Hydroxyurea and sickle cell anemia. Clinical utility of a myelosuppressive "switching" agent. The Multicenter Study of Hydroxyurea in Sickle Cell Anemia.
Painful crises in patients with sickle cell anemia are caused by vaso-occlusion and infarction. Occlusion of blood vessels depends on (at least) their diameter, the deformability of red cells, and the adhesion of blood cells to endothelium. Deoxygenated sickle cells are rigid because they contain linear polymers of hemoglobin S (Hb S); polymerization is highly concentration dependent, and dilution of Hb S by a nonsickling hemoglobin such as fetal hemoglobin (Hb F) would be expected to lead ultimately to a decrease in the frequency of painful crises. It might also be expected to decrease the severity of anemia, although the pathogenesis of anemia in sickle cell anemia (SS disease) is not clearly understood. Reversion to production of fetal rather than adult hemoglobin became practical with the discovery that HU was an orally effective and relatively safe "switching agent." Preliminary dose-ranging studies led to a double-blind randomized controlled clinical trial, the Multicenter Study of Hydroxyurea in Sickle Cell Anemia (MSH), designed to test whether patients treated with HU would have fewer crises than patients treated with placebo. The MSH was not designed to assess the mechanism(s) by which a beneficial effect might be achieved, but it was hoped that observations made during the study might illuminate that question. The 2 MSH treatment groups were similar to each other and were representative of African-American patients with relatively severe disease. The trial was closed earlier than expected, after demonstration that median crisis rate was reduced by almost 50% (2.5 versus 4.5 crises per year) in patients assigned to HU therapy. Hospitalizations, episodes of chest syndrome, and numbers of transfusions were also lower in patients treated with HU. Eight patients died during the trial, and treatment was stopped in 53. There were no instances of alarming toxicity. Patients varied widely in their maximum tolerated doses, but it was not clear that all were taking their prescribed treatments. When crisis frequency was compared with various clinical and laboratory measurements, pretreatment crisis rate and treatment with HU were clearly related to crisis rate during treatment. Pretreatment laboratory measurements were not associated with crisis rates during the study in either treatment group. It was not clear that clinical improvement was associated with an increase in Hb F. Crisis rates of the 2 treatment groups became different within 3 months. Mean corpuscular volumes (MCVs) and the proportion of Hb F containing red cells (F cells) rose, and neutrophil and reticulocyte counts fell, within 7 weeks. When patients were compared on the basis of 2-year crisis rates, those with lower crisis rates had higher F-cell counts and MCVs and lower neutrophil counts. Neutrophil, monocyte, reticulocyte, and platelet counts were directly associated, and F cells and MCV were inversely associated, with crisis rates in 3-month periods. In multivariable analyses, there was strong evidence of independent association of lower neutrophil counts with lower crisis rates. F-cell counts were associated with crisis rate only in the first 3 months of treatment; MCV showed an association over longer periods of time. Overall, the evidence that decreased neutrophil counts played a role in reducing crisis rates was strong. Increased F cells or MCV and evidence of cytoreduction by HU were also associated with decreased crisis rates, but no definitive statement can be made regarding the mechanism of action of HU because the study was not designed to address that question. Future studies should be designed to explore the mechanism of action of HU, to identify the optimal dosage regimen, and to study the effect of HU when combined with other antisickling agents.


Reconstructing the development of Baltic sea eutrophication 1850-2006.
A comprehensive reconstruction of the Baltic Sea state from 1850 to 2006 is presented: driving forces are reconstructed and the evolution of the hydrography and biogeochemical cycles is simulated using the model BALTSEM. Driven by high resolution atmospheric forcing fields (HiResAFF), BALTSEM reproduces dynamics of salinity, temperature, and maximum ice extent. Nutrient loads have been increasing with a noteworthy acceleration from the 1950s until peak values around 1980 followed by a decrease continuing up to present. BALTSEM shows a delayed response to the massive load increase with most eutrophic conditions occurring only at the end of the simulation. This is accompanied by an intensification of the pelagic cycling driven by a shift from spring to summer primary production. The simulation indicates that no improvement in water quality of the Baltic Sea compared to its present state can be expected from the decrease in nutrient loads in recent decades.


Cappuccino, a mouse model of Hermansky-Pudlak syndrome, encodes a novel protein that is part of the pallidin-muted complex (BLOC-1).
Hermansky-Pudlak syndrome (HPS) is a disorder of organelle biogenesis affecting 3 related organelles-melanosomes, platelet dense bodies, and lysosomes. Four genes causing HPS in humans (HPS1-HPS4) are known, and at least 15 nonallelic mutations cause HPS in the mouse. Where their functions are known, the HPS-associated proteins are involved in some aspect of intracellular vesicular trafficking, that is, protein sorting and vesicle docking and fusion. Biochemical and genetic evidence indicates that the HPS-associated genes encode components of at least 3 distinct protein complexes: the adaptor complex AP-3; the HPS1/HPS4 complex; and BLOC-1 (biogenesis of lysosome-related organelles complex-1), consisting of the proteins encoded at 2 mouse HPS loci, pallid (pa) and muted (mu), and at least 3 other unidentified proteins. Here, we report the cloning of the mouse HPS mutation cappuccino (cno). We show that the wild-type cno gene encodes a novel, ubiquitously expressed cytoplasmic protein that coassembles with pallidin and the muted protein in the BLOC-1 complex. Further, we identify a frameshift mutation in mutant cno/cno mice. The C-terminal 81 amino acids are replaced with 72 different amino acids in the mutant CNO protein, and its ability to interact in BLOC-1 is abolished. We performed mutation screening of patients with HPS and failed to identify any CNO defects. Notably, although defects in components of the HPS1/HPS4 and the AP-3 complexes are associated with HPS in humans, no defects in the known components of BLOC-1 have been identified in 142 patients with HPS screened to date, suggesting that BLOC-1 function may be critical in humans.


Canadian medical tourism companies that have exited the marketplace: Content analysis of websites used to market transnational medical travel.
Medical tourism companies play an important role in promoting transnational medical travel for elective, out-of-pocket medical procedures. Though researchers are paying increasing attention to the global phenomenon of medical tourism, to date websites of medical tourism companies have received limited scrutiny. This article analyzes websites of Canadian medical tourism companies that advertised international healthcare but ultimately exited the marketplace. Using content analysis of company websites as an investigative tool, the article provides a detailed account of medical tourism companies that were based in Canada but no longer send clients to international health care facilities. Internet searches, Google Alerts, searches on Google News Canada and ProQuest Newsstand, and searches of an Industry Canada database were used to locate medical tourism companies located in Canada. Once medical tourism companies were identified, the social science research method of content analysis was used to extract relevant information from company websites. Company websites were analyzed to determine: 1) where these businesses were based; 2) the destination countries and medical facilities that they promoted; 3) the health services they advertised; 4) core marketing messages; and 5) whether businesses marketed air travel, hotel accommodations, and holiday excursions in addition to medical procedures. In total, 25 medical tourism companies that were based in Canada are now defunct. Given that an estimated 18 medical tourism companies and 7 regional, cross-border medical travel facilitators now operate in Canada, it appears that approximately half of all identifiable medical tourism companies in Canada are no longer in business. 13 of the previously operational companies were based in Ontario, 7 were located in British Columbia, 4 were situated in Quebec, and 1 was based in Alberta. 14 companies marketed medical procedures within a single country, 9 businesses marketed health care at 2 or more destination nations, and 2 companies did not specify particular health care destinations. 22 companies operated as "generalist" businesses marketing many different types of medical procedures. 3 medical tourism companies marketed "specialist" services restricted to dental procedures or organ transplants. In general, medical tourism companies marketed health services on the basis of access to affordable, timely, and high-quality care. 16 businesses offered to make travel arrangements, 20 companies offered to book hotel reservations, and 17 medical tourism companies advertised holiday excursions. This article provides a detailed empirical analysis of websites of medical tourism companies that were based in Canada but exited the marketplace and are now inoperative. The article identifies where these companies were located in Canada, what countries and health care facilities they selected as destination sites, the health services they advertised, how they marketed themselves in a competitive environment, and what travel-related services they promoted in addition to marketing health care. The paper reveals a fluid marketplace, with many medical tourism companies exiting this industry. In addition, by disclosing identities of companies, providing their websites, archiving these websites or print copies of websites for future studies, and analyzing content of medical tourism company websites, the article can serve as a useful resource for future studies. Citizens, health policy-makers, clinicians, and researchers can all benefit from increased insight into Canada's medical tourism industry.


Growing the gas-giant planets by the gradual accumulation of pebbles.
It is widely held that the first step in forming gas-giant planets, such as Jupiter and Saturn, was the production of solid 'cores' each with a mass roughly ten times that of the Earth. Getting the cores to form before the solar nebula dissipates (in about one to ten million years; ref. 3) has been a major challenge for planet formation models. Recently models have emerged in which 'pebbles' (centimetre-to-metre-sized objects) are first concentrated by aerodynamic drag and then gravitationally collapse to form objects 100 to 1,000 kilometres in size. These 'planetesimals' can then efficiently accrete left-over pebbles and directly form the cores of giant planets. This model is known as 'pebble accretion'; theoretically, it can produce cores of ten Earth masses in only a few thousand years. Unfortunately, full simulations of this process show that, rather than creating a few such cores, it produces a population of hundreds of Earth-mass objects that are inconsistent with the structure of the Solar System. Here we report that this difficulty can be overcome if pebbles form slowly enough to allow the planetesimals to gravitationally interact with one another. In this situation, the largest planetesimals have time to scatter their smaller siblings out of the disk of pebbles, thereby stifling their growth. Our models show that, for a large and physically reasonable region of parameter space, this typically leads to the formation of one to four gas giants between 5 and 15 astronomical units from the Sun, in agreement with the observed structure of the Solar System.


Efficacy of endovascular stenting in dural venous sinus stenosis for the treatment of idiopathic intracranial hypertension.
Multiple pathophysiological mechanisms have been proposed for the increased intracranial pressure observed in idiopathic intracranial hypertension (IIH). The condition is well characterized, with intractable headaches, visual obscurations, and papilledema as dominant features, mainly affecting obese women. With the advent of MR venography and increased use of cerebral angiography, there has been recent emphasis on the significant number of patients with IIH found to have associated nonthrombotic dural venous sinus stenosis. This has led to a renewed interest in endovascular stenting as a treatment for IIH. However, the assumption that venous stenosis leads to a high pressure gradient that decreases CSF resorption through arachnoid villi requires further evidence. In this paper, the authors analyze the published results to date of dural venous sinus stenting in patients with IIH. They also present a case from their institution for illustration. The pathophysiological mechanism in IIH requires further elucidation, but venous sinus stenosis with subsequent intracranial hypertension appears to be an important mechanism in at least a subgroup of patients with IIH. Among these patients, 78% had complete relief or improvement of their main presenting symptoms after endovascular stenting. Resolution or improvement in papilledema was seen in 85.1% of patients. Endovascular stenting should be considered whenever venous sinus stenosis is diagnosed in patients with IIH.


Frequency of Mycobacterium bovis and mycobacteria in primary immunodeficiencies.
Susceptibility to mycobacterial diseases is observed in some primary immunodeficiency diseases. In this study, we aimed to evaluate mycobacterial infections in primary immunodeficiency diseases. Patients under follow-up by Ege University Pediatric Immunology Department for severe combined and combined immunodeficiencies, interleukin 12/ interferon gamma receptor deficiency, nuclear factor kappa-beta essential modulator deficiency and chronic granulomatosis disease were evaluated retrospectively in terms of the frequency and characteristics of mycobacterial infections using a questionnaire form for demographic properties, clinical features and laboratory tests. A diagnosis of mycobacterial infection was made clinically in a total of 25 patients including five (11.3%) of 45 patients who had severe combined immune deficiency, 12 (52.3%) of 21 patients who had chronic granulomatous disease, four patients (100%) who had interferon gamma receptor 2 partical deficiency, two patients (100%) who had interleukin 12 receptor beta 1 deficiency and one patient (100%) who had nuclear factor kapa-beta essential modulator deficiency. Mycobacterium strain could be typed in 14 (33%) of these 25 patients including Mycobacterium bovis, Mycobacterium chelonea, Mycobacterium elephantis, Mycobacterium fortuitum, and Mycobacterium tuberculosis. All patients were treated with anti-tuberculosis therapy. Thirty-six percent of these 25 patients underwent hematopoietic stem cell transplantation. Eight patients (five before, three after transplantation) died. Non-tuberculosis mycobacteria including mainly Mycobacterium bovis were observed with a higher rate compared to Mycobacterium tuberculosis in primary immunodeficiencies, especially in those affecting the interleukin 12/interferon gamma pathway. Early diagnosis of primary immunodeficiencies with neonatal screening program and preventing administration of the Bacille Calmette-Guerin vaccine in these patients is important.


Approximate Target Pre-Cueing Reduces Programming Quiet Eye and Movement Preparation Time: Evidence for Parameter Pre-Programming?
Purpose: We examined the effect of target pre-cues on quiet eye duration (QED). If quiet eye (QE) represents the initial and only period for the programming of movement parameters, then the precision of target pre-cues should not affect QED. In contrast, shorter QED after pre-cueing of targets implies some initial programming process to have occurred before QE. Method: Sixteen participants threw darts at targets projected onto a soft screen. We manipulated the precision of target pre-cues by highlighting an area within which the target would appear. These pre-cued areas were either the full screen (i.e., no cue), any half, quarter, or sixteenth of the screen. Participants threw eight times in each condition. Dependent measures included QED (programming and online segments), movement preparation time (MPT; from target presentation to initiation of movement), and radial error (cm). Results: Analysis revealed that programming QE was shorter when the target was pre-cued in the most precise sixteenth condition, compared to the no cue condition. Also, MPT was shorter when pre-cued in the sixteenth condition than in either the no cue or half screen conditions. Target pre-cueing conditions did not affect the other dependent variables. Conclusions: Shorter PQE following the most precise target pre-cueing implies that some pre-programming occurred before QE, perhaps through inhibition, but only when the pre-cue was specific enough to make pre-programming possible.


Effect of low dosages of powdered activated carbon on membrane bioreactor performance.
Previous research has demonstrated that powdered activated carbon (PAC), when applied at very low dosages and long SRTs, reduces membrane fouling in membrane bioreactors (MBRs). This effect was related to the formation of stronger sludge flocs, which are less sensitive to shear. In this contribution the long-term effect of PAC addition was studied by running two parallel MBRs on sewage. To one of these, PAC was dosed and a lower fouling tendency of the sludge was verified, with a 70% longer sustainable filtration time. Low PAC dosages showed additional advantages with regard to oxygen transfer and dewaterability, which may provide savings on operational costs.


Wolbachia enhance Drosophila stem cell proliferation and target the germline stem cell niche.
Wolbachia are widespread maternally transmitted intracellular bacteria that infect most insect species and are able to alter the reproduction of innumerous hosts. The cellular bases of these alterations remain largely unknown. Here, we report that Drosophila mauritiana infected with a native Wolbachia wMau strain produces about four times more eggs than the noninfected counterpart. Wolbachia infection leads to an increase in the mitotic activity of germline stem cells (GSCs), as well as a decrease in programmed cell death in the germarium. Our results suggest that up-regulation of GSC division is mediated by a tropism of Wolbachia for the GSC niche, the cellular microenvironment that supports GSCs.


Paracrine signalling of inflammatory cytokines from an in vitro blood brain barrier model upon exposure to polymeric nanoparticles.
Nanoparticle properties, such as small size relative to large highly modifiable surface area, offer great promise for neuro-therapeutics and nanodiagnostics. A fundamental understanding and control of how nanoparticles interact with the blood-brain barrier (BBB) could enable major developments in nanomedical treatment of previously intractable neurological disorders, and help ensure that nanoparticles not intended to reach the brain do not cause adverse effects. Nanosafety is of utmost importance to this field. However, a distinct lack of knowledge exists regarding nanoparticle accumulation within the BBB and the biological effects this may induce on neighbouring cells of the Central Nervous System (CNS), particularly in the long-term. This study focussed on the exposure of an in vitro BBB model to model carboxylated polystyrene nanoparticles (PS COOH NPs), as these nanoparticles are well characterised for in vitro experimentation and have been reported as non-toxic in many biological settings. TEM imaging showed accumulation but not degradation of 100 nm PS COOH NPs within the lysosomes of the in vitro BBB over time. Cytokine secretion analysis from the in vitro BBB post 24 h 100 nm PS COOH NP exposure showed a low level of pro-inflammatory RANTES protein secretion compared to control. In contrast, 24 h exposure of the in vitro BBB endothelium to 100 nm PS COOH NPs in the presence of underlying astrocytes caused a significant increase in pro-survival signalling. In conclusion, the tantalising possibilities of nanomedicine must be balanced by cautious studies into the possible long-term toxicity caused by accumulation of known 'toxic' and 'non-toxic' nanoparticles, as general toxicity assays may be disguising significant signalling regulation during long-term accumulation.


Diagnosis, treatment, and prevention of cerebral palsy.
Cerebral palsy is the most prevalent cause of persisting motor function impairment with a frequency of about 1/500 births. In developed countries, the prevalence rose after introduction of neonatal intensive care, but in the past decade, this trend has reversed. A recent international workshop defined cerebral palsy as "a group of permanent disorders of the development of movement and posture, causing activity limitation, that are attributed to non-progressive disturbances that occurred in the developing fetal or infant brain." In a majority of cases, the predominant motor abnormality is spasticity; other forms of cerebral palsy include dyskinetic (dystonia or choreo-athetosis) and ataxic cerebral palsy. In preterm infants, about one-half of the cases have neuroimaging abnormalities, such as echolucency in the periventricular white matter or ventricular enlargement on cranial ultrasound. Among children born at or near term, about two-thirds have neuroimaging abnormalities, including focal infarction, brain malformations, and periventricular leukomalacia. In addition to the motor impairment, individuals with cerebral palsy may have sensory impairments, cognitive impairment, and epilepsy. Ambulation status, intelligence quotient, quality of speech, and hand function together are predictive of employment status. Mortality risk increases incrementally with increasing number of impairments, including intellectual, limb function, hearing, and vision. The care of individuals with cerebral palsy should include the provision of a primary care medical home for care coordination and support; diagnostic evaluations to identify brain abnormalities, severity of neurologic and functional abnormalities, and associated impairments; management of spasticity; and care for associated problems such as nutritional deficiencies, pain, dental care, bowel and bladder continence, and orthopedic complications. Current strategies to decrease the risk of cerebral palsy include interventions to prolong pregnancy (eg, 17alpha-progesterone), limiting the number of multiple gestations related to assisted reproductive technology, antenatal steroids for mothers expected to deliver prematurely, caffeine for extremely low birth weight neonates, and induced hypothermia for a subgroup of neonates diagnosed with hypoxic-ischemic encephalopathy.


Effects of rotary instruments and ultrasonic irrigation on debris and smear layer scores: a scanning electron microscopic study.
This study evaluated debris and smear layer scores after two types of instruments manufactured from different alloys were used to ultrasonically activate irrigants during canal preparation. The influence of two rotary preparation techniques on cleanliness of the shaped canals was also studied. Apical stops were prepared to size 45 in 42 single-canalled extracted premolars and canines, which were divided into six equal groups. Groups 1, 2 and 3 were prepared by ProFile.04 (PF) while groups 4, 5 and 6 were prepared by Lightspeed (LS). All groups were irrigated using 5.25% NaOCl and 17% EDTA. Irrigants in groups 2 and 5 were ultrasonically activated using a size 15 steel K-file and by a blunt flexible nickel-titanium wire in groups 3 and 6. Groups 1 and 4 served as negative controls. Roots were split and canal walls examined at 15x, 200x and 400x magnification in an SEM. Smear layer and debris scores were recorded at 3, 6 and 9 mm levels using a 5-step scoring scale and a 200- micro m grid. Means were tested for significance using nonparametric Mann-Whitney U and Kruskal-Wallis tests. Debris and smear layer scores for the six groups varied from 1.98 +/- 1.04 to 3.47 +/- 0.97 and from 1.37 +/- 0.4 to 2.36 +/- 0.99, respectively. Although all groups had significantly higher smear layer and debris scores at the 3 mm levels compared to the 9 mm levels (P < 0.05), no significant differences were recorded due to the ultrasonic energy transmitted by the two alloys. Ultrasonically activated irrigants did not reduce debris or smear layer scores. This finding was not influenced by the material nor by the design of the instrument used to transmit ultrasonic activation.


Management of a caseous lymphadenitis outbreak in a new Iberian ibex (Capra pyrenaica) stock reservoir.
In 2010, an Iberian ibex (Capra pyrenaica hispanica) stock reservoir was established for conservation purposes in north-eastern Spain. Eighteen ibexes were captured in the wild and housed in a 17 hectare enclosure. Once in captivity, a caseous lymphadenitis (CLA) outbreak occurred and ibex handlings were carried out at six-month intervals between 2010 and 2013 to perform health examinations and sampling. Treatment with a bacterin-based autovaccine and penicillin G benzatine was added during the third and subsequent handlings, when infection by Corynebacterium pseudotuberculosis was confirmed. Changes in lesion score, serum anti-C. pseudotuberculosis antibodies and haematological parameters were analyzed to assess captivity effects, disease emergence and treatment efficacy. Serum acute phase proteins (APP) Haptoglobin (Hp), Amyloid A (SAA) and Acid Soluble Glycoprotein (ASG) concentrations were also determined to evaluate their usefulness as indicators of clinical status. Once in captivity, 12 out of 14 ibexes (85.7%) seroconverted, preceding the emergence of clinical signs; moreover, TP, WBC, eosinophil and platelet cell counts increased while monocyte and basophil cell counts decreased. After treatment, casualties and fistulas disappeared and both packed cell volume (PCV) and haemoglobin concentration significantly increased. Hp, SAA and ASG values were under the limit of detection or showed no significant differences. A role for captivity in contagion rate is suggested by the increase in antibody levels against C. pseudotuberculosis and the emergence of clinical signs. Although boosted by captivity, this is the first report of an outbreak of caseous lymphadenitis displaying high morbidity and mortality in wild ungulates. Treatment consisting of both vaccination and antibiotic therapy seemed to prevent mortality and alleviate disease severity, but was not reflected in the humoural response. Haematology and APP were not useful indicators in our study, perhaps due to the sampling frequency. Presumably endemic and irrelevant in the wild, this common disease of domestic small ruminants is complicating conservation efforts for the Iberian ibex in north-eastern Spain.


Patient blood management as the standard of care.
Blood transfusion is one of the most common hospital procedures in developed countries. However, inappropriate use of blood transfusion is common, and this is of considerable concern because transfusion is known to be associated with adverse events and is costly. Reductions in blood use have resulted from recent evidence indicating that restrictive use of red blood cell transfusions is associated with similar patient outcomes to liberal strategies and from a focus on patient blood management (PBM), which recognizes the importance of conserving the patient's own blood alongside the judicious use of transfusion. A recent Consensus Conference in Frankfurt developed practice and research recommendations for PBM but also indicated that additional studies are needed to provide better evidence for PBM interventions, including for improved patient outcomes and lower hospital costs as well as for reductions in blood utilization. In the meanwhile, it is of utmost importance to translate PBM guidelines into practical day-to-day recommendations and encourage their use to make PBM "the standard of care."


Danazol Treatment for Telomere Diseases.
Genetic defects in telomere maintenance and repair cause bone marrow failure, liver cirrhosis, and pulmonary fibrosis, and they increase susceptibility to cancer. Historically, androgens have been useful as treatment for marrow failure syndromes. In tissue culture and animal models, sex hormones regulate expression of the telomerase gene. In a phase 1-2 prospective study involving patients with telomere diseases, we administered the synthetic sex hormone danazol orally at a dose of 800 mg per day for a total of 24 months. The goal of treatment was the attenuation of accelerated telomere attrition, and the primary efficacy end point was a 20% reduction in the annual rate of telomere attrition measured at 24 months. The occurrence of toxic effects of treatment was the primary safety end point. Hematologic response to treatment at various time points was the secondary efficacy end point. After 27 patients were enrolled, the study was halted early, because telomere attrition was reduced in all 12 patients who could be evaluated for the primary end point; in the intention-to-treat analysis, 12 of 27 patients (44%; 95% confidence interval [CI], 26 to 64) met the primary efficacy end point. Unexpectedly, almost all the patients (11 of 12, 92%) had a gain in telomere length at 24 months as compared with baseline (mean increase, 386 bp [95% CI, 178 to 593]); in exploratory analyses, similar increases were observed at 6 months (16 of 21 patients; mean increase, 175 bp [95% CI, 79 to 271]) and 12 months (16 of 18 patients; mean increase, 360 bp [95% CI, 209 to 512]). Hematologic responses occurred in 19 of 24 patients (79%) who could be evaluated at 3 months and in 10 of 12 patients (83%) who could be evaluated at 24 months. Known adverse effects of danazol--elevated liver-enzyme levels and muscle cramps--of grade 2 or less occurred in 41% and 33% of the patients, respectively. In our study, treatment with danazol led to telomere elongation in patients with telomere diseases. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT01441037.).


Homeopathic proving symptoms: result of a local, non-local, or placebo process? A blinded, placebo-controlled pilot study.
Homeopathic pathogenetic trials (HPTs) (provings) are the pillar of homeopathy. Symptoms experienced by healthy volunteers are used to find the correct medicine for therapy. It is unclear whether these symptoms are specific or due to placebo noise. Furthermore, it is uncertain whether proving effects, if present at all, are due to a local or non-local process To develop a test model which allows for testing if homeopathic proving symptoms are caused by placebo or causative mechanisms, and if these symptoms are due to local or non-local processes. Randomised, blinded, placebo-controlled, parallel-group study, with 1-week baseline and 2-weeks proving period. 11 healthy volunteers from two different homeopathic schools. PROVING SUBSTANCE: An homeopathic medicine (Cantharis 30c), blindly chosen from 12 potential medicines, compared to placebo. Number of symptoms typical for the medicine in the experimental and control group during baseline and proving period. During baseline there was no difference in the number of typical or atypical symptoms in either group. During the proving period, both more typical symptoms for Cantharis (P= 0.03) and more atypical symptoms (P= 0.02) were observed compared to baseline. Between-group differences were not significant. Effect sizes for the difference between the proving and control group for typical symptoms was d=0.4, and for atypical symptoms d=0.6. This proving model could be valuable in studying the validity of proving symptoms of homeopathic substances in healthy volunteers. Homeopathic proving symptoms appear to be specific to the medicine and do not seem to be due to a local process. Since this was a pilot study using a small number of provers, rival hypotheses cannot be ruled out and the study needs replication.


Nonaqueous capillary electrophoresis mass spectrometry method for determining highly hydrophobic peptides.
A nonaqueous capillary electrophoresis mass spectrometry (NACE-MS) method was developed to separate and determine highly hydrophobic temporin peptides. The nonaqueous background electrolyte solution was a mixture of 20% acetonitrile, 78% methanol and 2% formic acid, with 20 mM ammonium formate. The separation of six peptides was completed within 12 min. The CE system was connected to a triple quadrupole mass spectrometer operating in MRM mode using a chemical modifier solution of 2 mM ammonium formate in ethanol with the flow through microvial interface. The mass spectrometer offered a second dimension of separation for peptides having identical migration times but different structures. The new method represents the first system capable of reliably determining hydrophobic peptides without using reversed phase liquid chromatography mass spectrometry.


Acute inflammation is associated with lower muscle strength, muscle mass and functional dependency in male hospitalised older patients.
Hospitalisation is associated with adverse health outcomes including loss of muscle strength, muscle mass and functional decline, which might be further aggravated by acute inflammation. This study aimed to determine whether acute inflammation, as denoted by C-reactive protein (CRP), is associated with muscle strength, muscle mass and functional dependency in hospitalised older patients. The observational, prospective EMPOWER study included 378 hospitalised patients aged 70 years and older. As part of the hospital assessment, 191 patients (50.5%) had CRP measured. Muscle strength and mass were measured using handheld dynamometry and bioelectrical impedance analysis respectively. Activities of Daily Living (ADL) were assessed using Katz score and Instrumental ADL (IADL) by Lawton and Brody score. Linear regression analyses and logistic regression analyses were performed stratified by sex and adjusted for age and comorbidities. Mean age was 79.7 years (SD 6.4) and 50.8% were males. On admission and discharge, males with elevated CRP had significantly lower handgrip strength and lower absolute muscle mass compared with males with normal CRP and those with no CRP measured. At three months post-discharge, males with elevated CRP were more likely to be ADL dependent than those with normal CRP and with no CRP measured. In females, no associations were found between CRP and muscle strength, muscle mass, ADL or IADL. Hospitalised older male patients with acute inflammation had lower muscle strength at admission and discharge and lower absolute muscle mass at admission and higher ADL dependency at three months post-discharge.


The Paradoxical Roles of Orphan Nuclear Receptor 4A (NR4A) in Cancer.
The three-orphan nuclear receptor 4A genes are induced by diverse stressors and stimuli, and there is increasing evidence that NR4A1 (Nur77), NR4A2 (Nurr1), and NR4A3 (Nor1) play an important role in maintaining cellular homeostasis and in pathophysiology. In blood-derived tumors (leukemias and lymphomas), NR4A expression is low and NR4A1-/-/NR4A3-/- double knockout mice rapidly develop acute myelocytic leukemia, suggesting that these receptors exhibit tumor suppressor activity. Treatment of leukemia and most lymphoma cells with drugs that induce expression of NR4A1and NR4A3 enhances apoptosis, and this represents a potential clinical application for treating this disease. In contrast, most solid tumor-derived cell lines express high levels of NR4A1 and NR4A2, and both receptors exhibit pro-oncogenic activities in solid tumors, whereas NR4A3 exhibits tumor-specific activities. Initial studies with retinoids and apoptosis-inducing agents demonstrated that their cytotoxic activity is NR4A1 dependent and involved drug-induced nuclear export of NR4A1 and formation of a mitochondrial proapoptotic NR4A1-bcl-2 complex. Drug-induced nuclear export of NR4A1 has been reported for many agents/biologics and involves interactions with multiple mitochondrial and extramitochondrial factors to induce apoptosis. Synthetic ligands for NR4A1, NR4A2, and NR4A3 have been identified, and among these compounds, bis-indole derived (CDIM) NR4A1 ligands primarily act on nuclear NR4A1 to inhibit NR4A1-regulated pro-oncogenic pathways/genes and similar results have been observed for CDIMs that bind NR4A2. Based on results of laboratory animal studies development of NR4A inducers (blood-derived cancers) and NR4A1/NR4A2 antagonists (solid tumors) may be promising for cancer therapy and also for enhancing immune surveillance.


An exploratory study to assess the activity of the acarine growth inhibitor, fluazuron, against Sarcoptes scabei infestation in pigs.
The most common treatments for scabies in human and veterinary settings are topical 5% permethrin or systemic treatment with ivermectin. However, these treatments have very little activity against arthropod eggs, and therefore repeated treatment is frequently required. In-vitro, biochemical and molecular studies have demonstrated that human mites are becoming increasingly resistant to both acaricides. To identify alternate acaricides, we undertook a pilot study of the in vivo activity of the benzoylphenyl urea inhibitor of chitin synthesis, fluazuron, in pigs with sarcoptic mange. Pigs (n = 5) were infested with S. scabei var suis, and randomised to treatment at the start of peak infestation with fluazuron at a dose of 10 mg/kg/day per os for 7 days (n = 3) or no treatment (n = 2). Clinical scores, skin scrapings for mite counts and blood sampling for pharmacokinetic analysis were undertaken. Fluazuron was well absorbed in treated pigs with measureable blood levels up to 4 weeks post treatment. No adverse effects were observed. Modest acaricidal activity of the compound was observed, with a reduction in severity of skin lesions in treated pigs, as well as a reduction in number of scabies mite's early life stages. The moderate efficacy of fluazuron against scabies mites indicates a lead to the development of alternate treatments for scabies, such as combination therapies that maybe applicable for human use in the future.


Comparative distribution of 2[125I]iodomelatonin binding in the brains of diurnal birds: outgroup analysis with turtles.
The roles that the pineal gland and its hormone melatonin play in the regulation of circadian rhythmicity and photoperiodism vary among vertebrate species. Recently, putative sites of melatonin action have been elucidated in several avian and mammalian species by application of in vitro binding of a radioiodinated melatonin agonist, 2[125I]iodomelatonin (IMEL) and autoradioradiography. These studies in mammals, birds and reptiles have indicated profound differences in the distribution of IMEL binding between these diverse groups, suggesting that these large differences in binding may reflect differences in melatonin function. The present study was performed to determine systematically whether the variance in IMEL binding among avian species corresponds to changes in circadian organization and/or phylogenetic relationships. The distribution of specific IMEL binding was determined in the brains from birds belonging to 14 different species in 5 Orders (Psittaciformes, Passeriformes, Columbiformes, Galliformes and Anseriformes) using in vitro binding, autoradiography and computer-assisted image analysis. The distribution was compared to a similar study in 3 species of turtles as an outgroup. The data indicated IMEL binding in retinorecipient structures of the circadian, tectofugal, thalamofugal and accessory optic visual pathways in all avian species. Relay nuclei and integrative structures of the tectofugal, thalamofugal, accessory optic, and limbic systems, however, bound the hormone to varying degrees. In turtles, binding was observed in retinorecipient structures of the thalamofugal visual pathway and in retinorecipient and integrative areas of the tectofugal visual pathway. No binding was observed in the pineal gland, tuberal hypothalamus or adenohypophysis in any avian or testudine species. This distribution is drastically different from that observed in mammals, where binding predominates in the pars tuberalis of the adenohypophysis and in the suprachiasmatic nucleus, suggesting that the circadian system may influence a wide array of sensory and integrative functions in birds and reptiles through the circadian secretion of melatonin, but that this capacity has been lost in mammals.


Knemometry is more sensitive to systemic effects of inhaled corticosteroids in children with asthma than 24-hour urine cortisol excretion.
Pharmacodynamic assessment of the systemic effect of inhaled corticosteroids (ICSs) is often done by measuring 24-hour urine free cortisol (UFC) excretion. Knemometry assessing short-term lower-leg growth rate (LLGR) is a more rarely used alternative. The primary aim of this study was to compare the sensitivity of LLGR and 24-hour UFC excretion for evaluating systemic exposure to ICSs in prepubertal children with asthma. The secondary aim was to evaluate factors influencing the precision of LLGR calculated by the traditional 1 leg nonparametric method versus a new 2 leg parametric method. The study evaluated 60 children with mild asthma aged 5 to 12 years participating in a randomized controlled trial of ICSs with longitudinal concomitant assessments of LLGR and 24-hour UFC excretion. The sensitivity of the safety assessments was analyzed by comparing LLGR and 24-hour UFC in the placebo run-in period with values in the ICS treatment period by using paired t tests. Factors with a potential influence on LLGR were analyzed by means of ANOVA and the Levene test of homogeneity. The mean LLGR was significantly reduced during the ICS versus placebo run-in periods: 0.18 mm/wk (SD, 0.55 mm/wk) versus 0.45 mm/wk (SD, 0.39 mm/wk), with a mean difference of 0.27 mm/wk (95% CI, 0.05-0.48 mm/wk; P = .02). In contrast, there was no difference in 24-hour UFC excretion: 6.91 nmol/mmol (SD, 4.67 nmol/mmol) versus 7.58 nmol/mmol (SD, 6.17 nmol/mmol), with a mean difference of 0.67 nmol/mmol (95% CI, -1.13 to 2.48 nmol/mmol; P = .46). We observed no significant difference in parametric determined LLGR caused by the child's age or sex, investigator, or season of measurement, whereas some differences were observed for the nonparametric LLGR. These findings suggest that knemometry is a more sensitive pharmacodynamic measure of systemic effects of ICSs than 24-hour UFC excretion and that a parametric determination of LLGR increases the sensitivity of the method. These findings should be considered by legislative authorities in the future.


The development of highly active acyclic chiral hydrazides for asymmetric iminium ion organocatalysis.
Double asymmetric induction has been employed as a tool to optimise pyrazolidinone-derived organocatalysts for the asymmetric iminium ion catalysed Diels-Alder reaction. Mechanistic studies revealed a superior hydrazide catalyst deriving from methanolysis of the chiral pyrazolidinone precursor. This catalyst displays unusually high endo diastereoselectivity and good enantioselectivity with a range of β-arylenals and cyclic dienes at catalyst loadings as low as 1 mol%.


The association between quality of care and the intensity of diabetes disease management programs.
Although disease management programs are widely implemented, little is known about their effectiveness. To determine whether disease management by physician groups is associated with diabetes care processes, control of intermediate outcomes, or the amount of medication used when intermediate outcomes are above target levels. Cross-sectional study. Patients were randomly sampled from 63 physician groups nested in 7 health plans sponsored by Translating Research into Action for Diabetes (87%) and from 4 health plans with individual physician contracts (13%). 8661 adults with diabetes who completed a survey (2000-2001) and had medical record data. Physician group and health plan directors described their organizations' use of physician reminders, performance feedback, and structured care management on a survey; their responses were used to determine measures of intensity of disease management. The current study measured 8 processes of care, including most recent hemoglobin A1c level, systolic blood pressure, serum low-density lipoprotein cholesterol level, and several measures of medication use. Increased use of any of 3 disease management strategies was significantly associated with higher adjusted rates of retinal screening, nephropathy screening, foot examinations, and measurement of hemoglobin A1c levels. Serum lipid level testing and influenza vaccine administration were associated with greater use of structured care management and performance feedback. Greater use of performance feedback correlated with an increased rate of foot examinations (difference, 5 percentage points [95% CI, 1 to 8 percentage points]), and greater use of physician reminders was associated with an increased rate of nephropathy screening (difference, 15 percentage points [CI, 6 to 23 percentage points]). No strategies were associated with intermediate outcome levels or level of medication management. Physician groups were not randomly sampled from population-based listings, and disease management strategies were not randomly allocated across groups. Disease management strategies were associated with better processes of diabetes care but not with improved intermediate outcomes or level of medication management. A greater focus on direct measurement, feedback, and reporting of intermediate outcome levels or of level of medication management may enhance the effectiveness of these programs.


Probing the structure and charge state of glutathione-capped Au25(SG)18 clusters by NMR and mass spectrometry.
Despite the recent crystallographic determination of the crystal structure of Au(25)(SCH(2)CH(2)Ph)(18) clusters, the question--whether all thiolate-capped, 25-atom gold clusters adopt the same structure, regardless of the types of thiols (e.g., long-chain alkylthiols, aromatic thiols, or other functionalized ones)--still remains unanswered. To crystallize long-chain or bulky ligand (e.g., glutathione)-capped Au(25)(SR)(18) clusters has proven to be difficult due to the major amorphousness caused by such ligands; therefore, one needs to seek other strategies to probe the structural information of such gold clusters. Herein, we report a strategy to probe the Au(25) core structure and surface thiolate ligand distribution by means of NMR in combination with mass spectrometry. We use glutathione-capped Au(25)(SG)(18) clusters as an example to demonstrate the utility of this strategy. One-dimensional (1D) and two-dimensional (2D) correlation NMR spectroscopic investigation of Au(25)(SG)(18) reveals fine spectral features that explicitly indicate two types of surface binding modes of thiolates, which is consistent with the ligand distribution in the Au(25)(SCH(2)CH(2)Ph)(18) cluster. Laser desorption ionization (LDI) mass spectrometry analysis shows that Au(25)(SG)(18) exhibits an identical ionization and core fragmentation pattern with phenylethylthiolate-capped Au(25) clusters. The charge state of the native Au(25)(SG)(18) clusters was determined to be -1 by comparing their optical spectrum with those of [Au(25)(SCH(2)CH(2)Ph)(18)](q) of different charge states (q = -1, 0). Taken together, our results led to the conclusion that glutathione-capped Au(25)(SG)(18) clusters indeed adopt the same structure as that of Au(25)(SCH(2)CH(2)Ph)(18). This conclusion is also valid for other types of thiolate-capped Au(25) clusters, including hexyl- and dodecylthiolates. Interestingly, the chiral optical responses (e.g., circular dichroism (CD) signals in the visible wavelength region) from the Au(25)(SG)(18) clusters seem to be imparted by the chiral glutathione ligands because no similar CD signals were observed in Au(25)(SCH(2)CH(2)Ph)(18).


Head and neck reconstruction using infrahyoid myocutaneous flaps.
The use of pedicled myocutaneous flaps in head and neck reconstruction is widely accepted. Here we describe our experience with infrahyoid flaps (IHFs) employed to cover surgical defects in the oral cavity and oropharynx in patients with benign and malignant tumors. The aim was to evaluate the success rate for infrahyoid myocutaneous flap procedures performed at a single institution. Retrospective study, at the Head and Neck Surgery Service, Unicamp. Fourteen IHFs were used to reconstruct surgical defects in eleven men (78.5%) and three women (21.5%) with a mean age of 66.4 years. The anterior floor of the mouth was reconstructed in nine patients (64.2%), the base of tongue in three (21.4%), the lateral floor in one (7.1%), and the retromolar area (7.1%) in one. Thirteen patients (92.8%) had squamous cell carcinoma (SCC) and one (7.2%) ameloblastoma. The disease stage was T3 in eight (61.5%) of the SCC cases and T4 in five (38.5%). No patient presented total flap loss or fistula. The most common complication was epidermolysis, which delayed the beginning of oral ingestion. The patients with SCC received postoperative radiotherapy without major consequences to the flap. IHF is a safe and reliable procedure for reconstructing head and neck surgical defects. Due to its thinness and malleability, its use for oral cavity and oropharynx defects provides favorable cosmetic and functional outcomes. Complications, when present, are easy to manage.


A cost-effectiveness analysis of interventions to increase repeat testing in patients treated for gonorrhea or chlamydia at public sexually transmitted disease clinics.
Persons who have been infected with chlamydia or gonorrhea (CT/GC) are at elevated risk for reinfection. The cost-effectiveness of interventions designed to encourage public sexually transmitted disease (STD) clinic patients to return for rescreening has not been well-evaluated. The goal of this study was to conduct a program- and societal-perspective cost-effectiveness analysis of five interventions designed to encourage public STD clinic patients infected with CT/GC to return for rescreening 3 months after initial treatment. Researchers at two STD clinics collected cost data for the five interventions. These were combined with study data on return rates and CT/GC positivity rates among returning patients to compare the cost-effectiveness of the interventions. The cost per patient counseled with a brief recommendation to return, followed by a telephone reminder after 3 months, was higher than two interventions: a brief recommendation to return with no reminder and a $20 incentive, received on return. However, the brief recommendation with a telephone reminder yielded the highest return rate (33%) and was the least costly in terms of cost per infection treated ($622 program, $813 societal). In-depth motivational counseling that helped clients identify risk factors and provided reasons for returning was more costly than a phone reminder alone and was not more effective. Phone reminders are more cost-effective than motivational counseling and improve return rates over a brief recommendation given at the time of initial treatment.


Association Between Immune Response to Cytomegalovirus and Cognition in the Health and Retirement Study.
Chronic infections and the subsequent immune response have recently been shown to be risk factors for cognitive decline and Alzheimer disease and related dementias (ADRD). While some studies have shown an association between cytomegalovirus (CMV), a chronic and highly prevalent infection, and cognition and/or ADRD, these studies have been limited by nonrepresentative and small samples. Using 2016 data on 5,617 adults aged 65 years or more from the Health and Retirement Study, we investigated the cross-sectional associations of both CMV serostatus and immunoglobulin G (IgG) antibody response with cognitive function using linear regression models adjusting for age, sex, race/ethnicity, and educational attainment. We further investigated potential effect-measure modification by educational attainment. Overall, both CMV seropositivity and higher IgG antibody response were associated with lower cognitive function, though the relationship was not statistically significant in adjusted models. Among participants with less than a high school diploma, CMV seropositivity and being in the first tertile of IgG response, relative to seronegative persons, were associated with lower scores on the Telephone Interview for Cognitive Status (-0.56 points (95% confidence interval: -1.63, 0.52) and -0.89 points (95% confidence interval: -2.07, 0.29), respectively), and the relationship was attenuated among those with higher education. Our results suggest that CMV may be a risk factor for cognitive impairment, particularly among persons with fewer educational resources.


Age and sex impact plasma NFL and t-Tau trajectories in individuals with subjective memory complaints: a 3-year follow-up study.
Plasma neurofilament light (NFL) and total Tau (t-Tau) proteins are candidate biomarkers for early stages of Alzheimer's disease (AD). The impact of biological factors on their plasma concentrations in individuals with subjective memory complaints (SMC) has been poorly explored. We longitudinally investigate the effect of sex, age, APOE ε4 allele, comorbidities, brain amyloid-β (Aβ) burden, and cognitive scores on plasma NFL and t-Tau concentrations in cognitively healthy individuals with SMC, a condition associated with AD development. Three hundred sixteen and 79 individuals, respectively, have baseline and three-time point assessments (at baseline, 1-year, and 3-year follow-up) of the two biomarkers. Plasma biomarkers were measured with an ultrasensitive assay in a mono-center cohort (INSIGHT-preAD study). We show an effect of age on plasma NFL, with women having a higher increase of plasma t-Tau concentrations compared to men, over time. The APOE ε4 allele does not affect the biomarker concentrations while plasma vitamin B12 deficiency is associated with higher plasma t-Tau concentrations. Both biomarkers are correlated and increase over time. Baseline NFL is related to the rate of Aβ deposition at 2-year follow-up in the left-posterior cingulate and the inferior parietal gyri. Baseline plasma NFL and the rate of change of plasma t-Tau are inversely associated with cognitive score. We find that plasma NFL and t-Tau longitudinal trajectories are affected by age and female sex, respectively, in SMC individuals. Exploring the influence of biological variables on AD biomarkers is crucial for their clinical validation in blood.


The risk of hepatocellular carcinoma decreases after the first 5 years of entecavir or tenofovir in Caucasians with chronic hepatitis B.
Whether there is a change of hepatocellular carcinoma (HCC) incidence in chronic hepatitis B patients under long-term therapy with potent nucleos(t)ide analogues is currently unclear. We therefore assessed the HCC incidence beyond year 5 of entecavir/tenofovir (ETV/TDF) therapy and tried to determine possible factors associated with late HCC occurrence. This European, 10-center, cohort study included 1,951 adult Caucasian chronic hepatitis B patients without HCC at baseline who received ETV/TDF for ≥1 year. Of them, 1,205 (62%) patients without HCC within the first 5 years of therapy have been followed for 5-10 (median, 6.8) years. HCCs have been diagnosed in 101/1,951 (5.2%) patients within the first 5 years and 17/1,205 (1.4%) patients within 5-10 years. The yearly HCC incidence rate was 1.22% within and 0.73% after the first 5 years (P = 0.050). The yearly HCC incidence rate did not differ within and after the first 5 years in patients without cirrhosis (0.49% versus 0.47%, P = 0.931), but it significantly declined in patients with cirrhosis (3.22% versus 1.57%, P = 0.039). All HCCs beyond year 5 developed in patients older than 50 years at ETV/TDF onset. Older age, lower platelets at baseline and year 5, and liver stiffness ≥12 kPa at year 5 were independently associated with more frequent HCC development beyond year 5 in multivariable analysis. No patient with low Platelets, Age, Gender-Hepatitis B score at baseline or year 5 developed HCC. The HCC risk decreases beyond year 5 of ETV/TDF therapy in Caucasian chronic hepatitis B patients, particularly in those with compensated cirrhosis; older age (especially ≥50 years), lower platelets, and liver stiffness ≥12 kPa at year 5 represent the main risk factors for late HCC development. (Hepatology 2017;66:1444-1453).


A Hamilton-Jacobi-Bellman approach to high angular resolution diffusion tractography.
This paper describes a new framework for white matter tractography in high angular resolution diffusion data. A direction-dependent local cost is defined based on the diffusion data for every direction on the unit sphere. Minimum cost curves are determined by solving the Hamilton-Jacobi-Bellman using an efficient algorithm. Classical costs based on the diffusion tensor field can be seen as a special case. While the minimum cost (or equivalently the travel time of a particle moving along the curve) and the anisotropic front propagation frameworks are related, front speed is related to particle speed through a Legendre transformation which can severely impact anisotropy information for front propagation techniques. Implementation details and results on high angular diffusion data show that this method can successfully take advantage of the increased angular resolution in high b-value diffusion weighted data despite lower signal to noise ratio.


Comparison of delayed enhancement patterns on multislice computed tomography immediately after coronary angiography and cardiac magnetic resonance imaging in acute myocardial infarction.
Recent experimental and limited clinical studies have demonstrated the usefulness of delayed enhancement multislice computed tomography (MSCT) for assessing myocardial infarct size (IS) and transmurality. The aim of this study is to compare MSCT enhancement patterns immediately after coronary angiography (CAG) in an acute myocardial infarction (AMI) setting with cardiac magnetic resonance (CMR) enhancement during the second week follow-up. 26 patients admitted for an AMI were evaluated by MSCT immediately after CAG without iodine re-injection. All but three were reperfused. The same patients had delayed enhancement CMR imaging at 10 (SD 4)-day follow-up. Myocardial enhancement was considered transmural (non-viable) when involving >75% of myocardial thickness, subendocardial (1 - < or =75%) or normal (viable for the two latter). Two or more >75% enhanced segments were required to define transmurality on patient-level or culprit artery-level analysis. A semi-quantitative scale score was defined for the 17 left ventricular segments. IS was computed from these scores. On segment analysis, sensitivity, specificity, accuracy, positive and negative predictive values of MSCT for transmurality assessment were 84%, 96%, 94%, 85% and 96%, respectively, compared to CMR. On patient analysis, these respective values were 90%, 80%, 88%, 95% and 67%. IS assessed by the two methods were highly correlated (r = 0.94, p<0.0001) and the regression line did not statistically differ from the identity line. MSCT enhancement immediately following CAG without iodine re-injection for an AMI is a reliable method for evaluating transmurality and IS. This very early evaluation could be an interesting alternative to CMR.


Correlative Light and Electron Microscopy Reveals the HAS3-Induced Dorsal Plasma Membrane Ruffles.
Hyaluronan is a linear sugar polymer synthesized by three isoforms of hyaluronan synthases (HAS1, 2, and 3) that forms a hydrated scaffold around cells and is an essential component of the extracellular matrix. The morphological changes of cells induced by active hyaluronan synthesis are well recognized but not studied in detail with high resolution before. We have previously found that overexpression of HAS3 induces growth of long plasma membrane protrusions that act as platforms for hyaluronan synthesis. The study of these thin and fragile protrusions is challenging, and they are difficult to preserve by fixation unless they are adherent to the substrate. Thus their structure and regulation are still partly unclear despite careful imaging with different microscopic methods in several cell types. In this study, correlative light and electron microscopy (CLEM) was utilized to correlate the GFP-HAS3 signal and the surface ultrastructure of cells in order to study in detail the morphological changes induced by HAS3 overexpression. Surprisingly, this method revealed that GFP-HAS3 not only localizes to ruffles but in fact induces dorsal ruffle formation. Dorsal ruffles regulate diverse cellular functions, such as motility, regulation of glucose metabolism, spreading, adhesion, and matrix degradation, the same functions driven by active hyaluronan synthesis.


Rhabdomyolysis in a Patient with Polyarteritis Nodosa.
Polyarteritis nodosa (PAN) is a medium vessel vasculitis affecting systemic organs. Muscle involvement of PAN usually lacks elevation of creatinine kinase (CK). We herein report a case of PAN with rhabdomyolysis. A 71-year-old man was hospitalized because of muscle weakness of the lower limbs that persisted for 1 month. On a physical examination, rapidly progressive lower proximal muscle weakness and bilateral drop foot were observed. His blood test showed an elevation in the C-reactive protein (19.5 mg/dL) and CK (13,435 IU/L) levels and negativity for anti-neutrophilic cytoplasmic antibody. Computed tomographic angiography showed stenosis of the left renal artery. Electromyogram indicated mono-neuritis multiplex pattern, and enhanced magnetic resonance imaging demonstrated discretely granular hyperintensities on T2 and slow tau inversion recovery in his femoral muscles. A femoral muscle-biopsy specimen showed fibrinoid necrosis of medium-sized vessels and disruption of the elastic lamina of the vessel wall in fascia. Furthermore, muscle necrosis was localized depending on the arterial distribution, suggesting ischemic changes in the muscles. Given these findings, he was diagnosed with PAN with rhabdomyolysis and treated with methyl-prednisolone pulse therapy followed by oral prednisolone at 50 mg/day. He was additionally treated with monthly intravenous cyclophosphamide at 500 mg. Sustained remission has been obtained for two months since the treatment. Although rhabdomyolysis rarely manifests with PAN, it should be included in a differential diagnosis of febrile patients presenting with acute myalgia and weakness with CK elevation.


Reliability and validity of measures from the Behavioral Risk Factor Surveillance System (BRFSS).
To assess the reliability and validity of measures on the BRFSS, to assist users in evaluating the quality of BRFSS data, and to identify areas for further research. Review and summary of reliability and validity studies of measures on the BRFSS and studies of measures that were the same or similar to those on the BRFSS from other surveys. Measures determined to be of high reliability and high validity were current smoker, blood pressure screening, height, weight, and BMI, and several demographic characteristics. Measures of both moderate reliability and validity included when last mammography was received, clinical breast exam, sedentary lifestyle, intense leisure-time physical activity, and fruit and vegetable consumption. Few measures were of low validity and only one measure was determined to be of low reliability. Several other measures were of high or moderate reliability or validity, but not both. The reliability or validity could not be determined for some measures, primarily due to lack of research. Most questions on the core BRFSS instrument were at least moderately reliable and valid, and many were highly reliable and valid. Additional research is needed for some measures.


The safety of therapeutic monoclonal antibodies: implications for cancer therapy including immuno-checkpoint inhibitors.
Monoclonal antibody-based treatment of cancer has been established as one of the most successful therapeutic strategies for both hematologic malignancies and solid tumors. In addition to targeting cancer antigens antibodies can also modulate immunological pathways that are critical to immune surveillance. Antibody therapy directed against several negative immunologic regulators (checkpoints) is demonstrating significant success in the past few years. Immune checkpoint inhibitors, ipilimumab, pembrolizumab and nivolumab, have shown significant clinical benefit in several malignancies and are already approved for advanced melanoma and squamous NSCLC. Based on their mechanism of action, these agents can exert toxicities that are unlike conventional cytotoxic chemotherapy, whose nature is close to autoimmune diseases - immune related adverse events (irAEs). In this review we focus on the spectrum of irAEs associated with immune checkpoint antibodies, discussing the pharmacological treatment strategy and possible clinical impact.


Internet-delivered interventions aimed at adolescents: a Delphi study on dissemination and exposure.
It appears that in practice exposure to Internet-delivered behaviour change interventions, encouraging a healthy lifestyle for adolescents with regard to health risk behaviours, is quite low. There is, however, a lack of evidence-based insight into how to disseminate such interventions and how to reach optimal exposure. A more extensive exploration is therefore timely since this knowledge is crucial to improve the public health impact of such interventions. By means of a three-round Delphi study factors associated with dissemination of and exposure (first visit, stay long enough and revisit) to Internet-delivered interventions aimed at adolescents had been identified, as well as the extent to which experts agree on the importance of these factors. Results showed that there was a high rate of consensus among experts from several disciplines with regard to the importance of factors like word of mouth recommendation, the interface of the intervention and utilization of all features provided by the Internet. Experts do not agree, however, on a gold standard for successful dissemination. Overall, the results of this exploration serve as a handle for the formation of further research questions to be tested and answered in research among adolescents.


A group of genes required for maintenance of the amnioserosa tissue in Drosophila.
The amnioserosa is an extraembryonic, epithelial tissue that covers the dorsal side of the Drosophila embryo. The initial development of the amnioserosa is controlled by the dorsoventral patterning genes. Here we show that a group of genes, which we refer to as the U-shaped-group (ush-group), is required for maintenance of the amnioserosa tissue once it has differentiated. Using several molecular markers, we examined amnioserosa development in the ush-group mutants: u-shaped (ush), hindsight (hnt), serpent (srp) and tail-up (tup). Our results show that the amnioserosa in these mutants is specified correctly and begins to differentiate as in wild type. However, following germ-band extension, there is a premature loss of the amnioserosa. We demonstrate that this cell loss is a consequence of programmed cell death (apoptosis) in ush, hnt and srp, but not in tup. We discuss the role of the ush-group genes in maintaining the amnioserosa's viability. We also discuss a possible role for the amnioserosa in germ-band retraction in light of these mutants' unretracted phenotype.


Treatment of subclinical hyperthyroidism: effect on left ventricular mass and function of the heart using magnetic resonance imaging technique.
The aim of this study was to investigate structure and function of the heart in subclinical hyperthyroidism (SH) before and after obtaining euthyroidism by radioactive iodine treatment, using high precision and observer-independent magnetic resonance imaging (MRI) technology. Cardiac MRI was performed before and after euthyroidism was obtained by radioactive iodine treatment in 12 otherwise healthy patients (11 women and one man, mean age 59 years, range 44-71 years) with a nodular goiter and SH, and compared with eight healthy controls investigated at baseline. Cardiac data were expressed as an index, as per body surface area, except for heart rate (HR) and ejection fraction. Post-treatment cardiac MRI was performed in median 139 days after a normalized serum TSH value had been recorded. During treatment, serum TSH increased from (median (range)) 0.01 (0.01-0.09) to 0.88 (0.27-3.99) mU/l. Patients with untreated SH had increased resting HR (P<0.01) as well as cardiac index (cardiac output as per body surface area) (P<0.01) compared with controls. Obtaining euthyroidism resulted in a significant decrease in left ventricular mass index (LVMI) of 2.7 g/m(2) (P=0.034), in HR of 8 bpm (P=0.001), and in cardiac index of 0.24 l/min per m(2) (P=0.017). Normalization of thyroid function by radioactive iodine treatment of SH resulted in significant reductions in clinically important heart parameters such as LVMI, HR, and cardiac index. SH should be regarded as a condition in which aggressive treatment should be considered to protect cardiac function.


The central role of inflammatory signaling in the pathogenesis of myelodysplastic syndromes.
In cancer biology, tumor-promoting inflammation and an inflammatory microenvironment play a vital role in disease pathogenesis. In the past decade, aberrant innate immune activation and proinflammatory signaling within the malignant clone and the bone marrow (BM) microenvironment were identified as key pathogenic drivers of myelodysplastic syndromes (MDS). In particular, S100A9-mediated NOD-like receptor protein 3 (NLRP3) inflammasome activation directs an inflammatory, lytic form of cell death termed pyroptosis that underlies many of the hallmark features of the disease. This circuit and accompanying release of other danger-associated molecular patterns expands BM myeloid-derived suppressor cells, creating a feed-forward process propagating inflammasome activation. Furthermore, somatic gene mutations of varied functional classes license the NLRP3 inflammasome to generate a common phenotype with excess reactive oxygen species generation, Wnt/β-catenin-induced proliferation, cation flux-induced cell swelling, and caspase-1 activation. Recent investigations have shown that activation of the NLRP3 inflammasome complex has more broad-reaching importance, particularly as a possible disease-specific biomarker for MDS, and, mechanistically, as a driver of cardiovascular morbidity/mortality in individuals with age-related, clonal hematopoiesis. Recognition of the mechanistic role of aberrant innate immune activation in MDS provides a new perspective for therapeutic development that could usher in a novel class of disease-modifying agents.


The vascular system as a target of metal toxicity.
Vascular system function involves complex interactions among the vascular endothelium, smooth muscle, the immune system, and the nervous system. The toxic metals cadmium (Cd), arsenic (As), and lead (Pb) can target the vascular system in a variety of ways, ranging from hemorrhagic injury to subtle pathogenic remodeling and metabolic changes. Acute Cd exposure results in hemorrhagic injury to the testis, although some strains of animals are resistant to this effect. A comparison of Cd-sensitive with Cd-resistant mouse strains showed that expression of the Slc39a8 gene, encoding the ZIP8 transporter, in the testis vasculature endothelium is responsible for this difference. Endogenously, ZIP8 is a Mn(2+)/HCO(3)(-)symporter that may also contribute to Cd damage in the kidney. Chronic Cd exposure is associated with various cardiovascular disorders such as hypertension and cardiomyopathy and it is reported to have both carcinogenic and anticarcinogenic activities. At noncytotoxic concentrations of 10-100nM, Cd can inhibit chemotaxis and tube formation of vascular endothelial cells. These angiostatic effects may be mediated through disruption of vascular endothelial cadherin, a Ca(2+)-dependent cell adhesion molecule. With regard to As, ingestion of water containing disease-promoting concentrations of As promotes capillarization of the liver sinusoidal endothelium. Because capillarization is a hallmark precursor for liver fibrosis and contributes to an imbalance of lipid metabolism, this As effect on hepatic endothelial cells may be a pathogenic mechanism underlying As-related vascular diseases. With regard to Pb, perinatal exposure may cause sustained elevations in adult blood pressure, and genetically susceptible animals may show enhanced sensitivity to this effect. Taken together, these data indicate that the vascular system is a critical target of metal toxicity and that actions of metals on the vascular system may play important roles in mediating the pathophysiologic effects of metals in specific target organs.


New Hope in Brain Glioma Surgery: The Role of Intraoperative Ultrasound. A Review.
Maximal safe resection represents the gold standard for surgery of malignant brain tumors. As regards gross-total resection, accurate localization and precise delineation of the tumor margins are required. Intraoperative diagnostic imaging (Intra-Operative Magnetic Resonance-IOMR, Intra-Operative Computed Tomography-IOCT, Intra-Operative Ultrasound-IOUS) and dyes (fluorescence) have become relevant in brain tumor surgery, allowing for a more radical and safer tumor resection. IOUS guidance for brain tumor surgery is accurate in distinguishing tumor from normal parenchyma, and it allows a real-time intraoperative visualization. We aim to evaluate the role of IOUS in gliomas surgery and to outline specific strategies to maximize its efficacy. We performed a literature research through the Pubmed database by selecting each article which was focused on the use of IOUS in brain tumor surgery, and in particular in glioma surgery, published in the last 15 years (from 2003 to 2018). We selected 39 papers concerning the use of IOUS in brain tumor surgery, including gliomas. IOUS exerts a notable attraction due to its low cost, minimal interruption of the operational flow, and lack of radiation exposure. Our literature review shows that increasing the use of ultrasound in brain tumors allows more radical resections, thus giving rise to increases in survival.


Locking and Non-locking Constructs Achieve Similar Radiographic and Clinical Outcomes for Internal Fixation of Intra-articular Distal Humerus Fractures.
Locking plates have been used increasingly for the management of distal humerus fractures. Studies that compare patient-centered outcomes between locking and non-locking fixation for distal humerus fractures are lacking. The purposes of this study were to (1) determine whether locking plates offered superior fixation compared with non-locking plates for distal humerus fractures, (2) determine whether the use of locking plates was associated with fewer complications, and (3) determine whether locking plate use resulted in superior radiographic outcome compared with non-locking plates. Lastly, another aim was to determine the average cost difference associated with locking plate use versus non-locking plate use for distal humerus fracture fixation. Demographic, clinical, and radiographic data including loss of fixation, range of motion, rate of infection, nonunion and reoperation, as well as measures of fixation were collected retrospectively and compared on 96 patients with surgically treated AO type 13C distal humerus fractures (65 locking, 31 non-locking) at 6-week and 6-month follow-up. Average costs of locking and non-locking constructs were calculated and compared. Three in 96 (3.1%) of all cases experienced loss of fixation, with no difference between the two groups. There was no difference between locking and non-locking groups with regard to the rate of nonunion, infection, and reoperation at 6 weeks and 6 months. On average, locking plate constructs were 348% more expensive than non-locking constructs. While there are some significant differences in radiographic parameters and cost between locking and non-locking constructs for internal fixation of intra-articular distal humerus fractures, there were no statistically significant differences in clinical outcome.


Molecular and Phenetic Characterization of the Bacterial Assemblage of Hot Lake, WA, an Environment with High Concentrations of Magnesium Sulfate, and Its Relevance to Mars.
Hot Lake (Oroville, WA) is an athalassohaline epsomite lake that can have precipitating concentrations of MgSO4 salts, mainly epsomite. Little biotic study has been done on epsomite lakes and it was unclear whether microbes isolated from epsomite lakes and their margins would fall within recognized halotolerant genera, common soil genera, or novel phyla. Our initial study cultivated and characterized epsotolerant bacteria from the lake and its margins. Approximately 100 aerobic heterotrophic microbial isolates were obtained by repetitive streak-plating in high-salt media including either 10% NaCl or 2 M MgSO4. The collected isolates were all bacteria, nearly evenly divided between Gram-positive and Gram-negative clades, the most abundant genera being Halomonas, Idiomarina, Marinobacter, Marinococcus, Nesterenkonia, Nocardiopsis, and Planococcus. Bacillus, Corynebacterium, Exiguobacterium, Kocuria, and Staphylococcus also were cultured. This initial study included culture-independent community analysis of direct DNA extracts of lake margin soil using PCR-based clone libraries and 16S rRNA gene phylogeny. Clones assigned Gram-positive bacterial clades (70% of total clones) were dominated by sequences related to uncultured actinobacteria. There were abundant Deltaproteobacteria clones related to bacterial sulfur metabolisms and clones of Legionella and Coxiella. These epsomite lake microbial communities seem to be divided between bacteria primarily associated with hyperhaline environments rich in NaCl and salinotolerant relatives of common soil organisms. Archaea appear to be in low abundance and none were isolated, despite near-saturated salinities. Growth of microbes at very high concentrations of magnesium and other sulfates has relevance to planetary protection and life-detection missions to Mars, where scant liquid water may form as deliquescent brines and appear as eutectic liquids.


An Insect Eye Inspired Miniaturized Multi-Camera System for Endoscopic Imaging.
In this work, we present a miniaturized high definition vision system inspired by insect eyes, with a distributed illumination method, which can work in dark environments for proximity imaging applications such as endoscopy. Our approach is based on modeling biological systems with off-the-shelf miniaturized cameras combined with digital circuit design for real time image processing. We built a 5 mm radius hemispherical compound eye, imaging a 180°×180° degrees field of view while providing more than 1.1 megapixels (emulated ommatidias) as real-time video with an inter-ommatidial angle ∆ϕ = 0.5° at 18 mm radial distance. We made an FPGA implementation of the image processing system which is capable of generating 25 fps video with 1080 × 1080 pixel resolution at a 120 MHz processing clock frequency. When compared to similar size insect eye mimicking systems in literature, the system proposed in this paper features 1000 × resolution increase. To the best of our knowledge, this is the first time that a compound eye with built-in illumination idea is reported. We are offering our miniaturized imaging system for endoscopic applications like colonoscopy or laparoscopic surgery where there is a need for large field of view high definition imagery. For that purpose we tested our system inside a human colon model. We also present the resulting images and videos from the human colon model in this paper.


High-Pressure Limit Rate Rules for α-H Isomerization of Hydroperoxyalkylperoxy Radicals.
Hydroperoxyalkylperoxy (OOQOOH) radical isomerization is an important low-temperature chain branching reaction within the mechanism of hydrocarbon oxidation. This isomerization may proceed via the migration of the α-hydrogen to the hydroperoxide group. In this work, a combination of high level composite methods-CBS-QB3, G3, and G4-is used to determine the high-pressure-limit rate parameters for the title reaction. Rate rules for H-migration reactions proceeding through 5-, 6-, 7-, and 8-membered ring transitions states are determined. Migrations from primary, secondary and tertiary carbon sites to the peroxy group are considered. Chirality is also investigated by considering two diastereomers for reactants and transition states with two chiral centers. This is important since chirality may influence the energy barrier of the reaction as well as the rotational energy barriers of hindered rotors in chemical species and transition states. The effect of chirality and hydrogen bonding interactions in the investigated energies and rate constants is studied. The results show that while the energy difference between two diastereomers ranges from 0.1-3.2 kcal/mol, chirality hardly affects the kinetics, except at low temperatures (atmospheric conditions) or when two chiral centers are present in the reactant. Regarding the effect of the H-migration ring size, it is found that in most cases, the 1,5 and 1,6 H-migration reactions have similar rates at low temperatures (below ∼830 K) since the 1,6 H-migration proceeds via a cyclohexane-like transition state similar to that of the 1,5 H-migration.


Comparison of multi-institutional pre-treatment verification for VMAT of nasopharynx with delivery errors.
Measurement-based pre-treatment verification with phantoms frequently uses gamma analysis to assess acceptable delivery accuracy. This study evaluates the sensitivity of a commercial system to simulated machine errors for three different institutions' Volumetric Modulated Arc Therapy (VMAT) planning approaches. VMAT plans were generated for ten patients at three institutions using each institution's own protocol (manually-planned at institution 1; auto-planned at institutions 2 and 3). Errors in Multi-Leaf Collimator (MLC) field size (FS), MLC shift (S), and collimator angle (C) of -5, -2, -1, 1, 2 and 5 mm or degrees were introduced. Dose metric constraints discriminated which error magnitudes were considered unacceptable. The smallest magnitude error treatment plans deemed clinically unacceptable (typically for a 5% dose change) were delivered to the ArcCHECK for all institutions, and with a high-dose point ion chamber measurement in 2 institutions. Error detection for different gamma analysis criteria was compared. Not all deliberately introduced VMAT plan errors were detected using a typical 3D 3%/3 mm global gamma pass rate of 95%. Considering all institutions, gamma analysis was least sensitive to negative FS errors. The most sensitive was a 2%/2 mm global analysis for institution 1, whilst for institution 2 it was 3%/3 mm global analysis. The majority of errors (58/59 for institution 1, 54/60 for institution 3) were detected using ArcCHECK and ion chamber measurements combined. Not all clinically unacceptable errors are detected. Combining ion chamber measurements with gamma analysis improved sensitivity and is recommended. Optimum gamma settings varied across institutions.


Effect of Coffee and Cocoa-Based Confectionery Containing Coffee on Markers of DNA Damage and Lipid Peroxidation Products: Results from a Human Intervention Study.
The effect of coffee and cocoa on oxidative damage to macromolecules has been investigated in several studies, often with controversial results. This study aimed to investigate the effect of one-month consumption of different doses of coffee or cocoa-based products containing coffee on markers of DNA damage and lipid peroxidation in young healthy volunteers. Twenty-one volunteers were randomly assigned into a three-arm, crossover, randomized trial. Subjects were assigned to consume one of the three following treatments: one cup of espresso coffee/day (1C), three cups of espresso coffee/day (3C), and one cup of espresso coffee plus two cocoa-based products containing coffee (PC) twice per day for 1 month. At the end of each treatment, blood samples were collected for the analysis of endogenous and H2O2-induced DNA damage and DNA oxidation catabolites, while urines were used for the analysis of oxylipins. On the whole, four DNA catabolites (cyclic guanosine monophosphate (cGMP), 8-OH-2'-deoxy-guanosine, 8-OH-guanine, and 8-NO2-cGMP) were detected in plasma samples following the one-month intervention. No significant modulation of DNA and lipid damage markers was documented among groups, apart from an effect of time for DNA strand breaks and some markers of lipid peroxidation. In conclusion, the consumption of coffee and cocoa-based confectionery containing coffee was apparently not able to affect oxidative stress markers. More studies are encouraged to better explain the findings obtained and to understand the impact of different dosages of these products on specific target groups.


A derivative of amiloride blocks both the light-regulated and cyclic GMP-regulated conductances in rod photoreceptors.
Vertebrate rod photoreceptors in the dark maintain an inward current across the outer segment membrane. The photoresponse results from a light-induced suppression of this dark current. The light-regulated current is not sensitive to either tetrodotoxin or amiloride, potent blockers of Na+ channels. Here, we report that a derivative of amiloride, 3',4'-dichlorobenzamil (DCPA), completely suppresses the dark current and light response recorded from rod photoreceptors. DCPA also blocks a cyclic GMP-activated current in excised patches of rod plasma membrane and a cGMP-induced Ca++ flux from rod disk membranes. These results are consistent with the notion that the Ca++ flux mechanism in the disk membrane and the light-regulated conductance in the plasma membrane are identical. DCPA also inhibits the Na/Ca exchange mechanism in intact rods, but at a 5-10-fold-higher concentration than is required to block the cGMP-activated flux and current. The blocking action of DCPA in 10 nM Ca++ is different from that in 1 mM Ca++, which suggests either that the conductance state of the light-regulated channel may be modified in high and low concentrations of Ca++, or that there may be two ionic channels in the rod outer segment membrane.


CT-1 (Cardiotrophin-1)-Gal-3 (Galectin-3) Axis in Cardiac Fibrosis and Inflammation.
Myocardial fibrosis is a main contributor to the development of heart failure (HF). CT-1 (cardiotrophin-1) and Gal-3 (galectin-3) are increased in HF and associated with myocardial fibrosis. The aim of this study is to analyze whether CT-1 regulates Gal-3. Proteomic analysis revealed that Gal-3 was upregulated by CT-1 in human cardiac fibroblasts in parallel with other profibrotic and proinflammatory markers. CT-1 upregulation of Gal-3 was mediated by ERK (extracellular signal-regulated kinase) 1/2 and Stat-3 (signal transducer and activator of transcription 3) pathways. Male Wistar rats and B6CBAF1 mice treated with CT-1 (20 µg/kg per day) presented higher cardiac Gal-3 levels and myocardial fibrosis. In CT-1-treated rats, direct correlations were found between cardiac CT-1 and Gal-3 levels, as well as between Gal-3 and perivascular fibrosis. Gal-3 genetic disruption in human cardiac fibroblasts and pharmacological Gal-3 inhibition in mice prevented the profibrotic and proinflammatory effects of CT-1. Dahl salt-sensitive hypertensive rats with diastolic dysfunction showed increased cardiac CT-1 and Gal-3 expression together with cardiac fibrosis and inflammation. CT-1 and Gal-3 directly correlated with myocardial fibrosis. In HF patients, myocardial and plasma CT-1 and Gal-3 were increased and directly correlated. In addition, HF patients with high CT-1 and Gal-3 plasma levels presented an increased risk of cardiovascular death. Our data suggest that CT-1 upregulates Gal-3 which, in turn, mediates the proinflammatory and profibrotic myocardial effects of CT-1. The elevation of both molecules in HF patients identifies a subgroup of patients with a higher risk of cardiovascular mortality. The CT-1/Gal-3 axis emerges as a candidate therapeutic target and a potential prognostic biomarker in HF.


Strategies for efficient disruption of metabolism in Mycobacterium tuberculosis from network analysis.
Tuberculosis continues to be a major health challenge, warranting the need for newer strategies for therapeutic intervention and newer approaches to discover them. Here, we report the identification of efficient metabolism disruption strategies by analysis of a reactome network. Protein-protein dependencies at a genome scale are derived from the curated metabolic network, from which insights into the nature and extent of inter-protein and inter-pathway dependencies have been obtained. A functional distance matrix and a subsequent nearness index derived from this information, helps in understanding how the influence of a given protein can pervade to the metabolic network. Thus, the nearness index can be viewed as a metabolic disruptability index, which suggests possible strategies for achieving maximal metabolic disruption by inhibition of the least number of proteins. A greedy approach has been used to identify the most influential singleton, and its combination with the other most pervasive proteins to obtain highly influential pairs, triplets and quadruplets. The effect of deletion of these combinations on cellular metabolism has been studied by flux balance analysis. An obvious outcome of this study is a rational identification of drug targets, to efficiently bring down mycobacterial metabolism.


Capacity to consent to voluntary hospitalization: searching for a satisfactory Zinermon screen.
Half a decade ago, the Zinermon court announced the need for clinicians to evaluate the competence of people with mental illness to consent to voluntary hospital admission, but the court did not specify the test of capacity that mental health professionals should use. As has occurred in other areas dealing with legal competence, there is a need for the field to develop standardized assessment procedures for evaluating capacity to consent to voluntary hospitalization. Both theoretical and practical considerations suggest that these procedures should be modeled after what S. K. Hoge has termed a "weak" model of consent. This and other studies of the ability of mentally ill persons to understand disclosed information suggest that their level of understanding may be assessed optimally with measures that utilize recognition rather than recall response elicitation formats.


Knowledge and perception on tuberculosis transmission in Tanzania: Multinomial logistic regression analysis of secondary data.
Tuberculosis (TB) is one of the most important public health problems in Tanzania and was declared as a national public health emergency in 2006. Community and individual knowledge and perceptions are critical factors in the control of the disease. The objective of this study was to analyze the knowledge and perception on the transmission of TB in Tanzania. Multinomial Logistic Regression analysis was considered in order to quantify the impact of knowledge and perception on TB. The data used was adopted as secondary data from larger national survey 2007-08 Tanzania HIV/AIDS and Malaria Indicator Survey. The findings across groups revealed that knowledge on TB transmission increased with an increase in age and level of education. People in rural areas had less knowledge regarding tuberculosis transmission compared to urban areas [OR = 0.7]. People with the access to radio [OR = 1.7] were more knowledgeable on tuberculosis transmission compared to those who did not have access to radio. People who did not have telephone [OR = 0.6] were less knowledgeable on tuberculosis route of transmission compared to those who had telephone. The findings showed that socio-demographic factors such as age, education, place of residence and owning telephone or radio varied systematically with knowledge on tuberculosis transmission.


Efficacy and safety of curcumin and its combination with boswellic acid in osteoarthritis: a comparative, randomized, double-blind, placebo-controlled study.
The aim of this clinical trial was to assess the efficacy and safety of curcuminoid complex extract from turmeric rhizome with turmeric volatile oil (CuraMed®) and its combination with boswellic acid extract from Indian frankincense root (Curamin®) vs placebo for the treatment of 40- to 70-year-old patients with osteoarthritis (OA). The effects of CuraMed® 500-mg capsules (333 mg curcuminoids) and Curamin® 500-mg capsules (350 mg curcuminoids and 150 mg boswellic acid) taken orally three times a day for 12 weeks in 201 patients was investigated in a three-arm, parallel-group, randomized, double-blinded, placebo-controlled trial. Primary outcome efficacy measures included OA physical function performance-based tests, the WOMAC recommended index of joint pain, morning stiffness, limitations of physical function, and the patients' global assessment of disease severity. Favorable effects of both preparations compared to placebo were observed after only 3 months of continuous treatment. A significant effect of Curamin® compared to placebo was observed both in physical performance tests and the WOMAC joint pain index, while superior efficacy of CuraMed vs placebo was observed only in physical performance tests. The effect size compared to placebo was comparable for both treatment groups but was superior in the Curamin® group. The treatments were well tolerated. Twelve-week use of curcumin complex or its combination with boswellic acid reduces pain-related symptoms in patients with OA. Curcumin in combination with boswellic acid is more effective. Combining Curcuma longa and Boswellia serrata extracts in Curamin® increases the efficacy of OA treatment presumably due to synergistic effects of curcumin and boswellic acid. This trial is registered at the database www.clinicaltrials.gov . https://clinicaltrials.gov/ct2/show/NCT02390349?term=EuroPharma&rank=1 . Study registration number: NCT02390349 .


Yoga versus physical exercise for cardio-respiratory fitness in adolescent school children: a randomized controlled trial.
Background Yoga is very effective in improving health especially cardio-respiratory fitness and also overall performance in adolescents. There are no large numbers of randomized controlled studies conducted on comparing yoga with physical activity for cardio-respiratory fitness in adolescent school children with large sample size. Objective Aerobic training is known to improve physical and cardio-respiratory fitness in children. Cardio-respiratory fitness is an important indicator of health in children. In this study we evaluate the effects of yoga versus physical exercise training on cardio-respiratory fitness in adolescent school children. Subjects Eight hundred two school students from 10 schools across four districts were recruited for this study. Methods In this prospective two arm RCT around 802 students were randomized to receive daily one hour yoga training (n = 411) or physical exercise (n = 391) over a period of two months. VO2 max was estimated using 20 m shuttle run test. However, yoga (n = 377) and physical exercise (n = 371) students contributed data to the analyses. Data was analysed using students t test. Results There was a significant improvement in VO2 max using 20 m Shuttle run test in both yoga (p < 0.001) and exercise (p < 0.001) group following intervention. There was no significant change in VO2 max between yoga and physical exercise group following intervention. However, in the subgroup with an above median cut-off of VO2 max; there was a significant improvement in yoga group compared to control group following intervention (p = 0.03). Conclusion The results suggest yoga can improve cardio-respiratory fitness and aerobic capacity as physical exercise intervention in adolescent school children.