Attitudes towards worm egg counts and targeted selective treatment against equine cyathostomins.
Gastrointestinal nematodes present a major threat to the health and welfare of equids worldwide. Anthelmintic resistance (AR) is increasingly reported and challenges effective control in horses and ponies in many regions. The use of faecal worm egg counts (FECs) to support targeted treatment (FEC-TT) and targeted selective treatment (FEC-TST) has been promoted as an effective deworming strategy that may prolong the useful life of anthelmintics and reduce the costs associated with parasite control. However, treatment applied at set intervals or on pre-determined dates remains common. A structural equation model was developed to identify factors influencing the uptake of FEC-directed treatment strategies, based on well-established socio-psychological theories of intentional health-related behaviours: the Theory of Planned Behaviour and the Health Belief Model. More than 850 valid responses were received from horse owners in the UK via an online survey. The intention to use FECs prior to deworming was not influenced by the perceived risk of anthelmintic resistance or that of gastrointestinal nematode infection but was positively influenced by a negative attitude towards anthelmintics, a positive attitude towards FECs, an increase in social pressure (e.g. significant others think the respondent should use FECs) and an increase in perceived control over their deworming programme. The results were consistent with a similar study conducted on FEC-TT in cattle in Belgium. An increase in respondents' self-perceived level of knowledge significantly increased the intention to use FECs via mediating factors. These results suggest that knowledge transfer activities aimed at increasing awareness and understanding of sustainable nematode control practices may be more effective at encouraging behaviour change than emphasising the dangers of nematodes and AR, which had limited influence on behaviour intention in this study population.


Secondhand smoke in public places: can Bangalore metropolitan transport corporation be a role model for effective implementation of Cigarette and Other Tobacco Products Act, 2003?
The Indian government enacted 'The cigarettes and other tobacco products act, 2003' (COTPA), which prohibits smoking in public places. To validate the efficacy of the Act of 2003, enacted by the Government of India, to prevent secondhand smoking in public places. The study is based on a non-random sample survey of 2,600 bus passengers carried out in the premises of three mega public road transport organizations in Karnataka state, India, in June 2007. The information was gathered through administration of structured schedules. A sample of 1,000 each for the terminus of Bangalore Metropolitan Transport Corporation (BMTC) and Karnataka State Road Transport Corporation (KSRTC) in Bangalore and, 600 for North West Karnataka Road Transport Corporation (NWKRTC) in Hubli-Dharwad city was distributed proportionately according to the number of platforms in each terminus. Simple Averages. There is some reduction in smoking in general as perceived by 69% of the passengers as compared to the scenario a year before the enactment of COTPA. The observed smoking is lower in the bus premises of BMTC where there is strict regulation, and higher in the bus premises of NWKRTC, which has not taken any regulatory measures. Knowing smoking is banned in public places can itself create awareness depending on the coverage extended by media and implementing an agency to reach the public. The implementation of an act depends on the willingness of stakeholders to act upon it. The implementation of COTPA as done by BMTC could well become a role model for replication elsewhere, if BMTC can strive harder to accomplish a 100% smoke-free zone.


Prevalence, distribution and antimicrobial susceptibility pattern of bacterial isolates from a tertiary Hospital in Malawi.
Bacterial infections are a significant cause of sickness and death in sub-Saharan Africa. This study aimed at establishing the prevalence, distribution and antimicrobial susceptibility pattern of major bacterial isolates from patients accessing medical care at a tertiary hospital in Malawi. We retrospectively reviewed bacteria culture and antimicrobial susceptibility records for 4617 patients from 2002 to 2014 at Mzuzu Central Hospital (MCH). No inclusion and exclusion criteria were followed. Data was analysed using excel (Microsoft office, USA) and GraphPad prism 7 software programs. The most prevalent isolates were S. aureus (34.7%, n = 783), Klebsiella species (17.4%, n = 393) and Proteus species (11.4%, n = 256). Most microorganisms were isolated from adults (88.3%, n = 3889) and pus was the main source (69.3%, n = 1224). S. pneumoniae was predominantly isolated from cerebrospinal fluid (60.3%, n = 44) largely collected from children (88.2%, n = 64). Overall, most bacteria exhibited high resistance to all regularly used antimicrobials excluding ciprofloxacin. Our report demonstrates an increase in bacterial infection burden in sites other than blood stream and subsequent increase in prevalence of antimicrobial resistance for all major isolates. Creating an epidemiological survey unit at MCH will be essential to help inform better treatment and management options for patients with bacterial infections.


Effects of continuous rate infusion of butorphanol in isoflurane-anesthetized calves.
To assess the hemodynamic changes and bispectral index (BIS) following administration of a continuous rate infusion (CRI) of butorphanol in isoflurane-anesthetized calves. Eight calves weighing 110 ± 12 kg were included in the study. Anesthesia was induced with 5% isoflurane in O2 delivered via face mask and maintained with end-tidal concentration of 1.4%. IPPV was set to a peak inspiratory airway pressure of 15 cmH2O and respiratory rate of six breaths minute-1. Forty minutes after the start of anesthetic maintenance, 0.1 mg kg-1butorphanol was administered intravenously, followed by a CRI of 20 µg kg-1 minute-1. Hemodynamic variables and BIS were recorded before butorphanol administration (T0), and at 10, 20, 40 and 80 minutes following the CRI. Anesthesia was discontinued after the last recording and the calves were allowed to recover. The time to sternal recumbency (SRE) and standing (ST) were evaluated. There were no significant differences between the moments in all hemodynamic variables and BIS. The time to SRE and ST was 9 ± 5 and 14 ± 7 minutes, respectively. The continuous rate infusion did not produce clinically relevant changes in hemodynamic or bispectral index values compared to baseline in mechanically ventilated and unstimulated calves anesthetized at 1.4% isoflurane.


GLI1 inactivation is associated with developmental phenotypes overlapping with Ellis-van Creveld syndrome.
GLI1, GLI2 and GLI3 form a family of transcription factors which regulate development by mediating the action of Hedgehog (Hh) morphogens. Accordingly, inactivating variants in GLI2 and GLI3 are found in several developmental disorders. In contrast, loss-of-function mutations in GLI1 have remained elusive, maintaining enigmatic the role of this gene in the human embryo. We describe eight patients from three independent families having biallelic truncating variants in GLI1 and developmental defects overlapping with Ellis-van Creveld syndrome (EvC), a disease caused by diminished Hh signaling. Two families had mutations in the last exon of the gene and a third family was identified with an N-terminal stop gain variant predicted to be degraded by the NMD-pathway. Analysis of fibroblasts from one of the patients with homozygous C-terminal truncation of GLI1 demonstrated that the corresponding mutant GLI1 protein is fabricated by patient cells and becomes upregulated in response to Hh signaling. However, the transcriptional activity of the truncated GLI1 factor was found to be severely impaired by cell culture and in vivo assays, indicating that the balance between GLI repressors and activators is altered in affected subjects. Consistent with this, reduced expression of the GLI target PTCH1 was observed in patient fibroblasts after chemical induction of the Hh pathway. We conclude that GLI1 inactivation is associated with a phenotypic spectrum extending from isolated postaxial polydactyly to an EvC-like condition.


Successful interdisciplinary treatment of a rare cause of acute myocardial ischaemia from intermittent tumour-associated obstruction of the left main coronary artery: a case report.
A papillary fibroelastoma of the aortic valve has been reported as a rare cause of myocardial ischaemia. An advanced combined interventional and surgical approach leading to sufficient therapy for the patient is presented in this case report. A 56-year-old female patient presented in an emergency room of a hospital with an acute coronary syndrome. Over 1.5 years, recurrent stable angina had been known in the patient and significant coronary artery disease has already been ruled out in a previous coronary angiogram. The patient was immediately transferred to the catheter laboratory due to cardiogenic shock where a drug-eluting stent was implanted to, firstly, recanalize the left main coronary artery (LMCA) and, secondly, to protect the left main ostium from obstruction by an echocardiographic-proven mass. During subsequent deterioration of haemodynamics caused by decreasing left ventricular function and acute severe mitral insufficiency, firstly an intra-aortic balloon pump and secondly a veno-arterial extracorporeal membrane oxygenation was established through the femoral vessels. The patient was transferred to our cardiac surgery unit and was successfully operated utilizing a valve-sparing technique by extracting the tumour mass from the left coronary cusp and extracting the stent carefully from the LMCA. Histology revealed a papillary fibroelastoma. A papillary fibroelastoma of the aortic valve with intermittent obstruction of the coronary arteries requires surgical therapy. Interventional recanalization and extracorporeal support might be useful strategies to ensure the patient's safety as a bridge to surgery.


Results of a prospective randomized clinical trial of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) followed by radiation therapy (RT) versus ABVD alone for stages I, II, and IIIA nonbulky Hodgkin disease.
To determine whether combined modality therapy (CMT) is superior to chemotherapy (CT) alone, 152 untreated Hodgkin disease patients with clinical stages (CSs) IA, IB, IIA, IIB, and IIIA without bulk disease were prospectively randomized to 6 cycles of doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD) alone or 6 cycles of ABVD followed by radiation therapy (RT) (3600 cGy: involved field for 11 patients, modified extended field for the rest). Of 76 patients randomized to receive RT, 65 actually received it, and 11 did not (4 progressed, 1 had bleomycin toxicity, 6 refused). For ABVD + RT, the complete remission (CR) percentage was 94% and no major response, 6%. For ABVD alone, 94% achieved a CR; 1.5%, a partial response (PR); and 4.5%, no major response. At 60 months CR duration, freedom from progression (FFP), and overall survival (OS) for ABVD + RT versus ABVD alone are 91% versus 87% (P = .61), 86% versus 81% (P = .61), and 97% versus 90% (P = .08), respectively (log-rank). The 95% confidence intervals for CR duration, FFP, and OS differences at 5 years were -8% to 15%, -8% to 18%, and -4% to 12%, respectively. Although significant differences were not seen, it is possible that a benefit in outcome of less than 20% for CMT might be seen in a larger trial.


IgG4 antibodies against Bm14 as an evaluation tool of mass drug administration in a co-endemic area of Brugia timori and Wuchereria bancrofti.
To evaluate the success of mass drug administration for lymphatic filariasis, WHO has recommended two rapid tests, Brugia Rapid (BR) to detect the presence of IgG4 antibodies against Brugia sp and Filariasis Test Strip (FTS) to detect antigens of Wuchereria bancrofti. As a country co-endemic for Brugia sp. and W. bancrofti, Indonesia needs a single diagnostic tool that can detect the exposure to both species. This study aimed to evaluate the efficacy of mass drug administration by measuring Bm14-specific IgG4 levels in blood samples of the population living in a co-endemic area of B. timori and W. bancrofti in Southwest Sumba Regency. A total of 132 plasma samples obtained before and one year after DEC-albendazole administration, which have been previously tested with BR and FTS, were examined for IgG4 against Bm14 using enzyme-linked immunosorbent assay. The results showed that before treatment all 32 individuals (100%) with BR+/ FTS+ were also positive for Bm14-specific IgG4, while in BR+ or FTS+ group there were >90% samples detected positive. At one year after treatment, positive results for Bm14-specific IgG4 were still detected in 96.9% samples with BR+/ FTS+, 78.8% samples with BR+/ FTS- and 82.9% samples with BR-/ FTS+. On the other hand, the BR-/ FTS- group also had high rate of Bm14-specific IgG4 positivity either before treatment (62,5%) and at one year after treatment (43.8%). The lowest decrease of Bm14-specific IgG4 positivity at one year after treatment was shown in the double positive group (3.1%), while the highest was in the double negative group (18.7%). The measurement of IgG4 against Bm14 has the potential as a sensitive diagnostic tool to evaluate the success of MDA in the areas co-endemic for B. timori and W. bancrofti.


Biochemical characterization of Mycobacterium tuberculosis LexA and structural studies of its C-terminal segment.
LexA is a protein that is involved in the SOS response. The protein from Mycobacterium tuberculosis and its mutants have been biochemically characterized and the structures of their catalytic segments have been determined. The protein is made up of an N-terminal segment, which includes the DNA-binding domain, and a C-terminal segment encompassing much of the catalytic domain. The two segments are defined by a cleavage site. Full-length LexA, the two segments, two point mutants involving changes in the active-site residues (S160A and K197A) and another mutant involving a change at the cleavage site (G126D) were cloned and purified. The wild-type protein autocleaves at basic pH, while the mutants do not. The wild-type and the mutant proteins dimerize and bind DNA with equal facility. The C-terminal segment also dimerizes, and it also shows a tendency to form tetramers. The C-terminal segment readily crystallized. The crystals obtained from attempts involving the full-length protein and its mutants contained only the C-terminal segment including the catalytic core and a few residues preceding it, in a dimeric or tetrameric form, indicating protein cleavage during the long period involved in crystal formation. Modes of tetramerization of the full-length protein similar to those observed for the catalytic core are feasible. A complex of M. tuberculosis LexA and the cognate SOS box could be modeled in which the mutual orientation of the two N-terminal domains differs from that in the Escherichia coli LexA-DNA complex. These results represent the first thorough characterization of M. tuberculosis LexA and provide definitive information on its structure and assembly. They also provide leads for further exploration of this important protein.


Ambient PM2.5 and Stroke: Effect Modifiers and Population Attributable Risk in Six Low- and Middle-Income Countries.
Short-term exposure to ambient fine particulate pollution (PM2.5) has been linked to increased stroke. Few studies, however, have examined the effects of long-term exposure. A total of 45 625 participants were interviewed and included in this study, the participants came from the Study on Global Ageing and Adult Health, a prospective cohort in 6 low- and middle-income countries. Ambient PM2.5 levels were estimated for participants' communities using satellite data. A multilevel logistic regression model was used to examine the association between long-term PM2.5 exposure and stroke. Potential effect modification by physical activity and consumption of fruit and vegetables was assessed. The odds of stroke were 1.13 (95% confidence interval, 1.04-1.22) for each 10 μg/m3 increase in PM2.5. This effect remained after adjustment for confounding factors including age, sex, smoking, and indoor air pollution (adjusted odds ratio=1.12; 95% confidence interval, 1.04-1.21). Further stratified analyses suggested that participants with higher levels of physical activity had greater odds of stroke, whereas those with higher consumption of fruit and vegetables had lower odds of stroke. These effects remained robust in sensitivity analyses. We further estimated that 6.55% (95% confidence interval, 1.97%-12.01%) of the stroke cases could be attributable to ambient PM2.5 in the study population. This study suggests that ambient PM2.5 may increase the risk of stroke and may be responsible for the astounding stroke burden in low- and middle-income countries. In addition, greater physical activity may enhance, whereas greater consumption of fruit and vegetables may mitigate the effect.


[An evaluation of the effect of 2,4-dichlorophenoxyacetic acid derivatives on humoral and cellular immunities].
A single oral administration of phenoxy herbicides, viz. 2,4-dichlorophenoxyacetic acid (2,4-D), amino salt, sodium salt, diethylene glycol, iso-octyl and octyl ethers in a dose of LD16, was found to produce a pronounced suppressive effect on humoral immunity on day 5. The 2,4-D derivatives under study, administered in the same dose, stimulated the manifestations of delayed-type hypersensitivity in mice immunized with sheep red blood cells. The effect of the inhibition of antibody formation to thymus-dependent antigen ranged in the order of the increase in the toxicity of substances: amino salt, diethylene glycol ether, 2,4-D, sodium salt, iso-octyl and octyl ethers. On the contrary, the intensity of delayed-type hypersensitivity was more pronounced with regard to substances having greater toxicity.


Chronic graft versus host disease with small bowel obstruction after unrelated hematopoietic stem cell transplantation in a patient with acute myeloid leukemia.
Chronic graft versus host disease (GVHD) is a frequent complication after allogeneic hematopoietic stem cell transplantation (HSCT), but simultaneous small bowel obstruction is rare. Here, we report a child with acute myeloid leukemia who received an allogeneic HSCT from an unrelated matched donor. After HSCT, the patient developed severe chronic GVHD involving the small intestine, leading to obstruction of the terminal ileum. Small bowel resection was performed, and the symptoms improved without severe complications. Bowel obstruction should be considered as a possible complication of chronic GVHD; surgery may be a valuable corrective measure.


Comparison of high-spin and low-spin nonheme Fe(III)-OOH complexes in O-O bond homolysis and H-atom abstraction reactivities.
The geometric and electronic structures and reactivity of an S = 5/2 (HS) mononuclear nonheme (TMC)Fe(III)-OOH complex are studied by spectroscopies, calculations, and kinetics and compared with the results of previous studies of S = 1/2 (LS) Fe(III)-OOH complexes to understand parallels and differences in mechanisms of O-O bond homolysis and electrophilic H-atom abstraction reactions. The homolysis reaction of the HS [(TMC)Fe(III)-OOH](2+) complex is found to involve axial ligand coordination and a crossing to the LS surface for O-O bond homolysis. Both HS and LS Fe(III)-OOH complexes are found to perform direct H-atom abstraction reactions but with very different reaction coordinates. For the LS Fe(III)-OOH, the transition state is late in O-O and early in C-H coordinates. However, for the HS Fe(III)-OOH, the transition state is early in O-O and further along in the C-H coordinate. In addition, there is a significant amount of electron transfer from the substrate to the HS Fe(III)-OOH at transition state, but that does not occur in the LS transition state. Thus, in contrast to the behavior of LS Fe(III)-OOH, the H-atom abstraction reactivity of HS Fe(III)-OOH is found to be highly dependent on both the ionization potential and the C-H bond strength of the substrate. LS Fe(III)-OOH is found to be more effective in H-atom abstraction for strong C-H bonds, while the higher reduction potential of HS Fe(III)-OOH allows it to be active in electrophilic reactions without the requirement of O-O bond cleavage. This is relevant to the Rieske dioxygenases, which are proposed to use a HS Fe(III)-OOH to catalyze cis-dihydroxylation of a wide range of aromatic compounds.


Adaptation and diversification on islands.
Charles Darwin's travels on HMS Beagle taught him that islands are an important source of evidence for evolution. Because many islands are young and have relatively few species, evolutionary adaptation and species proliferation are obvious and easy to study. In addition, the geographical isolation of many islands has allowed evolution to take its own course, free of influence from other areas, resulting in unusual faunas and floras, often unlike those found anywhere else. For these reasons, island research provides valuable insights into speciation and adaptive radiation, and into the relative importance of contingency and determinism in evolutionary diversification.


Inspiratory muscle activation increases with COPD severity as confirmed by non-invasive mechanomyographic analysis.
There is a lack of instruments for assessing respiratory muscle activation during the breathing cycle in clinical conditions. The aim of the present study was to evaluate the usefulness of the respiratory muscle mechanomyogram (MMG) for non-invasively assessing the mechanical activation of the inspiratory muscles of the lower chest wall in both patients with chronic obstructive pulmonary disease (COPD) and healthy subjects, and to investigate the relationship between inspiratory muscle activation and pulmonary function parameters. Both inspiratory mouth pressure and respiratory muscle MMG were simultaneously recorded under two different respiratory conditions, quiet breathing and incremental ventilatory effort, in 13 COPD patients and 7 healthy subjects. The mechanical activation of the inspiratory muscles was characterised by the non-linear multistate Lempel-Ziv index (MLZ) calculated over the inspiratory time of the MMG signal. Subsequently, the efficiency of the inspiratory muscle mechanical activation was expressed as the ratio between the peak inspiratory mouth pressure to the amplitude of the mechanical activation. This activation estimated using the MLZ index correlated strongly with peak inspiratory mouth pressure throughout the respiratory protocol in both COPD patients (r = 0.80, p<0.001) and healthy (r = 0.82, p<0.001). Moreover, the greater the COPD severity in patients, the greater the level of muscle activation (r = -0.68, p = 0.001, between muscle activation at incremental ventilator effort and FEV1). Furthermore, the efficiency of the mechanical activation of inspiratory muscle was lower in COPD patients than healthy subjects (7.61±2.06 vs 20.42±10.81, respectively, p = 0.0002), and decreased with increasing COPD severity (r = 0.78, p<0.001, between efficiency of the mechanical activation at incremental ventilatory effort and FEV1). These results suggest that the respiratory muscle mechanomyogram is a good reflection of inspiratory effort and can be used to estimate the efficiency of the mechanical activation of the inspiratory muscles. Both, inspiratory muscle activation and inspiratory muscle mechanical activation efficiency are strongly correlated with the pulmonary function. Therefore, the use of the respiratory muscle mechanomyogram can improve the assessment of inspiratory muscle activation in clinical conditions, contributing to a better understanding of breathing in COPD patients.


Two-dimensional near-infrared transillumination imaging of biomedical media with a chromium-doped forsterite laser.
Transillumination images of objects hidden in normal and cancerous human breast tissues and bovine, porcine, and gallinaceous (chicken) tissues as well as model-random-scattering media were recorded with 1250-nm light from a chromium-doped forsterite laser. A Fourier space gate and a polarization gate were used to sort out image-bearing photons and discriminate against multiply scattered image-blurring photons. Better contrast, higher spatial resolution, and deeper penetration of samples were achieved for imaging with 1250-nm light than those obtained at shorter wavelengths, such as 1064 nm from a neodymium-doped yttrium aluminum garnet (YAG) laser. Better contrast and higher resolution were also obtained when the object was imaged through normal human breast tissue than through cancerous breast tissue. Images with marked distinction between fatty and fibrous human breast tissues were obtained when the Cr:forsterite laser was tuned to 1225 nm, a wavelength that resonates with an optical absorption band of breast fat tissues. Imaging with linearly polarized light revealed that the image quality depends significantly on the orientation of the polarization of the incident light with respect to the fibers in the bovine tissue.


A novel mosquito-borne Orbivirus species found in South-east Asia.
The genus Orbivirus of the family Reoviridae includes a genetically diverse group of dsRNA arthropod-borne viruses that infect a wide variety of animal species. Here, we report the complete genome and phylogenetic analysis of a novel orbivirus (IAn-66411 or Sathuvachari virus, SVIV) isolated in 1963 from starlings (Brahminy myna) collected in Vellore, Tamil Nadu, India. Comparative genetic analysis of the SVIV polymerase (VP1 protein), core protein (VP3) and outer core protein (VP7) confirmed that SVIV is most closely related to the mosquito-borne orbiviruses, but that it is equally divergent from all known species. Therefore, SVIV should be tentatively considered as the prototype of a novel mosquito-associated Orbivirus species. These findings will aid in the development of molecular reagents that can identify genetically similar orbiviruses and help elucidate their geographical distribution, epidemiology, species tropism and possible disease association.


Muscle Responses to Passive Joint Movements in Infants During the First Year of Life.
Muscle tone represents one of the important concepts for characterizing changes in the state of the developing nervous system. It can be manifested in the level of activity of flexors and extensors and in muscle reactions to its passive stretching (StR) or shortening (ShR). Here we investigated such reactions in a cohort of healthy infants aged from 2 weeks to 12 months. We examined the presence and the characteristics of StR and ShR during slow passive cyclic flexion/extension movements (T~3 s) in the hip, knee, ankle, and elbow joints while awake infants were in the supine position. The results showed that most infants demonstrated prominent ShRs in response to passive joint rotations, although the StR was observed more frequently, suggesting that the ShR is an important component of adaptive motor behavior already at an early developmental stage. Interestingly, the occurrence of both StR and ShR in most muscles significantly decreased throughout the first year of life. Passive cyclic flexion/extension movements could also evoke rhythmic muscle responses in other joints or in the contralateral limb, however, such responses were predominantly observed in younger infants (<6 months). A noticeable manifestation of muscle reactions at an early developmental stage, along with spontaneous motor activity in this period of life, may reflect the processes underlying a formation of appropriate muscle tone and the self-organization of neural circuits. A substantial reduction of ipsilateral and contralateral muscle responses to passive movements with age is consistent with the idea of a functional reorganization of the motor circuitry during early development.


[Pupils reactions to transcranial magnetic stimulation in patients with glaucoma].
A comparative study of visual reactions was performed in 38 patients with primary open-angle glaucoma and in 53 healthy individuals. Pupillary sizes were recorded before, during, and after transcranial magnetic stimulation (TMS) of the primary visual cortex. A significant increase in papillary sizes was found during TMS in the patients with glaucoma, which was more pronounced then in the healthy individuals. After TMS, the sizes of pupils were significantly decreased in the patients with glaucoma; however, they were significantly larger than those before stimulation. In some patients, dysfunctions of visual reactions resulting from impaired regulatory influences of the central areas of the visual system are likely to be one of the pathophysiological mechanisms responsible for the development of glaucoma.


Impact of P-Glycoprotein-Mediated Drug-Endogenous Substrate Interactions on Androgen and Blood-Brain Barrier Permeability.
This report focuses on pharmacokinetic drug-endogenous substrate interactions (DEIs). We hypothesized that P-glycoprotein (P-gp)-mediated DEI might affect androgen kinetics, especially its blood-brain barrier (BBB) permeability. The intracellular accumulation of the endogenous substrates of P-gp, testosterone (TES) and androstenedione (ADO) was increased by several tested drugs in uptake studies using P-gp overexpressing cells, indicating that these drugs inhibit P-gp-mediated efflux of TES of ADO from the cells. In a transport study using rat BBB kit, we found that the BBB limited the penetration of TES and ADO into the central nervous system. In addition, tested drugs that cause DEI were found to increase BBB permeability of TES and ADO via P-gp inhibition. In short, this study provides new findings regarding the possibility that DEI may affect the kinetics of endogenous substrates of P-gp.


Role of ATP-sensitive K+ channels in CGRP-induced dilatation of basilar artery in vivo.
Stimulation of adenylate cyclase appears to activate ATP-sensitive K+ channels in the basilar artery. We tested the hypothesis that calcitonin gene-related peptide (CGRP), which increases intracellular adenosine 3',5'-cyclic monophosphate (cAMP) levels, activates ATP-sensitive K+ channels and thereby causes vasodilatation. Using a cranial window in anesthetized rats, we examined responses of the basilar artery to CGRP in vivo. We also examined responses of the artery to another vasoactive peptide, vasoactive intestinal peptide (VIP). Topical application of CGRP (10(-11) to 10(-8) M) increased diameter of the basilar artery. Responses of the basilar artery to CGRP were almost abolished by a CGRP1 receptor antagonist, CGRP-(8-37). Vasodilatation in response to VIP was much smaller than that produced by CGRP. Dilator responses of the basilar artery to 10(-9) and 10(-8) M CGRP were inhibited by glibenclamide (10(-6) M), a selective inhibitor of ATP-sensitive K+ channels, by 69 +/- 19 and 41 +/- 9%, respectively. NG-nitro-L-arginine methyl ester (10(-5) M), an inhibitor of nitric oxide synthase, did not attenuate dilator response to 10(-8) M CGRP but inhibited responses to 10(-9) M CGRP by 34 +/- 12%. Indomethacin did not alter dilator responses to CGRP. These findings suggest that a minor component of CGRP-induced dilatation of the basilar artery is mediated by endothelium-derived relaxing factor. Vasodilatation in response to CGRP appears to be mediated primarily by direct activation of CGRP1 receptors on vascular muscle.(ABSTRACT TRUNCATED AT 250 WORDS)


Liver resection and ablation for squamous cell carcinoma liver metastases.
Limited evidence exists to guide the management of patients with liver metastases from squamous cell carcinoma (SCC). The aim of this retrospective multicentre cohort study was to describe patterns of disease recurrence after liver resection/ablation for SCC liver metastases and factors associated with recurrence-free survival (RFS) and overall survival (OS). Members of the European-African Hepato-Pancreato-Biliary Association were invited to include all consecutive patients undergoing liver resection/ablation for SCC liver metastases between 2002 and 2019. Patient, tumour and perioperative characteristics were analysed with regard to RFS and OS. Among the 102 patients included from 24 European centres, 56 patients had anal cancer, and 46 patients had SCC from other origin. RFS in patients with anal cancer and non-anal cancer was 16 and 9 months, respectively (P = 0.134). A positive resection margin significantly influenced RFS for both anal cancer and non-anal cancer liver metastases (hazard ratio 6.82, 95 per cent c.i. 2.40 to 19.35, for the entire cohort). Median survival duration and 5-year OS rate among patients with anal cancer and non-anal cancer were 50 months and 45 per cent and 21 months and 25 per cent, respectively. For the entire cohort, only non-radical resection was associated with worse overall survival (hazard ratio 3.21, 95 per cent c.i. 1.24 to 8.30). Liver resection/ablation of liver metastases from SCC can result in long-term survival. Survival was superior in treated patients with liver metastases from anal versus non-anal cancer. A negative resection margin is paramount for acceptable outcome.


Interactions of the zinc-regulated factor (ZiRF1) with the mouse metallothionein Ia promoter.
A mouse cDNA clone, M96, encoding a metal-regulating-element (MRE)-binding protein, was analysed for its ability to act as a metal-regulated transcription factor. The metal depletion of a glutathione S-transferase (GST)-M96 fusion protein showed that Zn2+ ions modulate the MRE-binding activity, suggesting that the M96-encoded protein is a Zn2+-regulated factor (ZiRF1). The methylation interference assay showed the specific interactions of ZiRF1 with the MRE, MREd/c, present on the mouse metallothionein Ia promoter. Point mutations of the MREd/c nullified the metal-regulatory properties of this region. In mouse L-cell nuclear extracts, mobility-shift assays revealed a Zn2+-dependent MRE-binding complex (MBC) with DNA-recognition properties similar to those of ZiRF1. Antibodies raised against purified GST-ZiRF1 were able to specifically recognize MBC in Western-blot analyses. Competition analysis of MRE-binding proteins from mouse NIH3T3 cells with oligonucleotide matching the binding sites for SP1 and MTF1 confirmed that both the basal SP1 and the metal-regulated MBC/ZiRF1 interact with the MREd/c region. The significance of mutual interactions with the metal-responsive promoter regions of either metal-regulated or basal transcription factors is discussed.


FUT2 Facilitates Autophagy and Suppresses Apoptosis via p53 and JNK Signaling in Lung Adenocarcinoma Cells.
Lung cancer is the most common cancer with high morbidity and mortality worldwide. Our previous studies showed that fucosyltransferase 2 (FUT2) is highly expressed in lung adenocarcinoma (LUAD) and plays a vital role in the tumorigenesis of LUAD. However, the underlying mechanism is not fully understood. Autophagy has recently attracted increasing attention due to its pro-survival role in cancer progression and metastasis. Here, we found that FUT2 was up-regulated and had an AUC (Area Under Curve) value of 0.964 in lung adenocarcinoma based on the TCGA dataset. Knockdown of FUT2 weakened the autophagy response, as evidenced by a degradation of LC3-II and Beclin1. The phosphorylation levels of AMPK, ULK1, and PI3K III were significantly reduced by FUT2 knockdown. FUT2 promoted the translocation of p53 from the cytoplasm into the nucleus, which triggered the DRAM1 pathway and enhanced autophagy. Meanwhile, the knockdown of FUT2 increased the phosphorylation of JNK and promoted mitochondrial-mediated apoptosis. Furthermore, the knockdown of FUT2 inhibited the autophagy induced by Z-VAD-FMK and promoted the apoptosis suppressed by rapamycin. The autophagy and apoptosis regulated by FUT2 antagonized each other. Taken together, these findings provide a mechanistic understanding of how FUT2 mediated the crosstalk between autophagy and apoptosis, which determine lung cancer cell death and survival, leading to the progression of lung adenocarcinoma.


[Ear thermometry from the otologic viewpoint].
Tympanic thermometry (TT) detects infrared emissions reaching a probe placed in the ear canal directed toward the tympanic membrane. This has been reported to be an ideal site for clinical temperature measurements. TT provides results rapidly, taking only one second. It is clean, safe, and there is no mucous membrane contact. Studies have primarily focused on the use of TT in pediatric office and emergency room settings. In the literature published to date, the otological viewpoint has not played an important role. Specially there is no systematic investigation of the influence of cerumen on TT. Twenty patients were examined. All of them had a complete obstruction of the auditory canal by cerumen. TT was performed before and after the removal of cerumen. It was found to have a significant impact on the ear temperature reading. After the removal, the temperature was higher by 0.5 degree C. In conclusion, one should consider that there can be a systematic error when using TT to determine body temperature. Nevertheless there are some important advantages compared to other methods of temperature measurements. Especially in the hands of physicians and nurses TT is accurate and can be recommended. However, at home in the hand of non-professionals there are some limitations and restrictions, particular when used in children. Further studies will have to be performed with a focus on otological problems and to determine the accuracy of TT in the non-professional user.


Isolation and characterization of rice (Oryza sativa L.) E3-ubiquitin ligase OsHOS1 gene in the modulation of cold stress response.
Plants can cope with adverse environmental conditions through the activation of stress response signalling pathways, in which the proteasome seems to play an important role. However, the mechanisms underlying the proteasome-mediated stress response in rice are still not fully understood. To address this issue, we have identified a rice E3-ubiquitin ligase, OsHOS1, and characterized its role in the modulation of the cold stress response. Using a RNA interference (RNAi) transgenic approach we found that, under cold conditions, the RNAi::OsHOS1 plants showed a higher expression level of OsDREB1A. This was correlated with an increased amount of OsICE1, a master transcription factor of the cold stress signalling. However, the up-regulation of OsDREB1A was transient and the transgenic plants did not show increased cold tolerance. Nevertheless, we could confirm the interaction of OsHOS1 with OsICE1 by Yeast-Two hybrid and bi-molecular fluorescence complementation in Arabidopsis protoplasts. Moreover, we could also determine through an in vitro degradation assay that the higher amount of OsICE1 in the transgenic plants was correlated with a lower amount of OsHOS1. Hence, we could confirm the involvement of the proteasome in this response mechanism. Taken together our results confirm the importance of OsHOS1, and thus of the proteasome, in the modulation of the cold stress signalling in rice.


Addition of interleukin-6 receptor blockade to carfilzomib-based desensitization in a highly sensitized nonhuman primate model.
Sensitized patients, those who had prior exposure to foreign human leukocyte antigens, are transplanted at lower rates due to challenges in finding suitable organs. Desensitization strategies have permitted highly sensitized patients to undergo kidney transplantation, albeit with higher rates of rejection. This study assesses targeting plasma cell and interleukin (IL)-6 receptor for desensitization in a sensitized nonhuman primate kidney transplantation model. All animals were sensitized using two sequential skin transplants from maximally major histocompatibility complex-mismatched donors. Carfilzomib (CFZ)/tocilizumab (TCZ) desensitization (N = 6) successfully decreased donor-specific antibody (DSA) titers and prevented the expansion of B cells compared to CFZ monotherapy (N = 3). Dual desensitization further delayed, but did not prevent humoral rebound, as evidenced by a delayed increase in post-kidney transplant DSA titers. Accordingly, CFZ/TCZ desensitization conferred a significant survival advantage over CFZ monotherapy. A trend toward increased T follicular helper cells was also observed in the dual therapy group along the same timeline as an increase in DSA and subsequent graft loss. Cytomegalovirus reactivation also occurred in the CFZ/TCZ group but was prevented with ganciclovir prophylaxis. In accordance with prior studies of CFZ-based dual desensitization strategies, the addition of IL-6 receptor blockade resulted in desensitization with further suppression of posttransplant humoral response compared to CFZ monotherapy.


Tumor-targeted small molecule for dual-modal imaging-guided phototherapy upon near-infrared excitation.
Near-infrared (NIR) organic dyes have received increasing attention in recent years as diagnostic and therapeutic agents in the field of tumor research. In this study, IR-822, a near-infrared fluorescence (NIRF) heptamethine cyanine dye, was chosen as a fluorophore due to its high extinction coefficients, and native preferential tumor accumulation property. To enhance its specificity in tumor imaging, N1-(pyridin-4-ylmethyl)ethane-1,2-diamine (PY) was conjugated to IR-822 as a pH-sensing receptor, forming a fluorophore-spacer-receptor molecular probe (IR-PY) that can modulate the fluorescence emission intensity through a fast photoinduced electron-transfer process, which allowed the probe to "switch on" significantly in an acidic tumor microenvironment and which realized enhanced NIRF imaging in vivo. Having a strong NIR absorption at 600-850 nm, this small-molecule IR-PY showed not only high spatial resolution photoacoustic (PA) imaging in mice, but also effective tumor photothermal ablation in vivo. After photothermal therapy (PTT) with IR-PY under NIR 808 nm laser irradiation, the mice exhibited remarkable ablation with no tumor recurrence after treatment. Therefore, a single smart small-molecule probe IR-PY has been designed, synthesized and verified as an "all in one" multifunctional agent, including pH sensitivity, tumor targeting, "switch-on" near-infrared fluorescence imaging, high-spatial-resolution PA imaging and efficient near-infrared photothermal therapy, which is promising for clinical application in NIRF/PA dual-modal imaging-guided cancer diagnosis and treatment.


Helicobacter infection and cirrhosis in hepatitis C virus carriage: is it an innocent bystander or a troublemaker?
Since it has been shown that Helicobacter hepaticus causes both chronic hepatitis and hepatocellular carcinoma (HCC) in mice, it is suggested that differences in the progression of chronic hepatitis C may be due to a cofactor stemming from co-infection by bacteria, especially Helicobacter pylori, and/or other Helicobacter species. An assessment was made of the prevalence of H. pylori infection in HCV-positive cirrhotic patients. The presence of Helicobacter species (spp). was evaluated in resected liver tissue from HCC patients. Serum anti-H. pylori IgG antibodies were determined in 70 males with a clinical and/or histological diagnosis of cirrhosis and HCV infection and in 310 age-matched male blood donors. The prevalences of H. pylori antibody were 77% (54/70) and 59% (183/310) (P 0.004). Primers identifying 26 Helicobacter species were used to determine the presence of the genomic 16S rRNA of this genus in liver tissue resected from 25 cirrhotic HCC patients. Genomic sequences corresponding to H. pylori and H. pullorum were identified in 23 of these 25 livers. Together, these findings support the proposal that H. pylori is implicated in the pathogenesis and progression of cirrhosis, particularly in HCV-infected individuals. Involvement of Helicobacter spp. in HCC also seems highly possible.


Hypertonic cell volume regulation in mouse thick limbs. I. ADH dependency and nephron heterogeneity.
Differential interference contrast microscopy was used in combination with standard electrophysiological techniques in the in vitro perfused mouse medullary (mTALH) and cortical (cTALH) thick ascending limbs of Henle to evaluate the cell volume responses of these nephron segments to sudden increases in peritubular osmolality and to assess the role of antidiuretic hormone (ADH) and net NaCl absorption on hypertonic volume regulation. In the absence of CO2/HCO3- in external media, the cells of the mTALH behaved in a simple osmometric fashion, with an osmotic space equivalent to 70-80% of the total cell volume. However, in CO2/HCO3- -containing media, the cells of the mTALH, but not the cTALH, were able to increase their cell volume to the original volume after shrinkage in peritubular media made hypertonic with either NaCl or mannitol. This volume-regulatory increase response (VRI) in the mTALH was mediated by an increase in intracellular osmoles, and required peritubular ADH, at concentrations that stimulate maximally the rate of net NaCl absorption. This ADH effect on VRI could be mimicked by addition of dibutyryladenosine 3',5'-cyclic monophosphate to the bath in the absence of hormone. However, 10(-4) M luminal furosemide, a concentration that abolishes ADH-dependent NaCl absorption in the mTALH, had no effect on the VRI response. These results indicate that the cells of the mTALH, but not the cTALH, are capable of hypertonic volume regulation, that ADH (via adenosine 3',5'-cyclic monophosphate) is required for expression of the VRI response in the mTALH, and that the effects of ADH on net NaCl absorption and the VRI response in the mTALH are completely dissociable. Thus these results are consistent with a role for ADH in hypertonic VRI in the mammalian mTALH, which may operate to maintain constant cell volume in this nephron segment during antidiuresis.


Sagittal distal limb kinematics inside the hoof capsule captured using high-speed fluoroscopy in walking and trotting horses.
Kinematic evaluation of the distal limb of the horse using standard methods is challenging, mainly due to the hoof capsule restricting visualisation, but the recent development of a high-speed fluoroscopy (HSF) system has allowed in vivo cineradiographic assessment of moving skeletal structures at high speeds. The application of this non-invasive method to the equine distal limb is used to describe 'internal' distal limb kinematics including intra-horse and inter-horse variability, and variability between walk and trot. Distal limb kinematic data were collected at walk and trot from six non-lame horses using HSF set over a force plate. The dorsal proximal interphalangeal joint (PIPJ) angle and the dorsal distal interphalangeal joint (DIPJ) angle were measured at toe-on and at 25%, 50% and 75% of stance. The PIPJ and DIPJ showed overall extension through stance. The mean ± SD range of motion (ROM) during stance of the PIPJ was 9.7 ± 2.7° (walk) and 8.7 ± 3.0° (trot) and of the DIPJ was 28.6 ± 4.6° (walk) and 26.5 ± 6.3° (trot) showing significant differences between gaits and changes through stance (P < 0.001). Inter- and intra- horse variations were also significant for both joint angles (P < 0.001). HSF allowed for kinematic assessment of the distal limb within the hoof capsule. The ROM of the PIPJ observed was similar to results published in the literature whilst the ROM for the DIPJ was less than values previously reported. Future studies will use HSF to estimate strain in the tendons and ligaments within the hoof capsule, which are a common site of lameness in the horse.


Occurrence of oligoclonal bands in multiple sclerosis and other CNS diseases.
The results of cerebrospinal fluid agarose gel electrophoresis in 300 consecutive patients were correlated with neurological examinations and diagnoses, other cerebrospinal fluid studies, and the results of evoked potential examinations. The presence of oligoclonal bands was the most sensitive test for multiple sclerosis (MS); bands were present in from 100% (11/11) of patients with definite MS to 82% (27/33) of those with possible MS (classified by McAlpine criteria). The visual evoked response was the next most sensitive study. Thirty-eight patients without MS or related disorders had bands in the IgG region. Three patients had plasma cell dyscrasias. Seven patients had thick single bands. Single bands did not correlate with chronic polyneuropathy but appeared to be an artifact of storage. Twenty-eight patients had active neurological disease, including cerebral infarction (in 5), viral infection (in 4), remote effect of carcinoma (in 4), and acute and chronic polyneuropathies (in 6). In acute illnesses (i.e., vascular insults), repeat electrophoresis showed disappearance of bands. In continually active disease, bands persisted. These results indicate that the presence of oligoclonal bands provides sensitive supporting evidence for the diagnosis of MS but that bands may be present in other disorders, including those not directly related to infection or abnormal immune response. The data suggest that oligoclonal bands may represent an immune response to neurological injury that is prominent in disorders with a particularly intense or continuous antigenic stimulus.


Perspectives on massive coral growth rates in a changing ocean.
The tropical ocean environment is changing at an unprecedented rate, with warming and severe tropical cyclones creating obvious impacts to coral reefs within the last few decades and projections of acidification raising concerns for the future of these iconic and economically important ecosystems. Documenting variability and detecting change in global and regional climate relies upon high-quality observational records of climate variables supplemented, prior to the mid-19th century, with reconstructions from various sources of proxy climate information. Here we review how annual density banding patterns that are recorded in the skeletons of massive reef-building corals have been used to document environmental change and impacts within coral reefs. Massive corals provide a historical perspective of continuous calcification processes that pre-date most ecological observations of coral reefs. High-density stress bands, abrupt declines in annual linear extension, and evidence of partial mortality within the skeletal growth record reveal signatures of catastrophic stress events that have recently been attributed to mass bleaching events caused by unprecedented thermal stress. Comparison of recent trends in annual calcification with century-scale baseline calcification rates reveals that the frequency of growth anomalies has increased since the late 1990s throughout most of the world's coral reef ecosystems. Continuous coral growth histories provide valuable retrospective information on the coral response to environmental change and the consequences of anthropogenic climate change. Co-ordinated efforts to synthesize and combine global calcification histories will greatly enhance our understanding of current calcification responses to a changing ocean.


Anomalous Optoelectronic Properties of Chiral Carbon Nanorings…and One Ring to Rule Them All23.
Carbon nanorings are hoop-shaped, π-conjugated macrocycles that form the fundamental annular segments of single-walled carbon nanotubes (SWNTs). In a very recent report, the structures of chiral carbon nanorings (which may serve as chemical templates for synthesizing chiral nanotubes) were experimentally synthesized and characterized for the first time. Here in our Letter we show that the excited-state properties of these unique chiral nanorings exhibit anomalous and extremely interesting optoelectronic properties with excitation energies growing larger as a function of size (in contradiction with typical quantum confinement effects). Although the first electronic excitation in armchair nanorings is forbidden with a weak oscillator strength, we find that the same excitation in chiral nanorings is allowed because of a strong geometric symmetry breaking. Most importantly, among all the possible nanorings synthesized in this fashion, we show that only one ring, corresponding to a SWNT with chiral indices (n+3,n+1), is extremely special with large photoinduced transitions that are most readily observable in spectroscopic experiments.


Determination of genes and microRNAs involved in the resistance to fludarabine in vivo in chronic lymphocytic leukemia.
Chronic lymphocytic leukemia (CLL) cells are often affected by genomic aberrations targeting key regulatory genes. Although fludarabine is the standard first line therapy to treat CLL, only few data are available about the resistance of B cells to this purine nucleoside analog in vivo. Here we sought to increase our understanding of fludarabine action and describe the mechanisms leading to resistance in vivo. We performed an analysis of genomic aberrations, gene expression profiles, and microRNAs expression in CLL blood B lymphocytes isolated during the course of patients' treatment with fludarabine. In sensitive patients, the differentially expressed genes we identified were mainly involved in p53 signaling, DNA damage response, cell cycle and cell death. In resistant patients, uncommon genomic abnormalities were observed and the resistance toward fludarabine could be characterized based on the expression profiles of genes implicated in lymphocyte proliferation, DNA repair, and cell growth and survival. Of particular interest in some patients was the amplification of MYC (8q) observed both at the gene and transcript levels, together with alterations of myc-transcriptional targets, including genes and miRNAs involved in the regulation of cell cycle and proliferation. Differential expression of the sulfatase SULF2 and of miR-29a, -181a, and -221 was also observed between resistant and sensitive patients before treatment. These observations were further confirmed on a validation cohort of CLL patients treated with fludarabine in vitro. In the present study we identified genes and miRNAs that may predict clinical resistance of CLL to fludarabine, and describe an interesting oncogenic mechanism in CLL patients resistant to fludarabine by which the complete MYC-specific regulatory network was altered (DNA and RNA levels, and transcriptional targets). These results should prove useful for understanding and overcoming refractoriness to fludarabine and also for predicting the clinical outcome of CLL patients before or early during their treatment.


Comparing the Immediate Effects of a Total Motion Release Warm-up and a Dynamic Warm-up Protocol on the Dominant Shoulder in Baseball Athletes.
Gamma, SC, Baker, R, May, J, Seegmiller, JG, Nasypany, A, and Iorio, SM. Comparing the immediate effects of a total motion release warm-up and a dynamic warm-up protocol on the dominant shoulder in baseball athletes. J Strength Cond Res 34(5): 1362-1368, 2020-A decrease in total range of motion (ROM) of the dominant shoulder may predispose baseball athletes to increased shoulder injury risk; the most effective technique for improving ROM is unknown. The purpose of this study was to compare the immediate effects of Total Motion Release (TMR) to a generic dynamic warm-up program in baseball athletes. Baseball athletes (n = 20) were randomly assigned to an intervention group: TMR group (TMRG; n = 10) or traditional warm-up group (TWG; n = 10). Shoulder ROM measurements were recorded for internal rotation (IR) and external rotation (ER), the intervention was applied, and postmeasurements were recorded. Each group then received the other intervention and postmeasurements were again recorded. The time main effect (p ≤ 0.001) and the time × group interaction effect were significant (p ≤ 0.001) for IR and ER. Post hoc analysis revealed that TMR produced significant increases in mean IR (p ≤ 0.005, d = 1.52) and ER (p ≤ 0.018, d = 1.22) of the dominant shoulder initially. When groups crossed-over, the TMRG experienced a decrease in mean IR and ER after the dynamic warm-up, whereas the TWG experienced a significant increase in mean IR (p ≤ 0.001, d = 3.08) and ER (p ≤ 0.001, d = 2.56) after TMR intervention. Total Motion Release increased IR and ER of the dominant shoulder more than a dynamic warm-up. Dynamic warm-up after TMR also resulted in decreased IR and ER; however, TMR after dynamic warm-up significantly improved IR and ER. Based on these results, TMR is more effective than a generic dynamic warm-up for improving dominant shoulder ROM in baseball players.


Animal and human bites in children.
Mammals that live closely and interact with man and man himself can inflict injury on children in the home through bites. Previous reports on mammalian bites in Nigeria are few and mainly on dogs, though other mammals also inflict injuries on children. There are also no reports on the injuries arising from the bites of these other mammals. To document the range, pattern, distribution and complications of mammalian bites in children. The hospital records of all patients aged 18 years and below with history of animal and human bite admitted over a twelve-year period from January 1994 to December 2005 were analysed retrospectively. There were 105 episodes of human and animal bites recorded in the registers of the hospital but the case notes of only 83 (79%) could be found. The male to female ratio for cases bitten was 2: 1. There were 62 (74.7%) cases of dog bites, 17 (20.5%) of human bites, 3 (3.6%) rat bites and 1 (1.2%) monkey bite. Of the dog bites, 68% were by vagrant and unvaccinated animals. The children presented with superficial and deep tissue injuries. Rabies was the most severe complication noted. Dogs are the most common mammals involved in the biting of children. Such bites lead to many morbidities and mortalities; bacterial and viral infections and death. There is a need to enforce the existing policy on the control of dogs and animals generally.


Antimicrobial susceptibility patterns and sensitivity to tulathromycin in goat respiratory bacterial isolates.
Bacterial pneumonia is a common and often life-threatening respiratory problem in both meat and dairy goats. Options for approved antibiotic therapy in goats to combat these bacterial infections are severely limited and frequently drugs must be used in an extra-label manner. Tulathromycin, a triamilide macrolide antimicrobial drug shown to be effective against swine and cattle respiratory bacterial agents, has been identified as a potentially useful drug in caprines. The present study was conducted to determine the susceptibility of recognized bacterial respiratory pathogens to commonly prescribed antimicrobials, with a particular emphasis on the efficacy of tulathromycin against these agents. Minimum inhibitory concentration (MIC) testing using microbroth dilution was performed on a collection of 45 Mannheimia haemolytica, 11 Pasteurella multocida, and 11 Bibersteinia trehalosi isolates from the lungs of goats with clinical pneumonia. To further characterize efficacy of tulathromycin against these pathogens, minimum bactericidal concentration (MBC) testing and kinetic killing assays were conducted. Most isolates were susceptible to the antimicrobials tested; however, increased resistance as demonstrated by higher MIC values was seen in all species to penicillin, in P. multocida to sulfadimethoxine, and in B. trehalosi to the tetracyclines. All isolates were susceptible to tulathromycin, which demonstrated a high killing efficiency in both bactericidal assays. Results of this study indicate that most goat pneumonic bacterial pathogens remain susceptible to commonly prescribed antibiotics, although some evidence of resistance was seen to certain drugs; and that tulathromycin is highly effective against goat respiratory pathogens which could make it a valuable medication in this species.


Interplay between REST and nucleolin transcription factors: a key mechanism in the overexpression of genes upon increased phosphorylation.
Non-malignant cells can be transformed via the activation of kinases that control degradation of neural-restrictive silencer factor (REST). Here, we identify a mechanism that contributes to the activation of genes, expression of which is controlled by responsive elements containing overlapping binding sites for REST and nucleolin. We demonstrate that both phosphorylated and non-phosphorylated nucleolin-bound DNA; however, only phosphorylated nucleolin successfully competed with either full-length REST or a REST-derived DNA-binding peptide, REST68, for binding to the overlapping binding sites. We show that this interplay between the two transcription factors regulates the activation of cell survival and immunomodulatory genes in tumors and non-malignant cells with activated protein kinase C, which is accompanied with alterations in cell proliferation and apoptosis. We propose a model for the regulation of these genes, which brings a new insight into the molecular mechanisms that control cellular transformation driven by activation of protein kinases.


The role of the endothelial dependent relaxing factor in the regulation of cerebral circulation.
It has recently been demonstrated that vessel dilation induced by several physiological agents is dependent on an intact vascular endothelium. In order to explain this endothelium dependence, it has been hypothesized that a still unknown chemical substance, generically named Endothelium Dependent Relaxing Factor (EDRF) is necessary for physiological vasodilation. The role of this EDRF in the cerebrovascular physiology is not yet well understood. In this article the cerebrovascular physiological control is reviewed in relationship with possible EDRF actions. The importance of endothelial lesions in the cerebrovascular responses is discussed.


Lung phagocyte recruitment and metabolic alterations induced by cigarette smoke in humans and in hamsters.
Cigarette smokers had an increased number of alveolar macrophages (AM) that had temporally related increases in oxidative metabolism in vitro compared with that in nonsmokers. The AM from young asymptomatic human cigarette smokers had a selective increase in superoxide anion (O2) release compared with those from nonsmokers. The AM from older smokers had a more intense, generalized enhancement of oxidative metabolism. Smoking hamsters had similar patterns of lung phagocyte recruitment and increased macrophage oxidative metabolism. The accumulation of AM within the alveolar ducts in smoking hamsters was strikingly similar to that seen in human smokers. The temporal patterns of smoke-induced changes in oxidative metabolism by AM from hamsters and humans were the same. Filtration of particulate constituents from cigarette smoke completely abrogated the distal airway inflammation and the metabolic alterations observed in smoking hamsters.


Development of clinical utility of zoledronic acid and patient considerations in the treatment of osteoporosis.
Osteoporosis is a major health concern, which results in the increased risk of fractures. There is a high risk for the first or consecutive fractures leading to considerable morbidity and debilitating consequences if osteoporosis is untreated. Currently, bisphosphonates are the mainstay of treatment for osteoporosis though long-term persistence and adherence to bisphosphonates, especially those taken orally, remain low. This medication noncompliance has serious consequences on osteoporotic patients as it is associated with a significantly higher fracture risk. Intravenous (IV) zoledronic acid (ZOL), developed to increase compliance by overcoming the frequent and burdensome dosing requirements of oral bisphosphonates, is the first and the only once-yearly bisphosphonate globally approved for use in the treatment of up to 6 indications of osteoporosis. Several clinical studies have documented that a single infusion of IV ZOL resulted in decreased bone turnover and improved bone density for at least 12 months post infusion. This article traces the development of ZOL's clinical utility and evaluates its patient preference by collating data from all major clinical trials, studying the efficacy and safety of ZOL in the treatment of osteoporosis and other benign bone disorders.


Alternative therapies to address the unmet medical needs of patients with phenylketonuria.
Standard therapy for phenylketonuria (PKU), the most common inherited disorder in amino acid metabolism, is an onerous phenylalanine-restricted diet. Adherence to this stringent diet regimen decreases as patients get older, and this lack of adherence is directly associated with cognitive and executive dysfunction and psychiatric issues. These factors emphasize the need for alternative pharmacological therapies to help treat patients with PKU. Sapropterin dihydrochloride is a synthetic form of tetrahydrobiopterin, the cofactor of phenylalanine hydroxylase that in pharmacological doses can stabilize and increase residual enzyme activity in some patients with PKU. About one-third of all patients with PKU respond to oral sapropterin. Phenylalanine ammonia lyase (PAL) is a prokaryotic enzyme that converts phenylalanine to ammonia and trans-cinnamic acid. Phase I and II trials have shown that injectable recombinant Anabaena variabilis PAL produced in Escherichia coli conjugated with PEG can reduce phenylalanine levels in subjects with PKU. The most frequently reported adverse events were injection-site reactions, dizziness and immune reactions. Additionally, oral administration of PAL and delivery of enzyme substitution therapies by encapsulation in erythrocytes are being investigated. Novel therapies for patients with PKU appear to be options to reduce phenylalanine levels, and may reduce the deleterious effects of this disorder.


Community electrocardiography.
The report of the Joint Working Party on General Medical Services (1973) considered in detail the provision of electrocardiographic services for general practitioners. These are based either on primary health care teams using their own apparatus, or on hospitals offering open-access to their cardiac departments.In this survey I attempted to compare the proportions of general practitioners using their own electrocardiographs with those using hospital-based apparatus, and with those without direct access to any electrocardiograph facilities, and to evaluate the use made of such services, when available.


Establishment and Verification of Scoring System for Colorectal Adenoma Recurrence.
The purpose of this study was to establish and verify a risk-scoring system for colorectal adenoma recurrence. A total of 359 patients with colorectal adenoma who underwent polypectomy from October 2017 to December 2018 were included in this retrospective study. Information including taking traditional Chinese medicine, demographic characteristics, adenoma characteristics were collected. The patients will review the colonoscopy one year after surgery. The patients were divided into a modeling cohort (216 cases) and a model validation cohort (143 cases) according to the ratio of 6:4. Modeling and model verification were performed by logistic regression, ROC curve, nomogram (calibration chart) and other methods. After adjusting for confounding factors by logistic regression, it was found that taking Chinese medicine, the number, size, site, pathological type and morphology of adenoma were independent influencing factors for the recurrence of colorectal adenoma. The area under the ROC curve (AUC) in the model validation cohort of established risk scoring system was 0.771 (95% CI: 0.694-0.847), indicating that there was good consistency. The established risk prediction model of colorectal adenoma recurrence and its risk scoring system performed well and had high predictive value.


Double-stranded DNA in methanol-ethanol-buffer solvent system.
DNA in a solvent system consisting of roughly equal volumes of methanol and ethanol and 5% buffer has a conservative circular dichroism (CD) spectrum of very low intensity above 220 nm and an increase of epsilon258 comparable to that of denatured DNA (about 40%). A direct comparison of this spectrum with the CD of single-stranded DNA reveals many differences, indicating DNA in this solvent system has a conformation different from that of denatured DNA. When the alcohols are removed, the B form conformation and normal epsilon258 are restored in native DNA, while single-stranded DNA remains denatured. A double-stranded structure of DNA in the methanol-ethanol-buffer solvent system is confirmed by the neutral cesium chloride density gradient centrifugation of DNA in which one chain is labeled with [14C]thymidine and the other [3H]5-bromodeoxyuridine. The doubly labeled DNA exposed to the alcohol solvent system has a centrifugal pattern identical with that of control DNA; the two radioactivities cosediment and form a superimposing band, distinctly different from that of single-stranded DNA; 3H-labeled (thymidine) chains sediment further than 14C-labeled chains (5-bromo-deoxyuridine). Denatured DNA exhibits varying CD spectra depending on solvents. It is suggested that single-stranded DNA in different solvent systems assumes different modes of base stacking.


Single-cell and population level viral infection dynamics revealed by phageFISH, a method to visualize intracellular and free viruses.
Microbes drive the biogeochemical cycles that fuel planet Earth, and their viruses (phages) alter microbial population structure, genome repertoire, and metabolic capacity. However, our ability to understand and quantify phage-host interactions is technique-limited. Here, we introduce phageFISH - a markedly improved geneFISH protocol that increases gene detection efficiency from 40% to > 92% and is optimized for detection and visualization of intra- and extracellular phage DNA. The application of phageFISH to characterize infection dynamics in a marine podovirus-gammaproteobacterial host model system corroborated classical metrics (qPCR, plaque assay, FVIC, DAPI) and outperformed most of them to reveal new biology. PhageFISH detected both replicating and encapsidated (intracellular and extracellular) phage DNA, while simultaneously identifying and quantifying host cells during all stages of infection. Additionally, phageFISH allowed per-cell relative measurements of phage DNA, enabling single-cell documentation of infection status (e.g. early vs late stage infections). Further, it discriminated between two waves of infection, which no other measurement could due to population-averaged signals. Together, these findings richly characterize the infection dynamics of a novel model phage-host system, and debut phageFISH as a much-needed tool for studying phage-host interactions in the laboratory, with great promise for environmental surveys and lineage-specific population ecology of free phages.


P2X7 receptor activation mediates superoxide dismutase 1 (SOD1) release from murine NSC-34 motor neurons.
Mutant superoxide dismutase 1 (SOD1) can be constitutively released from motor neurons and transmitted to naïve motor neurons to promote the progression of amyotrophic lateral sclerosis (ALS). However, the biological impacts of this process and the precise mechanisms of SOD1 release remain to be fully resolved. Using biochemical and fluorescent techniques, this study aimed to determine if P2X7 receptor activation could induce mutant SOD1 release from motor neurons and whether this released SOD1 could be transmitted to motor neurons or microglia to mediate effects associated with neurodegeneration in ALS. Aggregated SOD1G93A, released from murine NSC-34 motor neurons transiently transfected with SOD1G93A, could be transmitted to naïve NSC-34 cells and murine EOC13 microglia to induce endoplasmic reticulum (ER) stress and tumour necrosis factor-alpha (TNFα) release, respectively. Immunoblotting revealed NSC-34 cells expressed P2X7. Extracellular ATP induced cation dye uptake into these cells, which was blocked by the P2X7 antagonist AZ10606120, demonstrating these cells express functional P2X7. Moreover, ATP induced the rapid release of aggregated SOD1G93A from NSC-34 cells transiently transfected with SOD1G93A, a process blocked by AZ10606120 and revealing a role for P2X7 in this process. ATP-induced SOD1G93A release coincided with membrane blebbing. Finally, aggregated SOD1G93A released via P2X7 activation could also be transmitted to NSC-34 and EOC13 cells to induce ER stress and TNFα release, respectively. Collectively, these results identify a novel role for P2X7 in the prion-like propagation of SOD1 in ALS and provide a possible explanation for the therapeutic benefits of P2X7 antagonism previously observed in ALS SOD1G93A mice.


FUNDAMENTAL DIFFERENCES BETWEEN NATURAL ANTIBODIES AND POLYREACTIVE IMMUNOGLOBULINS.
A problem of similarity and differences between so-called polyreactive immunoglobulins (PRIGs) and natural antibodies (NAbs), capable of cross-reacting with some structurally dissimilar antigens, has been considered. The analysis of mechanisms of an unspecific interaction between PRIGs or NAbs and antigens evidences for the fact that essential differences exist between these substances. These differences permit classifying the abovementioned substances as different types of immunoglobulin molecules. The major difference between PRIGs and NAbs may include both the mechanisms of the above mentioned immunoglobulin molecules binding to antigens and their interaction affinity, as well as an absolutely different influence of some low-molecular substances on the efficiency of the interaction with antigens. Relying on the obtained data it can be assumed that, since PRIGs and NAbs have fundamental differences, they may perform not only similar but also different functions of the immune system.


Landscape of immune microenvironment in hepatocellular carcinoma and its additional impact on histological and molecular classification.
Immune cells constitute an important element of tumor tissue. Accumulating evidence indicates their clinicopathological significance in predicting prognosis and therapeutic efficacy. Nonetheless, the combinations of immune cells forming the immune microenvironment and their association with histological findings remain largely unknown. Moreover, it is unclear which immune cells or immune microenvironments are the most prognostically significant. Here, we comprehensively analyzed the immune microenvironment and its intratumor heterogeneity in 919 regions of 158 hepatocellular carcinomas (HCCs), and the results were compared with the corresponding histological and prognostic data. Consequently, we classified the immune microenvironment of HCC into three distinct immunosubtypes: Immune-high, Immune-mid, and Immune-low. The Immune-high subtype was characterized by increased B-/plasma-cell and T cell infiltration, and the Immune-high subtype and B-cell infiltration were identified as independent positive prognostic factors. Varying degrees of intratumor heterogeneity of the immune microenvironment were observed, some of which reflected the multistep nature of HCC carcinogenesis. However, the predominant pattern of immunosubtype and immune cell infiltration of each tumor was prognostically important. Of note, the Immune-high subtype was associated with poorly differentiated HCC, cytokeratin 19 (CK19)+ , and/or Sal-like protein 4 (SALL4)+ high-grade HCC, and Hoshida's S1/Boyault's G2 subclasses. Furthermore, patients with high-grade HCC of the predominant Immune-high subtype had significantly better prognosis. These results provide a rationale for evaluating the immune microenvironment in addition to the usual histological/molecular classification of HCC. The immune microenvironment of HCC can be classified into three immunosubtypes (Immune-high, Immune-mid, and Immune-low) with additional prognostic impact on histological and molecular classification of HCC. (Hepatology 2018).


Mechanisms and Models in Heart Failure: A Translational Approach.
Despite multiple attempts to develop a unifying hypothesis that explains the pathophysiology of heart failure with a reduced ejection fraction (HFrEF), no single conceptual model has withstood the test of time. In the present review, we discuss how the results of recent successful phase III clinical development programs in HFrEF are built upon existing conceptual models for drug development. We will also discuss where recent successes in clinical trials do not fit existing models to identify areas where further refinement of current paradigms may be needed. To provide the necessary structure for this review, we will begin with a brief overview of the pathophysiology of HFrEF, followed by an overview of the current conceptual models for HFrEF, and end with an analysis of the scientific rationale and clinical development programs for 4 new therapeutic classes of drugs that have improved clinical outcomes in HFrEF. The 4 new therapeutic classes discussed are ARNIs, SGLT2 (sodium-glucose cotransporter 2) inhibitors, soluble guanylate cyclase stimulators, and myosin activators. With the exception of SGLT2 inhibitors, each of these therapeutic advances was informed by the insights provided by existing conceptual models of heart failure. Although the quest to determine the mechanism of action of SGLT2 inhibitors is ongoing, this therapeutic class of drugs may represent the most important advance in cardiovascular therapeutics of recent decades and may lead to rethinking or expanding our current conceptual models for HFrEF.


Versican: signaling to transcriptional control pathways.
Versican, a chondroitin sulfate proteoglycan, is one of the main components of the extracellular matrix, which provides a loose and hydrated matrix during key events in development and disease. Versican participates in cell adhesion, proliferation, migration, and angiogenesis, and hence plays a central role in tissue morphogenesis and maintenance. In addition, versican contributes to the development of a number of pathologic processes including atherosclerotic vascular diseases, cancer, tendon remodeling, hair follicle cycling, central nervous system injury, and neurite outgrowth. Versican is a complex molecule consisting of modular core protein domains and glycosaminoglycan side chains, and there are various steps of synthesis and processes regulating them. Also, there is differential temporal and spatial expression of versican by multiple cell types and in different developmental and pathological time frames. To fully appreciate the functional roles of versican as it relates to changing patterns of expression in development and disease, an in depth knowledge of versican's biosynthetic processing is necessary. The goal of this review is to evaluate the current status of our knowledge regarding the transcriptional control of versican gene regulation. We will be focusing on the signal transduction pathways, promoter regions, cis-acting elements, and trans-factors that have been characterized.


Injectable hydrogels for the sustained delivery of a HER2-targeted antibody for preventing local relapse of HER2+ breast cancer after breast-conserving surgery.
A high risk of local relapse is the main challenge of HER2+ breast cancer after breast-conserving surgery. We aimed to develop a long-acting delivery system for Herceptin, a HER2-targeting antibody, using injectable and thermosensitive hydrogels as the carrier to prevent the local relapse of HER2+ breast tumors while minimizing systemic side effects, especially cardiotoxicity. Methods: Two poly(lactic acid-co-glycolic acid)-b-poly(ethylene glycol)-b-poly(lactic acid-co-glycolic acid) (PLGA-PEG-PLGA) triblock copolymers with different PEG/PLGA proportions were synthesized. Their mixtures with rational mix proportions displayed sol-gel transitions in water with rising of temperature and the Herceptin-loaded hydrogel systems were then prepared. Both the in vivo antitumor and anti-relapse efficacies were evaluated after hypodermic injection of the Herceptin-loaded hydrogel, and the cardiotoxicity was also detected. Results: The gel performance, degradation rate and drug release kinetics of hydrogels were easily adjustable by simply varying the mix proportion. The hydrogel matrix with a specific mix proportion not only avoided initial burst release but also achieved sustained release of Herceptin in vitro for up to 80 days, which is the longest period of Herceptin delivery that has ever been reported. In vivo biodistribution studies performed in SK-BR-3 tumor-bearing mice revealed that a single hypodermic administration of the Herceptin-loaded hydrogel adjacent to the tumor tissue promoted the intratumoral antibody accumulation. This resulted in a better antitumor efficacy compared to weekly hypodermic injections of Herceptin solution for 28 days. A tumor relapse model was also established by imitative breast-conserving surgery on tumor-bearing mice, and both the single injection of the Herceptin-loaded hydrogel and the weekly injection of the Herceptin solution achieved superior anti-relapse efficacy. Furthermore, both antitumor and anti-relapse experiments demonstrated that the weekly pulsed administration of the Herceptin solution caused cardiotoxicity; however, the sustained release of Herceptin from the hydrogel effectively prevented this side effect. Conclusion: The Herceptin-loaded hydrogel has great potential for preventing the relapse of HER2+ breast tumors after breast-conserving surgery with enhanced therapeutic efficacy, improved patient compliance and significantly reduced side effects.


Interleukin 1 (IL 1) as a mediator of crystal arthritis. Stimulation of T cell and synovial fibroblast mitogenesis by urate crystal-induced IL 1.
We reported before that monosodium urate (MSU) crystals were potent stimulators of endogenous pyrogen (EP) production from human and rabbit mononuclear phagocytes, and proposed that this property of MSU crystals may be important in the pathogenesis of gout. EP activity is now attributed to interleukin 1 (IL 1) peptides but IL 1 is not the only pyrogenic monocyte-derived cytokine, since both interferon-alpha (alpha-IFN) and tumor necrosis factor (TNF) are also pyrogenic in rabbits. Using a T cell comitogenic assay based on a murine helper T cell clone that does not respond to IFN or TNF, we now report the release of IL 1 activity from human blood monocytes and synovial fluid mononuclear cells (MNC), following stimulation with MSU crystals. MSU-induced supernatants with IL 1 activity were neutralized with rabbit antiserum to human IL 1 and also stimulated the growth ([3H]thymidine incorporation) of long-term fibroblast-like cell lines derived from human synovial rheumatoid exudate. Two other crystals associated with articular inflammation were tested: hydroxyapatite was a much less potent stimulus compared with MSU crystals, and calcium pyrophosphate dihydrate did not stimulate IL 1 release from human monocytes or synovial fluid MNC. As a model for the inflammatory consequences of acute and chronic overproduction of IL 1, gout is the only sterile inflammatory disease where the local and systemic pathology is compatible with such overproduction; raised IL 1 levels have been found at the site of inflammation, and a necessary etiologic agent, crystalline urate, has been shown unequivocally to be a direct activator of mononuclear IL 1 release.


Ca(2+)-dependent p47phox translocation in hydroperoxide modulation of the alveolar macrophage respiratory burst.
Oxidative stress produces dual effects on the respiratory burst of rat alveolar macrophages. Preincubation with hydroperoxide concentrations [H2O2 or tert-butyl hydroperoxide (t-BOOH); < 50 microM] enhances stimulation of the respiratory burst, whereas higher concentrations inhibit stimulation. Both the enhancement and inhibition are markedly attenuated by buffering t-BOOH-induced changes in intracellular Ca2+ concentration ([Ca2+]i). Phosphorylation of the NADPH oxidase component p47phox and its translocation from cytoplasm to plasma membrane are essential in respiratory burst activation. Phorbol 12-myristate 13-acetate (PMA)-stimulated p47phox phosphorylation was negligibly affected by 25 or 100 microM t-BOOH. Nonetheless, 25 microM t-BOOH increased PMA-stimulated p47phox translocation, whereas 100 microM t-BOOH decreased PMA-stimulated translocation. In unstimulated cells, however, neither phosphorylation nor translocation of p47phox was affected by t-BOOH. Buffering of the t-BOOH-mediated changes of [Ca2+]i abolished the effects of t-BOOH on PMA-stimulated translocation in parallel to effects upon the respiratory burst. The results suggest that the dual effects of hydroperoxides are mediated, in part, by Ca(2+)-dependent processes affecting the assembly of the respiratory burst oxidase at steps that are separate from p47phox phosphorylation.


Ultracytochemical observations on intracytoplasmic lipids by enzymic digestive methods: histochemical trials.
The penetration of Rhizopus arrhizus lipase into ethionine fatty livers was examined histochemically. A free-floating, 30 microns thick Vibratome section of the livers perfused with aldehydes was shown to be suitable for ultracytochemical analysis by the lipase digestive method. Accessibility of phospholipids in the outer membrane of erythrocytes to Naja naja phospholipase A2 was observed under a light microscope, and intact red cells were used for the ultracytochemical analysis by the phospholipase digestive method. Ultracytochemical pictures of cytoplasmic lipids in these materials subjected to the enzymatic digestive method are presented.


Tumours of the skin.
Tumours occur more frequently in the skin than in any other part of the body. Epithelial tumours are described under the following headings: basal cell tumour, squamous cell carcinoma, papilloma, sebaceous gland tumour, tumour of hepatoid glands, sweat gland tumour, mixed tumour of apocrine sweat glands, carcinoma of apocrine sweat glands, tumour of hair follicle, and intracutaneous cornifying epithelioma. Tumours of the melanogenic system are divided into benign melanoma and malignant melanoma, the latter being subdivided into the following types: epithelioid, spindle cell, epithelioid and spindle cell, dendritic, and whorled.


Risk factors for hepatocellular carcinoma in patients with liver cirrhosis.
Although cirrhosis is known to predispose toward hepatocellular carcinoma (HCC), there is no agreement on the factors that can influence the risk for HCC in patients with cirrhosis. This study was designed to identify differences in cirrhosis-related risk factors for developing HCC in relation to epidemiological characteristics, stage of the disease and etiology. 512 patients from southwestern Spain with Child-Pugh stage A or B cirrhosis were examined periodically by ultrasonography, and alpha-fetoprotein (AFP) concentration was measured. The average length of follow-up was 37 months. A total of 52 cases of HCC were detected, which represented a risk of 17% after 5 years of follow-up. The Cox model showed that the risk of HCC increased by 8% per year of increasing age. Male sex (relative risk: 3.4), hepatitis C virus infection (relative risk: 4.6), hepatitis B virus infection (relative risk: 2.9) and AFP levels higher than 15 ng/ml (relative risk: 2.5) were also shown to be risk factors. Among alcoholic patients, only age (risk increased by 15% per year), and hepatitis C virus infection (relative risk: 5.4) were risk factors for HCC. However, in patients infected by hepatitis C virus, the main risk factors were age (relative risk increased by 8% per year), male sex (relative risk: 3.9), co-infection with hepatitis B virus (relative risk: 4.9), and increased AFP (relative risk: 2.8). Of the patients with HCC, 71% were infected with hepatitis C virus. Alcoholism, Child-Pugh stage and duration of cirrhosis did not increase the risk of the appearance of HCC. The risk of HCC increased to 17% after 5 years of follow-up in patients with Child-Pugh stage A or B cirrhosis. Hepatitis C virus infection was the main risk factor in patients with cirrhosis. Other risk factors were age, male sex, hepatitis B virus infection and altered AFP level.


Blood flow competition after aortic valve bypass: an evaluation using computational fluid dynamics.
Aortic valve bypass (AVB) (apico-aortic conduit) remains an effective surgical alternative for patients in whom surgical aortic valve replacement or transcatheter aortic valve implantation is not feasible. However, specific complications include thrombus formation, possibly caused by stagnation arising from flow competition between the antegrade and retrograde flow, but this has not been fully investigated. The aim of this study was to analyse flow characteristics after AVB and to elucidate mechanisms of intra-aortic thrombus using computational fluid dynamics (CFD). Flow simulation was performed on data obtained from a 73-year-old postoperative AVB patient. Three-dimensional cine phase-contrast magnetic resonance imaging at 3 Tesla was used to acquire flow data and to set up the simulation. The vascular geometry was reconstructed using computed tomography angiograms. Flow simulations were implemented at various ratios of the flow rate between the ascending aorta and the graft. Results were visualized by streamline and particle tracing. CFD demonstrated stagnation in the ascending aorta-arch when retrograde flow was dominant, indicating that the risk of thrombus formation exists in the ascending arch in cases with severe aortic stenosis and/or poor left ventricular function. Meanwhile, stagnation was observed in the proximal descending aorta when the antegrade and retrograde flow were equivalent, suggesting that the descending aorta is critical when aortic stenosis is not severe. Flow stagnation in the aorta which may cause thrombus was observed when retrograde flow was dominant and antegrade/retrograde flows were equivalent. Our results suggest that anticoagulants might be recommended even in patients who receive biological valves.


A giant phyllodes tumor of the breast causing severe disfigurement. A case report.
Phyllodes tumours (PTs) are rare fibroepithelial neoplasms representing about 0,2% to 2% of all breast tumors with an incidence of about 2.1 per million. The classification proposed by the World Health Organization for PTs into benign, borderline, and malignant is based on a combination of several histologic features. High-grade malignant phyllodes tumors may spread by hematogenous route. While smaller and moderate size malignant phyllodes may typically be seen, gigantic ones with larger than 10 cm in diameter are very rare. We report an unusual case of a giant malignant phyllodes tumor with metastases that grew over a 6 years period causing significant ulceration, body disfigurement and physical transformation. Our experience indicated that surgical treatment of malignant phyllodes tumor might be an option for improving patients' quality of life, regardless of the extremely poor prognosis. Breast, Malignant phyllodes tumor, Surgical treatment.


Femtosecond Kerr-gated wide-field fluorescence microscopy.
We present a Kerr-gated microscope capable of collecting diffraction-limited 2D fluorescence images with sub-100 fs time resolution. The concept is based on the insertion of a solid-state optical Kerr gate into a wide-field microscope. In addition to the considerably improved temporal resolution, the wide-field design allows for simultaneous tracking of several objects and ultrafast fluorescence lifetime imaging of doped and heterogeneous surfaces. The ultrafast fluorescence dynamics of gold nanoparticles is presented as an example of the capabilities of the instrument.


Vegetal localization of the maternal mRNA encoding an EDEN-BP/Bruno-like protein in zebrafish.
Asymmetric distribution of maternal mRNAs has not been well documented in zebrafish. Recently, we have shown that dazl mRNA is localized at the vegetal pole. Here we report a novel zebrafish gene, bruno-like (brul), which provides another example of vegetal mRNA localization. brul encodes an Elav-type RNA-binding protein that belongs to the Bruno-like family that includes mammalian CUG-BP, Xenopus EDEN-BP, and Drosophila Bruno. At 24 hpf, brul mRNA was abundant in lens fiber cells. At the onset of embryogenesis, maternal brul mRNA was detected at the vegetal pole, and it then migrated rapidly toward the blastoderm through yolk cytoplasmic streams. During oogenesis, brul mRNA became localized at the vegetal cortex at stage II, later than dazl mRNA. We found that anchoring of brul mRNA was dependent on microfilaments.


Prevalence of awake bruxism in the adult population: a systematic review and meta-analysis.
To evaluate the prevalence of awake bruxism (AB) in the adult population. Six main electronic databases and three sources of grey literature were searched to identify cross-sectional studies in which AB was assessed. The studies were independently selected by two reviewers in two phases, based on their eligibility criteria. The first one consisted of reading titles and abstracts, and the second one involved reading the full articles. The study quality assessment was obtained by using the "Joanna Briggs Institute Critical Appraisal Checklist for Studies Reporting Prevalence Data", and the "R Statistics" software was used to perform meta-analyses. Seventeen out of 3086 identified studies were included. None of the studies scored high in methodological quality across all 9 items of the JBI checklist. However, "the use of valid methods to identify pathology" and "appropriate statistical analysis" were considered to have high methodological quality in all the studies. The overall pooled prevalence of the meta-analysis was 15.44% (99% confidence interval: 10.81 to 20.72%) and there was no difference for sex, sampling method and according to consensus-based classification. The prevalence of AB in adults was low. There was substantial methodological variability, which highlights the need for standardized guidelines. Prevalence data are useful for raising patients' and clinicians' awareness of the AB. Moreover, since AB can lead to possible pain and overload of the stomatognathic system, this knowledge can also guide dentists to achieve an early diagnosis of AB and to provide appropriate care management.


Treatment of Spinal Tumors in a High Volume Center has Direct Impact on Local Recurrence, Morbidity, and Mortality.
En bloc resections of spine tumors aim at locally controlling the disease for both improving the patient's quality of life as well as improving mortality. The purpose of this study was to compare the outcome between patients who were initially treated in a high volume specialized center, and patients who initially underwent either invasive diagnostic procedure or an initial surgical attempt to treat the disease in a different center. A retrospective study of 1681 patients affected by spine tumors-treated from 1990 to 2015 by the same team. A total of 220 en bloc resections that were performed on 216 patients during that period. Most of the tumors were primary-165 cases (43 benign and 122 malignant), metastases occurred in 55 cases. One hundred sixty-eight patients (77.8%) were solely treated in the institute and were considered noncontaminated cases (NCCs) and 48 (22.2%) were previously treated elsewhere and were considered contaminated cases (CCs). Median follow-up was 45 months (0-371).Thirty-three local recurrences (15.28%) were recorded. Fourteen patients (29.17%) from the CC and 19 (11.31%) from the NCC group.A total of 153 complications were observed in 100 out of 216 patients (46.2%). Sixty-four of these patients (30%) suffered 1 complication, while the rest had 2 or more. Twenty-eight (58%) of the CC group and 72 (42.85%) of the NCC group, had at least 1 complication.Sixty patients died as a result of the disease during the follow-up period. Twenty-one (43.75%) and 39 (23.21%) patients died in the CC and NCC cohorts, respectively.CC, surgical margins of the resected tumor-intralesional, marginal, and malignant tumors, were statistically significant independent risk factors for local recurrence of the tumor. Contamination, local recurrence, neoadjuvant radiotherapy, the number of level resected, and metastatic tumors compared with primary malignant tumor, were shown to be independent risk factors for patient's death. It is apparent that there is a substantial added risk in performing either invasive diagnostic procedures or attempting a surgical resection of the tumor in a nonspecialized center. This risk includes both higher recurrences of the tumor as well as increased mortality. It is therefore reasonable to conclude that the whole treatment, from biopsy to resection, should be performed in the same center, and this center should be a high volume, specialized in treating these type of spine pathologies.The surgeon who treats the patient first has a great responsibility, as it is the first treatment that most affects prognosis. To reduce the chance of local recurrence, morbidity, and mortality, all invasive diagnosis and treatment, should be performed by an experienced team, as the consequences are dramatic.


Genotypic distribution of hepatitis C virus in different regions of Thailand.
The genotypic distribution of hepatitis C virus (HCV) isolated from blood donors from four major regions of Thailand was studied by reverse hybridization assays. PCR-amplified products from the 5' noncoding and core regions of the viral genome were hybridized to genotype- and subtype-specific probes which were immobilized on the nitrocellulose membrane. Of 332 anti-HCV-positive plasma samples studied, 71% contained HCV RNA. HCV genotype 3a was the most prevalent genotype (39%), followed by genotype 1b (20%) and genotype 6 group variants (18%). HCV genotype 1a was identified among 9% of all isolates. Other genotypes (genotype 1 which was neither 1a nor 1b, genotype 3b, and an unclassified genotype) were uncommon. There was no difference in the mean age of the donors infected with different HCV genotypes. The genotypic distribution pattern of HCV was similar among HCV isolates from different regions of Thailand.