Randomized controlled trial of an implantable continuous hemodynamic monitor in patients with advanced heart failure: the COMPASS-HF study.
The purpose of this study was to determine whether a heart failure (HF) management strategy using continuous intracardiac pressure monitoring could decrease HF morbidity. Patients with HF may experience frequent decompensations that require hospitalization despite intensive treatment and follow-up. The COMPASS-HF (Chronicle Offers Management to Patients with Advanced Signs and Symptoms of Heart Failure) study was a prospective, multicenter, randomized, single-blind, parallel-controlled trial of 274 New York Heart Association functional class III or IV HF patients who received an implantable continuous hemodynamic monitor. Patients were randomized to a Chronicle (Medtronic Inc., Minneapolis, Minnesota) (n = 134) or control (n = 140) group. All patients received optimal medical therapy, but the hemodynamic information from the monitor was used to guide patient management only in the Chronicle group. Primary end points included freedom from system-related complications, freedom from pressure-sensor failure, and reduction in the rate of HF-related events (hospitalizations and emergency or urgent care visits requiring intravenous therapy). The 2 safety end points were met with no pressure-sensor failures and system-related complications in only 8% of the 277 patients who underwent implantation (all but 4 complications were successfully resolved). The primary efficacy end point was not met because the Chronicle group had a nonsignificant 21% lower rate of all HF-related events compared with the control group (p = 0.33). A retrospective analysis of the time to first HF hospitalization showed a 36% reduction (p = 0.03) in the relative risk of a HF-related hospitalization in the Chronicle group. The implantable continuous hemodynamic monitor-guided care did not significantly reduce total HF-related events compared with optimal medical management. Additional trials will be necessary to establish the clinical benefit of implantable continuous hemodynamic monitor-guided care in patients with advanced HF.


Freeze-drying of emulsified systems: A review.
Colloidal systems such as emulsions, microemulsions and nanoemulsions are able to transport active molecules, enhance their solubility and stability and minimize their side effects. However, since they are dispersions with an aqueous continuous phase they have some disadvantages such as the risk of microbiological contamination, degradation by hydrolysis, physico-chemical instability and loss of pharmacological activity of the drug. Freeze drying, in which the water is removed from the preparation by sublimation under vacuum, has been suggested as a means to resolve these problems. Lyophilized products are very stable and are easy to transport and store. However, there is very little information in the literature about the application of this technique to emulsified systems. The aim of this review is to evaluate the lyophilization process as a tool for increasing the shelf life of emulsified systems such as emulsions, microemulsions and nanoemulsions. In addition, the mechanism of cryoprotection and the techniques that can be used to characterize the freeze-dried systems are discussed.


Expression of Neuropilin-2 in salivary adenoid cystic carcinoma: its implication in tumor progression and angiogenesis.
Neuropilin-2(Nrp2), which is a nontyrosine kinase transmembrane glycoprotein, can promote angiogenesis and is a poor prognostic factor in some human cancers. In the present study, to explore the expression and potential function of Nrp2 in salivary adenoid cystic carcinoma (SACC), immunohistochemistry was used to examine the Nrp2 expression in 50 SACCs and 20 normal salivary gland tissues nearby SACCs. The result showed that immunoreactivity for Nrp2 was detected in 47 of 50 SACCs, and its expression level had significant correlations with microvessel density, tumor size, TMN clinical stage, vascular invasion, and metastasis (P<0.05) of SACCs. In addition, inhibition of Nrp2 function by the receptor-ligand interaction-blocking antibody decreased cell migration, invasion, and angiogenic promotion without influences on the cell proliferation of Acc-3 cells. Taken together, the expression of Nrp2 protein is significantly correlated with tumor progression and angiogenesis in SACCs. These results suggest that Nrp2 may be a potential therapeutic target for SACCs.


Modification of the technique for placement of titanium plasma sprayed (TPS) screw implants.
Several modifications of instrumentation and technique are offered to improve the ease of application of TPS screws and enhance the success of the technique.


A trans-scalar approach to peacebuilding and transitional justice: Insights from the Democratic Republic of Congo.
Peace research has taken a local turn. Yet, conceptual ambiguities, risks of romanticization, and critiques of co-option of the "local" point to the need to look for novel ways to think about the interactions of actors ranging from the global to the local level. Gearoid Millar proposes a trans-scalar approach to peace based on a "consistency of purpose" and a "parity of esteem" for actors across scales. This article analyzes the concept of trans-scalarity in the peace process in Ituri, a province in the northeastern Democratic Republic of Congo (DRC). Drawing on qualitative data from more than a year of research in the DRC, I argue that while a trans-scalar approach was taken to end violence, it was not applied to transitional justice initiatives. The result was a negative, rather than a positive peace. By showing the high, but still untapped, potential of trans-scalarity, the article makes three contributions. First, it advances the debate on the local turn by adding empirical insights on trans-scalarity and further developing the concept's theoretical foundations. Second, it provides novel empirical insights on the transitional justice process in the DRC. Third, it links scholarship on peacebuilding and transitional justice, which have often remained disconnected.


Freeze-Dried Microfluidic Monodisperse Microbubbles as a New Generation of Ultrasound Contrast Agents.
We succeeded in freeze-drying monodisperse microbubbles without degrading their performance, that is, their monodispersity in size and echogenicity. We used microfluidic technology to generate cryoprotected highly monodisperse microbubbles (coefficient of variation [CV] <5%). By using a novel retrieval technique, we were able to freeze-dry the microbubbles and resuspend them without degradation, that is, keeping their size distribution narrow (CV <6%). Acoustic characterization performed in two geometries (a centimetric cell and a millichannel) revealed that the resuspended bubbles conserved the sharpness of the backscattered resonance peak, leading to CVs ranging between 5% and 10%, depending on the geometry. As currently observed with monodisperse bubbles, the peak amplitudes are one order of magnitude higher than those of commercial ultrasound contrast agents. Our work thus solves the question of storage and transportation of highly monodisperse bubbles. This work might open pathways toward novel clinical non-invasive measurements, such as local pressure, impossible to carry out with the existing commercial ultrasound contrast agents.


Isolation of mouse pancreatic islet Procr+ progenitors and long-term expansion of islet organoids in vitro.
Insulin production is required for glucose homeostasis. Pancreatic islet β cells are the only cells that produce insulin in humans; however, generation of functional β cells in vitro from embryonic or adult tissues has been challenging. Here, we describe isolation of pancreatic islet progenitors from adult mice, which enables the efficient generation and long-term expansion of functional islet organoids in vitro. This protocol starts with purification of protein C receptor (Procr)-expressing islet progenitors. Coculture with endothelial cells generates islet organoids in vitro that can be expanded by passage. Functional maturation is achieved as a consequence of a prolonged culture period and cyclic glucose stimulation. Primary islet organoids form in 7-10 days. Subsequently, each passage takes 1 week, with the final maturation step requiring 3 weeks of additional culture. The resulting organoids are predominantly composed of β cells but also contain small proportions of α, δ and pancreatic polypeptide cells. The organoids sense glucose and secrete insulin. This approach thus provides a strategy for β cell generation in vitro and an organoid system to study islet regeneration and diseases.


Isolation and characterization of human apolipoprotein A-I Fukuoka (110 Glu----Lys). A novel apolipoprotein variant.
A novel genetic variant of apolipoprotein(apo) A-I Fukuoka, has been identified in a Japanese family. This variant has a relative charge of +2 compared to normal apolipoprotein A-I (A-I4), on the isoelectric focusing gels and the same molecular mass and immunologic characteristics as normal apolipoprotein A-I. This variant, transmitted as an autosomal co-dominant inheritance was purified by preparative Immobiline isoelectric focusing. Sequence analysis after cleavage with lysyl endopeptidase and CNBr, followed by high-performance liquid chromatography revealed a single substitution of lysine at position 110, instead of the usual glutamic acid. This mutant apolipoprotein A-I has much the same potential as to activate lecithin-cholesterol acyltransferase.


Retinal detachment following endophthalmitis.
Fifty-five consecutive patients with a clinical diagnosis of bacterial endophthalmitis were reviewed. All patients were treated with systemic, periocular, topical, and intravitreal antibiotics. In addition, 33 of the patients underwent a pars plana vitrectomy. Nine retinal detachments occurred within six months of initial diagnosis. The higher frequency of retinal detachment in the vitrectomy group (21%) as compared to those patients managed without vitrectomy (9%) may be explained by a combination of surgical complications and the increased severity of endophthalmitis in the vitrectomy group. The two patients who developed retinal detachment during vitrectomy surgery rapidly progressed to no light perception. Conversely, the repair of retinal detachments diagnosed postoperatively had a good prognosis.


Tetralogy of Fallot with obstruction of the ventricular septal defect: spectrum of echocardiographic findings.
Tetralogy of Fallot with a restrictive ventricular septal defect and suprasystemic right ventricular pressure is an uncommon anomaly with a high mortality rate. In previous studies, the identity of the tissue obstructing the ventricular septal defect has usually not been determined preoperatively. This report describes the echocardiographic and anatomic features in 4 patients with a restrictive ventricular septal defect among 269 patients with tetralogy of Fallot undergoing surgical repair. Echocardiography determined the presence and identity of the obstructing tissue in all four patients. In one patient, the defect was small in association with marked septal hypertrophy. In three patients, accessory or excessive tricuspid valve tissue obstructed the defect in a manner similar to spontaneous closure of isolated membranous ventricular septal defects. Autopsy and catheterization findings are also presented of an additional case with a unique mechanism of obstruction by a tricuspid valve with Ebstein's anomaly. In patients with tetralogy of Fallot, recognition of an obstructed ventricular septal defect is important because it appears to have a poor prognosis.


Clinical and Genetic Etiologies of Neonatal Unconjugated Hyperbilirubinemia in the China Neonatal Genomes Project.
To investigate the clinical and genetic causes of neonatal unconjugated hyperbilirubinemia. We included 1412 neonates diagnosed with unconjugated hyperbilirubinemia (total serum bilirubin >95 percentile for age), from the China Neonatal Genomes Project between August 2016 and September 2019, in the current study. Clinical data and targeted panel sequencing data on 2742 genes including known unconjugated hyperbilirubinemia genes were analyzed. Among the 1412 neonates with unconjugated hyperbilirubinemia, 37% had severe unconjugated hyperbilirubinemia, with total serum bilirubin levels that met the recommendations for exchange transfusion. Known clinical causes were identified for 68% of patients. The most common clinical cause in the mild unconjugated hyperbilirubinemia group was infection (17%) and in the severe group was combined factors (21%, with infection combined with extravascular hemorrhage the most common). A genetic variant was observed in 55 participants (4%), including 45 patients with variants in genes associated with unconjugated hyperbilirubinemia and 10 patients with variants that were regarded as additional genetic findings. Among the 45 patients identified with unconjugated hyperbilirubinemia-related variants, the genes were mainly associated with enzyme deficiencies, metabolic/biochemical disorders, and red blood cell membrane defects. G6PD and UGT1A1 variants, were detected in 34 of the 45 patients (76%). Known clinical causes, which varied with bilirubin levels, were identified in approximately two-thirds of the patients. Genetic findings were identified in 4% of the patients, including in patients with an identified clinical cause, with G6PD and UGT1A1 being the most common genes in which variants were detected.


Subclinical thyroid disorders: the menace of the Trojan horse.
This review aims at summarizing some new data regarding the so-called subclinical thyroid disease and incorporate the knowledge in order to provide a basis for a more careful approach to these morbidities. SHyper represents a considerable risk factor for atrial fibrillation in the elderly and also for osteoporosis, which is a major cause of morbidity in postmenopausal women. SHypo is not an innocuous condition. It progresses to thyroid failure in patients with positive thyroid antibodies, it affects neurobehavior, it may influence cardiac contractility at exercise and it is associated with an impaired lipid profile that may provoke atherosclerosis. Therefore, both conditions should be screened more carefully in the community and treatment should be more often considered.


An innovative geographical approach: health promotion and empowerment in a context of extreme urban poverty.
This article describes and analyses a territorial intervention, the Vila Paciencia Initiative--a local development/health promotion programme implemented in a context of extreme poverty in the western district of Rio de Janeiro. The main goal of the programme was to empower individuals and communities. We emphasise the lessons learned and the potential for integrating them into local and regional health services, which could strengthen community participation and capacity-building and improve the effectiveness and community orientation of primary health care and other public policies directed to geographical development.


Synthesis of a cytochrome c derivative with prolonged in vivo half-life and determination of ascorbyl radicals in the circulation of the rat.
Since cytochrome c and acetylated cytochrome c disappear from the circulation with a half-life of 4 min, these proteins cannot be used for in vivo detection of superoxide radicals and related metabolites. To determine superoxide and other radicals in vivo, a cytochrome c derivative (SMAC) was synthesized by linking 1 mol of poly(styrene-co-maleic acid) butyl ester (SM) to cytochrome c, followed by acetylation of its lysyl amino groups. SMAC retained 8 and 80% of cytochrome c activity to react with ascorbyl and superoxide radicals, respectively. However, SMAC did not serve as a substrate for cytochrome c reductase and cytochrome c oxidase. When injected intravenously to the rat, SMAC circulated bound to albumin with a half-life of 130 min. SMAC was rapidly reduced in the circulation of intact animals. Treatment of animals with paraquat markedly enhanced the reduction of the circulating SMAC. We have synthesized an SM-conjugated superoxide dismutase (SOD) derivative (SM-SOD) that circulates bound to albumin with a half-life of 6 h. Kinetic analysis revealed that SM-SOD effectively inhibited the superoxide-dependent reduction of SMAC either in the presence or absence of 0.5 mM albumin. However, the reduction of the circulating SMAC was not inhibited by SM-SOD both in normal and paraquat-treated animals. Plasma samples from both animal groups also reduced cytochrome c and SMAC by an SOD-insensitive mechanism. However, after treatment with ascorbate oxidase, both plasma samples lost their activity to reduce cytochrome c and SMAC. These and other results suggest that ascorbyl radical might principally be responsible for the reduction of circulating SMAC and that plasma levels of ascorbyl radical might increase in paraquat-treated animals.


GIRK2 expression in dopamine neurons of the substantia nigra and ventral tegmental area.
G-protein-regulated inward-rectifier potassium channel 2 (GIRK2) is reported to be expressed only within certain dopamine neurons of the substantia nigra (SN), although very limited data are available in humans. We examined the localization of GIRK2 in the SN and adjacent ventral tegmental area (VTA) of humans and mice by using either neuromelanin pigment or immunolabeling with tyrosine hydroxylase (TH) or calbindin. GIRK2 immunoreactivity was found in nearly every human pigmented neuron or mouse TH-immunoreactive neuron in both the SN and VTA, although considerable variability in the intensity of GIRK2 staining was observed. The relative intensity of GIRK2 immunoreactivity in TH-immunoreactive neurons was determined; in both species nearly all SN TH-immunoreactive neurons had strong GIRK2 immunoreactivity compared with only 50-60% of VTA neurons. Most paranigral VTA neurons also contained calbindin immunoreactivity, and approximately 25% of these and nearby VTA neurons also had strong GIRK2 immunoreactivity. These data show that high amounts of GIRK2 protein are found in most SN neurons as well as in a proportion of nearby VTA neurons. The single previous human study may have been compromised by the fixation method used and the postmortem delay of their controls, whereas other studies suggesting that GIRK2 is located only in limited neuronal groups within the SN have erroneously included VTA regions as part of the SN. In particular, the dorsal layer of dopamine neurons directly underneath the red nucleus is considered a VTA region in humans but is commonly considered the dorsal tier of the SN in laboratory species.


Assay of ornithine carbamoyltransferase activity in human liver using carbon-labeled ornithine and thin-layer chromatography.
Ornithine carbamoyltransferase (EC 18.104.22.168) activity in human liver homogenates has been measured using 14C-labeled ornithine and unlabeled carbamoyl phosphate. A thin-layer chromatographic (TLC) procedure is used to separate the radioactive substrate and product, ornithine and citrulline, respectively, and the regions of the chromatogram corresponding to ornithine and citrulline are cut out and counted in a liquid scintillation spectrophotometer. The method has the following advantages: (1) the radioactive substrate ornithine is more stable in solution than carbamoyl phosphate, (2) 14C-labeled ornithine is available in higher specific activity than carbamoyl phosphate, (3) all radioactivity may be accounted for by using the TLC system, (4) the developed thin-layer chromatogram is stable indefinitely, (5) in contrast to colorimetric assays, other compounds in the raction mixture do not interfere with the citrulline determination, and (6) most importantly, the rate of the enzyme reaction at various time intervals can be determined by taking aliquots from the same incubation tube.


Myeloid cell-specific expression of Ship1 regulates IL-12 production and immunity to helminth infection.
Helminth infection leads to the local proliferation and accumulation of macrophages in tissues. However, the function of macrophages during helminth infection remains unclear. SH2-containing inositol 5'-phosphatase 1 (Ship1, Inpp5d) is a lipid phosphatase that has been shown to play a critical role in macrophage function. Here, we identify a critical role for Ship1 in the negative regulation of interleukin (IL)-12/23p40 production by macrophages during infection with the intestinal helminth parasite Trichuris muris. Mice with myeloid cell-specific deletion of Ship1 (Ship1(ΔLysM) mice) develop a non-protective T-helper type 1 cell response and fail to expel parasites. Ship1-deficient macrophages produce heightened levels of IL-12/23p40 in vitro and in vivo and antibody blockade of IL-12/23p40 renders Ship1(ΔLysM) mice resistant to Trichuris infection. Our results identify a critical role for the negative regulation of IL-12/23p40 production by macrophages in the development of a protective T(H)2 cell response.


Age-sensitivity of P3 in high-functioning adults.
In their interesting paper, Daffner et al. [Daffner KR, Ryan KK, Williams DM, Budson AE, Rentz DM, Scinto LFM, et al. Age-related differences in novelty and target processing among cognitively healthy high performing adults. Neurobiol Aging 2005;26:1283-95] argue that previous studies have found changes in ERP components in response to novel and target stimuli due to two methodological factors: (1) lack of control for differences in level of cognitive status between age groups, and (2) not controlling for a non-specific age-related processing difference for all stimulus types (standards, targets, and novel). The questions raised by Daffner et al. are interesting, but based on existing literature, their conclusion seems premature. In the following, we will present examples from empirical literature as well as re-analyses of some of our own work to illustrate problematic aspects of Daffner et al.'s position.


Prospective observation of vascular anastomoses between the retina and choroid in recurrent toxoplasmosis.
Prospective angiographic observations demonstrated the formation of both choroidoretinal arteriolar anastomoses as well as retinochoroidal venular anastomoses in the ocular fundus of a young man with recurrent ocular toxoplasmosis.


Correlation between the orbital and intraocular portions of the optic nerve in glaucomatous and ocular hypertensive eyes.
It has recently been reported that the retrobulbar optic nerve diameter (OND) and cross-sectional area (ONCSA) are reduced in glaucoma. This study was performed to investigate the correlation between the orbital and intraocular portions of the optic nerve. One eye of 20 volunteers (16 glaucoma subjects, 4 ocular hypertension subjects) underwent optic disc analysis using Heidelberg retinal tomography, and echographic measurements of the retrobulbar optic nerve. The male-to-female ratio was 6.5:3.5, and the mean age of our sample (+/- SD) was 62.25 +/- 13.7 years. Orbital optic nerve diameter and cross-sectional area correlated significantly and positively with the neuroretinal rim area (Spearman's rank correlation coefficient; OND: rs = 0.488, p = 0.0336; ONCSA: rs = 0.619, p = 0.0079), but not with any other topographical disc data. The retrobulbar optic nerve cross-sectional area-to-disc area ratio (ONCSA/D) was found to have a significant negative correlation with the cup area/disc area ratio (simple regression analysis; r = -3.948, p = 0.046), and a statistically demonstrable positive correlation with the neuroretinal rim area/disc area ratio (r = 0.451, p = 0.046). The results of this study indicate that orbital optic nerve dimensions are a reflection of the neuroretinal rim area of the optic disc. Echographic measurements of the retrobulbar nerve may be additive to the traditional triad of raised intraocular pressure, field defects and glaucomatous optic neuropathy that suggests a diagnosis of glaucoma.


Macronutrients and energy balance in obesity.
Energy balance is the difference between metabolizable energy intake and total energy expenditure. Energy intake is difficult to measure accurately; changes in body weight, for example, are not a good measure of the adequacy of energy intake, because fluctuations in body weight are common even if the overall trend is toward weight loss. It is now customary to assess energy requirements indirectly from total energy expenditure. Total energy expenditure consists of basal metabolism, postprandial thermogenesis, and physical activity. Energy expenditure is related to both body weight and body composition. A reduction in total energy expenditure accompanies weight loss, because basal metabolic rate decreases with the loss of lean tissue mass. Similarly, with weight gain, there is an increase in basal metabolic rate, because lean tissue mass grows to support the increase in fat tissue mass. Excess energy intake over energy expenditure causes weight gain and an accompanying increase in total energy expenditure. Following a period of adaptation, total energy expenditure will match energy intake and body weight will stabilize at a higher level. This same relationship holds for weight loss. Respiratory quotient (measured in steady state) is an indication of the proportion of energy expenditure derived from fat and carbohydrate oxidation. Over long periods of time, fat balance is equivalent to energy balance, as an excess of fat intake over fat oxidation causes fat storage.


Immune-privileged embryonic Swiss mouse STO and STO cell-derived progenitor cells: major histocompatibility complex and cell differentiation antigen expression patterns resemble those of human embryonic stem cell lines.
Embryonic mouse STO (S, SIM; T, 6-thioguanine resistant; O, ouabain resistant) and 3(8)21-enhanced green fluorescent protein (EGFP) cell lines exhibit long-term survival and hepatic progenitor cell behaviour after xenogeneic engraftment in non-immunosuppressed inbred rats, and were previously designated major histocompatibility complex (MHC) class I- and class II-negative lines. To determine the molecular basis for undetectable MHC determinants, the expression and haplotype of H-2K, H-2D, H-2L and I-A proteins were reassessed by reverse transcriptase-polymerase chain reaction (RT-PCR), cDNA sequencing, RNA hybridization, immunoblotting, quantitative RT-PCR (QPCR), immunocytochemistry and flow cytometry. To detect cell differentiation (CD) surface antigens characteristic of stem cells, apoptotic regulation or adaptive immunity that might facilitate progenitor cell status or immune privilege, flow cytometry was also used to screen untreated and cytokine [interferon (IFN)-gamma]-treated cultures. Despite prior PCR genotyping analyses suggestive of H-2q haplotypes in STO, 3(8)21-EGFP and parental 3(8)21 cells, all three lines expressed H-2K cDNA sequences identical to those of d-haplotype BALB/c mice, as well as constitutive and cytokine-inducible H-2K(d) determinants. In contrast, apart from H-2L(d[LOW]) display in 3(8)21 cells, H-2Dd, H-2Ld and I-Ad determinants were undetectable. All three lines expressed constitutive and cytokine-inducible CD34; however, except for inducible CD117([LOW]) expression in 3(8)21 cells, no expression of CD45, CD117, CD62L, CD80, CD86, CD90.1 or CD95L/CD178 was observed. Constitutive and cytokine-inducible CD95([LOW]) expression was detected in STO and 3(8)21 cells, but not in 3(8)21-EGFP cells. MHC (class I(+[LOW])/class II-) and CD (CD34+/CD80-/CD86-/CD95L-) expression patterns in STO and STO cell-derived progenitor cells resemble patterns reported for human embryonic stem cell lines. Whether these patterns reflect associations with mechanisms that are regulatory of immune privilege or functional tissue-specific plasticity is unknown.


Interactions of the organogold(III) compound Aubipyc with the copper chaperone Atox1: a joint mass spectrometry and circular dichroism investigation.
The so called "copper trafficking system" in mammalian cells is primarily devoted to the regulation of copper transport and homeostasis. This system, now well characterized, consists of a few strictly interconnected proteins that assist copper entrance inside cells and then promote metal transfer and delivery to essential copper-dependent cellular proteins (Boal and Rosenzweig 2009a; Banci et al., Mol Life Sci 67:2563-2589, 2010). Yet, the "copper trafficking system" may also facilitate the entrance inside cells of non-physiological metal species such as clinically established platinum drugs. ESI and MALDI MS methods are exploited here to characterize the interactions occurring between the experimental anticancer organogold(III) drug, Aubipyc, and the copper chaperone Atox1, a key protein of the copper trafficking system. The nature of the adducts that are formed when reacting Aubipyc with Atox1 is elucidated in detail. Characterization of the Aubipyc/Atox1 system is further supported by circular dichroism experiments. Binding competitions with mercury and bismuth ions were also explored. The relevance and the biological implications of the present results are discussed.


Visualizing gene expression: an unfolding story.
Eukaryotic transcription is a dynamic process in which RNA polymerases read DNA templates that are tightly wrapped around histones. In this issue of Cell, Janicki et al. (2004) provide a glimpse of the events that follow transcriptional induction, using an integrated cytological system observed in real time. They find that local decondensation of the template is accompanied by profound changes in chromatin composition.


MARCOS technique under intuitionistic fuzzy environment for determining the COVID-19 pandemic performance of insurance companies in terms of healthcare services.
Assessing and ranking private health insurance companies provides insurance agencies, insurance customers, and authorities with a reliable instrument for the insurance decision-making process. Moreover, because the world's insurance sector suffers from a gap of evaluation of private health insurance companies during the COVID-19 outbreak, the need for a reliable, useful, and comprehensive decision tool is obvious. Accordingly, this article aims to identify insurance companies' priority ranking in terms of healthcare services in Turkey during the COVID-19 outbreak through a multi-criteria performance evaluation methodology. Herein, alternatives are evaluated and then ranked as per 7 criteria and assessments of 5 experts. Experts' judgments and assessments are full of uncertainties. We propose a Measurement of Alternatives and Ranking according to the Compromise Solution (MARCOS) technique under an intuitionistic fuzzy environment to rank insurance companies. The outcomes yielded ten insurance companies ranking in terms of healthcare services in the era of COVID-19. The payback period, premium price, and network are determined as the most crucial factors. Finally, a comprehensive sensitivity analysis is performed to verify the proposed methodology's stability and effectiveness. The introduced approach met the insurance assessment problem during the COVID-19 pandemic very satisfactory manner based on sensitivity analysis findings.


[Change of the skin electrical resistance in the right iliac region in acute appendicitis].
The changes of skin electrical resistance in the dynamics of the disease were studied through the comparison of the right and left iliac regions. A reliable decrease of the right skin electrical resistance in various clinical forms of appendicitis, except for the gangrenous-perforating form, was found.


Multi-Scale Modeling of Vision-Guided Remodeling and Age-Dependent Growth of the Tree Shrew Sclera During Eye Development and Lens-Induced Myopia.
The sclera uses unknown mechanisms to match the eye's axial length to its optics during development, producing eyes with good focus (emmetropia). A myopic eye is too long for its own optics. We propose a multi-scale computational model to simulate eye development based on the assumption that scleral growth is controlled by genetic factors while scleral remodeling is driven by genetic factors and the eye's refractive error. We define growth as a mechanism that changes the tissue volume and mass while remodeling involves internal micro-deformations that are volume-preserving at the macroscale. The model was fitted against longitudinal refractive measurements in tree shrews of different ages and exposed to three different visual conditions: (i) normal development; (ii) negative lens wear to induce myopia; and (iii) recovery from myopia by removing the negative lens. The model was able to replicate the age- and vision-dependent response of the tree shrew experiments. Scleral growth ceased at younger age than scleral remodeling. The remodeling rate decreased as the eye emmetropized but increased at any age when a negative lens was put on. The predictive power of the model was investigated by calculating the susceptibility to scleral remodeling and the response to form deprivation myopia in tree shrews. Both predictions were in good agreement with experimental data that were not used to fit the model. We propose the first model that distinguishes scleral growth from remodeling. The good agreement of our results with experimental data supports the notion that scleral growth and scleral remodeling are two independently controlled mechanisms during eye development.


Preparation, analysis and properties of shaddock ped polysaccharide and its derivatives.
The shaddock ped polysaccharide (SPP) was extracted by ultrasound-assisted enzyme method. Phosphorylated shaddock ped polysaccharides (P-SPP) and acetylated shaddock ped polysaccharides (Ac-SPP) were obtained by chemical modification of SPP. The characterization methods such as infrared spectroscopy and nuclear magnetism were employed to characterize the structures of the two derivatives. The antioxidant activity of SPP and its derivatives was investigated by measuring their DPPH radical scavenging capacity, hydroxyl radical ion scavenging capacity and superoxide anion scavenging capacity. In comparison, P-SPP showed better antioxidant activity. The results indicated that the antioxidant activity of the polysaccharides varied with different chemical modifications.


Differential expression of DKK-1 binding receptors on stromal cells and myeloma cells results in their distinct response to secreted DKK-1 in myeloma.
The canonical Wnt signaling is concurrently important for osteoblast differentiation and myeloma cell proliferation. Its activation in myeloma cells and its inhibition in osteoblasts and their progenitors have been identified in the previous studies. Osteoblast progenitors and myeloma cells from a myeloma patient share the same bone marrow (BM) microenvironment, but respond differently to DKK-1 secreted by myeloma cells. The mechanisms remain unclear. Primary multiple myeloma (MM) cells were isolated from BM mononuclear cells of 12 MM patients. Human bone marrow stromal cells (SCs) were obtained from BM adherent cells of these MM patients and 10 healthy donors. The mRNA expression levels of DKK-1 binding receptor LRP5/6 and Kremen1/2 (Krm1/2) were analyzed by Real-time PCR in human myeloma cell line (HMCL) RPMI-8226, NCI-H929, U266, LP-1, CZ-1, KM-3, Sko-007, primary myeloma cells and SCs from 12 MM patients and SCs from 10 healthy donors. The binding capability of DKK-1 binding receptors to DKK-1 on primary myeloma cells and SCs was detected by flow cytometry assay. The mRNA expression levels of DKK-1 binding receptor LRP5/6 and Krm1/2 in SCs from patients with MM were significantly higher than those in myeloma cells and in SCs from healthy donors. The binding capability to DKK-1of DKK-1 binding receptors on SCs from MM patients was obviously higher than those on myeloma cells and SCs from healthy donors by flow cytometry assay. Similar to the effects of coculture with rhDKK1, coculture of SCs from healthy donors with myeloma cells in the presence or absence of a Transwell insert did up-regulate SCs' mRNA levels of LRP5/6 and Krm1/2, and down-regulate their mRNA levels of β-catenin. Compared with myeloma cells, the SCs from MM patients overexpress DKK-1 binding receptors LRP5/6 and Krm1/2 in response to DKK-1 secreted by myeloma cells, which results in intracellular Wnt signaling inhibition. Our study provides a novel insight into mechanisms of myeloma associated osteolytic lesions.


Impact of PGE1 on cyclosporine A induced up-regulation of TGF-beta1, its receptors, and related matrix production in cultured mesangial cells.
Transforming growth factor-beta1 (TGF-beta1) plays a major role in cyclosporine A (CsA) induced glomerulosclerosis. We have recently shown that CsA up-regulates the expression of TGF-beta1 and its receptors type I (TbetaR-I) and type II (TbetaR-II) in rat mesangial cells (MCs). Prostaglandins of the E series (PGEs) are known to exert substantial anti-fibrotic effects. Here, we assessed the effect of PGE1 on CsA induced up-regulation of TGF-beta1, TbetaR-I, TbetaR-II and related matrix production in MCs. Co-incubation with PGE1 reduced CsA induced up-regulation of TGF-beta1 and TbetaR-II at the mRNA and protein level. Alike, PGE1 reduced TbetaR-I protein expression, which is posttranscriptionally up-regulated by CsA. Whereas a low PGE(1) concentration decreased CsA induced production of fibronectin (FN) and plasminogen activator inhibitor type-1 (PAI-1), a higher PGE1 concentration did not change FN production, but further increased PAI-1 production. In vivo studies will show, whether treatment with PGE1 analogues will be useful in preventing CsA induced glomerulosclerosis.


2-Eth-oxy-5-methylbis[1,2,4]triazolo[1,5-a:4',3'-c]quinazoline.
The title compound, C(13)H(12)N(6)O, is a functionalized ditriazoloquinazoline with substituted eth-oxy and methyl groups attached at the 2-position of each triazole spacer. The fused-ring system is essentially planar [r.m.s. deviation = 0.016 (2) Å]. In the crystal, a weak C-H⋯N hydrogen bond connects the mol-ecules into a chain along [101].


Functional Group-Directed Photochemical Reactions of Aromatic Alcohols, Amines, and Thiols Triggered by Excited-State Hydrogen Detachment: Additive-free Oligomerization, Disulfidation, and C(sp2)-H Carboxylation with CO2.
Exploring new types of photochemical reactions is of great interest in the field of synthetic chemistry. Although excited-state hydrogen detachment (ESHD) represents a promising prospective template for additive-free photochemical reactions, applications of ESHD in a synthetic context remains scarce. Herein, we demonstrate the expansion of this photochemical reaction toward oligomerization, disulfidation, and regioselective C(sp2)-H carboxylation of aromatic alcohols, thiols, and amines. In the absence of any radical initiators in tetrahydrofuran upon irradiation with UV light (λ = 280 or 300 nm) under an atmosphere of N2 or CO2, thiols and catechol afforded disulfides and oligomers, respectively, as main products. Especially, the photochemical disulfidation proceeded highly selectively with the NMR and quantum yields of up to 69 and 0.46%, respectively. In stark contrast, the photolysis of phenylenediamines and aminophenols results in photocarboxylation in the presence of CO2 (1 atm). p-Aminophenol was quantitatively carboxylated by photolysis for 17 h with a quantum yield of 0.45%. Furthermore, the photocarboxylation of phenylenediamines and aminophenols proceeds in a highly selective fashion on the aromatic C(sp2)-H bond next to a functional group, which is directed by the site-selective ESHD of the functional groups for the formation of aminyl and hydroxyl radicals.


Screening and identification of human ZnT8-specific single-chain variable fragment (scFv) from type 1 diabetes phage display library.
Zinc transporter 8 (ZnT8) is a major autoantigen and a predictive marker in type 1 diabetes (T1D). To investigate ZnT8-specific antibodies, a phage display library from T1D was constructed and single-chain antibodies against ZnT8 were screened and identified. Human T1D single-chain variable fragment (scFv) phage display library consists of approximately 1×10(8) clones. After four rounds of bio-panning, seven unique clones were positive by phage ELISA. Among them, C27 and C22, which demonstrated the highest affinity to ZnT8, were expressed in Escherichia coli Top10F' and then purified by affinity chromatography. C27 and C22 specifically bound ZnT8 N/C fusion protein and ZnT8 C terminal dimer with one Arg325Trp mutation. The specificity to human islet cells of these scFvs were further confirmed by immunohistochemistry. In conclusion, we have successfully constructed a T1D phage display antibody library and identified two ZnT8-specific scFv clones, C27 and C22. These ZnT8-specific scFvs are potential agents in immunodiagnostic and immunotherapy of T1D.


Spatial analysis of drug poisoning deaths in the American West, particularly Utah.
Most states in the Western US have high rates of drug poisoning death (DPD), especially New Mexico, Nevada, Arizona and Utah (UT). This seems paradoxical in UT where illicit drug use, smoking and drinking rates are low. To investigate this, spatial analysis of county level DPD data and other relevant factors in the Western US and UT was undertaken. Poisson kriging was used to smooth the DPD data, populate data gaps and improve the reliability of rates recorded in sparsely populated counties. Links between DPD and economic, environmental, health, lifestyle, and demographic factors were investigated at four scales using multiple linear regression. LDS church membership and altitude, factors not previously considered, were included. Spatial change in the strength and sign of relationships was investigated using geographically weighted regression and significant DPD clusters were identified using the Local Moran's I. Economic factors, like the sharp social gradient between rural and urban areas were important to DPD throughout the west. Higher DPD rates were also found in areas of higher elevation and the desert rural areas in the south. The unique characteristics of DPD in UT in terms of health and lifestyle factors, as well as the demographic structure of DPD in the most LDS populous states (UT, Idaho, Wyoming), suggest that high DPD in heavily LDS areas are predominantly prescription opioid related whereas in other Western states a larger proportion of DPD might come from illicit drugs. Drug policies need to be adapted to the geographical differences in the dominant type of drug causing death. Educational materials need to be marketed to the demographic groups at greatest risk and take into account differences in population characteristics between and within States. Some suggestions about how such adaptations can be made are given and future research needs outlined.


Acetylation of puromycin by Streptomyces alboniger the producing organism.
Streptomyces alboniger produces the antibiotic puromycin and expresses an enzymic activity which acetylates the drug using acetyl CoA. The N-acetyl-puromycin formed is biologically inactive against protein synthesis in Bacillus subtilis (as assayed in vivo).


Long-term survival in a patient following resection for carcinoma of the gallbladder and rectum.
We describe a 66-year-old man who presented initially with acute cholecystitis. He was treated by cholecystostomy and biopsy of the gallbladder mucosa which revealed carcinoma of the gallbladder. Four weeks later a cholecystectomy was performed followed by resection of the common bile duct, common hepatic duct and segments IV and V of the liver and a hepaticojejunostomy. Sixteen months later an abdomino-perineal resection was performed for a moderately differentiated Dukes' stage C carcinoma of the rectum. He is alive and without evidence of recurrence seven years later. Few patients survive for this length of time following resection of either carcinoma of the gallbladder or rectum. This case report demonstrates the value of aggressive surgical treatment in patients with early carcinoma of the gallbladder.


Development of a scale measuring home-visiting nurses' attitudes toward patient safety: a cross-sectional study.
Home-visiting nurses are required to recognize risks in their work, ensure patient safety according to the characteristics of home-visiting nursing, and therefore, effectively support stability in patients' lives. In this study, we created a scale measuring home-visiting nurses' attitudes toward patient safety and examined its reliability and validity. A total of 2,208 home-visiting nurses from Japan were randomly selected as participants. From the 490 responses collected (response rate: 22.2%), 421 responses with no missing values, other than those related to participants' basic information (valid response rate: 19.0%), were analyzed. Participants were randomly divided into two groups: 210 for exploratory factor analysis (EFA) and 211 for confirmatory factor analysis (CFA). To examine the reliability of the home-visiting nurses attitude scale developed in this study, ceiling and floor effects, inter-item correlations, and item-total correlations were checked. Subsequently, EFA was performed to confirm the factor structure. CFA, composite reliability, average variance extracted, and Cronbach's alpha for each factor were extracted to confirm the factor structure of the scale and the validity of the model. The home-visiting nurses' attitudes toward patient safety were measured using 19 questionnaire items related to four factors: "Self-improvement for patient safety," "Incident awareness," "Counter measures based on incident experience," and "Nursing care to protect the lives of patients." Cronbach's α coefficients were 0.867, 0.836, 0.773, and 0.792 for Factors 1-4, respectively. Model indicators were χ2 = 305.155, df = 146, p < 0.001, TLI = 0.886, CFI = 0.902, RMSEA = 0.072 (90% confidence interval 0.061-0.083). From the results of the CFA, criterion-related validity, and Cronbach's α coefficient, this scale is considered reliable and valid and thus, highly appropriate. Therefore, it may be effective at measuring home-visiting nurses' attitudes toward patients' medical safety from both behavioral and awareness aspects.


The Safety and Efficacy of a Sustainable Marine Extract for the Treatment of Thinning Hair: A Summary of New Clinical Research and Results from a Panel Discussion on the Problem of Thinning Hair and Current Treatments.
Alopecia and thinning hair are highly prevalent conditions affecting a large proportion of men and women. Diffused hair loss is often more difficult to diagnose in women, mostly due to over-reliance on the assumption of hormonal influences, and it is commonly treated with a multi-therapy approach. Clinical studies have demonstrated the effectiveness of a nutraceutical supplement to provide essential nutrients that aid in stimulating existing hair growth and reducing hair shedding. The supplement Viviscal® contains a proprietary blend of proteins, lipids, and glycosaminoglycans derived from sustainable marine sources. We present here a summary of studies that have examined the safety and efficacy of this nutraceutical; as well as discussions on hair loss and current therapies from a recently convened expert panel in dermatology and plastic surgery.


Par-aPKC-dependent and -independent mechanisms cooperatively control cell polarity, Hippo signaling, and cell positioning in 16-cell stage mouse embryos.
In preimplantation mouse embryos, the Hippo signaling pathway plays a central role in regulating the fates of the trophectoderm (TE) and the inner cell mass (ICM). In early blastocysts with more than 32 cells, the Par-aPKC system controls polarization of the outer cells along the apicobasal axis, and cell polarity suppresses Hippo signaling. Inactivation of Hippo signaling promotes nuclear accumulation of a coactivator protein, Yap, leading to induction of TE-specific genes. However, whether similar mechanisms operate at earlier stages is not known. Here, we show that slightly different mechanisms operate in 16-cell stage embryos. Similar to 32-cell stage embryos, disruption of the Par-aPKC system activated Hippo signaling and suppressed nuclear Yap and Cdx2 expression in the outer cells. However, unlike 32-cell stage embryos, 16-cell stage embryos with a disrupted Par-aPKC system maintained apical localization of phosphorylated Ezrin/Radixin/Moesin (p-ERM), and the effects on Yap and Cdx2 were weak. Furthermore, normal 16-cell stage embryos often contained apolar cells in the outer position. In these cells, the Hippo pathway was strongly activated and Yap was excluded from the nuclei, thus resembling inner cells. Dissociated blastomeres of 8-cell stage embryos form polar-apolar couplets, which exhibit different levels of nuclear Yap, and the polar cell engulfed the apolar cell. These results suggest that cell polarization at the 16-cell stage is regulated by both Par-aPKC-dependent and -independent mechanisms. Asymmetric cell division is involved in cell polarity control, and cell polarity regulates cell positioning and most likely controls Hippo signaling.


Effects of Ag+ on frog skin: interactions with oxytocin, amiloride and ouabain.
Different biological effects of Ag+ (10(-4) M) were found depending on its presence in the outer or the inner solution bathing the frog skin. A marked increase in the electrical conductance and an interference with the action of oxytocin and amiloride were found only when Ag+ was added to the outer solution. Results suggest that Ag+ affects several transport processes, in particular the permeability of the Na entry pathways.


Regulation, the hybrid market, and species conservation: The case of conservation banking in California.
Conservation Banking in California is a long-established offset program. Banks are hybrid instruments that hover between market autonomy and regulatory oversight. Challenges that may affect outcomes of the program include aligning regulation with the scales and objectives of the hybrid market and conservation and interaction with other compensation instruments. I use an analytical framework combining social-ecological fit (does the regulation fit the spatial, functional, and temporal scales of the market or conservation?) and instrument interaction (are compensation instruments redundant, synergetic, etc.?) to analyze the institutional framework of the conservation banking program. Results show that the program fails to reflect the hybrid market or species conservation objectives, creating a social-ecological mismatch. The institutional framework disincentivizes banking, while its contribution in conserving species cannot be measured. Competing and redundant instruments can lead to weaker compensation. The program needs equal standards that reflect conservation objectives for all compensation instruments. Findings on fit can be useful for other banking programs, and considerations on instrument interaction could improve offsets anywhere.


Deficits on a probabilistic response-reversal task in patients with pediatric bipolar disorder.
Patients with bipolar disorder become hyperhedonic when manic and anhedonic when depressed; therefore, it is important to test whether patients with bipolar disorder show deficits on behavioral paradigms exploring reward/punishment mechanisms. A probabilistic response-reversal task was administered to 24 bipolar children and 25 comparison subjects. Patients made more errors during probabilistic reversal, took longer to learn the new reward object, and were less likely to meet the learning criterion. Children with bipolar disorder may have a reversal learning deficit.


Recognizing and Tackling Inhaler Technique Decay in Asthma and Chronic Obstructive Pulmonary Disesase (COPD) Clinical Practice.
A poor inhaler technique continues to represent a substantial barrier to effective asthma and chronic obstructive pulmonary disease management. It can result in perceived lack of treatment effectiveness even with apparent adherence to a prescribed regimen of inhaled maintenance therapies, potentially resulting in an unnecessary change or escalation of treatment. Many patients are not trained to inhaler mastery in real-world practice; furthermore, even where mastery is initially achieved, an ongoing assessment and education are seldom maintained. In this review, we present an overview of the evidence for deterioration of the inhaler technique over time after training, investigate the factors that contribute to this deterioration, and explore innovative approaches to addressing the problem. We also propose steps forward drawn from the literature and our clinical insights.


Protective effect of astaxanthin against SnS2 nanoflowers induced testes toxicity by suppressing RIPK1-RIPK3-MLKL signaling in mice.
The reproductive toxicity of SnS2 nanoflowers (SnS2 NFs) has been studied in our previous experiment, but the underlying mechanism is still not clear. Astaxanthin (ASX) is a red carotenoid pigment with antioxidant, anticancer and anti-inflammatory properties, showing neuroprotective properties via its antioxidant capacity. To examine the ASX effect on sub-chronic testis injury induced by SnS2 NFs, we randomly and equally divided 40 Kunming male mice into four groups (control, ASX control, NF and NF + ASX groups). Then, ASX dissolved in olive oil was administered intragastrically for 30 consecutive days. Results showed that ASX treatment improved the sperm parameters in mice. Meanwhile, the ASX treatment significantly attenuated testis histopathological injury and ultrastructure alterations induced by SnS2 NFs. It also alleviated testicular oxidative stress, inflammation, apoptosis and necroptosis in mice. Furthermore, ASX markedly upregulated the expression of Bcl-2 and downregulated the expressions of Fas, FasL, RIPK1, FADD, Bax, Cytochrome C, Caspase-9, Cleaved Caspase-8, Cleaved Caspase-3, RIPK3, MLKL and FLIP in the testis tissues compared with the NF group. Therefore, ASX had a markedly protective effect against SnS2 NFs in mice, and the potential mechanism is associated with its ability to inhibit the oxidative stress, inflammatory response, testicular apoptosis and necroptosis, as well as downregulating in the expression of the RIPK1-RIPK3-MLKL signaling and mitochondrial related apoptosis genes.


Gustatory function of sensilla chaetica on the labial palps and antennae of three tortricid moths (Lepidoptera: Tortricidae).
In adult Lepidoptera the labial palps are best known for their role in CO2 detection, but they can also bear sensilla chaetica which function is unknown. The number and distribution of sensilla chaetica in labial palps was studied using a bright field microscope. To determine if these sensilla have a gustatory function, we performed single sensillum electrophysiology recordings from palp and antennal sensilla of adult moths of Cydia pomonella (L.), Grapholita molesta (Busck) and Lobesia botrana (Denis and Shieffermüller). Each sensillum was stimulated with 3 doses of one of four test stimulus (sucrose, fructose, KCl and NaCl). Overall, responses (spikes/s-1) increased with dose, and were higher in the palps than in the antennae, and higher to sugars than to salts. With sugars the response increased with concentration in the palp but not in the antenna. With salts there was a drop in response at the intermediate concentration. The number and position of sensilla chaetica on labial palps was variable among individuals. Sensilla were located in the most exposed areas of the palp. Differences in sensilla distribution were detected between species. Such differences among species and between palps and antenna suggest that taste sensilla on the palps have an unforeseen role in adaptation.


Blemished noses in the art of three masters: Ghirlandaio, Rembrandt, and Warhol.
Blemished noses are portrayed in the paintings of such noted artists as Ghirlandaio, Rembrandt, and Andy Warhol. Sometimes, the deformity results from a skin disorder such as rhinophyma as in Ghirlandaio's An Old Man and his Grandson or a saddle nose deformity from congenital syphilis as in Rembrandt's Portrait of Gerard de Lairesse. Andy Warhol's Before and After portrays a large nose before and after cosmetic surgery. This contribution explores some of the lessons that can be learned, both artistically and medically, from these famous works of art.


Dural arteriovenous fistulas: a review of the literature and a presentation of a single institution's experience.
Dural arteriovenous fistulas (DAVFs) are arteriovenous shunts from a dural arterial supply to a dural venous channel, typically supplied by pachymeningeal arteries and located near a major venous sinus. A retrospective review was conducted to present the results of endovascular obliteration of DAVFs, with particular emphasis of newer liquid embolic agents, including Onyx-18 (MV3, Irvine, California, USA). A review of the literature was performed, and a presentation of the number of treatments, complications, and outcomes is included here. The number of arterial embolizations and need for transvenous embolization, open surgery, and radiosurgery was assessed as well as normalization of retrograde cortical venous drainage. Thirty-nine patients (22 men and 17 women) underwent endovascular treatment of DAVFs at our institution from 2001 to 2009. Ages ranged from 39 to 71 years (mean, 48 years). Seventy-nine percent of patients had retrograde cortical venous drainage. The average number of embolizations in all patients was 2.1. Twelve patients underwent 40 embolization treatments with Onyx, with an obliteration rate of 75% and cortical venous drainage obliteration rate of 85%. Seventy-one percent (28/39) of patients had complete treatment of the fistula: 21 by purely endovascular treatment and 7 with endovascular therapy followed by craniotomy, as well as seven patients who underwent stereotactic radiosurgery after embolization. Endovascular management of DAVFs is a safe and effective method of treating these complex lesions.


The role of location and motion information in the tracking and recovery of moving objects.
Observers in a multiple object tracking task can track about four to five independently moving targets among several moving distractors, even if all of the stimuli disappear for a 300-msec gap. How observers reacquire targets following such a gap reveals what kind of information they can maintain for targets. Previous research has suggested that participants maintain minimal information about a set of moving objects--namely, just their present spatial locations. We report five new experiments that demonstrate retention of location information for at least four objects, and extrapolated motion information for around two objects.


Ultrafast synthesis of laccase-copper phosphate hybrid nanoflowers for efficient degradation of tetracycline antibiotics.
The presence of antibiotics in the environment causes increasing attention due to their potential risks to ecosystems and public health. Laccases are versatile oxidases capable of degrading various organic contaminants including pharmaceuticals. However, the performance of bacterial laccases on tetracycline antibiotics (TCs) degradation is seldom investigated. In this work, a bacterial laccase from Bacillus amyloliquefaciens was immobilized as laccase-inorganic hybrid nanoflowers (Lac-hNFs) by a facile and rapid method. The immobilized laccase was employed to remove different TCs including tigecycline, which is a third-generation TC that its degradation by laccase has not been reported. Lac-hNFs were synthesized by sonication-mediated self-assembly of laccase and copper ions in 5 min at room temperature. About 95% of laccase could be encapsulated in the nanoflowers, and the obtained Lac-hNFs exhibited great enhancement in stability under harsh conditions. The immobilized laccase showed a half-life of 11.7 h at 60 °C, which was about 1.4-fold higher than that of the free enzyme. Meanwhile, Lac-hNFs retained 81% of the initial activity after incubation at 25 °C for 10 days. The laccase in combination with acetosyringone could efficiently decompose tetracycline, doxycycline, and tigecycline. More than 79% of the three TCs were transformed in 1 h. Compared with the free enzyme, Lac-hNFs demonstrated higher capacity in the removal of TCs. Furthermore, Lac-hNFs remained their high degradation capacity after five cycles of reuse. Bacterial growth inhibition test revealed that most of the toxicity of TCs was eliminated after Lac-hNFs treatment. The main transformation products were identified by LC-MS, and the possible degradation pathways were proposed. The interaction mechanism between laccase and TCs was also analyzed using molecular docking. This work provides an efficient way to remove toxic organic pollutants.


Dynamics of liver stiffness predicts complications in patients with HCV related cirrhosis treated with direct-acting antivirals.
Direct acting antivirals(DAAs) are effective in reducing inflammatory ant fibrotic markers in patients with chronic hepatitis C virus(HCV) infection and to prevent liver-related complications. Two-dimensional shear wave elastography(2D-SWE) is an effective technique for the assessment of liver fibrosis. To evaluate changes in liver stiffness(LS) in HCV cirrhotic patients undergoing DAA therapy and to identify non-invasive parameters that predict the occurrence of liver-related events. We enrolled 229 patients who received DAAs between January 2015 and October 2018. Ultrasound parameters and laboratory data were assessed before treatment and 24(T1) and 48(T2) weeks after end of treatment. Patients were followed up every 6 months to evaluate the development of HCC and other liver related complications. Multiple Cox regression analysis was used to determine parameters associated with the development of complications. Model for End-stage Liver Disease(MELD) score(HR 1.16; CI 95% 1.01-1.33; p = 0.026) and a change in LS at T2(1-year Delta LS) < 20%(HR 2.98; CI 95% 1.01-8.1; p = 0.03) were independently associated with HCC risk. One-year Delta-LS <20% was independently associated with the development of ascites(HR 5.08; CI 95% 1.03 - 25.14; p = 0.04). Dynamic changes of 2D-SWE-measured LS after DAA therapy may be a useful tool to identify patients who are at higher risk of liver related complications.


A case of rhinoscleroma cured with ciprofloxacin.
The diagnosis of rhinoscleroma was confirmed in a 17-year-old female patient from Tehran, Iran, suffering from a roundish tumour of the nose. Prior treatment with streptomycin and tetracycline had been unsuccessful. A three-month course of high-dose oral ciprofloxacin (750 mg b.i.d.) led to prompt cessation of the growth of the granuloma which was removed later by plastic surgery. Although serology alone appeared to have little value for the specific diagnosis of rhinoscleroma, a significant increase of IgG antibodies during treatment with ciprofloxacin confirmed infection by Klebsiella rhinoscleromatis in this case.


Preconcentration and determination of lead, cadmium and nickel from water samples using a polyethylene glycol dye immobilized on poly(hydroxyethylmethacrylate) microspheres.
A simple and sensitive preconcentration analysis-atomic absorption spectrometric procedure is described for the determination of lead, cadmium and nickel. The method is based upon on-line preconcentration of metal ions on a minicolumn of Cibacron Blue F3-GA immobilized on poly(hydroxyethylmethacrylate), poly(HEMA). The enrichment factors obtained were 42 for lead, 52 for cadmium and 63 for nickel (sample volume 10 mL and sample flow rate 5 mL/min). The relative standard deviations (n = 10), in 10 mL sample solutions containing 100 microg/L Pb(2+), 10 microg/L Cd(2+) and 100 microg/L Ni(2+) were 8.9, 3.7 and 3.5%, respectively. The limits of detection (blank + 3s) (n = 10), were found to be 12.01 microg/L for Pb(2+), 1.34 microg/L for Cd(2+) and 28.73 microg/L for Ni(2+). The accuracy of the system was checked with certified and tap water samples spiked with known amounts of metal ions. No significant difference was found between the achieved results and the certified values.


[The echographic dimensions of the liver in the term newborn and its relation to anthropometric variables].
We decided to undergo a study looking for normal liver size in relation with other anthropometric measures. Fifty healthy, appropriate for gestational age term-babies, born at the Hospital de Ginecopediatría Número 48, Centro Médico Nacional del IMSS, León, Guanajuato, México, were examined by hepatic ultrasound. The vertical diameter was 6.0 +/- 0.75 cm, transverse 8.26 +/- 0.72 cm, AP 5.44 +/- 0.5 cm. The longitudinal cross section area was 16.21 +/- 2.5 cm2, and the transverse cross section area 22.53 +/- 3.4 cm2. We found most important correlation between vertical diameter and longitudinal cross section area with the anthropometric measures. The hepatic measures correlate better with the weight. Ultrasound provides a rapid, accurate and convenient method for study the liver size and morphology in the neonate.


'Single-Seed-SpeedBulks:' a protocol that combines 'speed breeding' with a cost-efficient modified single-seed descent method for rapid-generation-advancement in oat (Avena sativa L.).
In plant breeding, one of the most cost-effective and efficient ways to increase genetic gain is to reduce the breeding cycle time. In general, modern breeding methods for self-pollinated crops should strive to develop fixed lines at the lowest possible cost and in the minimum possible amount of time. Previous studies on spring oat (Avena sativa L.) showed that combining high plant density with limited soil fertility and moisture levels in a growth media like sand effectively decreases the time and cost of generating fixed single-seed descent lines. More recently, 'speed breeding,' or the exposure to prolonged photoperiod regimes of 22 h, has been shown to decrease flowering time in oat significantly. The goal of this study was to combine 'speed breeding' with high-density planting in a limited soil fertility media to reduce further the costs and time required to develop oat single-seed-descent lines. We grew oat plants at low density in potting-mix (control), high density in potting-mix (HD-soil), and high density in sand (HD-sand) under 16 and 22 h of day length. We observed that oat plants grown in HD-sand and exposed to 22 h day length reduced their flowering time by around 20 and 5 days on average compared to those grown in control conditions at 16 and 22 h, respectively. We also observed that 85% of plants grown at high density in sand produced a single seed when grown in bulk conditions. In contrast, only 40% of plants grown at high density in potting-mix produced a single seed. Our novel protocol showed that oat plants grown in high-density bulks, using sand media and 22-hour day length, reduced their flowering time by 20 days compared to control conditions and produced plants with single seeds, following closely single-seed descent assumptions while significantly reducing labor costs and greenhouse space. This methodology can be deployed in oat breeding programs to help them accelerate their rate of genetic grain for multiple traits.


The Feasibility of Magnetic Resonance Imaging Without General Anesthesia Using the "Bundle and Scan" Technique for Infants With Sensorineural Hearing Loss.
The purpose of this study is to determine the feasibility of magnetic resonance imaging (MRI) without general anesthesia (GA) for infants being evaluated for sensorineural hearing loss (SNHL) using the bundle and scan technique. Retrospective study. Pediatric tertiary care hospital. All infants who underwent MRI using the bundle and scan technique as part of the diagnostic workup for unilateral or bilateral SNHL between June 2016 to April 2019 were included. The primary outcome was the proportion of clinically useful images produced. We reviewed 21 bundle and scan MRI examinations in infants being evaluated for SNHL. Patients had a median age of 10 (range: 6-25) weeks at the time of MRI. Motion artifact was noted in 38% (8/21) of cases. Eighty-six percent (18/21) of the magnetic resonance images produced using the bundle and scan technique were of diagnostic quality and/or sufficient for surgical planning for cochlear implantation. Repeat imaging with GA was required for three cases (14%) as the initial images were not clinically useful. All patients requiring GA had unilateral SNHL. All patients with bilateral SNHL successfully underwent MRI without GA using the bundle and scan technique. The results of our study demonstrate that it is feasible to perform MRI using the bundle and scan technique in the majority of young infants being evaluated for SNHL. This has the potential to help determine cochlear implant candidacy earlier, reduce exposure to GA, and reduce healthcare costs.


Performing up to Nordic principles? Geographic and socioeconomic equity in ambulatory care sensitive conditions among older adults in capital areas of Denmark, Finland and Sweden in 2000-2015.
Denmark, Finland and Sweden pursue equity in health for their citizens through universal health care. However, it is unclear if these services reach the older adult population equally across different socioeconomic positions or living areas. Thus, we assessed geographic and socioeconomic equity in primary health care (PHC) performance among the older adults in the capital areas of Denmark (Copenhagen), Finland (Helsinki) and Sweden (Stockholm) in 2000-2015. Hospitalisations for ambulatory care sensitive conditions (ACSC) were applied as a proxy for PHC performance. We acquired individual level ACSCs for those aged ≥ 45 in 2000-2015 from national hospitalisation registers. To identify whether the disparities varied by age, we applied three age groups (those aged 45-64, 65-75 and ≥ 75). Socioeconomic disparities in ACSCs were described with incidence rate ratios (IRR) and annual rates by education, income and living-alone; and then analysed with biennial concentration indices by income. Geographic disparities were described with biennial ACSC rates by small areas and analysed with two-level Poisson multilevel models. These models provided small area estimates of IRRs of ACSCs in 2000 and their slopes for development over time, between which Pearson correlations were calculated within each capital area. Finally, these models were adjusted for income to distinguish between geographic and socioeconomic disparities. Copenhagen had the highest IRR of ACSCs among those aged 45-64, and Helsinki among those aged ≥ 75. Over time IRRs decreased among those aged ≥ 45, but only in Helsinki among those aged ≥ 75. All concentration indices slightly favoured the affluent population but in Stockholm were mainly non-significant. Among those aged ≥ 75, Pearson correlations were low in Copenhagen (-0.14; p = 0.424) but high in both Helsinki (-0.74; < 0.001) and Stockholm (-0.62; < 0.001) - with only little change when adjusted for income. Among those aged ≥ 45 the respective correlations were rather similar, except for a strong correlation in Copenhagen (-0.51, 0.001) after income adjustment. While socioeconomic disparities in PHC performance persisted among older adults in the three Nordic capital areas, geographic disparities narrowed in both Helsinki and Stockholm but persisted in Copenhagen. Our findings suggest that the Danish PHC incorporated the negative effects of socio-economic segregation to a lesser degree.


Gonadotropin secreting pituitary adenoma associated with erythrocytosis: case report and literature review.
Most pituitary adenomas with FSH- or LH-positive immunohistochemistry are endocrinologically silent, and neurological symptoms due to their large volume are the first clinical signs; they are rarely reported to be secreting gonadotropins, this usually occurring in cases with clinical endocrine findings. Gonadotropinomas are often treated surgically because they are unresponsive to conventional medical therapies. Temozolomide was recently recommended for non-responder aggressive pituitary adenoma management. A 43-year-old male with a history of 5 years of erythrocytosis presented with severe headache, orthostatic dizziness, and difficulty walking. MRI documented a giant pituitary adenoma and high uptake of 111In-pentetreotide indicated somatostatin receptor (SSR) expression. Biochemical tests revealed a secreting gonadotropinoma. Therapy with somatostatin analogs and dopamine agonists improved the patient's headache, achieved partial hormone control, slightly reduced the size of the adenoma, and controlled erythrocytosis. Six months after the diagnosis, hormone escape occurred despite therapy, thus neurosurgery was performed. After the procedure the patient died of untreatable intracranial hypertension. The surgical specimen revealed SSR 2 and 3 expression, and temozolomide did not induce apoptosis in primary cell culture. Among gonadotropinomas, female gender (77%), macroadenoma (84%), young age at diagnosis (28 ± 12 years), delay from first symptoms to diagnosis (up to 15 years), and ovarian cysts/menstrual disorders in females or macro-orchidism in males were the foremost clinical and neuroimaging features. Male gonadotropin-secreting pituitary adenomas may have a variable clinical expression secondary to testosterone excess. Somatostatin analogs, dopamine agonists or temozolomide may have a role that needs to be assessed case by case.


Impact of 3-year lifestyle intervention on postprandial glucose metabolism: the SLIM study.
To determine the effect of a 3-year diet and exercise lifestyle intervention, based on general public health recommendations, on glucose tolerance, insulin resistance and metabolic cardiovascular risk factors in Dutch subjects with impaired glucose tolerance (IGT). The study was a randomized controlled lifestyle intervention over 3 years. A total of 147 IGT subjects (75 male, 72 female) were randomized to the intervention (INT) group or control (CON) group; 106 subjects (52 INT, 54 CON) completed 3 years of intervention. Annually, glucose, insulin and free fatty acid (FFA) concentrations were determined fasting and after an oral glucose tolerance test. Measurements of body weight, serum lipids, blood pressure and maximal aerobic capacity were also performed. Analysis of those who completed the 3-year trial, showed that the lifestyle intervention improved body weight (INT -1.08 +/- 4.30 kg; CON +0.16 +/- 4.91 kg, P = 0.01), homeostatis model assessment index for insulin resistance and 2-h FFA. Two-hour glucose concentrations improved in the INT group, the difference being most pronounced after 1 year, with a return to baseline values after 3 years, from 8.59 +/- 1.55 to 8.55 +/- 0.34 mm; in contrast, 2-h glucose deteriorated in the CON group-from 8.46 +/- 1.84 to 9.35 +/- 2.50 mm (P = 0.02). In the INT group, diabetes incidence was reduced by 58% (P = 0.025). Our lifestyle intervention showed a sustained beneficial effect on 2-h glucose concentrations, insulin resistance and 2-h FFA, even after 3 years. Our lifestyle intervention is effective, but for implementation more information is needed about factors influencing adherence.


Analysis of perchlorate in foods and beverages by ion chromatography coupled with tandem mass spectrometry (IC-ESI-MS/MS).
A new IC-ESI-MS/MS method, with simple sample preparation procedure, has been developed for quantification and confirmation of perchlorate (ClO4-) anions in water, fresh and canned food, wine and beer samples at low part-per-trillion (ng l(-1)) levels. To the best of our knowledge, this is the first time an analytical method is used for determination of perchlorate in wine and beer samples. The IC-ESI-MS/MS instrumentation consisted of an ICS-2500 ion chromatography (IC) system coupled to either an API 2000 or an API 3200 mass spectrometer. The IC-ESI-MS/MS system was optimized to monitor two pairs of precursor and fragment ion transitions, i.e., multiple reaction monitoring (MRM). All samples had oxygen-18 isotope labeled perchlorate internal standard (ISTD) added prior to extraction. Chlorine isotope ratio (35Cl/37Cl) was used as a confirmation tool. The transition of 35Cl16O4- (m/z 98.9) into 35Cl16O3- (m/z 82.9) was monitored for quantifying the main analyte; the transition of 37Cl16O4- (m/z 100.9) into 37Cl16O3- (m/z 84.9) was monitored for examining a proper isotopic abundance ratio of 35Cl/37Cl; and the transition of 35Cl18O4- (m/z 107.0) into 35Cl18O3- (m/z 89.0) was monitored for quantifying the internal standard. The minimum detection limit (MDL) for this method in de-ionized water is 5 ng l(-1) (ppt) using the API 2000 mass spectrometer and 0.5 ng l(-1) using the API 3200 mass spectrometer. Over 350 food and beverage samples were analyzed mostly in triplicate. Except for four, all samples were found to contain measurable amounts of perchlorate. The levels found ranged from 5 ng l(-1) to 463.5+/-6.36 microg kg(-1) using MRM 98.9-->82.9 and 100 microl injection.


Gene co-regulation and co-expression in the aryl hydrocarbon receptor-mediated transcriptional regulatory network in the mouse liver.
Four decades after its discovery, the aryl hydrocarbon receptor (AHR), a ligand-inducible transcription factor (TF) activated by the persistent environmental contaminant 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), remains an enigmatic molecule with a controversial endogenous role. Here, we have assembled a global map of the AHR gene regulatory network in female C57BL/6 mice orally gavaged with 30 µg/kg of TCDD from a combination of previously published gene expression and genome-wide TF-binding data sets. Using Kohonen self-organizing maps and subspace clustering, we show that genes co-regulated by common upstream TFs in the AHR network exhibit a pattern of co-expression. Directly bound, indirectly bound, and non-genomic AHR target genes exhibit distinct expression patterns, with the directly bound targets associated with highest median expression. Interestingly, among the directly bound AHR target genes, the expression level increases with the number of AHR-binding sites in the proximal promoter regions. Finally, we show that co-regulated genes in the AHR network activate distinct groups of downstream biological processes. Although the specific findings described here are restricted to hepatic effects under short-term TCDD exposure, this work describes a generalizable approach to the reconstruction and analysis of transcriptional regulatory cascades underlying cellular stress response, revealing network hierarchy and the nature of information flow from the initial signaling events to phenotypic outcomes. Such reconstructed networks can form the basis of a new generation of quantitative adverse outcome pathways.


Assignment of the DIA1 locus to chromosome 22.
Human/rodent hybrid cell cultures were examined for the presence of DIA1 and other marker enzymes. Many of these hybrids were also analysed for human chromosomes. Complete concordance was found only with chromosome 22.


Recent Developments in the Determination of PM2.5 Chemical Composition.
Fine particulate matter (named PM2.5) has become a prominent and dangerous form of air pollution. The chemical composition of PM2.5 mainly includes inorganic elements, water soluble ions, elemental carbon (EC), organic carbon (OC), and organic compounds. The detection method for inorganic elements mainly includes X ray fluorescence, inductively coupled plasma-atomic emission spectrometry, and inductively coupled plasma mass spectrometry. As for water soluble ions, ion chromatography is the most common detection method. EC and OC are usually detected by carbon analyzer. The organic compounds are determined by gas chromatography-mass spectrometry and liquid chromatography-mass spectrometry. In this paper, the merits and drawbacks of each analytical methods for the determination of PM2.5 chemical composition are summarized. This review also includes our discussion on the improvement of the analytical accuracy for the determination of PM2.5 chemical composition owing to the development of reference materials.


Interatrial conduction (activation) times.
Left atrial electrograms were recorded simultaneously from sites located in the coronary sinus, right pulmonary artery and esophagus in order to determine and correlate the interatrial conduction times obtained from these locations. Ten patients with normal-sized atria and 16 patients with isolated left atrial enlargement were studied. A high correlation existed between the P wave duration and the interatrial conduction times obtained from the coronary sinus and pulmonary artery; good correlations were also found for the interatrial conduction times recorded from the pulmonary artery and esophagus correlated well with those recorded from the distal coronary sinus (the generally accepted standard for the indirect interatrial conduction time measurements). In addition to providing information on the mechanism of atrial arrhythmias, the electrograms obtained from the various indirect left atrial recording sites provide satisfactory quantification of interatrial conduction.


Diagnosis and management of rhinitis: complete guidelines of the Joint Task Force on Practice Parameters in Allergy, Asthma and Immunology. American Academy of Allergy, Asthma, and Immunology.
This document contains complete guidelines for diagnosis and management of rhinitis developed by the Joint Task Force on Practice Parameters in Allergy, Asthma and Immunology, representing the American Academy of Allergy, Asthma and Immunology, the American College of Allergy, Asthma and Immunology and the Joint Council on Allergy, Asthma and Immunology. The guidelines are comprehensive and begin with statements on clinical characteristics and diagnosis of different forms of rhinitis (allergic, non-allergic, occupational rhinitis, hormonal rhinitis [pregnancy and hypothyroidism], drug-induced rhinitis, rhinitis from food ingestion), and other conditions that may be confused with rhinitis. Recommendations on patient evaluation discuss appropriate use of history, physical examination, and diagnostic testing, as well as unproven or inappropriate techniques that should not be used. Parameters on management include use of environmental control measures, pharmacologic therapy including recently introduced therapies and allergen immunotherapy. Because of the risks to patients and society from sedation and performance impairment caused by first generation antihistamines, second generation antihistamines that reduce or eliminate these side effects should usually be considered before first generation antihistamines for the treatment of allergic rhinitis. The document emphasizes the importance of rhinitis management for comorbid conditions (asthma, sinusitis, otitis media). Guidelines are also presented on special considerations in patients subsets (children, the elderly, pregnancy, athletes and patients with rhinitis medicamentosa); and when consultation with an allergist-immunologist should be considered.


Enlarged laminectomy and lateral mass screw fixation for multilevel cervical degenerative myelopathy associated with kyphosis.
Either an anterior approach or a posterior approach, which aims to decompress the spinal cord and restore the sagittal alignment, has been adopted to treat multilevel cervical degenerative myelopathy (CDM) associated with kyphosis. However, there is controversy on the optimal surgical strategy for the treatment of multilevel CDM with kyphotic deformity because of the complications of each surgical approach. The purpose of this study was to investigate the surgical efficacy of enlarged laminectomy (removing the inside edge of facet joints and decompressing the nerve foramina) and lateral mass screw fixation for the treatment of multilevel CDM associated with kyphosis. A retrospective radiographic and clinical study to access the efficacy of enlarged laminectomy with lateral mass screw fixation in the treatment of multilevel CDM related to kyphosis. A total of 43 patients (28 men and 15 women; average age, 59.6 years) with multilevel CDM correlated to kyphosis were obtained in the study. All radiological data were recorded on computer-based measurement from preoperative or postoperative X-ray, magnetic resonance imaging (MRI), and computed tomography. All neurological parameters were accessed in each patient. Analysis consisted of: Japanese Orthopedic Association (JOA) score, recovery rate, curvature index (CI), the expansion degree and drift-back distance of the spinal cord, axial symptom severity, and C5 root palsy. The recovery rate based on the JOA score was calculated for each patient. Cervical CI as well as the expansion degree and drift-back distance of the spinal cord was measured using MRI. Axial symptom severity was quantified by a visual analog scale (VAS). Statistical analysis was performed using paired t test with significance set at p<.05. Enlarged laminectomy was performed over a mean of 3.97 levels (range, 3-5 levels). Follow-up information was obtained at a mean of 2.8 years (range, 1.5-5 years) after surgery. Analysis of the final follow-up data showed significant differences before and after surgery in the JOA score (t=24.17, p<.001), CI improvement (t=21.89, p<.001), the anteroposterior diameter at the level of maximum compression of the spinal cord (t=9.54, p<.001), and VAS score (t=13.30, p<.001). The mean spinal cord posterior shift was 4.72±1.10 mm (range, 0-6.71 mm). X-rays confirmed that bone grafts were completely fused at a mean of 3 months after surgery. During the follow-up period, only two patients (4.7%) did not obtain complete recovery, four patients (9.3%) experienced axial symptoms; there were no C5 root palsy and instrument failures noted in this series. Enlarged laminectomy with fixation for the management of multilevel CDM is demonstrated to be an effective strategy for improving neurological function, restoring the normal cervical lordosis, and decreasing the incidence of axial symptoms and C5 root palsy, but there is a need for randomized controlled studies with long-term follow-up to confirm and clarify these results.


Intracellular antibodies: development and therapeutic potential.
Single-chain antibodies, synthesized by the cell and targeted to a particular cellular compartment, can be used to interfere in a highly specific manner with cell growth and metabolism. Recent applications of this technology include the phenotypic knockout of growth-factor receptors, the functional inactivation of p21ras and the inhibition of HIV-1 replication. Intracellular antibodies are likely to have a widespread impact in biological research as a simple and effective alternative to other forms of gene inactivation; they demonstrate clear potential as reagents for cancer therapy and for the control of infectious diseases.


Controlling for exposure changes the relationship between ethnicity, deprivation and injury: an observational study of child pedestrian injury rates in London.
Research has suggested that inequalities in risk exposure may help explain identified ethnic inequalities in child pedestrian injury risk. However, addressing risk exposure in epidemiological research presents theoretical and methodological challenges. This article conceptualises the risk of child pedestrian injury as related to both exposure levels (the quantity of time children spend as pedestrians) and the probability of a hazard where that exposure takes place (the quality of the road environment). To investigate the sensitivity of results on ethnic inequalities in child pedestrian injury risk in London to control for exposure and hazard levels. Using police records of injury 2000-2009, we modelled the relationship between ethnicity, deprivation and child pedestrian injury rates in London using characteristics of the road environment to control for hazard levels and restricting the analysis to the time of the weekday morning commute (7.00-9.00 am), when most children must make a journey to school, to control for exposure levels. Controlling for risk exposure in this way fundamentally changed the nature of the relationship between ethnicity, deprivation and child pedestrian injury. During the time of the morning commute to school, 'Black' children were found to have higher pedestrian injury rates in the least-deprived areas. To inform effective strategies for reducing injury inequality, it is vital that exposure to risk is both acknowledged and considered.


The efficacy and tolerability of adjunctive brivaracetam for the treatment of adult epilepsy: An Australian multi-center retrospective real-world observational cohort study.
Assess the efficacy and tolerability of add-on therapy brivaracetam (BRV) in adult patients with epilepsy in a real-world setting. This multi-center retrospective observational cohort study examined all adult patients who commenced on BRV at 11 Australian epilepsy centers between 2017 and 2020. Primary outcomes were seizure response (≥50% reduction in frequency) and seizure freedom 12 months post BRV commencement, and tolerability. We report three approaches to missing data (complete case analysis, CCA; last observation carried forward, LOCF; and intention to treat, ITT). Secondary outcomes included the durability of early BRV response and continuous seizure freedom from BRV initiation. Subgroup analysis examined patients with focal and generalized epilepsy and patients with refractory (≥4 prior ASMs) and highly refractory (≥7 prior ASMs) epilepsy. Outcomes were also assessed at 'personalized' seizure outcome time points based on baseline seizure frequency. Baseline and follow-up data were available for 228 patients. The mean age was 41.5 years (IQR 30, 50). Most had focal epilepsy (188/228, 82.5%). Median number of previous ASMs was 4 (2, 7), and concomitant ASMs 2 (2, 3). Twelve-month responder rate was: 46.3% using CCA (95% CI 34.0, 58.9); 39.5% using LOCF (33.1, 46.1); and 15.4% using ITT (10.9, 20.7). Twelve-month seizure freedom was: 23.9% using CCA (14.3, 35.9); 24.6% using LOCF (19.1, 30.7); and 7.9% using ITT (4.7, 12.1). The most frequent adverse effects were sedation or cognitive slowing (33/228, 14.5%), irritability or aggression (16/228, 7.0%), and low mood (14/228, 6.1%). Outcomes were similar using continuous outcome definitions and 'personalized' outcome assessment time points. Early responses were highly durable, with 3-month response maintained at all subsequent time points at 83%, and seizure freedom maintained at 85%. Outcomes were similar in focal (n = 187) and generalizsed (n = 25) subgroups. Outcomes were similar in refractory patients (n = 129), but lower in the highly refractory group (n = 62), however improvement with BRV was still observed with 12-month seizure freedom of 8.3% using CCA (1.0, 27), 6.5% using LOCF (1.8, 15.7); and 3.2% using ITT (0.4, 11.2). Meaningful real-world responder and seizure freedom rates can be still observed in a refractory epilepsy population. Brivaracetam response can occur early and appears to be maintained with minimal later relapse. The results should be interpreted with caution given the retrospective nature of the study and the quantities of missing data at later time points.


Turning disciplinary knowledge into solutions.
Turning disciplinary knowledge about preadolescents' and adolescents' exposure to risk factors for cancer as adults into solutions for preventing such an outcome requires that investigators from a variety of backgrounds and disciplines come together to share knowledge. Optimally, these collaborations would occur across two dimensions: (1) transdisciplinary, from the molecular or cellular level (e.g., animal studies of endocrine disruption) to the societal level (e.g., economic studies related to state tobacco policies); and (2) translational, using basic research findings in clinical and other sciences to implement prevention programs and public policy. Only when collaboration is commonplace can the disparate groups of investigators working on cancer prevention during preadolescence and adolescence gain a holistic picture of the risk factors, inform one another's work, and learn what we need to know to devise successful interventions for preventing cancer. Working transdisciplinarily also helps to ensure that messages to health professionals, policymakers, the news media, and the public are consistent and coordinated. At present, those investigating preadolescent and adolescent risk for adult cancer disseminate their knowledge individually, thus missing the opportunity to synthesize knowledge, coordinate dissemination, and implement prevention programs. In this article, we distinguish multidisciplinary, interdisciplinary, and transdisciplinary approaches; argue for the benefits of a transdisciplinary approach to devising successful solutions; and explore how to achieve transdisciplinary functioning.


Cytogenetic observations in infertile men working with insecticidal compounds.
The negative influence of some insecticides on male fertility has been noted. We report our cytogenetic observations on a group of infertile insecticide workers. Increased chromosomal breakage was a constant finding and the Y chromosome was especially damaged. This may account for impaired spermatogenesis. Furthermore, the involvement of heterochromatic chromosomal variants both in the individual susceptibility to the chemically induced damage and in the reproductive fitness is emphasized.


The effect of substrate, season, and agroecological zone on mycoflora and aflatoxin contamination of poultry feed from Khyber Pakhtunkhwa, Pakistan.
To study the effects of and interactions among feed types, seasons, and agroecological zones on the total fungal viable count and aflatoxins B1 (AFB1), B2 (AFB2), G1 (AFG1), and G2 (AFG2) production in poultry feed, an experiment was conducted using three-factorial design. A total of 216 samples of poultry feed ingredients, viz. maize, wheat, rice, cotton seed meal (CSM), and finished products, that is, starter and finisher broilers' rations, were collected from Peshawar, Swat, and D. I. Khan districts of Khyber Pakhtunkhwa, Pakistan, during the winter, spring, summer, and autumn seasons of the year 2007/2008. Analysis of variance showed that there was a complex interaction among all these factors and that this influenced the total fungal viable count and relative concentrations of the aflatoxins produced. Minimum total culturable fungi (6.43 × 10³ CFUs/g) were counted in CSM from D. I. Khan region in winter season while maximum (26.68 × 10³ CFUs/g) in starter ration from Peshawar region in summer. Maximum concentrations of AFB1 (191.65 ng/g), AFB2 (86.85 ng/g), and AFG2 (89.90 ng/g) were examined during the summer season whereas the concentration of AFG1 was maximum (167.82 ng/g) in autumn in finisher ration from Peshawar region. Minimum aflatoxins were produced in the winter season across all the three agroecological zones.


Aneurysm of the lingual artery.
A case report of a chronic aneurysm of the lingual artery with angiographic and computed tomographic findings.


Making Sense of Nonachalasia Esophageal Motor Disorders.
Achalasia is the prototypical obstructive motor disorder diagnosed using HRM, but non-achalasia motor disorders are often identified in symptomatic patients. The clinical relevance of these disorders are assessed using ancillary HRM maneuvers (multiple rapid swallows, rapid drink challenge, solid swallows) that augment the standard supine HRM evaluation by challenging peristaltic function. Finding obstructive motor physiology in non-achalasia motor disorders may raise the option of invasive management akin to achalasia. Certain non-achalasia disorders, particularly hypermotility disorders, may manifest as epiphenomena seen with esophageal hypersensitivity. Symptomatic management is offered for superimposed reflux disease, psychological disorders, functional esophageal disorders, and behavioral disorders.


Intrathecal neuropeptide Y inhibits behavioral and cardiovascular responses to noxious inflammatory stimuli in awake rats.
To test the hypothesis that administration of neuropeptide Y (NPY) to the spinal cord reduces inflammatory pain, we evaluated the effects of intrathecal NPY on behavioral and cardiovascular markers of the nociception associated with intraplantar formalin injection in rats. Before the administration of formalin, NPY dose dependently increased blood pressure, an effect that could be prevented with the coadministration of the Y2 antagonist, BIIE0246. This effect lasted only 20 min, and thus was over before initiation of the formalin test. NPY dose dependently inhibited the flinching, licking, pressor, and tachycardia responses associated with formalin injection. The Y1 receptor antagonist BIBO 3304 partially reversed the antinociceptive effect of NPY at a dose that did not by itself have an effect (3 microg). We conclude that intrathecal NPY acts in part via Y1 receptors to inhibit ongoing inflammatory nociception.


[Hyperhidrosis-aetiopathogenesis, diagnosis, clinical symptoms and treatment].
Although primary hyperhidrosis is a common disease, secondary symptomatic hyperhidrosis is rather rare. Primary hyperhidrosis is a complex neuropathic dysregulation with a genetic predisposition and is diagnosed when patients show pathologic sweating patterns and excessive sweating for at least 6 months and fulfill at least four of the following criteria: affected areas are axillae and/or palms and/or soles and/or forehead; symmetry; no night sweating; at least once a week; onset before the age of 25; positive family history; negative impact on daily activities. Frequently used therapies are topical aluminum salts and anticholinergics, iontophoresis in water, and intracutaneous botulinum toxin. Anticholinergics are also used as systemic treatment. Surgical procedures are used as a last result. Furthermore procedures using thermolysis have been developed.