Perceptions of malaria in a low endemic area in the Philippines: transmission and prevention of disease.
Qualitative methods were used to gather data on community perceptions of malaria in Morong, Bataan. People recognised an illness which they called "malarya' through a discrete set of symptoms: high fever and intense chills, with or without a severe headache. Self-medication was common. Enquiry into perceptions of cause and prevention of the disease revealed a complex mixture of beliefs involving environmental conditions, the mosquito vector and parasites, but included also various ideas about dirty water, diet, hunger and conditions of hygiene. The implications of these findings for disease control, and the relationship between knowledge and practices, are discussed.


Structural effects of Mg²⁺ on the regulatory states of three neuronal calcium sensors operating in vertebrate phototransduction.
The effects of physiological concentration of magnesium on the switch states of the neuronal calcium sensor proteins recoverin, GCAP1 and GCAP2 were investigated. Isothermal titration calorimetry was applied for binding studies. Circular dichroism spectroscopy was used to characterize protein thermal stability, secondary and tertiary structure in conditions of high and low [Ca²⁺], mimicking respectively the dark-adapted and light-exposed photoreceptor states during the phototransduction cascade. Further, molecular dynamics (MD) simulations were run to investigate the dynamical structural properties of GCAP1 in its activator, inhibitor and putative transitory states. Our results confirmed that Mg²⁺ is unable to trigger the typical Ca²⁺-induced conformational change of recoverin (myristoyl switch) while it decreases its thermal stability. Interestingly, Mg²⁺ seems to affect the conformation of GCAP2 both at high and low [Ca²⁺], however the variations are more substantial for myristoylated GCAP2 in the absence of Ca²⁺. GCAP1 is responsive to Mg²⁺ only in its low [Ca²⁺] state and Mg²⁺-GCAP1 tertiary structure slightly differs from both apo and Ca²⁺-bound states. Finally, MD simulations suggest that the GCAP1 state harboring one Mg²⁺ ion bound to EF2 acquires structural characteristics that are thought to be relevant for the activation of the guanylate cyclase. Moreover, all the putative Mg²⁺-bound states of myristoylated GCAP1 are structurally less flexible than Ca²⁺-bound states. GCAP1 acquires a more compact tertiary structure that is less accessible to the solvent, thereby inducing a different conformation to the myristoyl moiety, which might be crucial for the activation of the guanylate cyclase. This article is part of a Special Issue entitled: 13th European Symposium on Calcium.


The use of the single radial haemolysis test for assessing antibody response and protective antibody levels in an influenza B vaccine study.
Single radial haemolysis (SRH) and HAI tests were used to determine the levels of antibody in sera obtained from 118 volunteers taking part in a study of influenza B/Hong Kong/73 subunit vaccine. The two tests gave similar overall results, and showed good correlation, but SRH appeared to be more sensitive for the detection of low concentrations of antibody. A greater than or equal to 45% increase in SRH zone area was found to be equivalent to a significant increase in antibody titre and on the basis of this value, the HAI and SRH tests gave similar results for responses to immunization. The concentration of antibody equivalent to a 50% protective level against a challenge virus infection was a zone area of 45 mm2 for the SRH test; this was equivalent to an HAI titre of 1:20 which has previously been established as the 50% protective level.


Analysis of Myc Chromatin Binding by Calibrated ChIP-Seq Approach.
Here, we present a strategy to map and quantify the interactions between Myc and chromatin using a calibrated Myc ChIP-seq approach. We recommend the use of an internal spike-in control for post-sequencing normalization to enable detection of broad changes in Myc binding as can occur under conditions with varied Myc abundance. We also highlight a range of bioinformatic analyses that can dissect the downstream effects of Myc binding. These methods include peak calling, mapping Myc onto an integrated metagenome, juxtaposing ChIP-seq data with matching RNA-seq data, and identifying gene ontologies enriched for genes with high Myc binding. Our aim is to provide a guided strategy, from cell harvest through to bioinformatic analysis, to elucidate the global effects of Myc on transcription.


[Influence of gender on the sensory organisation test and the limits of stability in healthy subjects].
The sensory organization test and the limits of stability are the gold standard for dynamic posturography. It is postulated that these measurements vary depending on age, activity of the subject and musculoskeletal system, emotional condition or other factors. The aim of this study was to determine the influence of gender on the above-mentioned analyses. 70 healthy subjects (35 males and 35 females); mean age: 44.9 years. A clinical history was taken and a physical and otoneurological exploration was performed for each subject, along with a posturography study using the Neurocom SMART Balance Master platform model. The statistical study was carried out with the ANOVA test (p<0.05). Condition 5 presented the lowest percentage of balance in both sexes (64.36%). The highest percentage of balance in males was in Condition 1 (p<0.001) and the lowest in 3 (p=0.030). There were no differences in the sensory analysis. The lowest employment of ankle strategy was in Condition 5 for both sexes (88.61%); women used the ankle strategy in Condition 4 more efficiently (p=0.0129). There were also differences in the time of reaction towards the right (p=0.022) and the mean (p=0.011) (higher in females), and in the speed of movement backwards (p=0.001) and towards the right (p=0.04) (higher in males). In path length and directional control, there were no differences. Gender differences should be taken into consideration for vestibular rehabilitation. Greater speed in conducting the tests does not lead to better balance control.


Vascular endothelial growth factor, placenta growth factor and their receptors in isolated human trophoblast.
The expression of the angiogenic growth factors, vascular endothelial cell growth factor (VEGF) and placenta growth factor (PIGF) was demonstrated in isolated human term cytotrophoblast and in vitro differentiated syncytiotrophoblast. RNase protection assays demonstrated VEGF expression in both cytotrophoblast and syncytiotrophoblast while prominent PIGF expression was detected in both types of trophoblast by Northern blot analyses. VEGF expression increased approximately eightfold in trophoblast cultured under hypoxic conditions (1 per cent O2) yet PIGF expression decreased 73 +/- 5.5 per cent in the same trophoblast. These results suggest distinct regulatory mechanisms govern expression of VEGF and PIGF in trophoblast. Characterization of the VEGF/PIGF receptors, KDR and flt-1, revealed the presence of flt-1 mRNA in isolated cytotrophoblast and in vitro differentiated syncytiotrophoblast. KDR was not detected in the isolated trophoblast. Exogenous rhVEGF induced c-Jun N-terminal kinase (JNK) activity in the normal trophoblast indicating that the flt-1 receptors on trophoblast are functional. Trophoblast-derived VEGF/PIGF could act in a paracrine fashion to promote uterine angiogenesis and vascular permeability within the placental bed. In addition, presence of function flt-1 on normal trophoblast suggests that VEGF/PIGF functions in an autocrine manner to perform an as yet undefined role in trophoblast invasion, differentiation, and/or metabolic activity during placentation.


Clinical Updates in Mucositis-Related Symptom Management.
To provide an overview with the most up-to-date evidence on the management of cancer-treatment related mucositis. Peer-reviewed articles, textbooks, and the internet. A multitude of new and innovative treatments for the management of mucositis exist. Mucositis guidelines have changed to reflect the current evidence, but more research is needed on emerging modalities. Oncology nurses have a primary role in the assessment and early identification of mucositis. Educating patients and recommending evidence-based guidelines is paramount in preventing and ameliorating this challenging side effect of treatment.


[Artificial respiration as treatment of postoperative complications after cardiovascular surgery: indication, technique, results (author's transl)].
From 1972 to 1974 524 patients underwent surgery with extra corporal circulation. 83 (15,8%) patients had to be postoperatively ventilated for a prolonged period or reintubed after a symptomfree interval due to anticipated or manifested complications. 31 (37%) out of these expired. There was no death due to the prolonged ventilation itself, shown by the group, in which the causes for the above treatment were others but respiratory failure or insufficiency. All patients of this group survived. Indications, technique and results are described and discussed.


Repetitive sequences in the ITS1 region of the ribosomal DNA of Tunga penetrans and other flea species (Insecta, Siphonaptera).
Different Tunga penetrans isolates from various hosts obtained from South America (Fortaleza. Brazil) have been studied by nucleotide sequence comparison of the first and the second internal transcribed spacer (ITS1, ITS2) of the ribosomal deoxyribonucleic acid (rDNA) and part of the mitochondrial 16S rDNA. Results show no significant host-dependent sequence differences. No indication for intraindividual and intraspecific polymorphisms could be detected. Comparing the ITS1 spacer region of T. penetrans from South America with that from Africa (Togo, Cameroon), distinct length variations have been observed caused by a repetitive sequence motif of 99 bp. The ITS1 from the South American T. penetrans contain two tandemly repeated copies, whereas four of these units are present in the spacer of the African T. penetrans. The absence of homogenization of these units indicates a recent separation of both populations. However, the different number of repetitions together with two base substitutions put the evolutionary distance of only 135 years as postulated for the transfer of T. penetrans from South America to Africa into question. Repetitive sequences could also be detected within the ITS1 rDNA region of other flea species Ctenocephalides felis, Echidnophaga gallinacea, Pulex irritans, Spilopsyllus cuniculi, and Xenopsylla cheopis. The repeat units with lengths from 10 to 99 bp are arranged in pure tandem or interspersed. The repetitive elements observed in the ITS1 of various flea species may serve as a valuable tool for phylogeographic studies.


Anti-Adhesion Effects of Lactobacillus Strains on Caco-2 Cells Against Escherichia Coli and Their Application in Ameliorating the Symptoms of Dextran Sulfate Sodium-Induced Colitis in Mice.
The beneficial effects of probiotics on ameliorating ulcerative colitis (UC) have attracted much attention in recent years. Nevertheless, the number of these identified probiotics is still limited. In addition, the adhesion abilities of probiotics are considered to be a key determinant for probiotic efficacy. However, the relationship between the adhesion abilities of probiotics and their role in ameliorating UC has been poorly studied to date. This study measured the adhesion abilities of four Lactobacillus strains to Caco-2 cells and their anti-adhesion effects on Caco-2 cells against pathogenic bacteria, as well as their application in ameliorating the symptoms of dextran sulfate sodium-induced UC, and further illustrated the relationship between these two potential probiotic properties of probiotics and their beneficial effects on UC. Results suggested that the adhesion abilities of the four tested Lactobacillus strains exists highly strain-specific and the mechanisms of their anti-adhesion effect on Caco-2 cells against Escherichia coli may be different. Moreover, all these strains had promising effects on ameliorating UC by reducing inflammatory response and improving the intestinal mucosal barrier function, as well as promoting the production of SCFAs. In conclusion, the four tested Lactobacillus strains can be considered as alternative dietary supplements in alleviating UC. In addition, it could be concluded that there is no significant correlation between the adhesion abilities of probiotics and their role in ameliorating UC, which further illustrated that the adhesion properties of probiotics in vitro may not be suitable as the key criterion for screening potential strains with UC-alleviating effects.


Absolute structure of (3aS,5S,7aS,7bS,9aR,10R,12aR,12bS)-7b-hy-droxy-4,4,7a,9a,12a-penta-methyl-10-[(2'R)-6-methyl-heptan-2-yl]-2,8,9-trioxo-octa-deca-hydro-benzo[d]indeno-[4,5-b]azepin-5-yl acetate from 62-year-old crystals.
The structure of the title compound, C32H51NO6, was determined from 62-year-old crystals at room temperature and refined with 100 K data in a monoclinic (C2) space group. This compound with a triterpenoid structure, now confirmed by this study, played an important role in the determination of the structure of lanosterol. The mol-ecules pack in linear O-H⋯O hydrogen-bonded chains along the short axis (b), while parallel chains display weak van der Waals inter-actions that explain the needle-shaped crystal morphology. The structure exhibits disorder of the flexible methyl-heptane chain at one end of the main mol-ecule with a small void around it. Crystals of the compounds were resistant to data collection for decades with the available cameras and Mo Kα radiation single-crystal diffractometer in our laboratory until a new instrument with Cu Kα radiation operating at 100 K allowed the structure to be solved and refined.


The long term tsunami impact: Evolution of iron speciation and major elements concentration in tsunami deposits from Thailand.
The article describes the unique studies of the chemical composition changes of new geological object (tsunami deposits in south Thailand - Andaman Sea Coast) during four years (2005-2008) from the beginning of formation of it (deposition of tsunami transported material, 26 December 2004). The chemical composition of the acid leachable fraction of the tsunami deposits has been studied in the scope of concentration macrocompounds - concentration of calcium, magnesium, iron, manganese and iron speciation - the occurrence of Fe(II), Fe(III) and non-ionic iron species described as complexed iron (Fe complex). The changes of chemical composition and iron speciation in the acid leachable fraction of tsunami deposits have been observed with not clear tendencies of changes direction. For iron speciation changes the transformation of the Fe complex to Fe(III) has been recorded with no significant changes of the level of Fe(II).


A simple and rapid method for constructing ring-X chromosomes in Drosophila melanogaster.
Ring chromosomes are of basic interest to the geneticist and cell biologist who study their behavior in meiotic and mitotic divisions. In addition, the mitotic instability associated with some ring-X chromosomes has proven useful in Drosophila as a means to produce gynandromorphs for developmental studies. We describe a method to construct ring-X chromosomes in Drosophila via I-CreI-mediated exchange in rDNA, and then rapidly diagnose the recovery of ring chromosomes via FLP-mediated sister chromatid exchange within the ring. The method we describe provides a ready means to tailor the genetic content of ring-X chromosomes, making it suited to produce ring-X chromosomes for a variety of experimental purposes.


Toll-like receptor co-receptors as master regulators of the immune response.
Pattern recognition receptors (PRRs) are generally recognized as the initiators of all immune responses. PRRs bind molecular patterns associated with microorganisms or endogenous mediators released by stressed tissues. Upon ligand binding, PRRs induce the activation of an inflammatory process that ultimately leads to pathogen clearance or restoration of tissue homeostasis. PRRs govern these processes, regulating the activation of a complex network of transcription factors able to induce the appropriate immune response to a specific ligand. Toll-like-receptors (TLRs) are the first and best characterized PRR family, and for a long period of time they were believed to be autonomous proteins able to recognize and initiate all the immune response to a given stimulus. Recently this view was challenged by the discovery that so-called TLR co-receptors, such as CD14 and CD36, not only favor TLR-dependent signaling but can also transduce their own signal in a TLR-independent manner. Here we will discuss the capacity of TLR co-receptors to bind different microbial and endogenous ligands and to integrate TLR functions inducing specific signaling modules.


sn-1,2 dioctanoylglycerol mimics the effects of angiotensin II on aldosterone production and potassium permeability in isolated bovine glomerulosa cells.
In order to elucidate the possible role in glomerulosa cells of diacylglycerol released by angiotensin II we have studied the action of a synthetic diacylglycerol, sn-1,2-dioctanoylglycerol (DiC8), on aldosterone production and potassium permeability in bovine adrenal cells. DiC8 elicited an increase in 86Rb efflux from cells previously equilibrated with the isotope. The action of DiC8 on the rate coefficient for 86Rb efflux was similar to that previously described for angiotensin II (Am. J. Physiol. 254 (1988) E144-149), i.e. DiC8 induced an immediate increase in 86Rb efflux followed by a sustained decrease in potassium permeability. This DiC8 induced inhibition was observed even in the presence of depolarizing concentrations of potassium. The effect of DiC8 on aldosterone secretion from adrenal glomerulosa cells was measured using a perifusion system. DiC8 (300 microM) caused a significant increase of aldosterone production, comparable to that seen with angiotensin II (100 nM). These results indicate that DiC8 has similar effects to angiotensin II on both potassium permeability and steroidogenesis, which suggests that activation of protein kinase C is involved in the changes of ionic permeability induced by this hormone in bovine adrenal glomerulosa cells.


MYCN Impact on High-Risk Neuroblastoma: From Diagnosis and Prognosis to Targeted Treatment.
Among childhood cancers, neuroblastoma is the most diffuse solid tumor and the deadliest in children. While to date, the pathology has become progressively manageable with a significant increase in 5-year survival for its less aggressive form, high-risk neuroblastoma (HR-NB) remains a major issue with poor outcome and little survivability of patients. The staging system has also been improved to better fit patient needs and to administer therapies in a more focused manner in consideration of pathology features. New and improved therapies have been developed; nevertheless, low efficacy and high toxicity remain a staple feature of current high-risk neuroblastoma treatment. For this reason, more specific procedures are required, and new therapeutic targets are also needed for a precise medicine approach. In this scenario, MYCN is certainly one of the most interesting targets. Indeed, MYCN is one of the most relevant hallmarks of HR-NB, and many studies has been carried out in recent years to discover potent and specific inhibitors to block its activities and any related oncogenic function. N-Myc protein has been considered an undruggable target for a long time. Thus, many new indirect and direct approaches have been discovered and preclinically evaluated for the interaction with MYCN and its pathways; a few of the most promising approaches are nearing clinical application for the investigation in HR-NB.


Erythroid response to treatment with G-CSF plus erythropoietin for the anaemia of patients with myelodysplastic syndromes: proposal for a predictive model.
Previous studies have shown that approximately 40% of patients with myelodysplastic syndrome (MDS) and anaemia respond to treatment with human recombinant granulocyte-CSF (G-CSF) plus erythropoietin (epo). The present study was designed to investigate pre-treatment variables for their ability to predict erythroid responses to this treatment. 98 patients with MDS (30 RA, 31 RARS, 32 RAEB, five RAEB-t) were treated with a combination of G-CSF (0.3-3.0 microg/kg/d, s.c.) and epo (60-300 U/kg/d, s.c.) for at least 10 weeks. Minimum criteria for erythroid response was a 100% reduction of red blood cell (RBC) transfusion need or an increase in haemoglobin level of > or = 1.5 g/dl. 35 patients (36%) showed responses to treatment. Medium duration of response was 11-24 months. In multivariate analysis, serum erythropoietin levels and initial RBC-transfusion need retained high statistical significance (P < 0.01). Using pre-treatment serum epo levels as a ternary variable (< 100, 100-500 or > 500 U/l) and RBC transfusion need as a binary variable (< 2 or > or = 2 units per month), the analysis provided a predictive score for erythroid response. This score divided patients into three groups: one group with a high probability of erythroid responses (74%), one intermediate group (23%) and one group with poor responses to treatment (7%). This predictive scoring system could be used in decisions regarding use of these cytokines for treating the anaemia of MDS, both for defining patients who should not be given the treatment and for selecting patients for inclusion in prospective trials.


Tyrosine kinase inhibitors in lung cancer.
Identification of driver mutations in growth related protein kinases, especially tyrosine kinases, has led to clinical development of an array of tyrosine kinase inhibitors in various malignancies, including lung cancer. Improved understanding of tyrosine kinase biology has led to faster drug development, identification of resistance mechanisms, and ways to overcome resistance. This review discusses the clinical data supporting the use and practical aspects of management of patients on epidermal growth factor receptor and anaplastic lymphoma kinase tyrosine kinase inhibitors.


Exposures and reported symptoms associated with occupational deployment to the Buncefield fuel depot fire, England 2005.
An explosion at the Buncefield fuel depot outside London occurred on 11 December 2005. We conducted a retrospective cohort study of airborne exposures and health status for workers deployed. Deployed individuals were identified through their occupational health departments. We sent a self-completion questionnaire asking about health symptoms during the burn and post-burn phases. The prevalence of health symptoms in workers was compared to symptoms in local residents not under the smoke plume. Of 1949 eligible individuals, 815 returned questionnaires (response rate 44%). Respiratory protection was used by 39%. Symptoms were reported by 41% of individuals during the burn phase compared with 26% in the post-burn phase. In a final multivariable model, reporting of any symptoms was associated with deployment inside the inner fire cordon during the burn phase (OR 2.07, 95% CI 1.24 to 3.47) and wearing a face mask (OR 2.33, 95% CI 1.67 to 3.26). Compared with the general public, eye irritation (prevalence ratio (PR) 2.1, 95% CI 1.5 to 3.0), coughing (PR 1.3, 95% CI 1.0 to 1.8) and headaches (PR 1.7, 95% CI 1.2 to 2.5) were more common in workers deployed during the burn phase but not the post-burn phase. Increased reporting of symptoms close to the fire during the burn phase was consistent with increased exposure to products of combustion, although no major acute illness was reported. That only a minority of individuals used face masks, which were not protective for symptoms, raises questions about the availability of adequate respiratory protection for such incidents.


Insights into the structural variation between pentapeptide repeat proteins--crystal structure of Rfr23 from Cyanothece 51142.
Cyanothece sp. PCC 51142 contains 35 pentapeptide repeat proteins (PRPs), proteins that contain a minimum of eight tandem repeated five-residues (Rfr) of the general consensus sequence A[N/D]LXX. Published crystal structures of PRPs show that the tandem pentapeptide repeats adopt a type of right-handed quadrilateral beta-helix called an Rfr-fold. To characterize how structural features of Rfr-folds might vary with different amino acid sequences, the crystal structure of Cyanothece Rfr23 (174 residues) was determined at 2.4A resolution. The structure is dominated by an Rfr-fold capped at the N-terminus with a nine-residue alpha-helix (M26(*)-E34). The Rfr-fold of Rfr23 contains four structural features previously unobserved in Rfr-folds. First, Rfr23 is composed entirely of type II beta-turns. Second, the pentapeptide repeats are not consecutive in the primary amino acid sequence. Instead, Rfr23 contains 24-residues protruding outside one corner of the first complete N-terminal coil of the Rfr-fold (L56-P79) (24-residue insertion). Third, a disulfide bond between C39 and C42 bridges the beta-turn between the first and second pentapeptide repeats in the first coil (disulfide bracket). NMR spectroscopy indicates that the reduction of the disulfide bracket with the addition of DTT destroys the entire Rfr-fold. Fourth, a single-residue perturbs the Rfr-fold slightly in the last coil between the C-terminal two pentapeptide repeats (single-residue bulge).


Peroneal artery safe zone in the posterolateral approach to the distal tibia: A CT angiogram based anatomical study.
The posterolateral approach to the distal tibia is commonly used for stabilisation of ankle fractures as it allows good visualisation and direct reduction of the posterior distal tibia and malleolar fragments. This approach can also be used for internal fixation of an associated lateral malleolus fracture. The aim of our study is to describe the surgical anatomy of the peroneal artery (PA) in relation to the tibial plafond and the distal fibula; thereby suggesting a safe zone during proximal dissection of posterolateral approach. Using Computed Tomography Angiographic (CTA) study, the course of the PA in relation to the tibial plafond and distal fibula was analysed in 142 lower limbs (bilateral limbs of 71 adult patients; 43 males and 28 females). Axial, coronal, and sagittal CT sections were cross-linked to specify the position of the PA. The PA course was identified and the level of its distal bifurcation over the tibia was marked. Perpendicular measurements were made from this point to the tibial plafond and tip of distal fibula. The PA bifurcated distally at mean 58.3±24.2mm (SD) (range: 37.0-115.0mm) proximal to the right tibial plafond and mean 81.9±24.4mm (range: 54.0-137.0mm) from the right distal fibular tip. In the contralateral side, the PA bifurcated at mean 57.9±23.3mm (range: 36.0-125.0mm) proximal to the left tibial plafond and 81.8±23.9mm (range: 54.0-147.0mm) from the left distal fibular tip. The difference between the right and the left side of distal bifurcation point diameter of the same patient was assessed, range (0.0-58.0mm) with median 2.0mm and IQR 10.0mm. Three different PA vasculature patterns were identified. It is important for surgeons to be aware of the surgical anatomy of PA to avoid inadvertent injury during posterolateral approach to distal tibia. The PA may bifurcate as close as 36mm from the tibial plafond with possible variation bilaterally. Therefore, special attention needs to be considered by the operating surgeon while dissecting in this region due to the wide anatomical variation in vasculature. However, once the PA is mobilised, any fixation modality including posterior buttress plate could be safely performed.


Histopathological and cell biological characteristics of ductal carcinoma in situ (DCIS) of the breast-a comparison between the primary DCIS and subsequent ipsilateral and contralateral tumours.
The rate of ipsilateral local recurrence after ductal carcinoma in situ (DCIS) varies (between 5% and 30%) and depends on the type of operation (mastectomy vs. breast-conserving operation), and whether postoperative radiotherapy has been used. Ipsilateral local recurrence can either emanate from the primary lesion or be a new primary tumour. Contralateral lesions may also develop after DCIS. We compared histopathological and cell biological characteristics in 37 subsequent ipsilateral tumours (25 DCIS and 12 invasive cancers) and 13 subsequent contralateral invasive breast cancers with their corresponding primary DCIS. The histopathological parameters were re-evaluated and the cell biological factors were analysed using conventional immunohistochemical techniques in paraffin-embedded material. The concordance rate for high grade (nuclear grade 3) vs. non-high grade (nuclear grades 1+2) between the primary DCIS and the subsequent ipsilateral tumour was higher than between the primary DCIS and the subsequent contralateral invasive cancer (68% vs. 31%). Similar patterns in the concordance rates between the primary DCIS and ipsilateral vs. contralateral tumours were also found in the oestrogen receptor status (83% vs. 50%) and the progesterone receptor status (87% vs. 58%). The pattern persisted in the other factors examined (p53, c-erbB2, bcl-2 and Ki67), although it was less pronounced. The overall high rate of concordance in the characteristics between the primary DCIS and the subsequent ipsilateral tumours suggests that, in most cases, they represent true local recurrences. Subsequent contralateral tumours are more likely to be new primary cancers.


New insights regarding glucocorticoids, stress and gonadotropin suppression.
This review highlights our recent work investigating the inhibitory effects of acute, physiologic stress-like increases in cortisol on reproductive neuroendocrine activity in sheep, the mechanisms responsible for this suppression, and the relevance of enhanced glucocorticoid secretion to stress-induced inhibition of gonadotropin secretion in this species. Initial studies established that cortisol rapidly suppresses pulsatile luteinizing hormone secretion. In ovariectomized ewes, this inhibition reflects the reduction of pituitary responsiveness to gonadotropin-releasing hormone mediated by the type II glucocorticoid receptor, rather than the suppression in hypothalamic gonadotropin-releasing hormone release. Studies in ovary-intact ewes, however, uncovered an alternative mode of cortisol action. During the follicular phase of the estrous cycle, cortisol reduces luteinizing hormone pulse frequency, most likely via the inhibition of gonadotropin-releasing hormone pulsatility. Recent preliminary evidence in ovariectomized ewes demonstrates increased cortisol secretion is essential for disruption of pulsatile luteinizing hormone secretion in response to a psychosocial stress. Taken together, our observations reveal diverse inhibitory actions of cortisol on gonadotropin secretion and that this glucocorticoid is not only sufficient, but necessary for suppression of reproductive neuroendocrine activity in response to certain types of stress.


The opiate receptor binding interactions of 3H-methionine enkephalin, an opioid peptide.
3H-Methionine enkephalin binds stereospecifically with high affinity to opiate receptors in rat brain membranes. Equilibrium experiments indicate two distinct dissociation constants with KD values of 1.8 and 5.8 nM respectively. 3H-Methionine enkephalin associates and dissociates from the opiate receptor with 8--10 fold slower kinetics than 3H-opiates. Though several opiates have similar affinities for sites labeled by 3H-methionine enkephalin, 3H-dihydromorphine and 3H-naloxone, some opiates such as morphine, dihydromorphine and oxymorphone are only one tenth as potent in competing for 3H-methionine enkephalin as for 3H-dihydromorphine and 3H-naloxone binding. As with other opiate agonists, 5--10 mM sodium selectively decreases the binding of 3H-methionine enkephalin. At 26 degrees C, 0.1--1.0 mM manganese but not magnesium or calcium increases the binding of 3H-methionine enkephalin, while at 0 degrees C manganese decreases the binding of methionine enkephalin.


Lesion-specific cortical activation following sensory stimulation in patients with subacute stroke.
Sensory stimulation can play a fundamental role in the activation of the primary sensorimotor cortex (S1-M1), which can promote motor learning and M1 plasticity in stroke patients. However, studies have focused mainly on investigating the influence of brain lesion profiles on the activation patterns of S1-M1 during motor tasks instead of sensory tasks. Therefore, the objective of this study is to explore the lesion-specific activation patterns due to different brain lesion profiles and types during focal vibration (FV). In total 52 subacute stroke patients were recruited in this clinical experiment, including patients with basal ganglia hemorrhage/ischemia, brainstem ischemia, other subcortical ischemia, cortical ischemia, and mixed cortical-subcortical ischemia. Electroencephalograms (EEG) were recorded following a resting state lasting for 4 min and three sessions of FV. FV was applied over the muscle belly of the affected limb's biceps for 3 min each session. Beta motor-related EEG power desynchronization overlying S1-M1 was used to indicate the activation of S1-M1, while the laterality coefficient (LC) of the activation of S1-M1 was used to assess the interhemispheric asymmetry of brain activation. (1) Regarding brain lesion profiles, FV could lead to the significant activation of bilateral S1-M1 in patients with basal ganglia ischemia and other subcortical ischemia. The activation of ipsilesional S1-M1 in patients with brainstem ischemia was higher than that in patients with cortical ischemia. No activation of S1-M1 was observed in patients with lesions involving cortical regions. (2) Regarding brain lesion types, FV could induce the activation of bilateral S1-M1 in patients with basal ganglia hemorrhage, which was significantly higher than that in patients with basal ganglia ischemia. Additionally, LC showed no significant correlation with the modified Barthel index (MBI) in all patients, but a positive correlation with MBI in patients with basal ganglia lesions. These results reveal that sensory stimulation can induce lesion-specific activation patterns of S1-M1. This indicates FV could be applied in a personalized manner based on the lesion-specific activation of S1-M1 in stroke patients with different lesion profiles and types. Our study may contribute to a better understanding of the underlying mechanisms of cortical reorganization.


Exploring the accuracy and precision of BP measurements.
Accurate and precise BP measurements are crucial to clinical decision-making and interventions as healthcare professionals aim to prevent complications from hypertension, yet the literature provides no gold standard for measuring BP. This article discusses the additional research necessary to develop best practices and improve patient outcomes.


The use of table fixation staples to control massive presacral hemorrhage: a successful alternative treatment. Report of a case.
Management of presacral hemorrhage has always been a challenge for surgeons because such bleeding can rapidly destabilize a patient during pelvic surgery. Conventional hemostatic measures are often effective for arresting this type of hemorrhage, however, sometimes conventional measures make the problem worse. A number of alternative hemostatic techniques have been proposed. This case report describes a successful tamponade of presacral hemorrhage with a titanium table fixation staple and a cancellous bone graft fixed to the sacrum. The bleeding was stopped immediately and the patient recovered uneventfully. We think this is an effective alternative method for controlling massive hemorrhage from a large hole in presacral fascia.


Predictors of nursing students' intention to receive COVID-19 vaccination: A multi-university study in Saudi Arabia.
This study examined the predictors of student nurses' intention to vaccinate against COVID-19. We measured the nursing students' risk perceptions, anxiety, fears and beliefs on COVID-19 vaccine; attitudes towards it and vaccine literacy (VL). This study is a multi-university study utilizing the quantitative, cross-sectional and predictive approach. Using convenience sampling (n = 1170), we surveyed 10 Saudi universities from November 26, 2020, to December 31, 2020. Forward stepwise multinomial logistic regression was performed in identifying the factors predicting student nurses' intention to vaccinate against COVID-19. The overall mean in the risk perception, anxiety and fear was 9.59 (SD = 2.82, possible range = 1-15), 3.95 (SD = 4.77, possible range = 0-20) and 18.17 (SD = 6.65, possible range = 7-35) respectively. They also reported a mean of 29.90 (SD = 6.56, possible range = 8-40) on COVID-19 belief. COVID-19 positive and negative attitudes mean score was 3.64 (SD = 0.92) and 2.72 (SD = 0.90) in a 1-4 range of scores respectively. The functional and interactive-critical COVID-19 VL of the students were at moderate levels. More than half of the respondents (55.9%) intended to be vaccinated against COVID-19, 17.6% did not intend to do so and 26.5% were unsure. High-risk perceptions, low levels of COVID-19 anxiety, positive beliefs and attitudes towards COVID-19 vaccine, and high levels of interactive-critical COVID-19 VL were significant predictors of student nurses' intentions to vaccinate against COVID-19. Policymakers could consider the factors identified in this study and why the students did not intend to receive the vaccine in planning a nationwide vaccination program. The colleges of nursing could also utilize the findings in developing educational programs that aim to improve VL and beliefs and attitudes towards COVID-19 vaccine.


Telematics enabled virtual simulation system for radiation treatment planning.
In this paper, GALENOS, a Telematics Enabled Virtual Simulation System for Radiation Treatment Planning (RTP) is described. The design architecture of GALENOS is in accordance with the dual aim of virtual simulation of RTP, i.e. to allow (a) delineation of target volume and critical organs, and (b) placement of irradiation fields. An important feature of GALENOS is the possibility for on-line tele-collaboration between health care professionals under a secure framework. The advantages of GALENOS include elimination of patient transfers between departments and health care institutions as well as availability of patient data at sites different than those of his/her physical presence.


A facile preparation of polyaniline/cellulose hydrogels for all-in-one flexible supercapacitor with remarkable enhanced performance.
In this paper, a series of conductive polymer hydrogels based on the β-cyclodextrin grafted cellulose hydrogels with nanostructured polyaniline embedding in three-dimensional networks have been developed. The obtained conductive hydrogels show high flexible and adequate adhesive behavior that endows easy fabrication of all-in-gel supercapacitors, in which the conductive hydrogels can be directly sandwiched between carbon cloths to fabricate extensive all-in-one supercapacitor devices without secondary packaging. The all-in-one supercapacitor delivers superior areal specific capacitance of 1003.50 m F/cm2 without compromising rate capability, which is much higher than those previous reported hydrogels-based supercapacitors. Meanwhile, the supercapacitor exhibits maximum energy density of 89.20 μWh/cm2 and high power density of 800.00 μW/cm2, as well as reliable durability with capacitance retention of 90 % after 2000 consecutive charge-discharge cycles. Three all-in-one supercapacitors in series connection can drive a flash light-emitting diode, which conveys a potential application for eco-friendly energy storage devices.


Neurobehavioural investigations in adolescents exposed to environmental pollutants.
Environmental exposures to industrial pollutants have been associated with lowered intelligence and behavioural problems. The Flemish Environmental and Health Study focussed on biomonitoring of exposure and associated health effects. This part of the study investigated neurobehavioural performance in adolescents in relation to lead (blood Pb), cadmium (urine Cd), polychlorinated biphenyls (PCB concentration of congeners 138, 153 and 180) and compounds with 'dioxin-like' activity (measured by the CALUX-assay). One-hundred and twenty girls and 80 boys (mean age 17.4 years) were enrolled. The NES battery was used to assess simple reaction time, switching attention, digit span forward, hand-eye coordination and symbol-digit substitution (SDS). Multiple regression analysis was performed to study dose-effect relationships between the neurobehavioural outcome variables and the exposure parameters in boys and girls. Slowing of SDS with increasing logPbB and logCdU was seen in boys only (PbB 39-1549nmol/L, CdU 0.02-0.40nmol/mmol creatinine). No dose-effect relations were found with serum PCB concentrations or CALUX-TEQs. Only one of several tests showed a performance decrease related to given environmental exposures to heavy metals. Further studies are needed to clarify whether the pattern of results reflects gender effects or the different exposure characteristics of boys and girls in our study.


A family study of genetic and environmental factors determining polymorphic hydroxylation of debrisoquin.
Debrisoquin hydroxylation capacity determined as the ratio of debrisoquin to 4-OH-debrisoquin (DMR) in urine after a single oral dose (10 mg) was studied in 52 nuclear families comprising 226 subjects. The relative importance of genetic and environmental factors for DMR was studied by path analysis. There was a significant negative correlation between DMR and coffee intake but no significant correlations between DMR and sex, age, alcohol intake, or smoking habits. Path analysis showed that genetic heritability was 0.79 while cultural heritability was only 0.06. Complex segregation analysis gave evidence for a major locus with incomplete dominance (d = 0.28) between a recessive and an additive gene. The frequency of the major gene was 0.31, allowing an estimate of the frequency of slow hydroxylators in the Swedish population of 9.4%. There was also evidence for a multifactorial component accounting for 14% of the total variation. It was not possible to distinguish between the different genotypes within the rapid hydroxylator phenotype. Our data agree with previous studies in British and German populations showing that two alleles at a major autosomal locus can explain most of the observed variation in DMR. The frequency of slow hydroxylators in Sweden is very similar to that reported in other European studies. The debrisoquin metabolic phenotype seems to be extensively controlled by a monogenic system and not significantly influenced by environmental factors or age.


Inhibition of succinate oxidation and K+ transport in mitochondria during hibernation.
Respiration of liver mitochondria of ground squirrels changes with physiological state. The inhibition of respiration at the level of dehydrogenases occurs during hibernation which is spontaneously removed during arousal. The main mechanism causing a decrease in respiration during hibernation seems to be the inhibition of succinate oxidation, induced by oxaloacetic acid. This is evidenced by the removal of the inhibition by glutamic and isocitric acids. A close correlation between the changes of K+ transport in mitochondria and of the physiological state of hibernator is observed. During hibernation the K+ transport rate decreases 3 times and during arousal it increases 1.5-fold in comparison with the active animals. The K+ content in mitochondria of hibernating and active ground squirrels is the same, whereas during arousal it increases 2-fold.


Involvement of protein kinase C in the regulation of ornithine decarboxylase mRNA by phorbol esters in rat hepatoma cells.
The tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) stimulates a rapid increase in ornithine decarboxylase (EC 126.96.36.199; ODC) activity in target cells. Here we demonstrate that this process involves a rapid accumulation of ODC mRNA, which is maximal 3 h after treatment (three- to eightfold greater than control cells) and decays to control levels within 18 h. Stimulation of ODC mRNA by TPA is blocked by phorbol dibutyrate down-regulation of protein kinase C (PKC). ODC mRNA was also induced by the PKC activators, phospholipase C and 1-oleoyl-2-acetyl-rac-glycerol, and blocked by kinase inhibitors (trifluoroperazine, H7, and palmitoyl-L-carnitine), consistent with a requirement for PKC activation in the induction mechanism. However, the non-PKC-specific protein kinase inhibitor HA1004 also suppressed expression of ODC mRNA in response to TPA, under conditions where it did not inhibit PKC, suggesting that additional kinases may be involved in the intracellular signalling process. The stability of the ODC mRNA (control value = 6.2 +/- 1.6 h) is not significantly changed by either TPA (5.7 +/- 0.8 h) or by cycloheximide (6.0 h). These results are inconsistent with any contribution from altered mRNA half-life towards the accumulation of ODC mRNA following treatment with phorbol ester tumor promoters.


Composite electrolytes engineered by anion acceptors for boosted high-voltage solid-state lithium metal batteries.
Solid-state batteries (SSBs) are considered as the most promising option to replace commercial lithium-ion batteries due to their ability to address the flammability of liquid organic electrolytes and facilitate the energy density of lithium batteries. Herein, by introducing tris(trimethylsilyl) borate (TMSB) as anion acceptors, we successfully develop the light and thin electrolyte (TMSB-PVDF-HFP-LLZTO-LiTFSI, PLFB) with a wide voltage window to couple the lithium metal anode with the high-voltage cathodes. Consequently, as-prepared PLFB can greatly boost the generation of free Li+ and improve the Li+ transference numbers (tLi+=0.92) at room temperature. Moreover, combined with theoretical calculation and experimental results, the changes in the composition and properties of the composite electrolyte membrane with the addition of anionic receptors are systematically studied, which further implies the intrinsic mechanism of the stability difference. In addition, the PLFB-based SSB assembled by LiNi0.8Co0.1Mn0.1O2 cathode and lithium anode exhibits a high capacity retention of 86% after loop 400 cycles. This investigation on boosted battery performance by immobilized anions not only contributes to the directional construction of dendrite-free and lithium-ion permeable interface, but also brings new opportunities for the screening and design of the next generation of high-energy SSBs.


The medicinal flora of Native North America: an analysis.
This paper describes an analysis of the plants of North America which have been used medicinally by Native North Americans. A method using regression residuals is developed for analyzing large quantities of data, divided into subgroups of varying sorts and sizes. The analysis shows that the medicinal species utilized by Native North Americans are distributed in a highly non-random fashion across subclasses and families as well as across groups defined in terms of growth habit and life pattern. This distribution makes sense in terms of both the defensive chemistry and the "complexity" of plants.


Family history of cognitive disabilities in first-degree relatives of autistic and mentally retarded children.
We compared with a family history method the rate of cognitive disabilities (CD) in 156 first-degree relatives of 49 autistic (AU) probands to that found in 55 first-degree relatives of 18 mentally retarded (MR) probands. Broadly defined CD were found in, respectively, 17 and 16% of the relatives of the AU and MR probands. However, the characteristics of the probands associated with a family history of CD are different in AU and MR: Female and low IQ AU probands have more first-degree relatives with CD. Our findings suggest that a positive family history of CD is not specific to autism when compared to mental retardation. The observation that female and low IQ probands have higher family history of CD may suggest heterogeneity within autistic children and provides leads for future family studies.


Neuronal network activity and connectivity are impaired in a conditional knockout mouse model with PCDH19 mosaic expression.
Mutations in PCDH19 gene, which encodes protocadherin-19 (PCDH19), cause Developmental and Epileptic Encephalopathy 9 (DEE9). Heterogeneous loss of PCDH19 expression in neurons is considered a key determinant of the disorder; however, how PCDH19 mosaic expression affects neuronal network activity and circuits is largely unclear. Here, we show that the hippocampus of Pcdh19 mosaic mice is characterized by structural and functional synaptic defects and by the presence of PCDH19-negative hyperexcitable neurons. Furthermore, global reduction of network firing rate and increased neuronal synchronization have been observed in different limbic system areas. Finally, network activity analysis in freely behaving mice revealed a decrease in excitatory/inhibitory ratio and functional hyperconnectivity within the limbic system of Pcdh19 mosaic mice. Altogether, these results indicate that altered PCDH19 expression profoundly affects circuit wiring and functioning, and provide new key to interpret DEE9 pathogenesis.


Influence of infrared camera model and evaluator reproducibility in the assessment of skin temperature responses to physical exercise.
Infrared thermography (IRT) has been gaining in popularity in clinical and scientific research due to the increasing availability of affordable infrared cameras. This study aims to determine the similarity of measurement performance between three models of IRT camera during assessment of skin temperature before and after physical exercise. Three models of FLIR thermographic cameras (E60bx, Flir-One Pro LT, and C2) were tested. Thermal images were taken of the foot sole, anterior leg, and anterior thigh from 12 well-trained men, before and after a 30-min run on a treadmill. Image files were blinded and processed by three evaluators to extract the mean, maximum, and standard deviation of skin temperature of the region of interest. Time for data processing and rate of perceived effort was also recorded. Data processing was slower on the E60bx (CI95% E60 vs C2 [0.2, 2.6 min], p = 0.02 and ES = 0.6); vs. Flir-One [0.0, 3.4 min], p = 0.03 and ES = 0.6) and was associated with lower effort perception (E60 3.0 ± 0.1 vs. Flir-One 5.6 ± 0.2 vs C2 7.0 ± 0.2 points; p < 0.001 and ES > 0.8). The C2 and Flir-One cameras underestimated the temperature compared with the E60. In general, measuring mean temperature provided higher camera and examiner intra-class correlations than maximum and standard deviation, especially before exercise. Moreover, post exercise mean skin temperatures provided the most consistent values across cameras and evaluators. We recommend the use of mean temperature and caution when using more than one camera model in a study.


Management of infective complications in patients with advanced hematologic malignancies in home care.
A home care service has been implemented at our center with the aim of offering domiciliary assistance to patients with hematologic malignancies in advanced phase. We report our experience concerning the home management of these patients in the setting of infective complications. Of 151 patients in home care, 70 (46%) developed a total of 109 febrile episodes, performance status and neutrophil count significantly affecting the incidence of infections. Fever was of unknown origin in 51% of cases and microbiologically and clinically documented infections accounted for 26 and 23% of the cases, respectively. Oral ciprofloxacin in patients not neutropenic and intravenous ceftriaxone plus amikacin in neutropenic patients was shown to be effective and suitable for empiric home antibacterial treatment; in fact, 65% of febrile episodes responded to the initial antibacterial therapy with a further 16% after modification. Overall, 19.3% of the infective episodes were fatal, the prognosis appearing to be similar to that usually observed in the same category of patients in an inpatient setting. Our experience appears to show that a home care program could be the option of choice for patients with advanced cancer even in the setting of infective complications. It could improve the quality of life of patients and of their families, and it could save these subjects the risk of developing infections by resistant nosocomial isolates.


Results of bilateral cataract extraction with posterior chamber intraocular lens implantation in children.
A retrospective study was undertaken to evaluate long-term anatomic and visual outcomes in eyes of children who underwent bilateral intraocular lens implantation. The study design was a review of medical records of 24 children operated on for bilateral cataracts and posterior chamber-intraocular lenses. Twenty-four children operated on for bilateral cataracts by 1 surgeon between February 1980 and February 1995 were studied. Cataract extraction with bilateral posterior chamber-intraocular lens implantation was performed. Best-corrected visual acuity, visual acuity without correction, intraocular pressure, manifest refraction, and any intraoperative or postoperative complications were measured. At last follow-up (mean follow-up, 50.8 months; range, 10-149 months), the intraocular lens was in good position and the intraocular pressure was normal without medication in all eyes. Four years after surgery, 79.2% (19 of 24) of first eyes achieved a best-corrected visual acuity of 20/40 or better compared to 66.7% (16 of 24) of second eyes. No eye had any loss in best-corrected visual acuity. In first eyes of 3- to 8-year olds at the time of surgery, 73.3% (11 of 15) achieved a spherical equivalent within 2 diopters of the intended at 4 years after surgery compared to 80% of second eyes. In the 9- to 18-year-old group, 88.9% (8 of 9) of first eyes and 100% of second eyes achieved a spherical equivalent within 2 diopters of the intended at 4 years after surgery. Intraoperative and postoperative complications were minimal. Long-term anatomic and visual results have been gratifying in this series of patients with bilateral implants.


Contemporary real-world outcomes of surgical aortic valve replacement in 141,905 low-risk, intermediate-risk, and high-risk patients.
The introduction of transcatheter aortic valve replacement mandates attention to outcomes after surgical aortic valve replacement (SAVR) in low-risk, intermediate-risk, and very high-risk patients. The study population included 141,905 patients who underwent isolated primary SAVR from 2002 to 2010. Patients were risk-stratified by Society of Thoracic Surgeons (STS) predicted risk of mortality (PROM) <4% (group 1, n = 113,377), 4% to 8% (group 2, n = 19,769), and >8% (group 3, n = 8,759). The majority of patients were considered at low risk (80%), and only 6.2% were categorized as being at high risk. Outcomes were analyzed based on two time periods: 2002 to 2006 (n = 63,754) and 2007 to 2010 (n = 78,151). The mean age was 65 years in group 1, 77 in group 2, and 77 in group 3 (p < 0.0001). The median STS PROM for the entire population was 1.84: 1.46% in group 1, 5.24% in group 2, and 11.2% in group 3 (p < 0.0001). Compared with PROM, in-hospital mean mortality was lower than expected in all patients (2.5% vs 2.95%) and when analyzed within risk groups was as follows: group 1 (1.4% vs 1.7%), group 2 (5.1% vs 5.5%), and group 3 (11.8% vs 13.7%) (p < 0.0001). In the most recent surgical era, operative mortality was significantly reduced in group 2 (5.4% vs 6.4%, p = 0.002) and group 3 (11.9% vs 14.4%, p = 0.0004) but not in group 1. Nearly 80% of patients undergoing SAVR have outcomes that are superior to those by the predicted risk models. In the most recent era, early results have further improved in medium-risk and high-risk patients. This large real-world assessment serves as a benchmark for patients with aortic valve stenosis as therapeutic options are further evaluated.


Environmental heat stress enhances mental fatigue during sustained attention task performing: evidence from an ASL perfusion study.
This study was to investigate the potential enhancing effect of heat stress on mental fatigue progression during sustained attention task using arterial spin labeling (ASL) imaging. Twenty participants underwent two thermal exposures in an environmental chamber: normothermic (NT) condition (25°C, 1h) and hyperthermic (HT) condition (50°C, 1h). After thermal exposure, they performed a twenty-minute psychomotor vigilance test (PVT) in the scanner. Behavioral analysis revealed progressively increasing subjective fatigue ratings and reaction time as PVT progressed. Moreover, heat stress caused worse performance. Perfusion imaging analyses showed significant resting-state cerebral blood flow (CBF) alterations after heat exposure. Specifically, increased CBF mainly gathered in thalamic-brainstem area while decreased CBF predominantly located in fronto-parietal areas, anterior cingulate cortex, posterior cingulate cortex, and medial frontal cortex. More importantly, diverse CBF distributions and trend of changes between both conditions were observed as the fatigue level progressed during subsequent PVT task. Specifically, higher CBF and enhanced rising trend were presented in superior parietal lobe, precuneus, posterior cingulate cortex and anterior cingulate cortex, while lower CBF or inhibited rising trend was found in dorsolateral frontal cortex, medial frontal cortex, inferior parietal lobe and thalamic-brainstem areas. Furthermore, the decrease of post-heat resting-state CBF in fronto-parietal cortex was correlated with subsequent slower reaction time, suggesting prior disturbed resting-state CBF might be indicator of performance potential and fatigue level in following task. These findings may provide proof for such a view: heat stress has a potential fatigue-enhancing effect when individual is performing highly cognition-demanding attention task.


Doping dependence of the coupling of electrons to bosonic modes in the single-layer high-temperature Bi2Sr2CuO6 superconductor.
A recent highlight in the study of high-T(c) superconductors is the observation of band renormalization or self-energy effects on the quasiparticles. This is seen in the form of kinks in the quasiparticle dispersions as measured by photoemission and interpreted as signatures of collective bosonic modes coupling to the electrons. Here we compare for the first time the self-energies in an optimally doped and strongly overdoped, nonsuperconducting single-layer Bi-cuprate (Bi2Sr2CuO6). In addition to the appearance of a strong overall weakening, we also find that the weight of the self-energy in the overdoped system shifts to higher energies. We present evidence that this is related to a change in the coupling to c-axis phonons due to the rapid change of the c-axis screening in this doping range.


Triphasic waves in cerebral carcinomatosis. Another nonmetabolic cause.
A 59-year-old woman with a metastatic adenocarcinoma of unknown origin and no metabolic abnormalities developed a diffuse encephalopathy, with generalized triphasic waves seen on the electroencephalogram. Postmortem examination revealed widespread, multifocal perivascular carcinomatosis of the cerebral cortices. Triphasic waves have been described with dementing processes, subdural hematomas, and cerebrovascular disease, but they are more commonly seen with metabolic encephalopathies. This case demonstrates an additional nonmetabolic cause of triphasic waves.


Unusual abscess formation in colon cancer with mucinous components.
Colon cancer with mucinous components was accompanied by bacterial infection and abscess formation.


Impact of GBA variants on longitudinal freezing of gait progression in early Parkinson's disease.
Freezing of gait (FOG) is a common disabling gait disturbance among patients with Parkinson's disease (PD), but the influence of genetic variants on the incidence of FOG has been poorly studied to date. We aimed to evaluate the association of GBA variants with the risk of FOG development in a large early PD cohort. This study included 371 early PD patients from the Parkinson's Progression Markers Initiative (PPMI) who were divided into a GBA variant carrier group (GBA-PD group, n = 44) and an idiopathic PD group without GBA variants (iPD group, n = 327). They were followed up for up to 5 years to examine the progression of FOG. The cumulative incidence of FOG and risk factors for FOG were assessed using Kaplan‒Meier and Cox regression analyses. At baseline, the GBA-PD group had lower CSF β-amyloid 1-42 (Aβ42) levels and more severe motor and nonmotor symptoms than the iPD group. During the 5-year follow-up, the GBA-PD group had a higher incidence of FOG than the iPD group, and the FOG progression rate was related to GBA variant severity. In the multivariable Cox model without CSF Aβ42, GBA variants were significant predictors of future FOG, and the association remained significant after adding CSF Aβ42 to the model. In the subgroup analyses, the effect of GBA variants was not observed in the "low-level" group. However, in the "high-level" group, GBA variants independently increased the risk of FOG, and this association was stronger than the association with CSF Aβ42. GBA variants are novel genetic risk factors for future FOG development in early PD patients. This association seemed to be mediated by both Aβ-dependent pathways and Aβ-independent pathways.


Vitellogenin polypeptide levels in one susceptible and one cadmium-resistant strain of Oncopeltus fasciatus (Heteroptera: Lygaeidae), and its role in cadmium resistance.
The heavy metal Cd has recently been shown to have endocrine disrupting activity in different vertebrate species. In the insect Oncopeltus fasciatus, Cd exposure delays ovarian maturation and inhibits vitellogenesis, probably through a reduction in vitellogenin (Vg) polypeptide synthesis. An O. fasciatus strain was selected in the laboratory for Cd resistance with gradually increasing Cd concentrations for 50 generations. Cd-selected (OCdR) insects were 2.7-2.3 times more resistant to chronic exposure to Cd than susceptible (OS) insects. OCdR females showed increased (up to 90%) Vg polypeptide levels in hemolymph. Vg polypeptide synthesis was equally decreased in OCdR and OS females after acute Cd exposure, indicating that resistance in the OCdR strain was not due to a reduced sensitivity of the target of Cd. Vg polypeptide concentrations and ovarian maturation in acutely exposed OCdR females, however, were equal to those of control OS females. OCdR females chronically exposed to Cd showed a 30% decrease in Vg polypeptide concentrations, relative to control OS females. It is concluded that increased Vg polypeptide levels play an important role in resistance to the toxic effects of Cd on reproduction in the OCdR strain, and that this novel Cd resistance mechanism has the potential to evolve in vertebrate species in which Cd inhibits Vg synthesis by disruption of the endocrine system.


A novel JAK inhibitor JTE-052 reduces skin inflammation and ameliorates chronic dermatitis in rodent models: Comparison with conventional therapeutic agents.
Janus kinases (JAKs) are required for several inflammatory cytokine signalling pathways and are implicated in the pathogenesis of chronic dermatitis, including atopic dermatitis and psoriasis. JAK inhibitors are therefore promising therapeutic candidates for chronic dermatitis. In this study, we evaluated the effects of the novel JAK inhibitor JTE-052 on inflammatory responses associated with chronic dermatitis, and compared its profile with those of conventional therapeutic agents in rodent models of chronic dermatitis. JTE-052 inhibited the Th1-, Th2- and Th17-type inflammatory responses of human T cells and mast cells in vitro. Oral administration of JTE-052 inhibited skin inflammation in hapten-induced chronic dermatitis in mice, associated with reduced levels of inflammatory cytokines in the skin and immunoglobulin (Ig) E in serum. In contrast, although ciclosporin partly inhibited skin inflammation, it did not reduce interleukin (IL)-4 production in skin, and enhanced IgE production in serum. Oral administration of JTE-052 also inhibited skin inflammation in mouse models of atopic dermatitis and psoriasis induced by a mite extract, thymic stromal lymphopoietin or IL-23. The maximal efficacy of JTE-052 in these dermatitis models was superior to the conventional therapeutic agents, ciclosporin and methotrexate. Topical application of JTE-052 ointment ameliorated hapten-induced chronic dermatitis in rats more effectively than tacrolimus ointment. Furthermore, JTE-052 ointment did not cause the thinning of normal skin associated with topical corticosteroids. These results indicate that JTE-052 is a promising candidate as an anti-inflammatory drug for various types of chronic dermatitis, with a distinctly different profile from conventional therapy following either oral or topical application.


Cleavage of peptide-4-nitroanilide substrates with varying chain length by human leukocyte elastase.
Two series of substrates with the formulas H-Alan-Val-4-nitroanilide and 3-carboxypropionyl-Alan-Val-4-nitroanilide (n = 1, 2 and 3) were synthesized. Elongation of the peptide chain yields increasingly better substrates for human leukocyte elastase both in terms of Km and kcat. These results indicate an extended substrate binding site for the enzyme.


The local component of the acute cardiovascular response to simulated apneas in brain-dead humans.
To investigate the local cardiovascular response to hypoxemia and hypercapnia in a simulated central apnea model in which the central autonomic regulation was absent. Experimental study. A university hospital. A simulated central apnea model achieved by a particular setting of the mechanical ventilator in 10 brain-dead patients. Hemodynamic studies using right-heart catheterization and continuous monitoring of arterial blood gas levels. Hypercapnic hypoxic apneas were associated with no change in heart rate, fall in mean systemic arterial pressure and systemic vascular resistance (from 83 +/- 9 to 68 +/- 7 mm Hg and 1,115 +/- 82 to 768 +/- 58 dyne.s.cm(-5), respectively; each p < 0.05), and rise in mean pulmonary artery pressure, pulmonary vascular resistance, and pulmonary capillary wedge pressure (PCWP) [from 17 +/- 1.5 to 26 +/- 3 mm Hg, 102 +/- 27 to 166 +/- 43 dyne.s.cm(-5), and 10 +/- 1 to 14 +/- 2 mm Hg, respectively; each p < 0.05]. Our results suggest that in the absence of central autonomic regulation in humans, apnea-induced hypoxemia and/or hypercapnia are associated with peripheral vasodilatation and pulmonary vasoconstriction, which are probably local in origin, as well as a significant increase in PCWP indicating cardiac dysfunction.


AIDS-related progressive multifocal leukoencephalopathy.
Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system caused by reactivation of JC virus (JCV). We described the profile of laboratory-confirmed PML cases among AIDS patients. A total of 43 HIV patients with clinical conditions compatible with PML were obtained; 5 cases were confirmed by JCV testing. The main clinical finding was mental confusion. Median CD4 count was 54 cells/mm³. Three of the five confirmed PML cases died; the time between diagnosis and death was 2, 5, and 6 months. It is important to consider JCV infection as a differential diagnosis.


Effect of endothelial cell heterogeneity on nanoparticle uptake.
Endothelial cells exhibit distinct properties in morphology and functions in different organs that can be exploited for nanomedicine targeting. In this work, endothelial cells from different organs, i.e. brain, lung, liver, and kidney, were exposed to plain, carboxylated, and amino-modified silica. As expected, different protein coronas were formed on the different nanoparticle types and these changed when foetal bovine serum (FBS) or human serum were used. Uptake efficiencies differed strongly in the different endothelia, confirming that the cells retained some of their organ-specific differences. However, all endothelia showed higher uptake for the amino-modified silica in FBS, but, interestingly, this changed to the carboxylated silica when human serum was used, confirming that differences in the protein corona affect uptake preferences by cells. Thus, uptake rates of fluid phase markers and transferrin were determined in liver and brain endothelium to compare their endocytic activity. Overall, our results showed that endothelial cells of different organs have very different nanoparticle uptake efficiency, likely due to differences in receptor expression, affinity, and activity. A thorough characterization of phenotypic differences in the endothelia lining different organs is key to the development of targeted nanomedicine.


Ratings of Emotional Expressions in Static and Dynamic Facial Recordings Before and After Upper Face Botulinum Injections-An Observational Prospective Study.
Botulinum toxin A (BTX), a neurotoxin widely used for facial aesthetics, causes dose-dependent muscle paralysis. It was hypothesized that treatment of mimic muscles with BTX might have a positive impact on emotional expression in static images (photographs), but a negative impact in dynamic recordings (videos). The aim of this study was to compare of emotional expression recorded in photographs and videos before and after treatment with BTX. Twenty healthy women (mean age, 45 years) received a dose of 19 mouse units of XEOMIN (Merz, Frankfurt am Main, Germany) into the procerus, occipitofrontalis, and orbicularis oculi muscles. Photographs and videos of the participants' faces with neutral and happy expressions were recorded before treatment and 2 weeks later. Recordings were rated by naive raters blind to the conditions and in balanced order. Videos were generally rated as more pleasant, arousing, attractive, and genuine than photographs (all Ps > 0.001). This was especially the case for videos with neutral expression (P = 0.003). Independent of presentation mode and facial expression, women were rated as more attractive after BTX treatment (P = 0.03). In contrast to the hypothesis, the reduced mobility had no detectable negative impact on dynamic emotional expression, but videos received more positive ratings, particularly for neutral expressions. It is thus recommended to assess emotional expression with dynamic recordings to evaluate the effects of treatment with BTX. BTX seems to improve perceived attractiveness, although the cause of this effect remains unclear.


Endarterectomy for calcified porcelain aorta associated with aortic valve stenosis.
A calcified porcelain aorta may complicate aortic valve insertion and require an alternative, more complex method for valve replacement. The reason for this is that sutures cannot be inserted through the calcific plates in the annulus and ascending aorta. In 6 patients with an average age of 73.8 years (range, 65 to 81 years), we performed the simpler procedure of aortic endarterectomy of the calcific plates with the aortic valve replacement. We realized that there may be an increased risk of postoperative complications, particularly stroke. The calcific plates were fractured to allow debridement of the calcium. In addition, an end-arterectomy was performed of the left main coronary ostium in 2 patients, and 5 patients also had coronary artery bypass grafting performed. All 6 patients underwent successful operations without major complications. On follow-up, echocardiography or computed tomographic scans in 3 patients have not shown dilation of the ascending aorta. Endarterectomy of the aorta may be an option in the management of patients with calcification of the aorta.


Decompressive Craniectomy for Malignant Ischemic Stroke: An Institutional Experience of 145 Cases in a Brazilian Medical Center.
Malignant ischemic stroke (MIS) occurs in a subgroup of patients with cerebrovascular accident who sustain massive or significant cerebral infarction. It is characterized by neurological deterioration owing to progressive edema, raised intracranial pressure, and cerebral herniation. Decompressive craniectomy (DC) is a surgical technique that can be used to treat select cases of this condition in the presence of medically refractory intracranial hypertension. This study aimed to identify prognostic factors associated with clinical outcome, including timing of the procedure, and postoperative mortality. We analyzed surgical characteristics associated with prognosis in 145 patients who underwent DC secondary to MIS between 2013 and 2018, assessing clinical outcome at discharge and 6 and 12 months after discharge. Our inclusion criteria were DC secondary to MIS in adult patients with raised intracranial pressure signs. Our analysis showed that although patients from cities >100 km from the neurosurgical center had a worse prognosis, only the surgical head side (left vs. right, P = 0.001), hospitalization length (P < 0.001), and earlier timing of procedure (P < 0.001) were statistically relevant in having worse outcomes. Patients in whom more time passed from presentation to the neurosurgical procedure, owing to living in a distant city or taking more time to be seen by a specialist, tended to have a worse prognosis. The timing of procedure, surgical side, and hospitalization length were independent predictors in determining the prognosis of patients who underwent DC after an MIS.


The Risk of Cardiovascular Events on Cannabis' Highest Day.
Knowledge of the acute cardiovascular effects of cannabis consumption remains largely unknown and is important given the changing landscape of legalization of recreational cannabis use. "4/20" is an annual event where many individuals gather to consume cannabis. An increased risk of adverse health events such as motor vehicle accidents has previously been reported to occur on "4/20." In this study, population-based administrative databases in Ontario, Canada, were used to evaluate the association between "4/20" and cardiovascular events. An increased risk of cardiovascular events on a population level was not observed on "4/20." Additional research into the changes in the prevalence of the use of cannabis with recreational legalization and acute and chronic risk with cannabis use is suggested.


Comparison of the AAPT Fibromyalgia Diagnostic Criteria and Modified FAS Criteria with Existing ACR Criteria for Fibromyalgia in Korean Patients.
Recently, new sets of diagnostic criteria were proposed, including criteria by the ACTTION-American Pain Society Pain Taxonomy (AAPT) group and Fibromyalgia Assessment Status (FAS) 2019 modified criteria for fibromyalgia (FM). Here, we explored the performances of the AAPT criteria and modified FAS criteria for diagnosing FM compared to existing American College of Rheumatology (ACR) criteria. We enrolled 95 patients with FM and 108 patients who had other rheumatologic disorders, including rheumatoid arthritis, systemic lupus erythematosus, osteoarthritis, and myofascial pain syndrome. All patients were classified using proposed criteria including the 1990, 2010, 2011, and 2016 versions of the ACR criteria. In patients with existing FM diagnoses, FM was diagnosed in 56.8% using the AAPT criteria and in 60.0% using the modified FAS criteria. However, FM was diagnosed in 37.9%, 97.9%, 90.5%, and 94.7% of those patients using the 1990, 2010, 2011, and 2016 ACR criteria, respectively. For the AAPT criteria, the sensitivity was 56.8% and the specificity was 94.4%. For the modified FAS criteria, the sensitivity was 60.0% and the specificity was 92.6%. The areas under the receiver-operating characteristic curve were 0.852 (95% confidence interval [CI] 0.801-0.903) for the AAPT criteria and 0.903 (95% CI 0.861-0.944) for the modified FAS criteria, which were lower than the existing ACR criteria. Although the AAPT criteria and modified FAS criteria have simplified the diagnostic criteria to facilitate patient identification, their poor diagnostic accuracy will limit the adoption and spread of these criteria in routine clinical practice.


A Meaningful and Actionable Professionalism Assessment: Validity Evidence for the Professionalism Mini-Evaluation Exercise (P-MEX) Across 8 Years.
With the growing importance of professionalism in medical education, it is imperative to develop professionalism assessments that demonstrate robust validity evidence. The Professionalism Mini-Evaluation Exercise (P-MEX) is an assessment that has demonstrated validity evidence in the authentic clinical setting. Identifying the factorial structure of professionalism assessments determines professionalism constructs that can be used to provide diagnostic and actionable feedback. This study examines validity evidence for the P-MEX, a focused and standardized assessment of professionalism, in a simulated patient setting. The P-MEX was administered to 275 pediatric residency applicants as part of a 3-station standardized patient encounter, pooling data over an 8-year period (2012 to 2019 residency admission years). Reliability and construct validity for the P-MEX were evaluated using Cronbach's alpha, exploratory factor analysis (EFA), and confirmatory factor analysis (CFA). Cronbach's alpha for the P-MEX was 0.91. The EFA yielded 4 factors: doctor-patient relationship skills, interprofessional skills, professional demeanor, and reflective skills. The CFA demonstrated good model fit with a root-mean-square error of approximation of .058 and a comparative fit index of .92, confirming the reproducibility of the 4-factor structure of professionalism. The P-MEX demonstrates construct validity as an assessment of professionalism, with 4 underlying subdomains in doctor-patient relationship skills, interprofessional skills, professional demeanor, and reflective skills. These results yield new confidence in providing diagnostic and actionable subscores within the P-MEX assessment. Educators may wish to integrate the P-MEX assessment into their professionalism curricula.


Predicting pulmonary tuberculosis in immigrants: a retrospective cohort study.
Our objective was to investigate whether pulmonary tuberculosis (PTB) can be predicted from features of a targeted medical history and basic laboratory investigations in immigrants. A retrospective cohort of 391 foreign-born adults referred to the Edmonton Tuberculosis Clinic (Edmonton, AB, Canada) was studied using multiple logistic regression analysis to predict PTB. Seven characteristics of disease were used as explanatory variables. Cross-validation assessed performance. Each predictor was tested on two outcomes: "culture-positive" and "smear-positive". Receiver operating characteristic (ROC) curves were generated and the area under the ROC curve (AUC) was quantified. Symptoms, subacute duration of symptoms, risk factors for reactivation of latent TB infection and anaemia were all associated with a positive culture (adjusted OR 1.79, 2.24, 1.72 and 2.28, respectively; p<0.05). Symptoms, inappropriate prescription of broad-spectrum antibiotics and a "typical" chest radiograph were associated with smear-positive PTB (adjusted OR 2.91, 1.55 and 12.34, respectively; p<0.05). ROC curve analysis was used to test each model, yielding AUC=0.91 for the outcome "culture-positive" disease and AUC=0.94 for the outcome "smear-positive" disease. PTB among the foreign-born can be predicted from a targeted medical history and basic laboratory investigations, raising the threshold of suspicion in settings where the disease is relatively rare.


Diaphragmatic hernia in the fetus: prenatal diagnosis and outcome in 94 cases.
Most babies born with congenital diaphragmatic hernia (CDH) die after birth. The natural course of CDH in the human fetus is not known. We found 94 cases of fetal CDH in the records of surgeons and obstetricians surveyed in the United States and Canada. We found the following: (1) prenatal diagnosis of CDH is accurate and current techniques can detect lethal nonpulmonary anomalies and prevent diagnostic errors; (2) despite optimal conventional therapy, most fetuses with detectable CDH will die in the neonatal period (80% mortality); (3) polyhydramnios is both a common prenatal marker for CDH (present in 76% of fetuses) and a predictor for poor clinical outcome (only 11% survived); (4) fetal CDH is a dynamic process--nonsurvivors have larger defects and may have more viscera displaced into the chest at an earlier stage of development. Surgical intervention before birth may be necessary to improve survival of the fetus with CDH and polyhydramnios.


An electrophoretic analysis of selected enzymes of the coconut crab, Birgus latro.
1. Employing starch gel electrophoresis at pH 8.6, a single anodal band of L(+)-lactate dehydrogenase activity was found in skeletal muscle of Birgus latro. 2. Two anodal malate dehydrogenase isozymes were observed in heart, skeletal muscle and pericardial gland tissue. Lung and gill exhibited the faster moving band only. 3. Multiple bands of esterase activity were detected in all tissues examined employing alpha-naphthylacetate or alpha-butyrate as substrate. 4. Multiple molecular forms of superoxide dismutase were observed in all tissues examined. 5. Lung exhibited a single cathodal band of carbonic anhydrase activity.


Limited awareness of HIV Status hinders uptake of treatment among female sex workers and sexually exploited adolescents in Wau and Yambio, South Sudan.
Several factors determine uptake of HIV testing services (HTS) by female sex workers (FSW), including their knowledge of HIV and their awareness of services supporting people who are HIV-positive. HTS provided entry into the UNAIDS 90-90-90 cascade of care. We conducted a cross-sectional biobehavioural survey (BBS) to determine HIV prevalence and progress towards UNAIDS 90-90-90 cascade targets among this population in South Sudan. Respondent-driven sampling (RDS) was used to recruit women and sexually exploited girls aged 13-18 years who exchanged sex for goods or money in the past 6 months and resided in the town for at least 1 month. Consenting participants were interviewed and tested for HIV and, if positive, they were also tested for their viral load (VL). Data were weighted in RDS Analyst and analyzed with Stata 13. A total of 1,284 participants were recruited. The overall HIV cascade coverages were 64.8% aware of their HIV-positive status; 91.0% of those aware of their positive status were on ART; and VL suppression among those on ART was 93.0%. Being unaware of their HIV-positive status limits, the uptake of HIV treatment among FSW in South Sudan. This underscores the importance of optimized case-finding approaches to increase HTS among FSW and sexually exploited minors.


From advance directives to advance care planning: current legal status, ethical rationales and a new research agenda.
This paper uses a case example to review the current legal status of advance directives, as well as their ethical rationale. We draw attention to ongoing efforts to institutionalize advance directives, and to some of the tractable and intractable reasons why advance directives are ineffective. We then introduce the concept of advance care planning, and argue that we should not assume that advance care directives have a place in this process. We conclude by offering three reasons why this assumption may operate, and by suggesting that contingency and uncertainty may sometimes overwhelm all rational approaches to medical care.


A multiple regression based method for indirect compensation of hemispherical resonator gyro temperature error.
In order to improve the measuring accuracy of the Hemispherical Resonator Gyro under variable temperature, aiming at the problem of "external temperature is unavailable and internal temperature is unmeasurable," a multiple regression based method is proposed for compensating temperature error in the gyro. The relationship between the internal temperature and the resonant frequency of the gyro is analyzed theoretically. According to a constant temperature experiment, a linear relationship between them is derived based on the least square method. The analysis of a temperature-rising experiment shows that the correlation of the gyro output with the internal temperature is much higher than that with the external temperature. Therefore, taking the resonant frequency as an independent variable, a multiple regression model is established for compensating the temperature error. The compensation effect of the model is verified by temperature-rising and temperature-dropping experiments, which show that the output sequence before compensation is not stable, while it is stable after compensation. After compensation, the drift of the gyro decreases by 62.76% and 48.48%, respectively, and its measuring accuracy becomes equivalent to that at the constant temperature. The experimental results verify the feasibility and effectiveness of the model developed for indirect compensation of temperature error.


Independent socio-demographic and clinical correlates associated with the perception of quality of life of women with postpartum depressionin North-central, Nigeria.
Quality of life (QoL) is probably the most desired outcome of all health care policies and monitoring. This concept is seldom used on women in the postpartum, especially in the developing world. This study aimed at determining the independent socio-clinical variables associated with the perception of QoL of women with postpartum depression. A two-stage cross-sectional procedure was used to recruit 550 participants, out of whom 531 participants completed the questionnaires with 116 participants found to have postpartum depression and were the studied population, in Nigeria. The Socio-demographic questionnaire, the Edinburgh Postnatal Depression Scale, the World Health Organization Quality of Life-Bref-26 and the Depression Module of the Structured Clinical Interview for DSM-IV axis I Diagnosis were used. Participants with postpartum depression had significantly poor perception of QoL in all the four domains of the WHOQoL-BREF-26. The independent socio-demographic and clinical correlate associated with poor perception for both rating of QoL and satisfaction with health was education (β = 0.321, p < .001 and β = 0.0326, p = .002, respectively); for physical domain [(modes of delivery) (β = -0.28, p = .016)]; psychological domain [(age <35years) (β = 0.391, p = .010)] and for social relationships [(complications during delivery) (β = 0.257, p = .043)]. The determination of the predictors of QoL, which is an indicator of disease outcome will improve service delivery to women of childbearing age.


Effects of anti-osteoporosis medications on total hip arthroplasty risks in osteoporotic patients with hip osteoarthritis in Taiwan: a nationwide cohort study.
This nationwide cohort study examined the potential disease-modifying effect of anti-osteoporosis medication on hip osteoarthritis. The results revealed that the usage of anti-osteoporosis medication is not associated with decreased risk in undergoing total hip arthroplasty in patient with hip osteoarthritis. This study aimed to assess the association between use of anti-osteoporosis medications (AOMs) and the risk of undergoing total hip arthroplasty (THA) in patients with hip osteoarthritis (OA). Using the 2008-2013 National Health Insurance Research Database, we identified patients who were first diagnosed as having hip OA. All identified patients were followed until THA, death of any cause, or December 31, 2013, whichever occurred first. All AOM exposures were divided into three categories: bisphosphonates use, non-bisphosphonates use, and no use of AOMs and assessed in a time-varying manners. The primary outcome was THA. The secondary outcome was the differences in the longitudinal utilization of NSAIDs between AOM users and non-users. Time-dependent Cox proportional hazards models were used to investigate the effect of AOM use on the risk of THA. We identified 35,870 patients who were first diagnosed as having hip OA and had no history of AOM use between 2009 and 2012. Among them, 3162 and 1667 patients had their first prescription of bisphosphonates and other non-bisphosphonates AOMs during the follow-up period. Mean age of bisphosphonates users, non-bisphosphonates users, and non-users was 75.62, 76.84, and 67.39 years, respectively. Bisphosphonates or non-bisphosphonates users did not show significant change when compared to non-users in terms of risk of undergoing THA [adjusted hazard ratio (aHR) 0.972, 95% confidence interval (CI) 0.743-1.273; aHR 0.926, 95% CI 0.672-1.277]. Our results showed that the use of AOMs is not associated with decreased risk of THA in patients with hip OA.


Onset and duration of cycloplegic action of 1% cyclopentolate - 1% tropicamide combination.
To study the time course (onset, time and duration of maximal cycloplegia, and the full duration) of cycloplegic action of 1% Cyclopentolate - 1% Tropicamide. Seventy-seven students, aged 15-24 years were purposively sampled from the University of Cape Coast and Cape Coast Technical Institute. Subjective near addition (ADD) determination and pupil diameter measurement before and after a drop of the test agent (1% Cyclopentolate - 1% Tropicamide combination in the right eye) and the control (1% Cyclopentolate in the left eye) were performed. Measurements of subjective near ADD and pupil diameter were made after the initial reading at 5 minutes interval for the first hour and every 30 minutes for the next 7 hours for each participant. Time of onset, time of peak cycloplegia, duration of peak cycloplegia and duration of total cycloplegic effect was indirectly determined. 1% Cyclopentolate - 1% Tropicamide combination had rapid onset of cycloplegia (5-10 minutes), shorter time of maximal cycloplegia (55 versus 90 minutes), and recovery (7 versus ≥ 8hours) in the majority (79.2%) of subjects. Cyclopentolate -Tropicamide combination was comparable to Cyclopentolate in depth of cycloplegia produced, and clinically superior to 1% Cyclopentolate in rapidity of cycloplegic onset, time of maximal cycloplegia and recovery from cycloplegia.


Linking energy metabolism to dysfunctions in mitochondrial respiration--a metabolomics in vitro approach.
The study presented here describes the application of metabolite profiling of highly polar, intracellular metabolites after incubation of a mammalian fibroblast cell line with inhibitors of mitochondrial function. A metabolomics approach was used to assess the complex response of the cellular energy metabolism. Metabolic profiles of phosphorylated and carboxylated intracellular metabolites were assessed by UPLC-MS/MS and used to predict the mode of mitochondrial toxicity. Based on distinct metabolic patterns, multivariate data analysis allowed for the discrimination of two groups of toxins: inhibitors of the electron transport in mitochondrial membranes (complex IV inhibitors) and uncouplers of oxidative phosphorylation. Beyond these known interferences, metabolic profiling was able to reveal additional inhibitory effects on the cellular energy metabolism. Most prominently, for three of the toxins, metabolic patterns also disclosed an enhanced activity of the glycerol phosphate shuttle inferring the inhibition of NADH dehydrogenase at complex I. Secondly, inhibition of the electron transport was accompanied by a limiting availability of citric acid cycle intermediates and aspartate. Concomitantly, specific perturbations of the purine nucleotide cycle were observed. We have shown here that metabolomic approaches may assist to predict complex modes of action of toxic compounds on cellular level as well as to unravel specific dysfunctions in the energy metabolism.


Psychological effects of a suspicious prostate cancer screening test followed by a benign biopsy result.
To evaluate the psychological implications of an apparently false-positive screening result for prostate cancer. The sample comprised 167 men with a benign biopsy result in response to a suspicious screening test result (biopsy group) and 233 men with a normal prostate-specific antigen (PSA) test result (control group). The men responded to a questionnaire within about 6 weeks of their biopsy or PSA results. They were asked about demographic characteristics, medical history, psychological effects, biopsy experience, and prostate cancer knowledge. The survey response rate was 85% (400/471). The mean (+/- SD) age of respondents was 60 +/- 9 years (range, 40 to 88 years); 88% (n = 350) were white. Forty-nine percent (81/167) of men in the biopsy group reported having thought about prostate cancer either "a lot" or "some of the time", compared with 18% (42/230) in the control group (P < 0.001). In addition, 40% (67/167) in the biopsy group reported having worried "a lot" or "some of the time" that they may develop prostate cancer, compared with 8% (18/231) in the control group (P < 0.001). Men who underwent prostate biopsy more often reported having thought and worried about prostate cancer, despite having received a benign result. This underrecognized human cost of screening should be considered in the debate about the benefits and harms of prostate cancer screening.


Highly Graphitized Porous Carbon-FeNi3 Fabricated from Oleic Acid for Advanced Lithium-Sulfur Batteries.
Improving the electrical conductivity of sulfur, suppressing shuttle/dissolution of polysulfide, and enhancing reaction kinetics in Li-S batteries are essential for practical applications. Here, for the first time, we have used inexpensive oleic acid as a single carbon source, and have added commercial SiO2 as a template to form a porous structure, whereas introducing Fe(NO3 )3 and Ni(NO3 )2 as catalysts to increase the degree of graphitization. Moreover, the dual metal salts Fe(NO3 )3 and Ni(NO3 )2 can also form FeNi3 alloy, and our results show that FeNi3 nanoparticles accelerate the kinetic conversion reactions of polysulfide. By virtue of the well-developed porous structure and high degree of graphitization, the highly graphitized porous carbon-FeNi3 (GPC-FeNi3 ) has high conductivity to ensure fast charge transfer, and the hierarchically porous structure facilitates ion diffusion and traps polysulfide. Thus, a GPC-FeNi3 /S cathode displays excellent electrochemical performance. At current rates of 0.2 and 1 C, a cathode of the GPC-FeNi3 /S composite with a sulfur content of 70 % delivers high initial discharge capacities of 1108 and 880 mA h g-1 , respectively, and retains reversible specific capacities of 850 mA h g-1 after 200 cycles at 0.2 C and 625 mA h g-1 after 400 cycles at 1 C.


Monthly migraine days, tablet utilization, and quality of life associated with Rimegepant - post hoc results from an open label safety study (BHV3000-201).
The objective of this study was to describe patterns in monthly migraine days (MMD) and tablet utilization, and to estimate health-related quality of life (HRQoL) measures in patients treated as needed (PRN) with rimegepant 75 mg over 52-weeks. Eligible subjects were adults with ≥1 year history of migraine and ≥ 6 MMD at baseline, who used rimegepant 75 mg up to once daily PRN (at their discretion) for up to 52-weeks in an open-label safety study (BHV3000-201; NCT03266588). Mean MMD were calculated at each 4-week period, along with mean monthly tablets taken. Migraine-specific quality of life (MSQv2) data were mapped to EQ-5D utilities and used to characterize HRQoL over time. A published network meta-analysis was used to characterize pain hours as well as time periods spent migraine free. One thousand forty four subjects were included in this post-hoc analysis. Overall mean MMD were 10.9 at baseline and decreased to 8.9 by week 52. Tablet use remained stable over the follow-up period. A total of 0.08 incremental QALYs were associated with rimegepant use. For subjects with 6 or more MMD, acute treatment of migraine attacks with rimegepant 75 mg on a PRN basis over one-year of follow-up was found to be associated with reduced MMD frequency without an increase in monthly tablet utilization, and improved HRQoL. There was no evidence of medication-related increases in MMDs when rimegepant 75 mg was used as needed for the acute treatment of migraine over 52-weeks. ClinicalTrials.gov identifier NCT03266588 .


Eight-year survival of a recurrent glioblastoma patient treated with molecularly tailored therapy: a case report.
Treatment options for recurrent glioblastoma are scarce; targeted therapy trials were disappointing, probably due to enrollment of patients without molecular selection. We treated with bevacizumab and erlotinib a 66-year-old male suffering from recurrent glioblastoma, IDH-wildtype and MGMT unmethylated, after three neurosurgeries. Treatment was tailored on molecular profile of recurrent tumor-namely, EGFRvIII positivity, VEGF overexpression, normal PTEN, low total VEGF and VEGF-121 mRNA-and resulted in complete, exceptionally durable response (51-month progression-free survival). Notably, histology of further recurrence after therapy was reminiscent of sarcoma. We suggest a thorough molecular screening for personalization of targeted therapy in recurrent glioblastoma.


Cytomegalovirus-induced sensorineural hearing loss with persistent cochlear inflammation in neonatal mice.
Congenital cytomegalovirus (CMV) infection is the leading cause of sensorineural hearing loss (SNHL) in children. During murine (M)CMV-induced encephalitis, the immune response is important for both the control of viral dissemination and the clearance of virus from the brain. While the importance of CMV-induced SNHL has been described, the mechanisms surrounding its pathogenesis and the role of inflammatory responses remain unclear. This study presents a neonatal mouse model of profound SNHL in which MCMV preferentially infected both cochlear perilymphatic epithelial cells and spiral ganglion neurons. Interestingly, MCMV infection induced cochlear hair cell death by 21 days post-infection, despite a clear lack of direct infection of hair cells and the complete clearance of the virus from the cochlea by 14 dpi. Flow cytometric, immunohistochemical, and quantitative PCR analysis of MCMV-infected cochlea revealed a robust and chronic inflammatory response, including a prolonged increase in reactive oxygen species production by infiltrating macrophages. These data support a pivotal role for inflammation during MCMV-induced SNHL.