition and is rapid (< 200 ms) in the presence of micromolar free calcium. I1 and I2 modulation can be treated as linear, independent processes to account for most exchange modulation patterns observed: (a) When cytoplasmic calcium is increased or decreased in the presence of high cytoplasmic sodium, outward exchange current turns on or off, respectively, on a time scale of multiple seconds. (b) When sodium is applied in the absence of cytoplasmic calcium, no outward current is activated. However, the full outward current is activated within solution switch time when cytoplasmic calcium is applied together with sodium. (c) The calcium dependence of peak outward current attained upon application of cytoplasmic sodium is shifted by approximately 1 log unit to lower concentrations from the calcium dependence of steady-state exchange current. (d) The time course of outward current decay upon decreasing cytoplasmic calcium becomes more rapid as calcium is reduced into the submicromolar range. (e) Under nearly all conditions, the time courses of current decay during application of cytoplasmic sodium and/or removal of cytoplasmic calcium are well fit by single exponentials. Both of the modulation processes are evidently affected by MgATP. Similar to the effects of cytoplasmic calcium, MgATP slows the entrance into I1 inactivation and accelerates the recovery from inactivation. MgATP additionally slows the decay of outward exchange current upon removal of cytoplasmic calcium by 2-10-fold, indicative of an effect on I2 inactivation. Finally, the effects of cytoplasmic calcium on sodium-calcium exchange current are reconstructed in simulations of the I1 and I2 modulation processes as independent reactions.


A prospective clinical and bacteriologic study of inguinal buboes in Thai men.
One-hundred thirteen men (mean age, 23 years) who presented with inguinal buboes to a government-operated hospital for sexually transmitted diseases (STDs) in Bangkok were studied between February 1987 and February 1989. The median duration of preceding symptoms was 7 days (range, 1-62 days). The majority of patients (74; 65%) had received treatment previously; 31 (27%) were febrile, 13 (12%) had extrainguinal lymphadenopathy, and 31 (27%) had concurrent active genital ulcers. There was no history of genital ulceration in 66 (58%) of the patients. Pus was obtained from 51 of the 110 buboes aspirated for culture; 21 (41%) of these cultures yielded Haemophilus ducreyi, and 2 (3.9%) were positive for Chlamydia trachomatis on immunofluorescence microscopy. Saline (1 mL) was injected and reaspirated from the buboes of 35 of the other 59 patients; 3 buboes yielded H. ducreyi and 9 were positive for C. trachomatis. All cultures for other aerobic and anaerobic bacteria and viruses in intact buboes were negative. Syphilis serology was positive in only one case. Patients attending STD clinics in this region who have large, fluctuant, edematous inguinal buboes containing pus should receive presumptive treatment for chancroid. If there is no pus, then the bubo is more likely to be caused by lymphogranuloma venereum.


Thermalized connectivity networks of jammed packings.
Jammed packings of repulsive elastic spheres have emerged as a rich model system within which the elastic properties of disordered glassy materials may be elucidated. Most of the work on these packings has focused on the case of vanishing temperature. Here, we explore the elastic properties of the associated connectivity network for finite temperatures, ignoring the breaking of bonds and the formation of new ones. Using extensive Monte Carlo simulations, we find that, as the temperature is increased, the resulting spring network shrinks and exhibits a rapidly softening bulk modulus via a cusp. Moreover, the shear modulus stiffens in a fixed volume ensemble but not in a fixed pressure ensemble. These counter-intuitive behaviors may be understood from the characteristic spectrum of soft modes near isostaticity, which resembles the spectrum of a rod near its buckling instability. Our results suggest a generic mechanism for negative thermal expansion coefficients in marginal solids. We discuss some consequences of bond breaking and an apparent analogy between thermalization and shear.


Surfactant protein A2 mutations associated with pulmonary fibrosis lead to protein instability and endoplasmic reticulum stress.
Rare heterozygous mutations in the gene encoding surfactant protein A2 (SP-A2, SFTPA2) are associated with adult-onset pulmonary fibrosis and adenocarcinoma of the lung. We have previously shown that two recombinant SP-A2 mutant proteins (G231V and F198S) remain within the endoplasmic reticulum (ER) of A549 cells and are not secreted into the culture medium. The pathogenic mechanism of the mutant proteins is unknown. Here we analyze all common and rare variants of the surfactant protein A2, SP-A2, in both A549 cells and in primary type II alveolar epithelial cells. We show that, in contrast with all other SP-A2 variants, the mutant proteins are not secreted into the medium with wild-type SP-A isoforms, form fewer intracellular dimer and trimer oligomers, are partially insoluble in 0.5% Nonidet P-40 lysates of transfected A549 cells, and demonstrate greater protein instability in chymotrypsin proteolytic digestions. Both the G231V and F198S mutant SP-A2 proteins are destroyed via the ER-association degradation pathway. Expression of the mutant proteins increases the transcription of a BiP-reporter construct, expression of BiP protein, and production of an ER stress-induced XBP-1 spliced product. Human bronchoalveolar wash samples from individuals who are heterozygous for the G231V mutation have similar levels of total SP-A as normal family members, which suggests that the mechanism of disease does not involve an overt lack of secreted SP-A but instead involves an increase in ER stress of resident type II alveolar epithelial cells.


Photo-consistent reconstruction of semitransparent scenes by density-sheet decomposition.
This paper considers the problem of reconstructing visually realistic 3D models of dynamic semitransparent scenes, such as fire, from a very small set of simultaneous views (even two). We show that this problem is equivalent to a severely underconstrained computerized tomography problem, for which traditional methods break down. Our approach is based on the observation that every pair of photographs of a semitransparent scene defines a unique density field, called a Density Sheet, that 1) concentrates all its density on one connected, semitransparent surface, 2) reproduces the two photos exactly, and 3) is the most spatially compact density field that does so. From this observation, we reduce reconstruction to the convex combination of sheet-like density fields, each of which is derived from the Density Sheet of two input views. We have applied this method specifically to the problem of reconstructing 3D models of fire. Experimental results suggest that this method enables high-quality view synthesis without overfitting artifacts.


Trace metals in oysters: molecular and cellular mechanisms and ecotoxicological impacts.
Oysters are important benthic bivalves in coastal and estuarine environments. They are widely farmed due to their rapid growth and taste; they are also widely applied in environmental monitoring of coastal pollution due to their accumulation of contaminants. Most importantly, oysters are among the few marine organisms that are considered to be hyper-accumulators of many toxic metals, such as cadmium, copper and zinc. As such, there is a tremendous call to study the interactions between metals and oysters, especially due to the increasing metal pollution in many coastal and estuarine waters. Over the past decades, many studies have focused on metal accumulation in oysters as well as the ecotoxicological effects of metals on oysters. In this review, we summarize the recent progress in our understanding of the molecular and cellular mechanisms of metal accumulation, sequestration and toxicity in oysters. Applications of modern technologies such as omics and nanoscale imaging have added significantly to our knowledge of metal biology in oysters. Variations between different metals also demonstrate the diversity of the interactions between oysters and metals. Despite this recent progress, however, there is a need for further study of the molecular mechanisms of metal uptake and toxicity as well as the joint effects of metal mixtures on oyster populations. Oysters have higher numbers of stress responsive genes than most animals, which may have been induced by gene duplication during the evolution of their intertidal environmental adaptations. The divergent expression of stress responsive genes may explain the different tolerances for metals among different species. These fundamental studies may eventually provide promising solutions for reducing toxic metal concentrations in oysters for safe consumption by humans. To conclude, the complexity of life history and metal chemistry of oysters coupled with emerging pollution and application of modern techniques represents an important and exciting research area in modern ecotoxicology.


Assessing Motivational Differences Between Young and Older Adults When Playing an Exergame.
Background: Currently, exergames are used by different age groups for both recreational and training/rehabilitation purposes. However, little is known about how to design exergames so that they are motivating for specific age groups and health outcomes. Objective: In this article, we compare motivational factors between healthy young and older adults by analyzing their assessments of the same balance training exergame. Materials and Methods: We performed a laboratory-based assessment of a custom-made balance training exergame with 12 healthy young and 10 healthy older adults. Their answers to a semistructured text input questionnaire were analyzed qualitatively. Results: Both age groups were motivated by a combination of intrinsic and extrinsic motivational factors. We found that the young adults tended to be motivated by the game challenge and the in-game reward system (scores). In contrast, the older adults were more motivated by the perceived health effects (both physical and cognitive) and the joy of playing, with less regard for the in-game rewards. Conclusion: The differences in motivational factors that were identified between young and older adults have several design implications. For older adults less effort can be put on designing the in-game reward system and more on showing the player the potential health effects of their play. Furthermore, the competition aspect can be downplayed and more focus placed on simply making the gaming experience itself as joyful as possible.


Horizontal transmission of Metarhizium anisopliae between Spoladea recurvalis (Lepidoptera: Crambidae) adults and compatibility of the fungus with the attractant phenylacetaldehyde.
The compatibility of the entomopathogenic fungus Metarhizium anisopliae ICIPE 30 which was proved to be pathogenic to adult Spoladea recurvalis, and phenylacetaldehyde (PAA) floral attractant for lepidopteran moths, was investigated under laboratory and field conditions through spatial and temporal separations. Horizontal transmission of M. anisopliae ICIPE 30 between adult S. recurvalis and the number of conidia picked up by a single moth from the autoinoculation device were also determined under laboratory tests. When freshly emerged moths were inoculated with fungal conidia ("donors") and maintained together with an equal number of untreated freshly emerged moths ("recipients") in the laboratory, they were able to transmit infection to untreated moths resulting to 76.9% mortality with an LT50 value of 6.9 days. The quantity of conidia a moth could acquire and retain from the autoinoculation device in the laboratory was assessed at 0, 24, 48, and 72 h post-inoculation. The overall mean number of conidia acquired by a single moth was significantly higher immediately after exposure (0 h) (14.3 ± 2.5 × 105) than at 24, 48, and 72 h after inoculation (F = 10.26, Df = 3,8, P = 0.003), though a single moth still retained 4.6 ± 0.9 × 105 conidia 72 h post inoculation. Laboratory results showed that PAA completely inhibited the germination of the conidia 8 days post exposure, while the conidial viability was not affected in the control treatment without PAA. Under field conditions, the inhibitory effects of PAA on conidial germination was minimized by placing it at a distance of 5-10 cm from M. anisopliae isolate ICIPE 30 conidia. There was no significant difference in conidial germination in the control treatment and in treatments where PAA was placed at 5 cm and 10 cm away from M. anisopliae isolate ICIPE 30. Conidial germination was low in the autoinoculation device that had PAA directly exposed to the fungus. PAA is therefore compatible with M. anisopliae ICIPE 30 for use in integrated management of S. recurvalis, if spatially separated 5 cm away from the fungus and could thus be combined in an autocontamination devices for the control of S. recurvalis.


The serum level of free testosterone is reduced in amyotrophic lateral sclerosis.
Sporadic amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder affecting upper and lower motoneurons. There is an approximately 2:1 higher incidence of ALS in men compared to women, and this has raised the hypothesis of an involvement of sex hormones in the etiopathogenesis of the disorder. In this work, the serum levels of dehydroepiandrosterone sulphate (DHEAS), 17-betaestradiol, free and total testosterone were measured in 35 patients with defined or probable ALS, according to the El-Escorial/WFN revisited criteria, and compared to those obtained from 57 disease controls, matched for age and gender to the ALS group. We found no differences between ALS cases and disease controls in the serum levels of DHEAS, 17-betaestradiol and total testosterone. Conversely, free testosterone was significantly decreased in the ALS group. Given that testosterone crosses the blood-brain barrier only as unbound form, we suggest a possible involvement of this sex hormone in the pathophysiology of this severe motor neuron disease.


Magnetic resonance imaging assessment of macrophage accumulation in mouse brain after experimental traumatic brain injury.
Macrophages contribute to secondary damage and repair after central nervous system (CNS) injury. Micron-sized paramagnetic iron oxide (MPIO) particles can label macrophages in situ, facilitating three-dimensional (3D) mapping of macrophage accumulation following traumatic brain injury (TBI), via ex vivo magnetic resonance microscopy (MRM) and in vivo monitoring with magnetic resonance imaging (MRI). MPIO particles were injected intravenously (iv; 4.5 mg Fe/Kg) in male C57BL/6J mice (n = 21). A controlled cortical impact (CCI) was delivered to the left parietal cortex. Five protocols were used in naive and injured mice to assess feasibility, specificity, and optimal labeling time. In vivo imaging was carried out at 4.7 Tesla (T). Brains were then excised for 3D MRM at 11.7 T. Triple-label immunofluorescence (MPIO via Dragon Green, macrophages via F480, and nuclei via 4,6-diamidino-2-phenylindole [DAPI]) of brain sections confirmed MPIO particles within macrophages. MRM of naives showed an even distribution of a small number of MPIO-labeled macrophages in the brain. MRM at 48-72 h after CCI and MPIO injection revealed MPIO-labeled macrophages accumulated in the trauma region. When MPIO particles were injected 6 days before CCI, MRM 48 h after CCI also revealed labeled cells at the injury site. In vivo studies of macrophage accumulation by MRI suggest that this approach is feasible, but requires additional optimization. We conclude that MPIO labeling and ex vivo MRM mapping of macrophage accumulation for assessment of TBI is readily accomplished. This new technique could serve as an adjunct to conventional MR approaches by defining inflammatory mechanisms and therapeutic efficacy of anti-inflammatory agents in experimental TBI.


Germ line transformation of mammals by pronuclear microinjection.
The most popular approach for generating transgenic mammals is the direct injection of transgenes into one pronucleus of a fertilized oocyte. In the past 15 years microinjection has been successfully applied in laboratory as well as in farm animals. The frequency of transgenic founders, although highly different between the species, is efficient enough to render this technique applicable to a wide range of mammals. The expression levels and patterns of a transgene are initially influenced by the construction of the transgene. However, the overall phenotype of a transgenic organism is influenced by several genetic and environmental factors. Due to the features of this technique not all of the genetic factors can be experimentally controlled by the scientist. In this article we will emphasize some peculiarities which have to be taken into account for the successful performance of transgenesis by pronuclear microinjection.


An Algorithm for Improving Hospital Performance Measures: A Department-centered Approach.
In recent years, it has become increasingly important to improve efficiency and economic balance in hospitals. The department chairperson (or Chair) contends with a production function consisting of inputs and outcomes, rife with managerial constraints. These constraints can be reduced with proper management by diverting resources and activity. Lack of a proper management algorithm at the department level is a significant impediment to improving operational efficiency in hospitals without significant additional costs. In this work we aimed to develop and implement a management algorithm in a teaching hospital department, in order to improve performances and quality of care. From September 2012 to December 2017 we developed a novel management algorithm for a surgical department and implemented it in the Head and Neck Surgery Department at Rambam Medical Center, Haifa, Israel. Changes were made to the organization structure and the concept of service provision. We defined core measures reflecting operative actions and outcomes and identified actions that could affect these measures. Based on our analysis of outcomes we constructed a management intervention process that defines operative actions leading to improved performance. The result was over 400% improvement in the department's outcome measures including quality, activity, and service. Analysis of data from the Israeli Ministry of Health revealed that the department's ranking in performance measures and volume improved from no. 14 of 23 departments in Israel in 2011, to no. 1 in 2013, which was sustained through 2014-2016. Improvement in efficiency also translated to economic balance and transformation from deficit to profitability. If this algorithm is implemented in the rest of the system, it is expected to improve the function of the hospital as a whole. Our results have the potential to foster the development of a new organizational culture of measurement and improvement in the hospital, and subsequently in the entire health system.


Diversity and distribution of a deeply branched novel proteobacterial group found in anaerobic-aerobic activated sludge processes.
A novel coccobacilli group found previously in enhanced biological phosphorus removal (EBPR) systems was further revealed to have a high degree of diversity and distribution in various activated sludge systems. Phylogenetic analysis based on 14 existing and 18 newly retrieved 16S rRNA sequences revealed that these sequences formed a novel cohesive cluster with seven subgroups in the gamma-Proteobacteria. Fluorescence in situ hybridization with a set of probes designed specifically targeting the novel group at different hierarchical levels showed that the novel group with a coccoid (2-4 micro m) to occasionally long-rod (up to 20 micro m) shape widely distributed and in some cases predominated in sludge samples taken from nine lab- and full-scale EBPR systems (10-50% of total cells) and four conventional activated sludge systems (1-10%). Variation of predominance was also observed among those subgroups in systems showing deteriorated or effective EBPR activity.


Influence of host gender on infection rate, density and distribution of the parasitic fungus, Hesperomyces virescens, on the multicolored Asian lady beetle, Harmonia axyridis.
Hesperomyces virescens Thaxter (Laboulbeniales: Laboulbeniaceae) is a parasitic fungus that infects lady beetles (Coleoptera: Coccinellidae) via horizontal transmission between adults at overwintering and feeding sites. The differential behavior of male and female hosts could have profound effects on intensity of infection and positioning of fungus on the host's integument. The influence of host gender on infection rate, density and distribution of this parasite on the multicolored Asian lady beetle, Harmonia axyridis (Pallas) (Coleoptera: Coccinellidae), was determined at a feeding site. Adult H. axyridis were sampled from pecan, Carya illinoinensis (Wangenh.) K. Koch, trees in northern Mississippi, USA, during summer and early fall 2003-2004. Results indicated that the behavior of male or female beetles on pecan trees had only a limited effect on the intensity of infection. When averaged over the entire season, the percentage of H. axyridis infected with H. virescens was not influenced by host gender. In 2003, a seasonal average of 54 and 39% of males and females, respectively, were infected; whereas in 2004, 36 and 41% of male and female beetles, respectively, were infected. The percentage of males infected with H. virescens was correlated with the number of males captured at the site in 2003; infection rate decreased as male abundance increased. Infection rate did not correlate with female abundance in 2003 or male or female abundance in 2004. Host gender had a considerable effect on the density and distribution of the fungus. Hesperomyces virescens mature thalli were denser on male rather than female beetles. Also, thallus density was often greatest on the elytra, meso- and metathorax, and abdomen of males and elytra of females, than on other body parts, in 2003. In 2003 and 2004, approximately 59 and 97% and 67 and 96% of males and females, respectively, had mature thalli distributed on the elytra. Prevalence of H. virescens thalli on the dorsum of H. axyridis females suggests that mating behavior is important in fungal transmission. However, prevalence of thalli on the dorsum of H. axyridis males suggests that behaviors other than mating contribute to the transmission of H. virescens onto male beetles. Spread of H. virescens ascospores from infected to uninfected H. axyridis adults of different generations, at feeding sites, might be vital to maintaining stable populations of the fungus.


Clinical features, outcomes and treatment in children with drug induced Stevens-Johnson syndrome and toxic epidermal necrolysis.
Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), which can be considered a late-onset allergic reaction, can cause serious long-term sequelae. SJS/TEN are considered a spectrum of life-threatening adverse drug reactions. They have the same clinical manifestations and the only difference is in the extent of epidermal detachment. These conditions are associated with high mortality, although incidence of SJS/TEN is rare in children. SJS/TEN is an adverse drug reaction influenced by genes that involve pharmacokinetics, pharmacodynamics and immune response. Infective agents are additional influencing factors. Anticonvulsants and antibiotics, and especially sulphonamides and non-steroidal anti-inflammatory drugs, are among the drugs that were predominantly suspected of triggering SJS/TEN. No evidence-based standardized treatment guidelines for SJS or TEN are currently available. The usual treatment is mainly founded on the withdrawal of the suspected causative agent and supportive therapy. In pediatric patients, the specific therapeutic strategies are controversial and comprise systemic corticosteroids and the use of intravenous immunoglobulin (IVIG). More recently, new therapeutic approaches have been used, such as immunosuppressive therapies, including cyclosporine and TNF-α inhibitors.


App-Based Delivery of Clinical Emotional Freedom Techniques: Cross-Sectional Study of App User Self-Ratings.
The burgeoning area of mobile health (mHealth) has experienced rapid growth in mobile apps designed to address mental health issues. Although abundant apps offer strategies for managing symptoms of anxiety and stress, information regarding their efficacy is scarce. This study aimed to assess the effect of an mHealth app on user self-ratings of psychological distress in a sample of 270,461 app users. The Tapping Solution App guides users through the therapeutic protocols of Clinical Emotional Freedom Techniques (EFT), an evidence-based psychophysiological intervention that combines acupressure with elements of cognitive and exposure therapies. App users provided self-ratings of emotional intensity before and after app sessions (termed "tapping meditations") using an 11-point Subjective Units of Distress scale. App user data for 23 tapping meditations, which addressed psychological symptoms of anxiety and stress, were gathered between October 2018 and October 2019, totaling 380,034 completed app sessions. Across 12 anxiety-tapping meditations, the difference in emotional intensity ratings from presession (mean 6.66, SD 0.25) to postsession (mean 3.75, SD 0.30) was statistically significant (P<.001; 95% CI -2.92 to -2.91). Across 11 stress-tapping meditations, a statistically significant difference was also found from presession (mean 6.91, SD 0.48) to postsession (mean 3.83, SD 0.54; P<.001; 95% CI -3.08 to -3.07). The results are consistent with the literature on the efficacy of Clinical EFT for anxiety and stress when offered in conventional therapeutic formats. The findings provide preliminary support for the effectiveness of the mHealth app in the immediate reduction of self-rated psychological distress. As an adjunct to professional mental health care, the app promises accessible and convenient therapeutic benefits.


Leucocyte telomere shortening in relation to newly diagnosed type 2 diabetic patients with depression.
The goal of this study is to investigate the association between oxidative stress and telomere length shortening in the comorbid depression and diabetes. Therefore, 71 patients with newly diagnosed type 2 diabetes (T2D) and 52 subjects with normal glycemic level (control, Ctrl) were enrolled. Depressive status was identified with the Depression Subscale of Hospital Anxiety and Depression Scale (HADS-D). Leukocyte telomere length ratio (T/S ratio) was determined with quantitative PCR. Oxidative stress status was evaluated with 8-hydroxy-desoxyguanosine (8-OHdG) assay kit. Some other biochemical blood testing was also performed. The data showed that T2D patients had higher proportion of depression evaluated by the HADS-D (x(2) = 4.196, P = 0.041). T/S ratio was significantly negatively correlated with 8-OHdG, HADS-D, age, HbA1c, FPG, and HOMA-IR. In addition, HADS-D was significantly positively correlated with HbA1c, FPG, HOMA-IR, and 8-OHdG. Both HADS-D and 8-OHdG were the major independent predictors for T/S ratio. This study indicates that oxidative stress contributes to both telomere length shortening and depression development in newly diagnosed type 2 diabetic patients, while in depression status, some other mechanisms besides oxidative stress may also affect the telomere length.


Th9 cytokines response and its possible implications in the immunopathogenesis of leprosy.
Leprosy is an infectious-contagious disease whose clinical evolution depends on the interaction of the infectious agent with the immune response of the host, leading to a clinical spectrum that ranges from lepromatous leprosy (susceptibility, LL) to tuberculoid leprosy (resistance, TT). The immune response profile will depend on the pattern of cytokine production and on the activity of macrophages during infection. Classically, the clinical evolution of leprosy has been associated with Th1/Th2 cytokine profiles, but the role of new cytokine profiles such as T helper 9 (Th9) remains to be elucidated. To evaluate the tissue expression profile of these cytokines, a cross-sectional study was conducted using a sample of 30 leprosy skin lesion biopsies obtained from patients with leprosy, 16 TT and 14 lepromatous LL. Immunohistochemical analysis revealed a significant difference in interleukin (IL)-9, IL-4 transforming growth factor (TGF)-β and IL-10 levels between the two groups. IL-9 was more expressed in TT lesions compared with LL lesions. Higher expression of IL-4, IL-10 and TGF-β was observed in LL compared with TT. IL-4, IL-10 and TGF-β tended to be negatively correlated with the expression of IL-9, indicating a possible antagonistic activity in tissue. The results suggest that Th9 lymphocytes may be involved in the response to Mycobacterium leprae, positively or negatively regulating microbicidal activity of the local immune system in the disease.


Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation.
Hypoxia-inducible factor (HIF) is a transcriptional complex that plays a central role in the regulation of gene expression by oxygen. In oxygenated and iron replete cells, HIF-alpha subunits are rapidly destroyed by a mechanism that involves ubiquitylation by the von Hippel-Lindau tumor suppressor (pVHL) E3 ligase complex. This process is suppressed by hypoxia and iron chelation, allowing transcriptional activation. Here we show that the interaction between human pVHL and a specific domain of the HIF-1alpha subunit is regulated through hydroxylation of a proline residue (HIF-1alpha P564) by an enzyme we have termed HIF-alpha prolyl-hydroxylase (HIF-PH). An absolute requirement for dioxygen as a cosubstrate and iron as cofactor suggests that HIF-PH functions directly as a cellular oxygen sensor.


New mechanisms of glucocorticoid-induced insulin resistance: make no bones about it.
Glucocorticoids are a powerful tool used to treat a range of human illnesses, including autoimmune diseases and cancer, and to prevent rejection following organ transplantation. While lifesaving for many, they come with a steep price, often leading to obesity, insulin resistance, diabetes, and osteoporosis. In this issue of the JCI, Brennan-Speranza and colleagues provide evidence that the osteoblast-derived peptide osteocalcin is one of the drivers of the metabolic derangements associated with glucocorticoid therapy. This novel mechanism could open up new avenues for the treatment of these disorders.


Better Patient Care At High-Quality Hospitals May Save Medicare Money And Bolster Episode-Based Payment Models.
US policy makers are making efforts to simultaneously improve the quality of and reduce spending on health care through alternative payment models such as bundled payment. Bundled payment models are predicated on the theory that aligning financial incentives for all providers across an episode of care will lower health care spending while improving quality. Whether this is true remains unknown. Using national Medicare fee-for-service claims for the period 2011-12 and data on hospital quality, we evaluated how thirty- and ninety-day episode-based spending were related to two validated measures of surgical quality-patient satisfaction and surgical mortality. We found that patients who had major surgery at high-quality hospitals cost Medicare less than those who had surgery at low-quality institutions, for both thirty- and ninety-day periods. The difference in Medicare spending between low- and high-quality hospitals was driven primarily by postacute care, which accounted for 59.5 percent of the difference in thirty-day episode spending, and readmissions, which accounted for 19.9 percent. These findings suggest that efforts to achieve value through bundled payment should focus on improving care at low-quality hospitals and reducing unnecessary use of postacute care.


Flexibility along the neck of the neogene terror bird Andalgalornis steulleti (Aves Phorusrhacidae).
Andalgalornis steulleti from the upper Miocene-lower Pliocene (≈6 million years ago) of Argentina is a medium-sized patagornithine phorusrhacid. It was a member of the predominantly South American radiation of 'terror birds' (Phorusrhacidae) that were apex predators throughout much of the Cenozoic. A previous biomechanical study suggests that the skull would be prepared to make sudden movements in the sagittal plane to subdue prey. We analyze the flexion patterns of the neck of Andalgalornis based on the neck vertebrae morphology and biometrics. The transitional cervical vertebrae 5th and 9th clearly separate regions 1-2 and 2-3 respectively. Bifurcate neural spines are developed in the cervical vertebrae 7th to 12th suggesting the presence of a very intricate ligamentary system and of a very well developed epaxial musculature. The presence of the lig. elasticum interespinale is inferred. High neural spines of R3 suggest that this region concentrates the major stresses during downstrokes. The musculoskeletal system of Andalgalornis seems to be prepared (1) to support a particularly big head during normal stance, and (2) to help the neck (and the head) rising after the maximum ventroflexion during a strike. The study herein is the first interpretation of the potential performance of the neck of Andalgalornis in its entirety and we considered this an important starting point to understand and reconstruct the flexion pattern of other phorusrhacids from which the neck is unknown.


Costs of treatment for elderly women with early-stage breast cancer in fee-for-service settings.
This study provides population-based estimates of the treatment costs for elderly women with early-stage breast cancer, with emphasis on costs of modified radical mastectomy (MRM) compared with breast-conserving surgery (BCS) and radiation therapy (RT). Women with breast cancer from the Surveillance, Epidemiology, and End Results cancer registries were linked with their Medicare claims, 1990 through 1998. Each claim was assigned to an initial, continuing, or terminal care phase after a cancer diagnosis. Mean monthly phase-specific costs were determined for all health care and for treatment related only to cancer. Cumulative long-term costs of care that accrue during a women's remaining lifetime were calculated by treatment group. Initial care costs for the 6 months after diagnosis for women who underwent BCS with RT were approximately $450 per month higher than for women with MRM. During the continuing-care phase, costs for women undergoing BCS with RT were significantly less expensive than for MRM cases. The two groups had similar costs in the terminal-care phase. Assuming the same survival distributions, long-term costs for women undergoing BCS with RT were not statistically different than for women undergoing MRM. Although mastectomy was less costly in the initial phase, the lifetime costs of BCS with RT and mastectomy were equivalent. Thus, women's preferences, resources to cover out-of-pocket costs, and life situations should be the major factors addressed in shared decision making about treatment options.


Diagnosis of suspicious breast lesions using an empirical mathematical model for dynamic contrast-enhanced MRI.
The purpose of this study was to test whether an empirical mathematical model (EMM) of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) can distinguish between benign and malignant breast lesions. A modified clinical protocol was used to improve the sampling of contrast medium uptake and washout. T(1)-weighted DCE magnetic resonance images were acquired at 1.5 T for 22 patients before and after injection of Gd-DTPA. Contrast medium concentration as a function of time was calculated over a small region of interest containing the most rapidly enhancing pixels. Then the curves were fitted with the EMM, which accurately described contrast agent uptake and washout. Results demonstrate that benign lesions had uptake (P<2.0 x 10(-5)) and washout (P<.01) rates of contrast agent significantly slower than those of malignant lesions. In addition, secondary diagnostic parameters, such as time to peak of enhancement, enhancement slope at the peak and curvature at the peak of enhancement, were derived mathematically from the EMM and expressed in terms of primary parameters. These diagnostic parameters also effectively differentiated benign from malignant lesions (P<.03). Conventional analysis of contrast medium dynamics, using a subjective classification of contrast medium kinetics in lesions as "washout," "plateau" or "persistent" (sensitivity=83%, specificity=50% and diagnostic accuracy=72%), was less effective than the EMM (sensitivity=100%, specificity=83% and diagnostic accuracy=94%) for the separation of benign and malignant lesions. In summary, the present research suggests that the EMM is a promising alternative method for evaluating DCE-MRI data with improved diagnostic accuracy.


Comprehensive support of family caregivers: Are there health system cost offsets?
To examine the effect of the Department of Veterans Affairs' (VA) Program of Comprehensive Assistance for Caregivers (PCAFC) on total VA health care costs for Veterans. VA claims. Using a pre-post cohort design with nonequivalent control group, we estimated the effect of PCAFC on total VA costs up through 6 years. The treatment group included Veterans (n = 32 394) whose caregivers enrolled in PCAFC. The control group included an inverse probability of treatment weighted sample of Veterans whose caregivers were denied PCAFC enrollment (n = 38 402). May 2009-September 2017. Total VA costs pre-PCAFC application date were no different between groups. Veterans in PCAFC were estimated to have $13 227 in VA costs in the first 6 months post-PCAFC application, compared to $10 806 for controls. Estimated VA costs for both groups decreased in the first 3 years with a narrowing, but persistent and significant, difference, through 5.5 years. No significant difference in VA health care costs existed at 6 years, approximately $10 000 each, though confidence intervals reflect significant uncertainty in cost differences at 6 years. Increased costs arose from increased outpatient costs of participants. Sample composition changes may explain lack of significance in cost differences at 6 years because these costs comprise of early appliers to PCAFC. Examining 10-year costs could elucidate whether there are long-term cost offsets from increased engagement in outpatient care.


A metalloproteinase disintegrin that releases tumour-necrosis factor-alpha from cells.
Mammalian cells proteolytically release (shed) the extracellular domains of many cell-surface proteins. Modification of the cell surface in this way can alter the cell's responsiveness to its environment and release potent soluble regulatory factors. The release of soluble tumour-necrosis factor-alpha (TNF-alpha) from its membrane-bound precursor is one of the most intensively studied shedding events because this inflammatory cytokine is so physiologically important. The inhibition of TNF-alpha release (and many other shedding phenomena) by hydroxamic acid-based inhibitors indicates that one or more metalloproteinases is involved. We have now purified and cloned a metalloproteinase that specifically cleaves precursor TNF-alpha. Inactivation of the gene in mouse cells caused a marked decrease in soluble TNF-alpha production. This enzyme (called the TNF-alpha-converting enzyme, or TACE) is a new member of the family of mammalian adamalysins (or ADAMs), for which no physiological catalytic function has previously been identified. Our results should facilitate the development of therapeutically useful inhibitors of TNF-alpha release, and they indicate that an important function of adamalysins may be to shed cell-surface proteins.


Opportunities for Orphan Crops: Expected Economic Benefits From Biotechnology.
An enabling, evidence-based decision-making framework is critical to support agricultural biotechnology innovation, and to ensure farmers' access to genetically modified (GM) crops, including orphan crop varieties. A key element, and often a challenge in the decision-making process, involves the balancing of identified potential risks with expected economic benefits from GM crops. The latter is particularly challenging in the case of orphan crops, for which solid economic data is scarce. To address this challenge, the International Food Policy Research Institute (IFPRI) in collaboration with local economists analyzed the expected economic benefits to farmers and consumers from the adoption of GM crops in 5 sub-Saharan African countries. This paper focuses on case studies involving insect-resistant cowpea in Nigeria and Ghana; disease-resistant cassava in Uganda and Tanzania; and disease-resistant banana in Uganda. Estimations from these case studies show substantial economic benefits to farmers and consumers from the timely adoption and planting in farmers' fields of GM orphan crops. Our analysis also shows how the benefits would significantly be reduced by regulatory or other delays that affect the timely release of these crops. These findings underscore the importance of having an enabling policy environment and regulatory system-covering, among other elements, biosafety and food/feed safety assessment, and varietal release registration-that is efficient, predictable, and transparent to ensure that the projected economic benefits are delivered and realized in a timely manner.


International trends in the uptake of cancer risk reduction strategies in women with a BRCA1 or BRCA2 mutation.
Women with a BRCA1 or BRCA2 mutation face high risks of breast and ovarian cancer. In the current study, we report on uptake of cancer screening and risk-reduction options in a cohort of BRCA mutation carriers from ten countries over two time periods (1995 to 2008 and 2009 to 2017). Eligible subjects were identified from an international database of female BRCA mutation carriers and included women from 59 centres from ten countries. Subjects completed a questionnaire at the time of genetic testing, which included past use of cancer prevention options and screening tests. Biennial follow-up questionnaires were administered. Six-thousand two-hundred and twenty-three women were followed for a mean of 7.5 years. The mean age at last follow-up was 52.1 years (27-96 years) and 42.3% of the women had a prior diagnosis of breast cancer. In all, 27.8% had a prophylactic bilateral mastectomy and 64.7% had a BSO. Screening with breast MRI increased from 70% before 2009 to 81% at or after 2009. There were significant differences in uptake of all options by country. For women who received genetic testing more recently, uptake of prophylactic mastectomy and breast MRI is significantly higher than those who received genetic testing more than 10 years ago. However, uptake of both BSO and breast MRI is not optimal, and interventions to increase uptake are needed.


Dye coupling between pyramidal neurons in developing rat prefrontal and frontal cortex is reduced by protein kinase A activation and dopamine.
During early postnatal development, lamina II/III pyramidal cells in rat neocortex are extensively coupled via gap junctions. The factors regulating gap junction permeability, as well as the mechanisms underlying the developmental uncoupling process are not understood. To investigate the influence of protein kinase A-mediated phosphorylation on dye coupling in the developing neocortex, pyramidal cells in slices of rat frontal and prefrontal cortex were injected intracellularly with the tracer neurobiotin. Control injections revealed clusters of about 30 dye-coupled neurons. Preincubation with forskolin or direct activation of protein kinase A with Sp-cAMPS reduced the number of coupled cells by about 70%. A significant reduction in dye coupling was also observed following incubation with dopamine. Application of receptor selective agonists and antagonists revealed that the uncoupling was mediated by both dopamine D1 and D2 receptors. The protein kinase A inhibitor Rp-cAMPS reduced the effect of dopamine, suggesting that the neurotransmitter regulates gap junction permeability via protein kinase A activation. In the presence of either forskolin, Sp-cAMPS, or dopamine, neurons displayed a significantly higher input resistance compared to control conditions. During the second postnatal week, transient application of forskolin to single neurons reversibly increased input resistance. At later developmental stages when coupling incidence had declined, this action of forskolin was no longer observed. Our data demonstrate a dependence of gap junction permeability on protein kinase A activity and on dopamine receptor activation in developing rat neocortical neurons. These mechanisms may modulate junctional permeability during the period of circuit formation.


Global patterns in endemicity and vulnerability of soil fungi.
Fungi are highly diverse organisms, which provide multiple ecosystem services. However, compared with charismatic animals and plants, the distribution patterns and conservation needs of fungi have been little explored. Here, we examined endemicity patterns, global change vulnerability and conservation priority areas for functional groups of soil fungi based on six global surveys using a high-resolution, long-read metabarcoding approach. We found that the endemicity of all fungi and most functional groups peaks in tropical habitats, including Amazonia, Yucatan, West-Central Africa, Sri Lanka, and New Caledonia, with a negligible island effect compared with plants and animals. We also found that fungi are predominantly vulnerable to drought, heat and land-cover change, particularly in dry tropical regions with high human population density. Fungal conservation areas of highest priority include herbaceous wetlands, tropical forests, and woodlands. We stress that more attention should be focused on the conservation of fungi, especially root symbiotic arbuscular mycorrhizal and ectomycorrhizal fungi in tropical regions as well as unicellular early-diverging groups and macrofungi in general. Given the low overlap between the endemicity of fungi and macroorganisms, but high conservation needs in both groups, detailed analyses on distribution and conservation requirements are warranted for other microorganisms and soil organisms.


A focus group study of factors that promote and constrain the use of satellite-derived fire products by resource managers in southern Africa.
Semi-structured focus group interviews were employed to examine factors that affect the likelihood that resource managers in southern Africa will use information on vegetation fires provided by two satellite-derived products: an active fire product and a burned area product. The two products are updated regularly and aim to deliver the state-of-the-art in the global monitoring of fires from satellite remote-sensing. Both products are derived from data transmitted by the Moderate Resolution Imaging Spectroradiometer (MODIS) sensors carried onboard NASA's Aqua and Terra satellites. The active fire product can be accessed for free via the internet and on media by users working anywhere in the world; the burned area product will be accessible in a similar manner in 2006. The MODIS fire products provide systematic, near-global coverage and are freely available; as such, they give resource managers new opportunities to obtain or supplement information they need to manage vegetation fires effectively. However, the availability of these products does not mean that resource managers will use them, and many other factors are involved. To understand factors that affect whether southern African resource managers will use the two products, two focus groups were held with members of the Southern African Fire Network (SAFNet) in Malawi, Africa, August 2004. Analysis of the group discussions reveals a number of factors that influence whether they will use the products. The qualitative, in depth nature of the group discussions revealed 12 main factors that influence product use; not least the low international internet bandwidths for African countries outside of South Africa. Analysis of the group discussions also suggests how the uptake of MODIS fire products by resource managers in southern Africa might be enhanced by affecting specific changes to how MODIS products are packaged and delivered.


Molecular, genetic and evolutionary analysis of a paracentric inversion in Arabidopsis thaliana.
Chromosomal inversions can provide windows onto the cytogenetic, molecular, evolutionary and demographic histories of a species. Here we investigate a paracentric 1.17-Mb inversion on chromosome 4 of Arabidopsis thaliana with nucleotide precision of its borders. The inversion is created by Vandal transposon activity, splitting an F-box and relocating a pericentric heterochromatin segment in juxtaposition with euchromatin without affecting the epigenetic landscape. Examination of the RegMap panel and the 1001 Arabidopsis genomes revealed more than 170 inversion accessions in Europe and North America. The SNP patterns revealed historical recombinations from which we infer diverse haplotype patterns, ancient introgression events and phylogenetic relationships. We find a robust association between the inversion and fecundity under drought. We also find linkage disequilibrium between the inverted region and the early flowering Col-FRIGIDA allele. Finally, SNP analysis elucidates the origin of the inversion to South-Eastern Europe approximately 5000 years ago and the FRI-Col allele to North-West Europe, and reveals the spreading of a single haplotype to North America during the 17th to 19th century. The 'American haplotype' was identified from several European localities, potentially due to return migration.


Telehealth: into the mainstream?
Teleheath, and its subset telemedicine, extend across a range of technologies allowing patients to seek diagnosis, treatment, and other services from clinicians by electronic means. Telephone, videoconferencing, iPads, and apps are all employed. In its most established form, hospitals and medical centers use telehealth to reach patients in underserved rural areas. Proponents of telehealth suggest it can relieve medical workforce shortages; save patients time, money, and travel; reduce unnecessary hospital visits; improve the management of chronic conditions; and improve continuing medical education. But telehealth also faces ongoing challenges. States require physicians to be licensed in each state where they treat patients, even if from a distance. Most clinicians have not been trained in telehealth. Security concerns linger. Who should have access to telehealth and how it should be reimbursed are questions without fixed answers. This issue brief looks at telehealth's promise and its challenges and considers opportunities for policymakers to help in charting its future course.


Factors related to silent myocardial damage in hemodialysis patients.
Both traditional and non-traditional risk factors play a role for the development of cardiovascular disease in hemodialysis patients. However, a specific relationship between these risk factors and silent myocardial damage is unknown. Demographic, anthropometric, clinical, and laboratory data were collected. Silent myocardial damage was defined by elevated cardiac troponin I values above cutoff values. In total, 113 hemodialysis patients were included. Cardiac troponin I concentrations were below cutoff value (<2.3 ng/mL) in 103 (91.2%) patients (Group 1), whereas 10 (8.8%) patients had elevated concentrations (Group 2). Group 1 patients had higher levels of hemoglobin (p = 0.002) and high-density lipoprotein cholesterol (p = 0.002) and lower C-reactive protein (p = 0.003) and tumor necrosis factor-alpha (p = 0.005) levels, as well as less incidence of left ventricular hypertrophy (p = 0.045), when compared to Group 2 patients. Diabetes mellitus (Beta = +0.160, p = 0.021), left ventricular hypertrophy (Beta = +0.247, p < 0.0001), uncontrolled blood pressure (Beta = +0.170, p = 0.016), normalized protein equivalent of total nitrogen appearance (Beta = -0.230, p = 0.001), hemoglobin (Beta = -0.302, p < 0.0001), and tumor necrosis factor-alpha (Beta = +0.506, p < 0.0001) were found to be independently associated with cardiac troponin I levels in multiple linear regression analysis. Both traditional and non-traditional risk factors are related with silent myocardial damage, which is considered to an antecedent of major cardiovascular events. Hemodialysis patients, even when asymptomatic, must be closely followed up for the presence of these risk factors.


Near-triploid and near-tetraploid acute lymphoblastic leukemia of childhood.
Cytogenetic and DNA flow cytometric analyses of leukemic cells from 1,971 children with newly diagnosed acute lymphoblastic leukemia (ALL) identified stem lines with modal chromosome numbers greater than 65 in 26 patients (1.3%). Near-triploidy (66 to 73 chromosomes) was found in six cases and near-tetraploidy (82 to 94 chromosomes) in 20. A striking morphologic finding was the presence of clumped chromatin with grooved nuclei or Rieder cell formation in 20 cases. Other than a slight excess of the pre-B immunophenotype, the near-triploid cases did not appear to differ substantially from the general ALL population in clinical features. In contrast, near-tetraploid cases were more often associated with a T-cell immunophenotype (47% v 14%, P less than .001) and L2 morphology (30% v 22%, P less than .01), and were older at diagnosis (median age, 8.6 v 4.8 years, P = .01) than cases with other ploidies. Moreover, an unusually high proportion of near-tetraploid cases tested (6 of 15) expressed one or more of the myeloid-associated antigens CD13, CD15, and CD33. Despite the use of contemporary intensive chemotherapy and short follow-up for most patients, 6 of the 20 near-tetraploid cases have relapsed or died. This study suggests that the near-tetraploid subtype differs from other cases of hyperdiploid greater than 50 ALL, which have been associated with a favorable prognosis.


Mathematical and computational models of drug transport in tumours.
The ability to predict how far a drug will penetrate into the tumour microenvironment within its pharmacokinetic (PK) lifespan would provide valuable information about therapeutic response. As the PK profile is directly related to the route and schedule of drug administration, an in silico tool that can predict the drug administration schedule that results in optimal drug delivery to tumours would streamline clinical trial design. This paper investigates the application of mathematical and computational modelling techniques to help improve our understanding of the fundamental mechanisms underlying drug delivery, and compares the performance of a simple model with more complex approaches. Three models of drug transport are developed, all based on the same drug binding model and parametrized by bespoke in vitro experiments. Their predictions, compared for a 'tumour cord' geometry, are qualitatively and quantitatively similar. We assess the effect of varying the PK profile of the supplied drug, and the binding affinity of the drug to tumour cells, on the concentration of drug reaching cells and the accumulated exposure of cells to drug at arbitrary distances from a supplying blood vessel. This is a contribution towards developing a useful drug transport modelling tool for informing strategies for the treatment of tumour cells which are 'pharmacokinetically resistant' to chemotherapeutic strategies.


A characterization of cytostatic factor activity from Xenopus eggs and c-mos-transformed cells.
In Xenopus oocytes, the mos proto-oncogene product is required during meiosis I for the activation of maturation promoting factor (MPF) and the subsequent breakdown of the germinal vesicle (GVBD). In addition, the mos product has been shown to be a candidate "initiator" of meiotic maturation and is an active component of cytostatic factor (CSF), an activity responsible for metaphase II arrest. Here we demonstrate that pp39mos is required throughout oocyte maturation. We found that in progesterone stimulated oocytes, depletion of mos RNA immediately before GVBD terminally decreased MPF. Likewise, oocytes depleted of mos RNA and induced to mature with crude MPF proceeded through GVBD but lacked the MPF activity required to arrest mature oocytes at metaphase II. Thus, during maturation the mos product is required, directly or indirectly, to sustain MPF activity. On the other hand, mouse NIH/3T3 cells transformed by the constitutive expression of pp39mosxc possessed CSF activity but lacked constitutive levels of MPF or its associated histone H1 kinase activity. Moreover, cytosols prepared from transformed NIH/3T3 cells or Xenopus eggs had similar levels of CSF activity, but pp39mos levels were greater than 40-fold higher in the transformed cell extract. These analyses show that maintenance of CSF during interphase does not result in the maintenance of MPF.


The genomic evolution of human prostate cancer.
Prostate cancers are highly prevalent in the developed world, with inheritable risk contributing appreciably to tumour development. Genomic heterogeneity within individual prostate glands and between patients derives predominantly from structural variants and copy-number aberrations. Subtypes of prostate cancers are being delineated through the increasing use of next-generation sequencing, but these subtypes are yet to be used to guide the prognosis or therapeutic strategy. Herein, we review our current knowledge of the mutational landscape of human prostate cancer, describing what is known of the common mutations underpinning its development. We evaluate recurrent prostate-specific mutations prior to discussing the mutational events that are shared both in prostate cancer and across multiple cancer types. From these data, we construct a putative overview of the genomic evolution of human prostate cancer.


Mechanism by which DHA inhibits the aggregation of KLVFFA peptides: A molecular dynamics study.
Docosahexaenoic acid (DHA) is one of the omega-3 polyunsaturated fatty acids, which has shown promising applications in lowering Aβ peptide neurotoxicity in vitro by preventing aggregation of Aβ peptides and relieving accumulation of Aβ fibrils. Unfortunately, the underlying molecular mechanisms of how DHA interferes with the aggregation of Aβ peptides remain largely enigmatic. Herein, aggregation behaviors of amyloid-β(Aβ)16-21 peptides (KLVFFA) with or without the presence of a DHA molecule were comparatively studied using extensive all-atom molecular dynamics simulations. We found that DHA could effectively suppress the aggregation of KLVFFA peptides by redirecting peptides to unstructured oligomers. The highly hydrophobic and flexible nature of DHA made it randomly but tightly entangled with Leu-17, Phe-19, and Phe-20 residues to form unstructured but stable complexes. These lower-ordered unstructured oligomers could eventually pass through energy barriers to form ordered β-sheet structures through large conformational fluctuations. This study depicts a microscopic picture for understanding the role and mechanism of DHA in inhibition of aggregation of Aβ peptides, which is generally believed as one of the important pathogenic mechanisms of Alzheimer's disease.


The pace of shifting climate in marine and terrestrial ecosystems.
Climate change challenges organisms to adapt or move to track changes in environments in space and time. We used two measures of thermal shifts from analyses of global temperatures over the past 50 years to describe the pace of climate change that species should track: the velocity of climate change (geographic shifts of isotherms over time) and the shift in seasonal timing of temperatures. Both measures are higher in the ocean than on land at some latitudes, despite slower ocean warming. These indices give a complex mosaic of predicted range shifts and phenology changes that deviate from simple poleward migration and earlier springs or later falls. They also emphasize potential conservation concerns, because areas of high marine biodiversity often have greater velocities of climate change and seasonal shifts.


Stroke in a resource-constrained hospital in Madagascar.
Stroke is reported as the most frequent cause of in-hospital death in Madagascar. However, no descriptive data on hospitalized stroke patients in the country have been published. In the present study, we sought to investigate the feasibility of collecting data on stroke patients in a resource-constrained hospital in Madagascar. We also aimed to characterize patients hospitalized with stroke. We registered socio-demographics, clinical characteristics, and early outcomes of patients admitted for stroke between 23 September 2014 and 3 December 2014. We used several validated scales for the evaluation. Stroke severity was measured by the National Institutes of Health Stroke Scale (NIHSS), disability by the modified Rankin Scale (mRS), and function by the Barthel Index (BI). We studied 30 patients. Sixteen were males. The median age was 62.5 years (IQR 58-67). The NIHSS and mRS were completed for all of the patients, and BI was used for the survivors. Three patients received a computed tomography (CT) brain scan. The access to laboratory investigations was limited. Electrocardiographs (ECGs) were not performed. The median NIHSS score was 16.5 (IQR 10-35). The in-hospital stroke mortality was 30%. At discharge, the median mRS score was 5 (IQR 4-6), and the median BI score was 45 (IQR 0-72.5). Although the access to brain imaging and supporting investigations was deficient, this small-scale study suggests that it is feasible to collect essential data on stroke patients in a resource-constrained hospital in Madagascar. Such data should be useful for improving stroke services and planning further research. The hospitalized stroke patients had severe symptoms. The in-hospital stroke mortality was high. At discharge, the disability category was high, and functional status low.


Effect of garlic powder consumption on body composition in patients with nonalcoholic fatty liver disease: A randomized, double-blind, placebo-controlled trial.
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease that is becoming a public health problem in recent decades. Obesity and overweight play a key role in NAFLD pathogenesis. Thus, weight loss (especially body fat mass) is one component of therapeutic strategies in NAFLD. Results from experimental studies have shown that garlic (Allium sativum L.) can reduce body weight and body fat mass. However, the effect of garlic on body fat mass and weight in the human population, which is addressed in this study, is still obscure. In this clinical trial, 110 subjects with NAFLD were randomly assigned to the intervention or the control group. The intervention group received two garlic tablets (containing 400 mg of garlic powder) daily while the control group received placebo tablets. Dietary intake and physical activity of participants were obtained by a validated questionnaire. Body composition was measured by bioelectrical impedance analysis. Data were analyzed using SPSS software version 16. In the intervention group, significant reductions were observed in body weight and body fat mass (P < 0.05). We also observed a significant reduction in body weight in the control group, but there were no significant changes in total body water and lean body mass in both groups (P > 0.05). In the intervention group, the percentage change in body weight was significantly greater than the control group (-2.6 vs. -0.7, P = 0.02). No serious side effects associated with the intervention were reported. Our trial suggests that garlic supplemfrom experimental studies have shown thatentation can reduce body weight and fat mass among subjects with NAFLD.


Late acute graft-versus-host disease: a prospective analysis of clinical outcomes and circulating angiogenic factors.
Late acute (LA) graft-versus-host disease (GVHD) is persistent, recurrent, or new-onset acute GVHD symptoms occurring >100 days after allogeneic hematopoietic cell transplantation (HCT). The aim of this analysis is to describe the onset, course, morbidity, and mortality of and examine angiogenic factors associated with LA GVHD. A prospective cohort of patients (n = 909) was enrolled as part of an observational study within the Chronic GVHD Consortium. Eighty-three patients (11%) developed LA GVHD at a median of 160 (interquartile range, 128-204) days after HCT. Although 51 out of 83 (61%) achieved complete or partial response to initial therapy by 28 days, median failure-free survival was only 7.1 months (95% confidence interval, 3.4-19.1 months), and estimated overall survival (OS) at 2 years was 56%. Given recently described alterations of circulating angiogenic factors in classic acute GVHD, we examined whether alterations in such factors could be identified in LA GVHD. We first tested cases (n = 55) and controls (n = 50) from the Chronic GVHD Consortium and then validated the findings in 37 cases from Mount Sinai Acute GVHD International Consortium. Plasma amphiregulin (AREG; an epidermal growth factor [EGF] receptor ligand) was elevated, and an AREG/EGF ratio at or above the median was associated with inferior OS and increased nonrelapse mortality in both cohorts. Elevation of AREG was detected in classic acute GVHD, but not chronic GVHD. These prospective data characterize the clinical course of LA GVHD and demonstrate alterations in angiogenic factors that make LA GVHD biologically distinct from chronic GVHD.


Watch-wearing as a marker of conscientiousness.
Several aspects of an individual's appearance have been shown to predict personality and related behaviour. While some of these cues are grounded in biology (e.g., the human face), other aspects of a person's appearance can be actively controlled (e.g., clothing). In this paper, we consider a common fashion accessory, the wristwatch. In an exploratory sample (N > 100) and a confirmatory sample (N > 600), we compared big-five personality traits between individuals who do or do not regularly wear a standard wristwatch. Significantly higher levels of conscientiousness were observed in participants who wore a watch. In a third study (N = 85), watch wearers arrived significantly earlier to appointments in comparison to controls. These results are discussed in relation to enclothed cognition and the rise of wearable technology including smartwatches.


Long-term follow-up of a randomized AAV2-GAD gene therapy trial for Parkinson's disease.
BACKGROUND. We report the 12-month clinical and imaging data on the effects of bilateral delivery of the glutamic acid decarboxylase gene into the subthalamic nuclei (STN) of advanced Parkinson's disease (PD) patients. METHODS. 45 PD patients were enrolled in a 6-month double-blind randomized trial of bilateral AAV2-GAD delivery into the STN compared with sham surgery and were followed for 12 months in open-label fashion. Subjects were assessed with clinical outcome measures and 18F-fluorodeoxyglucose (FDG) PET imaging. RESULTS. Improvements under the blind in Unified Parkinson's Disease Rating Scale (UPDRS) motor scores in the AAV2-GAD group compared with the sham group continued at 12 months [time effect: F(4,138) = 11.55, P < 0.001; group effect: F(1,35) = 5.45, P < 0.03; repeated-measures ANOVA (RMANOVA)]. Daily duration of levodopa-induced dyskinesias significantly declined at 12 months in the AAV2-GAD group (P = 0.03; post-hoc Bonferroni test), while the sham group was unchanged. Analysis of all FDG PET images over 12 months revealed significant metabolic declines (P < 0.001; statistical parametric mapping RMANOVA) in the thalamus, striatum, and prefrontal, anterior cingulate, and orbitofrontal cortices in the AAV2-GAD group compared with the sham group. Across all time points, changes in regional metabolism differed for the two groups in all areas, with significant declines only in the AAV2-GAD group (P < 0.005; post-hoc Bonferroni tests). Furthermore, baseline metabolism in the prefrontal cortex (PFC) correlated with changes in motor UPDRS scores; the higher the baseline PFC metabolism, the better the clinical outcome. CONCLUSION. These findings show that clinical benefits after gene therapy with STN AAV2-GAD in PD patients persist at 12 months. TRIAL REGISTRATION. ClinicalTrials.gov NCT00643890. FUNDING. Neurologix Inc.


Medullary cystic kidney disease type 1 in a large Native-American kindred.
Autosomal dominant medullary cystic kidney disease type 1 (MCKD1; Mendelian Inheritance in Man 174000) is a hereditary tubulointerstitial renal disease. For MCKD1, a locus on chromosome 1q21 is published. Although there are characteristic biopsy and imaging findings for MCKD, clinical diagnosis of this disorder is still very difficult because unique phenotypic features are not always present in individual cases. In a large Native-American kindred with apparent autosomal dominant nephropathy, clinical findings in more than 50 individuals were collected and evaluated. Haplotype analysis for 34 individuals was performed. We report the difficulties establishing the diagnosis of MCKD in a large Native-American kindred solely by means of clinical criteria. This kindred shows a wider range of age of disease onset than previously reported. Gout and hypertension were common, but no patient reported symptoms of salt wasting. By means of haplotype analysis linkage was shown to the MCKD1 locus (logarithm of the odds score, 3.34). Establishing a diagnosis of MCKD solely on clinical findings is difficult because signs and symptoms may be subtle, renal cysts may be absent in more than 50% of affected individuals, and renal histological abnormalities are nonspecific. In patients presenting with renal insufficiency from apparent interstitial disease, a thorough family history and genetic linkage studies are required to establish a diagnosis of MCKD. We suspect MCKD is underdiagnosed and the true incidence of MCKD1 in the general population may be underestimated. No further living-related transplantation should be performed until genetic testing can exclude potentially affected donors.


Stage-specific links between plasma neurofilament light and imaging biomarkers of Alzheimer's disease.
Neurofilament light (NfL) is a marker of neuroaxonal injury, a prominent feature of Alzheimer's disease. It remains uncertain, however, how it relates to amyloid and tau pathology or neurodegeneration across the Alzheimer's disease continuum. The aim of this study was to investigate how plasma NfL relates to amyloid and tau PET and MRI measures of brain atrophy in participants with and without cognitive impairment. We retrospectively examined the association between plasma NfL and MRI measures of grey/white matter volumes in the Alzheimer's Disease Neuroimaging Initiative [ADNI: n = 1149; 382 cognitively unimpaired control subjects and 767 cognitively impaired participants (mild cognitive impairment n = 420, Alzheimer's disease dementia n = 347)]. Longitudinal plasma NfL was measured using single molecule array (Simoa) technology. Cross-sectional associations between plasma NfL and PET amyloid and tau measures were independently assessed in two cohorts: ADNI [n = 198; 110 cognitively unimpaired, 88 cognitively impaired (MCI n = 67, Alzheimer's disease dementia n = 21), data accessed October 2018]; and Translational Biomarkers in Aging and Dementia [TRIAD, n = 116; 74 cognitively unimpaired, 42 cognitively impaired (MCI n = 16, Alzheimer's disease dementia n = 26), data obtained November 2017 to January 2019]. Associations between plasma NfL and imaging-derived measures were examined voxel-wise using linear regression (cross-sectional) and linear mixed effect models (longitudinal). Cross-sectional analyses in both cohorts showed that plasma NfL was associated with PET findings in brain regions typically affected by Alzheimer's disease; associations were specific to amyloid PET in cognitively unimpaired and tau PET in cognitively impaired (P < 0.05). Longitudinal analyses showed that NfL levels were associated with grey/white matter volume loss; grey matter atrophy in cognitively unimpaired was specific to APOE ε4 carriers (P < 0.05). These findings suggest that plasma NfL increases in response to amyloid-related neuronal injury in preclinical stages of Alzheimer's disease, but is related to tau-mediated neurodegeneration in symptomatic patients. As such, plasma NfL may a useful measure to monitor effects in disease-modifying drug trials.


Molecular genetics of RecQ helicase disorders.
The RecQ helicases belong to the Superfamily II group of DNA helicases, and are defined by amino acid motifs that show sequence similarity to the catalytic domain of Escherichia coli RecQ. RecQ helicases have crucial roles in the maintenance of genome stability. In humans, there are five RecQ helicases and deficiencies in three of them cause genetic disorders characterised by cancer predisposition, premature aging and/or developmental abnormalities. RecQ helicase-deficient cells exhibit aberrant genetic recombination and/or DNA replication, which result in chromosomal instability and a decreased potential for proliferation. Here, we review the current knowledge of the molecular genetics of RecQ helicases, focusing on the human RecQ helicase disorders and mouse models of these conditions.


Iron deficiency anaemia in a coeliac: a cause for concern?
A 70-year-old woman with a 15-year history of coeliac disease was admitted for treatment and investigation of symptomatic anaemia. Of note, she was recently commenced on aspirin therapy for retinal artery occlusion. This followed a normal gastro-duodenoscopy, colonoscopy and CT abdomen as workup for iron deficiency anaemia. On this occasion, the patient was further investigated with small bowel capsule endoscopy. This revealed an ulcerated lesion in her proximal jejunum suspicious for malignancy, namely lymphoma. A biopsy of the lesion confirmed adenomatous changes and high-grade dysplasia without malignant changes. Given the endoscopic appearances of the lesion, she was further evaluated with a small bowel MRI. This revealed a 3 cm lesion with associated lymphadenopathy but no distant metastases. She proceeded to resection of her small bowel which confirmed an invasive adenocarcinoma of her proximal jejunum. She is currently undergoing adjuvant chemotherapy on an outpatient basis.


GABAergic basket cells expressing cholecystokinin contain vesicular glutamate transporter type 3 (VGLUT3) in their synaptic terminals in hippocampus and isocortex of the rat.
Vesicular glutamate transporter type 3 (VGLUT3) containing neuronal elements were characterized using antibodies to VGLUT3 and molecular cell markers. All VGLUT3-positive somata were immunoreactive for CCK, and very rarely, also for calbindin; none was positive for parvalbumin, calretinin, VIP or somatostatin. In the CA1 area, 26.8 +/- 0.7% of CCK-positive interneuron somata were VGLUT3-positive, a nonoverlapping 22.8 +/- 1.9% were calbindin-positive, 10.7 +/- 2.5% VIP-positive and the rest were only CCK-positive. The patterns of coexpression were similar in the CA3 area, the dentate gyrus and the isocortex. Immunoreactivity for VGLUT3 was undetectable in pyramidal and dentate granule cells. Boutons colabelled for VGLUT3, CCK and GAD were most abundant in the cellular layers of the hippocampus and in layers II-III of the isocortex. Large VGLUT3-labelled boutons at the border of strata radiatum and lacunosum-moleculare in the CA1 area were negative for GAD, but were labelled for vesicular monoamine transporter type 2, plasmalemmal serotonin transporter or serotonin. No colocalization was found in terminals between VGLUT3 and parvalbumin, vesicular acetylcholine transporter and group III (mGluR7a,b; mGluR8a,b) metabotropic glutamate receptors. In stratum radiatum and the isocortex, VGLUT3-positive but GAD-negative boutons heavily innervated the soma and proximal dendrites of some VGLUT3- or calbindin-positive interneurons. The results suggest that boutons coexpressing VGLUT3, CCK and GAD originate from CCK-positive basket cells, which are VIP-immunonegative. Other VGLUT3-positive boutons immunopositive for serotonergic markers but negative for GAD probably originate from the median raphe nucleus and innervate select interneurons. The presumed amino acid substrate of VGLUT3 may act on presynaptic kainate or group II metabotropic glutamate receptors.


Kidney cancer and hydrocarbon exposures among petroleum refinery workers.
To evaluate the hypothesis of increased kidney cancer risk after exposure to hydrocarbons, especially those present in gasoline, we conducted a case-control study in a cohort of approximately 100,000 male refinery workers from five petroleum companies. A review of 18,323 death certificates identified 102 kidney cancer cases, to each of whom four controls were matched by refinery location and decade of birth. Work histories, containing an average of 15.7 job assignments per subject, were found for 98% of the cases and 94% of the controls. To each job, industrial hygienists assigned semiquantitative ratings for the intensity and frequency of exposures to three hydrocarbon categories: nonaromatic liquid gasoline distillates, aromatic hydrocarbons, and the more volatile hydrocarbons. Ratings of "present" or "absent" were assigned for seven additional exposures: higher boiling hydrocarbons, polynuclear aromatic hydrocarbons, asbestos, chlorinated solvents, ionizing radiation, and lead. Each exposure had either no association or a weak association with kidney cancer. For the hydrocarbon category of principal a priori interest, the nonaromatic liquid gasoline distillates, the estimated relative risk (RR) for any exposure above refinery background was 1.0 (95% confidence interval [CI] 0.5-1.9). Analyses of cumulative exposures and of exposures in varying time periods before kidney cancer occurrence also produced null or near-null results. In an analysis of the longest job held by each subject (average duration 9.2 years or 40% of the refinery work history), three groups appeared to be at increased risk: laborers (RR = 1.9, 95% CI 1.0-3.9); workers in receipt, storage, and movements (RR = 2.5, 95% CI 0.9-6.6); and unit cleaners (RR = 2.3, 95% CI 0.5-9.9).


Pulmonary function and symptoms in workers exposed to wood dust.
Exposure to wood dust can cause a variety of lung problems, including chronic airflow obstruction. Forced vital capacity (FVC), forced expiratory volume in one second (FEV1), forced expiratory ratio (FEV1/FVC x 100), forced expiratory flow (FEF), forced mid expiratory flow (FMF), peak expiratory flow (PEF), and respiratory symptoms (cough, phlegm, breathlessness, wheezing, and nasal symptoms) were recorded in 145 non-smoking workers (77 male, 68 female) exposed to wood dust in a furniture factory in Umtata, Republic of Transkei, and 152 non-smoking control subjects (77 male, 75 female) from a bottling factory with a clean environment. After adjustment for age and standing height the forced expiratory indices were significantly lower in the exposed male workers than in the control subjects. FEF and PEF in the exposed men were 81.3% and 89.4% of predicted values and were lower than other indices. FVC in exposed men showed a significant inverse correlation with exposure (expressed in number of years of employment). The FVC was reduced by 26 ml per year of employment. The proportion of men with an FEV1/FVC below 70 was higher in exposed workers than in control subjects and higher in the exposed workers with more years of employment. The exposed workers had more respiratory symptoms than the control subjects, the prevalence, especially of cough and nasal symptoms, increasing with the increase in the number of years of employment. Workers exposed to pine and fibre dust have more respiratory symptoms and a greater risk of airflow obstruction.


Treatment of diverticular disease of the colon and prevention of acute diverticulitis: a systematic review.
Diverticular disease of the colon is a common disorder, characterized by recurrent symptoms and complications such as diverticulitis, requiring hospital admissions and surgery. This study aimed to systematically review the evidence for medical therapy of diverticular disease in reducing symptoms and preventing acute diverticulitis. MEDLINE and Embase databases (1966 to February 2010). The studies selected were prospective clinical trials on uncomplicated diverticular disease of the colon. Four investigators independently reviewed articles, extracted data, and assessed study quality according to standardized criteria. The main outcomes measured were improvement in symptoms, complete remission of symptoms, and prevention of acute diverticulitis. We identified 31 studies, including 6 placebo-controlled trials. The methodological quality of these studies was suboptimal. Only 10 trials provided a detailed description of the patient history, 8 assessed symptoms by the use of a validated questionnaire, and 14 appropriately defined inclusion and exclusion criteria. Only one long-term double-blind placebo-controlled study was identified. This reported a significant improvement in symptoms and greater prevalence of symptom-free patients at 1 year with fiber plus rifaximin in comparison with fiber alone. The efficacy of treatment in preventing acute diverticulitis was evaluated in 11 randomized trials. Four trials compared rifaximin plus fiber vs fiber alone and failed to show a significant difference between treatments. However, cumulative data from these trials revealed a significant benefit following rifaximin and fiber (1-year rate of acute diverticulitis: 11/970 (1.1%) vs 20/690 (2.9%); P = .012), but with a number needed to treat of 57, to prevent an attack of acute diverticulitis. : Heterogeneity of the study design, patients' characteristics, regimens and combination of studied treatment, and outcome reporting precluded the pooling of results and limited interpretation. The treatment for diverticular disease relies mainly on data from uncontrolled studies. Treatment showed some evidence of improvement in symptoms, but its role in the prevention of acute diverticulitis remains to be defined.


Psychiatric assessment of mood instability: qualitative study of patient experience.
Mood instability is a common reason for psychiatric referral. Very little is known about how patients with unstable mood experience assessment and diagnosis. To investigate the experiences of assessment and diagnosis among patients with mood instability and to suggest improvements to this process. Qualitative study, gathering data through individual interviews with 28 people experiencing mood instability and receiving a psychiatric assessment in secondary care. Participants described the importance of receiving an explanation for their symptoms; the value of a good interpersonal relationship with their clinician(s); being listened to and acknowledged; and being involved in and informed about clinical decisions. These needs were not, however, consistently met. Receiving a psychiatric diagnosis, including a diagnosis of bipolar disorder or borderline personality disorder, evoked both positive and negative responses among participants, relating to stigma, personal understanding and responsibility, prognosis and treatment. Patients with mood instability seek explanation for their symptoms and difficulties, empathetic care and consistent support as much as cure. Clinicians may incorrectly assume what patients' attitudes towards diagnosis are, a mismatch which may hamper the development of a strong therapeutic relationship. Clear, patient-centred communication, which acknowledges the patient's experience, may result in greater patient engagement and satisfaction.


Resveratrol induces expression of the slow, oxidative phenotype in mdx mouse muscle together with enhanced activity of the SIRT1-PGC-1α axis.
Slower, more oxidative muscle fibers are more resistant to the dystrophic pathology in Duchenne muscular dystrophy (DMD) patients as well as in the preclinical mdx mouse model of DMD. Therefore, one therapeutic strategy for DMD focuses on promoting expression of the slow, oxidative myogenic program. In the current study, we explored the therapeutic potential of stimulating the slow, oxidative phenotype in mdx mice by feeding 6-wk-old animals with the natural phenol resveratrol (RSV; ~100 mg·kg(-1)·day(-1)) for 6 wk. Sirtuin 1 (SIRT1) activity and protein levels increased significantly, as well as peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) activity, in the absence of alterations in AMPK signaling. These adaptations occurred concomitant with evidence of a fast, glycolytic, to slower, more oxidative fiber type conversion, including mitochondrial biogenesis and increased expression of slower myosin heavy chain isoforms. These positive findings raised the question of whether increased exposure to RSV would result in greater therapeutic benefits. We discovered that an elevated RSV dose of ~500 mg·kg(-1)·day(-1) across a duration of 12 wk was clearly less effective at muscle remodeling in mdx mice. This treatment protocol failed to influence SIRT1 or AMPK signaling and did not result in a shift towards a slower, more oxidative phenotype. Taken together, this study demonstrates that RSV can stimulate SIRT1 and PGC-1α activation, which in turn may promote expression of the slow, oxidative myogenic program in mdx mouse muscle. The data also highlight the importance of selecting an appropriate dosage regimen of RSV to maximize its potential therapeutic effectiveness for future application in DMD patients.