Success of exchange reamed intramedullary nailing for femoral shaft nonunion or delayed union.
To investigate the success of exchange reamed femoral nailing in the treatment of femoral nonunion after intramedullary (IM) nailing, and to analyze factors that may contribute to failure of exchange reamed femoral nailing. Retrospective consecutive clinical series. Level I trauma center and tertiary university hospital. Twenty-three patients were identified whose radiographs failed to show progression of healing for four months after treatment with a reamed IM femoral nail. Nineteen patients had undergone primary IM nailing of an acute femoral shaft fracture, one patient had been converted to an IM nail after initially being treated in an external fixator, and three patients had previously undergone an unsuccessful exchange reamed nailing. All patients were treated by exchange reamed femoral nailing. The diameter of the new nail was one to three millimeters larger than that of the previous nail (the majority were two millimeters larger). The intramedullary canal was overreamed by one millimeter more than the diameter of the nail. Most of the nails were statically locked, and care was taken to avoid distraction of the nonunion site by reverse impaction after distal interlocking was performed or by applying compression with a femoral distractor. Radiographic evaluation of union was determined by the presence of healing on at least three of four cortices. Factors reviewed included the patient's age, smoking history, mechanism of injury, associated injuries, whether the initial fracture was open or closed, the pattern and location of the fracture, the type of nonunion, the increase in nail diameter, whether the nail was dynamically or statically locked, and the results of any intraoperative cultures. Tobacco use was found to have a detrimental impact on the success of exchange reamed nailing. All eight of the nonsmokers healed after exchange reamed nailing, whereas only ten of the fifteen smokers (66.7 percent) healed after exchange reamed nailing. Overall, exchange reamed femoral nailing was successful in eighteen cases (78.3 percent). Three patients achieved union with additional procedures. Intramedullary cultures were positive in five cases; all of these achieved successful union. Exchange reamed nailing remains the treatment of choice for most femoral diaphyseal nonunions. Exchange reamed IM nailing has low morbidity, may obviate the need for additional bone grafting, and allows full weight-bearing and active rehabilitation. Tobacco use appears to have an adverse effect on nonunion healing after exchange reamed femoral nailing.


Detailed illumination model for bifacial solar cells.
We present a detailed illumination model for bifacial photovoltaic modules in a large PV field. The model considers direct light and diffuse light from the sky and treats the illumination of the ground in detail, where it discriminates between illumination of the ground arising from diffuse and direct light. The model calculates the irradiance components on arbitrarily many positions along the module. This is relevant for finding the minimal irradiance, which determines the PV module performance for many PV modules. Finally, we discuss several examples. The code for the model is available online (DOI: 10.5281/zenodo.3543570).


Paraneoplastic Limbic Encephalitis in a Human Epidermal Growth Factor Receptor-2-positive Gastric Cancer Patient Treated with Trastuzumab-combined Chemotherapy: A Case Report and Literature Review.
Paraneoplastic neurological syndromes (PNSs) are rare nervous system dysfunctions in cancer patients, which are primarily observed with small-cell lung cancer, gynecological cancer, and thymoma. We herein present an uncommon case of PNS in an anti-Hu antibody-positive patient with human epidermal growth factor receptor (HER)-2-positive gastric cancer (GC), who developed limbic encephalitis and a worsening cognitive function. Trastuzumab-combined chemotherapy was initiated and appeared to be partially effective for controlling the neurological symptoms and tumor volume. Chemotherapy failure eventually led to uncontrollable neurological symptoms. This is the first case demonstrating that trastuzumab-combined chemotherapy may be effective for controlling neurological symptoms of PNS in HER2-positive GC patients.


Color vision in the black howler monkey (Alouatta caraya).
Electrophysiological and molecular genetic studies have shown that howler monkeys (Alouatta) are unique among all studied platyrrhines: they have the potential to display trichromatic color vision among males and females. This study examined the color discrimination abilities of four howler monkeys (Alouatta caraya) through a series of tasks involving a behavioral paradigm of discrimination learning. The animals were maintained and housed as a group in the Zoological Gardens of Brasília and were tested in their own home cages. Stimuli consisting of pairs of Munsell color chips were presented in random brightness values to assure that discriminations were based on color rather than brightness cues. All the animals (three males, one female) successfully discriminated all the stimulus pairs, including those that would be expected to be difficult for a dichromatic monkey. These results are consistent with the earlier predictions suggesting that howler monkeys are routinely trichromatic.


[Neurological Behcet syndrome. Presentation of three cases].
Behçet's disease is a multisystemic illness in which neurological abnormalities are seen in 5-48% of cases. We present 3 patients (2 men and 1 women) diagnosed as having Behçet's disease, according to the criteria of the 'International Study Group for Behçet's Disease' of 1990. We describe the clinical findings in these patients, the results of investigations done (MR or CT, evoked potentials-PEV, PESS, PEATC-EEG, ECN, CSF and neuropsychological tests), their course and response to treatment with hyperimmune human gammaglobulim at a dose of 400 mg/kg body weight in 2 patients. All three patients had repeated episodes of meningitis and alterations of the cranial nerves; two patients had epileptic seizures and two had signs of cerebellar disorders and dementia at some time during their illness. One patient died and the other two survived with severe disabilities. Cranial CT showed a cerebral infarct in one patient; evoked potentials showed axon damage in the two patients in whom this was studied. In the only patient in whom ECN was done, signs of axonal polyneuropathy were found. In all three patients there was pleocytosis in the CSF. In the patients in whom hyperimmune human gammaglobulin was given, the results were: one improved after this treatment; in the other there was clinical deterioration, but this was considered to be secondary to a curettage done the day before. The presence of neurological findings in Behçet's disease not caused by cerebral vein thrombosis worsens the prognosis of these patients.


Choline and choline metabolite patterns and associations in blood and milk during lactation in dairy cows.
Milk and dairy products are an important source of choline, a nutrient essential for human health. Infant formula derived from bovine milk contains a number of metabolic forms of choline, all contribute to the growth and development of the newborn. At present, little is known about the factors that influence the concentrations of choline metabolites in milk. The objectives of this study were to characterize and then evaluate associations for choline and its metabolites in blood and milk through the first 37 weeks of lactation in the dairy cow. Milk and blood samples from twelve Holstein cows were collected in early, mid and late lactation and analyzed for acetylcholine, free choline, betaine, glycerophosphocholine, lysophosphatidylcholine, phosphatidylcholine, phosphocholine and sphingomyelin using hydrophilic interaction liquid chromatography-tandem mass spectrometry, and quantified using stable isotope-labeled internal standards. Total choline concentration in plasma, which was almost entirely phosphatidylcholine, increased 10-times from early to late lactation (1305 to 13,535 µmol/L). In milk, phosphocholine was the main metabolite in early lactation (492 µmol/L), which is a similar concentration to that found in human milk, however, phosphocholine concentration decreased exponentially through lactation to 43 µmol/L in late lactation. In contrast, phosphatidylcholine was the main metabolite in mid and late lactation (188 µmol/L and 659 µmol/L, respectively), with the increase through lactation positively correlated with phosphatidylcholine in plasma (R2 = 0.78). Unlike previously reported with human milk we found no correlation between plasma free choline concentration and milk choline metabolites. The changes in pattern of phosphocholine and phosphatidylcholine in milk through lactation observed in the bovine suggests that it is possible to manufacture infant formula that more closely matches these metabolites profile in human milk.


New Microbe Killers: Self-Assembled Silver(I) Coordination Polymers Driven by a Cagelike Aminophosphine.
New Ag(I) coordination polymers, formulated as [Ag(µ-PTAH)(NO3)2]n (1) and [Ag(µ-PTA)(NO2)]n (2), were self-assembled as light- and air-stable microcrystalline solids and fully characterized by NMR and IR spectroscopy, electrospray ionization mass spectrometry (ESI-MS(±), elemental analysis, powder (PXRD) and single-crystal X-ray diffraction. Their crystal structures reveal resembling 1D metal-ligand chains that are driven by the 1,3,5-triaza-7-phospaadamantane (PTA) linkers and supported by terminal nitrate or nitrite ligands; these chains were classified within a 2C1 topological type. Additionally, the structure of 1 features a 1D→2D network extension through intermolecular hydrogen bonds, forming a two-dimensional hydrogen-bonded network with fes topology. Furthermore, both products 1 and 2 exhibit remarkable antimicrobial activity against different human pathogen bacteria (S. aureus, E. coli, and P. aeruginosa) and yeast (C. albicans), which is significantly superior to the activity of silver(I) nitrate as a reference topical antimicrobial.


Oxygen-functionalized few-layer graphene sheets as active catalysts for oxidative dehydrogenation reactions.
Nanostructured graphitic forms of carbons have shown intersting potential for catalysis research and are ideal candidates to substitute the conventional metal-oxide catalysts because they can be easily disposed, which enables a greener, more sustainable catalytic process. Few-layer graphene and its functionalized form offer the opportunity to investigate the nature of graphitic active sites for oxidation reactions in well-defined carbon-based catalysts. In this paper, we report the utilization of oxygen-functionalized few-layer graphene sheets containing variable amounts of oxygen in the heterogeneous catalytic oxidative dehydrogenation (ODH) reaction of isobutane at 400ºC. Interestingly, there is poor correlation between oxygen content and catalytic performance. Carbonyl groups were found to be highly stable, and graphene that had higher sp(2) character, the lowest oxygen content, and fewer edge sites presented the lowest specific rate of isobutane reaction, although the isobutene selectivity remained high. The reoxidation of the graphene surface occurred at the same rate as the ODH reaction suggesting a Mars-van Krevelen type of mechanism, similar to that which takes place on oxide surfaces. These results appear to suggest that a higher fraction of exposed edges where oxygen active sites can be formed and exchanged should lead to more active catalysts for ODH reactions.


Concentrations of mycophenolic acid and glucuronide metabolites under concomitant therapy with cyclosporine or tacrolimus.
Mycophenolate mofetil [MMF, the prodrug of mycophenolic acid (MPA)] is usually administered at double doses with cyclosporine than with tacrolimus because it is believed that MPA exposure is lower during cyclosporine therapy. This study aimed to compare 12 hour, steady-state concentration-time profiles of MPA and its phenol- and acyl-glucuronide metabolites (MPAG and AcMPAG, respectively) in stable kidney transplant recipients maintained either on cyclosporine (n = 12) or tacrolimus (n = 12). During the absorption phase in the cyclosporine group, dose-normalized concentrations of total and free MPA were significantly higher but the overall area under the concentration-time curve (AUC0-12) was not significantly different. Additionally, exposure to AcMPAG was higher in the cyclosporine group (P < 0.05). Ten of 12 patients in the cyclosporine group were on ketoconazole therapy; however, the exposure to MPA or MPAG was not different when MMF was given orally to Sprague-Dawley rats with or without ketoconazole. In conclusion, cyclosporine modulates the disposition of MPA and metabolites differently from tacrolimus; however, patients on cyclosporine may not require double doses of MMF to achieve the same exposure.


Heteroelements in polyoxometalates: a study on the influence of different group 15 elements on polyoxometalate formation.
In the field of polyoxometalate (POM) chemistry, different heteroelements are integrated into the cage-like structures, to obtain different structural types of so-called heteropolyanions (HPAs). While it is generally accepted, that some elements favor certain types of structure, a systematic study is still missing. In this article, we present a systematic investigation of the influence of the group 15 elements nitrogen, phosphorous, arsenic, and antimony on the formation of different POM structure types. Our study is comprised of DFT calculations and corresponding experimental structural analysis. In this context, the DFT study establishes the thermodynamics of formation of different coordination geometries with various heteroelements on two POM structure types, the Keggin and the Anderson-Evans structures. Our POM synthesis experiments were performed at two different pH values (1 and 5) and resulted in a variety of heteropolytungstates, which were identified and characterized by elemental analysis as well as single crystal X-ray diffraction and vibrational spectroscopy. With these methods, we were able to establish a clear trend, showing that heavier elements lead to formation of different structure types than lighter elements. These results signify a large step towards a better understanding of POM formation specifically with respect to the choice of heteroelement.


In vivo detection of superoxide anion in bean sprout based on ZnO nanodisks with facilitated activity for direct electron transfer of superoxide dismutase.
Here, we report on a novel superoxide anion (O2(*-)) biosensor based on direct electron transfer of copper, zinc-superoxide dismutase (Cu, Zn-SOD) at zinc oxide nanodisks surface for in vivo tracking of O2(*-) in bean sprouts. Direct electron transfer of SOD is achieved at ZnO nanodisks film prepared by a one-step electrodeposited method, with a high heterogeneous electron rate constant of 17 +/- 2 s(-1). Spectroscopic data demonstrate that SOD strongly immobilized onto the nanostructured ZnO surfaces processes its inherent activity toward O2(*-) dismutation. A combination of the facilitated direct electron transfer and the bifunctional enzymatic catalytic activities of the SOD substantially provides a dual electrochemical approach to determination of O2(*-) with high selectivity, wide linear range, long stability, and good reproducibility. In particular, SOD adsorbed on the ZnO nanodisks film is capable of sensing O2(*-) cathodically at a very positive potential, 0 mV (vs Ag|AgCl), where the common interfering species such as hydrogen peroxide, uric acid, ascorbic acid, and 3,4-dihydroxyphenylacetic acid were effectively avoided. The excellent analytical performance of the present O2(*-) biosensor, combined with the remarkable characteristics of nanostructured ZnO films, such as biocompatibility, ease of preparation, and facile to miniaturize, paves an electrochemical way for reliable and durable in vivo determination of O2(*-) in bean sprouts.


[Self-medication and health academic staff].
As self-medication is a worldwide problem of public health, this article had as objective to evaluate the behavior of the future health professionals with regard to the drug utilization, particularly, to the self-medication practice. 223 academic students from a public university in Recife City were interviewed, selected by proportional share in each course. A questionnaire on the drug utilization was applied, 15 days before the interview. From the 223 students, 65.5% reported drug use in the last 15 days. 42.3% used drugs through the physician's prescription and 57.7% through the self-medication. The most used drugs were the analgesics (24.0%) and vitamins (18.9%) and the main reason was pain (30.5%). The drug utilization among academic students in Recife City is high but it is inside the parameter according to others analysis. However we have expected a low and more rationalized utilization.


Asia Pacific road transportation emissions, 1900-2050.
Asia Pacific (AP) is the largest regional vehicle market and accounted for 48% of global sales in 2019. Air quality is a pressing issue in many AP countries and together with increased vehicle sales has led to intense scrutiny of vehicle emissions. The heterogeneity of socio-economic features and transportation patterns in AP countries has resulted in different emission levels and control policies. We present an assessment of the historical and future emissions of on-road transportation and strategies to tackle emission challenges. First, we collected historical country-level population, economic development, vehicle ownership, and transportation policy data from 1900 to 2020, and forecast future development of on-road transportation activity (both passenger and freight) based on its historical relationship with socio-economic development through 2050. We considered major countries (China, India, Japan, South Korea, Australia) individually and other AP countries as a group. Second, we generated a series of emission control scenarios with various stringency levels after a comprehensive review of vehicle control measures implemented in AP countries. The control packages included transportation mode shifts, pollutant emission standards, fuel consumption standards, fuel and powertrain diversification, improvement in fuel quality, and economic and transportation policies. Localized emission factors for greenhouse gases (GHGs) and criteria air pollutants (carbon monoxide (CO), nitrogen oxides (NOx), and particulate matter (PM)) were collected and estimated in line with the emission control measures. Third, we estimated historical and future emissions of AP on-road transportation from 1900 to 2050. The results showed that major air pollutants (NOx, CO, and PM2.5) from on-road vehicles peaked in 2000-2010 and are now declining despite increasing vehicle population. Control of GHGs is more challenging than for criteria air pollutants. In our reference scenario where existing policies and emission standards are implemented and new technologies are adopted according to national plans, road transportation GHG emissions in AP peak in approximately 2040.


Infection pressure in apes has driven selection for CD4 alleles that resist lentivirus (HIV/SIV) infection.
Simian immunodeficiency viruses (SIVs) comprise a large group of primate lentiviruses that endemically infect African monkeys. HIV-1 spilled over to humans from this viral reservoir, but the spillover did not occur directly from monkeys to humans. Instead, a key event was the introduction of SIVs into great apes, which then set the stage for infection of humans. Here, we investigate the role of the lentiviral entry receptor, CD4, in this key and fateful event in the history of SIV/HIV emergence. First, we reconstructed and tested ancient forms of CD4 at two important nodes in ape speciation, prior to the infection of chimpanzees and gorillas with these viruses. These ancestral CD4s fully supported entry of diverse SIV isolates related to the virus(es) that made this initial jump to apes. In stark contrast, modern chimpanzee and gorilla CD4s are more resistant to these viruses. To investigate how this resistance in CD4 was gained, we acquired CD4 sequences from 32 gorilla individuals of 2 species, and identified alleles that encode 8 unique CD4 proteins. Function testing of these identified allele-specific CD4 differences in susceptibility to virus entry. By engineering single point mutations from gorilla CD4 alleles into a permissive human CD4 receptor, we demonstrate that acquired SNPs in gorilla CD4 did convey resistance to virus entry. We provide a population genetic analysis to support the theory that selection is acting in favor of more and more resistant CD4 alleles in apes with endemic SIV infection (gorillas and chimpanzees), but not in other ape species (bonobo and orangutan) that lack SIV infections. Taken together, our results show that SIV has placed intense selective pressure on ape CD4, acting to drive the generation of SIV-resistant CD4 alleles in chimpanzees and gorillas.


Pituitary dysfunction in granulomatosis with polyangiitis: the Mayo Clinic experience.
Pituitary involvement in granulomatosis with polyangiitis (GPA) has been described in case reports. The aim of this study was to describe the clinical presentation and outcomes of pituitary disease in patients with GPA evaluated at a tertiary referral center. A retrospective review of patients with GPA-related pituitary disease seen at the Mayo Clinic in Rochester, Minnesota. A total of 637 patients with antineutrophil cytoplasmic antibodies-associated vasculitis were followed at our institution from 1996 through 2011. Eight patients (1.3%) with clinically confirmed pituitary involvement formed the basis of this study. None. Pituitary function was assessed with hormonal testing, including TSH, free T4, cortisol, ACTH, prolactin, FSH, LH, estradiol, T, IGF-1, and simultaneous serum and urine osmolalities. Secondary hypogonadism and diabetes insipidus were the predominant manifestations of pituitary disease (87.5 and 75% of patients, respectively). All patients had abnormal pituitary imaging. A sellar mass with central cystic change and peripheral enhancement was the commonest imaging finding. Pituitary disease was managed with glucocorticoids in combination with cyclophosphamide or rituximab, achieving disease remission in all but one patient. However, permanent anterior pituitary dysfunction was noted in 63% of the patients. Diabetes insipidus was more often reversible, with resolution in 66.7% of the patients. Pituitary involvement in GPA is rare, but it needs to be recognized to avoid unnecessary biopsies of sellar lesions encountered in the context of GPA, and to minimize the risk of irreversible pituitary function loss by prompt implementation of definitive medical therapy for the vasculitis.


Prevalence, seriousness and reporting of work-related violence in the Danish elderly care.
A survey study (paper and pencil) among staff of elderly care institutions in 36 Danish municipalities (n = 9949) was conducted in 2005 with a response rate of 78%. The majority of the participants of the study were women (96%). The paper presents the prevalence, perpetrators, seriousness (self-rated seriousness, injuries, sick leave and type of violence) of work-related physical violence towards care workers in the Danish elderly care and the frequency of reporting the incidents to the safety organization. The findings show that every fourth caregiver was exposed to violence in 2005. Care personnel working in nursing homes and integrated institutions had the highest prevalence of violence (40%) and were also most often (10%) exposed to violence. Clients were most often (>90% of cases) the perpetrators. The most frequent types of violence were hitting (63%) and scratching/pinching (63%). Being held (32%) or kicked (27%) was also mentioned as frequent types of violence; use of weapon, throwing or hitting with a hard objects were more seldom. Nearly 1/3 of the exposed respondents rated at least one incident as very serious. There were significant associations between self-rated seriousness and type of violence, injuries and sick leave. The incidents were, in particular when perpetrators were clients, often rated as not serious. Only 22% of the victims of violence reported the violent incidents to the safety organizations. Reports of violent incidents were significantly associated with frequency of exposure, type of violence, physical injury, sick leave and perpetrators. The more frequent and most serious cases were reported most often and cases where the perpetrators were clients were reported less often than when perpetrators were others. It has been suggested that underreporting of violence occurs because it is time consuming, lacks supervisory support, because it won't make any difference, because it is part of the job, and also because there is a tendency to 'downplay' the violence in the elderly care. Suggestions for researches and policy makers are made.


Developing an Electronic Social Care Record: a tale from the Tyne.
This paper reports on the development process of an Electronic Social Care Record (ESCR), which used an adapted approach to Participatory Design (PD). PD is an established range of methodologies and principles for involving users in the design and implementation of systems or products. University researchers worked as part of a wider team including corporate social service stakeholders, a multidisciplinary children's social service team, and a technology provider, to develop a system that supports the integration of information of various teams/disciplines which need to work together to intervene with children who are in need. Using action research and ethnographic techniques, the researchers sought to understand and address the challenges faced by the various stakeholders when designing a system to deliver an ESCR.


High Positive Correlations between ANRIL and p16-CDKN2A/p15-CDKN2B/p14-ARF Gene Cluster Overexpression in Multi-Tumor Types Suggest Deregulated Activation of an ANRIL-ARF Bidirectional Promoter.
The CDKN2B-AS1 gene, also called ANRIL, is located at the human CDKN2A/B locus at 9p21.3 and transcribed by RNA polymerase II into a long non-coding RNA of 3834 bp. The CDKN2B-AS1 gene overlaps a critical region of 125 kb covering the CDKN2B gene. The CDKN2A/B locus encompasses three major tumor suppressors juxtaposed and joined into a p16-CDKN2A/p15-CDKN2B/p14-ARF gene cluster. CDKN2A encodes splice variants p16-CDKN2A and p14-ARF, and CDKN2B encodes p15-CDKN2B. ANRIL shares a bidirectional promoter with the p14-ARF gene and is transcribed from the opposite strand to the cluster. We performed an analysis of the expression level of ANRIL and tumor suppressor p16-CDKN2A, p15-CDKN2B, and p14-ARF genes using quantitative RT-PCR in a multitumor panel. We observed the overexpression of the four genes ANRIL, p16-CDKN2A, p15-CDKN2B, and p14-ARF in the great majority of the 17 different cancer types. ANRIL was upregulated in 13/17 tumors compared to normal tissues, ranging from 5% (prostate cancer) to 91% (cervix cancer), with variable expression of p16-CDKN2A, p15-CDKN2B, and p14-ARF genes. A high positive correlation was identified between levels of expression of ANRIL and the three tumor suppressors. The strongest positive association was observed with p14-ARF (p < 0.001) in all but one (lung squamous cell carcinoma) of the examined tumor types. This correlation suggests coordinated deregulated mechanisms in all cancer types through aberrant activation of a bidirectional p14-ARF/ANRIL promoter. Furthermore, significant positive correlation was unexpectedly established in prostatic carcinomas, in contradiction with previous data.


Adriamycin stimulates low-affinity Ca2+ binding and lipid peroxidation but depresses myocardial function.
Studies have been performed to examine the effects of different concentrations of adriamycin (10(-9)-10(-3) M) on sarcolemmal ATP-independent Ca2+ binding, contractility, ultrastructure, energy [ATP and creatine phosphate (CrP)] stores, and lipid peroxide activity in the rat myocardium. Low-affinity Ca2+ binding was stimulated, whereas high-affinity Ca2+ binding was inhibited by adriamycin in sarcolemmal vesicles isolated from ventricles. These alterations were accompanied by changes in the number of Ca2+ binding sites without affecting the membrane affinity for Ca2+. Peak developed force as well as positive and negative dF/dt in the isolated papillary muscle were depressed. The percent changes in contractility due to adriamycin were not affected by extracellular Ca2+ concentration. Ultrastructural changes in the papillary muscles due to adriamycin included mitochondrial swelling, presence of intramitochondrial granules, increased lysosomes, and disruption of myofibrils. ATP and CrP content of the papillary muscles was significantly reduced by the drug. Lipid peroxides, estimated by quantitating malondialdehyde content, were elevated by adriamycin. Most of these changes due to adriamycin became apparent at 10 microM or higher concentrations of the drug, and the maximum effect was seen at 1 mM of adriamycin. The in vitro depressant effect of adriamycin may not be related to changes in the low-affinity Ca2+ binding sites, but instead it appears to be associated with a lower energy state and myocardial cell damage.


Melanoma. Associated antigens in benign melanocytic disorders.
Three instances of depigmentation occurring in children with congenital large nevocytic nevi are reported. Serologic studies for tumour-associated antigens to melanoma were performed by indirect immunofluorescence and complement fixation on these patients and others with benign melanocytic disorders. Positive reactivity in several children was observed. The small numbers studied and lack of uniformity of other testing methods leave open the question of relevance of such reactivity to malignant conversion or protection in congenital nevi.


The cationic amino acid exporter Slc7a7 is induced and vital in zebrafish tissue macrophages with sustained efferocytic activity.
Most tissues harbor a substantial population of resident macrophages. Here, we elucidate a functional link between the Slc7a7 cationic amino acid transporter and tissue macrophages. We identified a mutant zebrafish devoid of microglia due to a mutation in the slc7a7 gene. We found that in Slc7a7-deficient larvae, macrophages do enter the retina and brain to become microglia, but then die during the developmental wave of neuronal apoptosis, which triggers intense efferocytic work from them. A similar macrophage demise occurs in other tissues, at stages where macrophages have to engulf many cell corpses, whether due to developmental or experimentally triggered cell death. We found that Slc7a7 is the main cationic amino acid transporter expressed in macrophages of zebrafish larvae, and that its expression is induced in tissue macrophages within 1-2 h upon efferocytosis. Our data indicate that Slc7a7 is vital not only for microglia but also for any steadily efferocytic tissue macrophages, and that slc7a7 gene induction is one of the adaptive responses that allow them to cope with the catabolism of numerous dead cells without compromising their own viability.


Sphingosine kinase transmits estrogen signaling in human breast cancer cells.
Current understanding of cytoplasmic signaling pathways that mediate estrogen action in human breast cancer is incomplete. Here we report that treatment with 17beta-estradiol (E2) activates a novel signaling pathway via activation of sphingosine kinase (SphK) in MCF-7 breast cancer cells. We found that E2 has dual actions to stimulate SphK activity, i.e. a rapid and transient activation mediated by putative membrane G protein-coupled estrogen receptors (ER) and a delayed but prolonged activation relying on the transcriptional activity of ER. The E2-induced SphK activity consequently activates downstream signal cascades including intracellular Ca2+ mobilization and Erk1/2 activation. Enforced expression of human SphK type 1 gene in MCF-7 cells resulted in increases in SphK activity and cell growth. Moreover, the E2-dependent mitogenesis were highly promoted by SphK overexpression as determined by colony growth in soft agar and solid focus formation. In contrast, expression of SphKG82D, a dominant-negative mutant SphK, profoundly inhibited the E2-mediated Ca2+ mobilization, Erk1/2 activity and neoplastic cell growth. Thus, our data suggest that SphK activation is an important cytoplasmic signaling to transduce estrogen-dependent mitogenic and carcinogenic action in human breast cancer cells.


Study of processing parameters influencing the properties of diltiazem hydrochloride microspheres.
Diltiazem hydrochloride-ethylcellulose microspheres were prepared by the water-in-oil emulsion-solvent evaporation technique. Small and spherical microspheres having a mean microsphere diameter in the range of 40-300 microm and entrapment efficiency of approximately 60-90% were obtained. Scanning electron micrographs of drug-loaded microspheres showed the presence of uniformly distributed small pores and absence of drug crystals on their surface, indicating simultaneous precipitation of drug and the polymer from the solvent during solvent evaporation. Differential scanning calorimetric analysis confirmed the absence of any drug-polymer interaction. The in vitro release profile could be altered significantly by changing various processing parameters to give a controlled release of drug from the microspheres. The stability studies of the drug-loaded microspheres showed that the drug was stable at storage temperatures, 5-55 degreesC, for 12 weeks.


Surfaces immobilized with oligo-prolines prevent protein adsorption and cell adhesion.
In this study, oligo-prolines, (Pro)n (n = 6 and 9) inspired by the backbone structure of collagen, were evaluated as a novel non-ionic anti-fouling peptide. Two oligo-prolines with a cysteine residue were synthesized and immobilized on gold substrates via Au-thiol binding. The surfaces immobilized with oligo-prolines, and forming a polyproline-II conformation, indicated hydrophilic properties (water contact angle ≈ 25 degrees). The degree of adsorption of human serum albumin, human fibrinogen, and bovine serum components on these surfaces was quantified using a quartz crystal. The immobilization of oligo-prolines prevented the adsorption of proteins and serum components including small molecules, such as fatty acids. Pro9 specifically indicated good resistance to the adsorption of all components due to the highly-packed Pro9 chains on the surface. The adhesion of fibroblasts was drastically suppressed on the surfaces immobilized with oligo-prolines. Our findings suggest that oligo-proline-immobilized surfaces, specifically Pro9-s, are useful for the development of novel vascular devices that have ultra-low fouling properties.


A model for radar images and its application to adaptive digital filtering of multiplicative noise.
Standard image processing techniques which are used to enhance noncoherent optically produced images are not applicable to radar images due to the coherent nature of the radar imaging process. A model for the radar imaging process is derived in this paper and a method for smoothing noisy radar images is also presented. The imaging model shows that the radar image is corrupted by multiplicative noise. The model leads to the functional form of an optimum (minimum MSE) filter for smoothing radar images. By using locally estimated parameter values the filter is made adaptive so that it provides minimum MSE estimates inside homogeneous areas of an image while preserving the edge structure. It is shown that the filter can be easily implemented in the spatial domain and is computationally efficient. The performance of the adaptive filter is compared (qualitatively and quantitatively) with several standard filters using real and simulated radar images.


Median Approximations for Genomes Modeled as Matrices.
The genome median problem is an important problem in phylogenetic reconstruction under rearrangement models. It can be stated as follows: Given three genomes, find a fourth that minimizes the sum of the pairwise rearrangement distances between it and the three input genomes. In this paper, we model genomes as matrices and study the matrix median problem using the rank distance. It is known that, for any metric distance, at least one of the corners is a [Formula: see text]-approximation of the median. Our results allow us to compute up to three additional matrix median candidates, all of them with approximation ratios at least as good as the best corner, when the input matrices come from genomes. We also show a class of instances where our candidates are optimal. From the application point of view, it is usually more interesting to locate medians farther from the corners, and therefore, these new candidates are potentially more useful. In addition to the approximation algorithm, we suggest a heuristic to get a genome from an arbitrary square matrix. This is useful to translate the results of our median approximation algorithm back to genomes, and it has good results in our tests. To assess the relevance of our approach in the biological context, we ran simulated evolution tests and compared our solutions to those of an exact DCJ median solver. The results show that our method is capable of producing very good candidates.


Establishing a composite auricle allotransplantation model in rats: introduction to transplantation of facial subunits.
Allografts from cadaveric sources may be an alternative for replacing the missing auricle. In this report, the technical aspects of orthotopic composite auricle allotransplantation and an effective short-term immunosuppression protocol in a rat model are described. A total of seven transplantations were performed in the experimental group. The donors were Brown Norway (RT1(n)) rats and the recipients were Lewis (RT1(1)) rats. In the pilot study, 11 isotransplantations (Lewis to Lewis) were performed in either heterotopic (n = 4) or orthotopic (n = 7) locations to establish the surgical technique. Composite auricle allografts were harvested and transplanted based on the posterior facial vein, the external carotid artery, and the great auricular nerve. A plastic square mold sutured over the transplants was used to prevent mechanical trauma to the transplants. Cyclosporine A initiated as 16 mg/kg/day for 2 weeks and tapered to a dosage of 8 mg/kg/day for another 2 weeks was the only immunosuppression regimen. All allografts survived with perfect viability for the follow-up period of 30 days. There were no signs of rejection, infection, or graft-versus-host disease, although significant weight loss was observed resulting from the immunosuppressive treatment. However, signs of rejection started 4 to 6 days after cessation of the cyclosporine A treatment, including edema, localized epidermal desquamation, and erythema formation that eventually progressed to necrosis within 11 to 14 days. The histologic outcomes were well correlated with the macroscopic appearance. It is feasible to elevate and transplant the composite auricle in rats as a single neurosensorial facial subunit. A tapered dose of cyclosporine A from 16 mg/kg to 8 mg/kg allows maintaining allograft survival for 30 days across a strong major histocompatibility complex barrier. This model is reliable and reproducible and has the potential to be used for future immunologic studies to prevent or to induce transplantation tolerance.


[Translated article] Electromyographic axillary nerve injury in fractures of the proximal humerus: Prospective, observational study, analysing the fracture pattern.
Description and analysis of the relation between the proximal humerus fracture patterns and the traumatic injury of the axillary nerve. Prospective, observational study of a consecutive case series that analysed proximal humerus fractures. Radiographic evaluation was performed, and AO (Arbeitsgemeinshaft für Osteosynsthesefragen) system was used to classify the fractures. Electromyography was used to diagnose the axillary nerve injury. Thirty-one patients on 105 who had a proximal humerus fracture met inclusion criteria. Eighty-six percent of the patients included were women and 14% men. The mean age was 71.8 years (30-96 years). Of the patients included in the study, 58% had normal or mild axonotmesis EMG, 23% had axillary nerve neuropathy without muscle denervation and 19% had injury with axillary nerve denervation. Patients who suffered complex fractures of the proximal humerus (AO11B and AO11C) had a higher risk of presenting axillary neuropathy type lesions with muscle denervation in the EMG, this relationship being statistically significant (p<0.001). Patients who have more risk on presenting axillary nerve neuropathy with muscle denervation in electromyography are those who present complex proximal humerus fractures AO11B and AO11C (p<0.001).


[Surgical treatment of malignant tumors of the thoracic wall].
23 patients with malignant tumors of the thoracic wall, invading bone structures, were operated in the period of 2005-2009 years. Thoracic wall reconstruction was performed in 20 (77%) of patients. The type of the reconstruction was defined by tumor localization, volume of resection, anatomic features of transplantational tissue flaps. Surgical method remains the mainstay in the treatment of the thoracic wall tumors. Although in cases of highly malignant bone or soft tissue sarcomas, only combined and complex methods allow the achievement of satisfactory results.


Diagnostic Criteria for Adult-Onset Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Cervical Adenitis (PFAPA) Syndrome.
To identify a set of variables that could discriminate patients with adult-onset periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome from subjects with fever of unknown origin (FUO). We enrolled 74 adults diagnosed with PFAPA syndrome according to the currently used pediatric diagnostic criteria and 62 additional patients with FUO. After having collected clinical and laboratory data from both groups, univariate and multivariate analyses were performed to identify the variables associated with PFAPA diagnosis. Odds ratio (OR) values, their statistical significance, and corresponding 95% confidence interval (CI) were evaluated for each diagnostic factor both at the univariate and multivariate analyses. Diagnostic accuracy was evaluated by the area under receiver operating characteristic (ROC) curve, while the leave-one-out cross-validation procedure was used to ensure that the model maintains the same diagnostic power when applied to new data. According to the multivariate analysis, the clinical variables that discriminated PFAPA patients were: fever episodes associated with cervical lymphadenitis (OR = 92; p < 0.0001), fever attacks associated with erythematous pharyngitis (OR = 231; p < 0.0001), increased inflammatory markers during fever attacks (OR = 588; p = 0.001), and the lack of clinical and laboratory signs of inflammation between flares (OR = 1202; p < 0.0001). These variables were considered for a diagnostic model which accounted for their OR values. The diagnostic accuracy of the proposed set of criteria corresponded to an area under ROC curve of 0.978 (95% CI 0.958-0.998), with a model sensitivity and specificity equal to 93.4% (95% CI 87.5-96.5%) and 91.7% (95% CI 82.8-96.7%), respectively. we have provided herein a set of clinical diagnostic criteria for adult-onset PFAPA syndrome. Our criteria represent an easy-to-use diagnostic tool aimed at identifying PFAPA patients among subjects with FUO with a high-predictive potential, as shown by its very high sensitivity and specificity.


Analysis of synaptic inputs to on-off amacrine cells of the carp retina.
To elucidate the synaptic transmission between bipolar cells and amacrine cells, the effect of polarization of a bipolar cell on an amacrine cell was examined by simultaneous intracellular recordings from both cells in the isolated carp retina. When either an ON or OFF bipolar cell was depolarized by an extrinsic current step, an ON-OFF amacrine cell was transiently depolarized at the onset of the current but no sustained polarization during the current was detected. The current hyperpolarizing the OFF bipolar cell also produced the transient depolarization of the amacrine cell at the termination of the current. These responses had a latency of approximately 10 ms. The amplitude of the current-evoked responses changed gradually with current intensity within the range used in these experiments. They were affected by polarization of the amacrine cell membrane; the amplitude of the current-evoked responses as well as the light-evoked responses was increased when the amacrine cell membrane was hyperpolarized, while the amplitude was decreased when the cell was depolarized. These results confirm directly that ON-OFF amacrine cells receive excitatory inputs from both ON and OFF bipolar cells: the ON transient is due to inputs from ON bipolar cells, and the OFF transient to inputs from OFF bipolar cells. The steady polarization of bipolar cells is converted into transient signals during the synaptic process.


Palmitic acid-modified poly-L-lysine for non-viral delivery of plasmid DNA to skin fibroblasts.
Palmitic acid conjugates of poly-L-lysine (PLL-PA) were prepared, and their ability to deliver plasmid DNA into human skin fibroblasts was evaluated in vitro. The conjugates were capable of condensing a 4.7 kb plasmid DNA into 50-200 nm particles (mean +/- SD = 112 +/- 34 nm), which were slightly smaller than the particles formed by PLL (mean +/- SD = 126 +/- 51 nm). Both PLL and PLL-PA were readily taken up by the cells, but PLL-PA delivered the plasmid DNA into a higher proportion of cells. DNA delivery was found to be reduced by endocytosis inhibitor Brefeldin A, suggesting an active mechanism of particle uptake. Using enhanced green fluorescent protein (EGFP) as a reporter gene, PLL-PA was found to give the highest number of EGFP-positive cells among several carriers tested, including polyethyleneimine, Lipofectamine-2000, and an adenovirus. Although some carriers gave a higher percentage of EGFP-positive cells than PLL-PA, they were also associated with higher toxicities. We conclude that PLL-PA is a promising gene carrier for non-viral modification of human fibroblasts.


Reconstructing the Complex Evolutionary History of the Papuasian Schefflera Radiation Through Herbariomics.
With its large proportion of endemic taxa, complex geological past, and location at the confluence of the highly diverse Malesian and Australian floristic regions, Papuasia - the floristic region comprising the Bismarck Archipelago, New Guinea, and the Solomon Islands - represents an ideal natural experiment in plant biogeography. However, scattered knowledge of its flora and limited representation in herbaria have hindered our understanding of the drivers of its diversity. Focusing on the woody angiosperm genus Schefflera (Araliaceae), we ask whether its morphologically defined infrageneric groupings are monophyletic, when these lineages diverged, and where (within Papuasia or elsewhere) they diversified. To address these questions, we use a high-throughput sequencing approach (Hyb-Seq) which combines target capture (with an angiosperm-wide bait kit targeting 353 single-copy nuclear loci) and genome shotgun sequencing (which allows retrieval of regions in high-copy number, e.g., organellar DNA) of historical herbarium collections. To reconstruct the evolutionary history of the genus we reconstruct molecular phylogenies with Bayesian inference, maximum likelihood, and pseudo-coalescent approaches, and co-estimate divergence times and ancestral areas in a Bayesian framework. We find strong support for most infrageneric morphological groupings, as currently circumscribed, and we show the efficacy of the Angiosperms-353 probe kit in resolving both deep and shallow phylogenetic relationships. We infer a sequence of colonization to explain the present-day distribution of Schefflera in Papuasia: from the Sunda Shelf, Schefflera arrived to the Woodlark plate (present-day eastern New Guinea) in the late Oligocene (when most of New Guinea was submerged) and, subsequently (throughout the Miocene), it migrated westwards (to the Maoke and Bird's Head Plates and thereon) and further diversified, in agreement with previous reconstructions.


Deregulated TGF-β/BMP Signaling in Vascular Malformations.
Correct organization of the vascular tree requires the balanced activities of several signaling pathways that regulate tubulogenesis and vascular branching, elongation, and pruning. When this balance is lost, the vessels can be malformed and fragile, and they can lose arteriovenous differentiation. In this review, we concentrate on the transforming growth factor (TGF)-β/bone morphogenetic protein (BMP) pathway, which is one of the most important and complex signaling systems in vascular development. Inactivation of these pathways can lead to altered vascular organization in the embryo. In addition, many vascular malformations are related to deregulation of TGF-β/BMP signaling. Here, we focus on two of the most studied vascular malformations that are induced by deregulation of TGF-β/BMP signaling: hereditary hemorrhagic telangiectasia (HHT) and cerebral cavernous malformation (CCM). The first of these is related to loss-of-function mutation of the TGF-β/BMP receptor complex and the second to increased signaling sensitivity to TGF-β/BMP. In this review, we discuss the potential therapeutic targets against these vascular malformations identified so far, as well as their basis in general mechanisms of vascular development and stability.


The diagnosis and management of the Spitz nevus in the pediatric population: a systematic review and meta-analysis protocol.
Spitz nevi are uncommon melanocytic neoplasms found in children. Historically, the diagnosis and management of these tumors has lacked consensus among oncologists, pathologists, plastic surgeons, and dermatologists. Once interpreted and treated as a "juvenile melanoma", many have argued for the benignancy of such tumors in certain patient age groups, encouraging a conservative approach. The lack of consensus surrounding the diagnosis and perceived malignant potential of these tumors has led physicians to approach them on a case-by-case basis and institutional protocols. To date, no evidence-based management guideline exists. The objective of this systematic review is to both collect and appraise the evidence on the diagnosis and management of these tumors. A comprehensive electronic literature search will be conducted in PubMed, MEDLINE, Embase, and the Cochrane Library from inception to December 2016. Our search involved collaborating with a healthcare librarian to create a strategy for the OVID/MEDLINE databases. A search of electronic databases for oncology, pathology, plastic surgery, and dermatology abstracts will be performed. Key search terms will include, among several others, "Spitz nevi," "Spitzoid melanoma," "juvenile tumor," and "pediatric". The language of publication will be restricted to English and French. Wherever data allows, meta-analyses will be used to assess differences between Spitz nevi and the tumor of comparison. Additionally, data extraction and summarization using tables will be performed. This review has been registered with PROSPERO (CRD42016034045). This review will systematically and comprehensively review diagnostic and management practices associated with the Spitz nevus. This overview of current literature will hopefully provide the foundation for future standardization of clinical practice. PROSPERO CRD42016034045.


Leveraging non-targeted metabolite profiling via statistical genomics.
One of the challenges of systems biology is to integrate multiple sources of data in order to build a cohesive view of the system of study. Here we describe the mass spectrometry based profiling of maize kernels, a model system for genomic studies and a cornerstone of the agroeconomy. Using a network analysis, we can include 97.5% of the 8,710 features detected from 210 varieties into a single framework. More conservatively, 47.1% of compounds detected can be organized into a network with 48 distinct modules. Eigenvalues were calculated for each module and then used as inputs for genome-wide association studies. Nineteen modules returned significant results, illustrating the genetic control of biochemical networks within the maize kernel. Our approach leverages the correlations between the genome and metabolome to mutually enhance their annotation and thus enable biological interpretation. This method is applicable to any organism with sufficient bioinformatic resources.


Infrared drying of dill leaves: Drying characteristics, temperature distributions, performance analyses and colour changes.
Thin-layer drying behaviour of dill leaves samples under three different infrared radiation power intensities was investigated. Diffusion Approach was found to be the best model that describes the drying behaviour of dill leaves. Effective diffusivity values were 6.97 × 10-9, 6.84 × 10-9 and 8.96 × 10-9 m2/s for power intensities of 1790, 1970 and 2070 W/m2, respectively. According to the first and second law efficiencies, the infrared drying system was more efficient at higher power intensities (p < 0.05). However, the total colour change was maximum at the highest power intensity. For the investigated infrared drying conditions, 1970 W/m2 was recommended as the best-infrared power intensity applied for drying of dill leaves by taking into account both performance analyses and quality changes.


Isolated thyroid metastasis from renal cell carcinoma.
Metastatic neoplasms of the thyroid are uncommon when compared to primary tumors of the gland. Renal cell carcinoma (RCC) is a highly aggressive tumor of the urinary system. It can spread all over the body. Isolated solitary metastases of RCC to the thyroid are very rarely observed. A 64-year-old woman with a history of left radical nephrectomy for RCC, was referred to our clinic with palpable thyroid nodule. Ultrasound confirmed the nodule on the left lobe. Histopathological examination of the thyroidectomy specimen revealed that there were two solitary metastasis of RCC. No other distant metastasis were detected. Metastatic tumors of the thyroid gland are very rare. When patients with thyroid nodule are referred to our clinic with the history of other malignancies, we must consider metastasis. Thyroidectomy is recommended in the case of isolated thyroid metastasis of RCC.


Pain and functional imaging.
Functional neuroimaging has fundamentally changed our knowledge about the cerebral representation of pain. For the first time it has been possible to delineate the functional anatomy of different aspects of pain in the medial and lateral pain systems in the brain. The rapid developments in imaging methods over the past years have led to a consensus in the description of the central pain responses between different studies and also to a definition of a central pain matrix with specialized subfunctions in man. In the near future we will see studies where a systems perspective allows for a better understanding of the regulatory mechanisms in the higher-order frontal and parietal cortices. Also, pending the development of experimental paradigms, the functional anatomy of the emotional aspects of pain will become better known.


The patriarch hypothesis : An alternative explanation of menopause.
Menopause is puzzling because life-history theory predicts there should be no selection for outliving one's reproductive capacity. Adaptive explanations of menopause offered thus far turn on women's long-term investment in offspring and grandoffspring, all variations on the grandmother hypothesis. Here, I offer a very different explanation. The patriarch hypothesis proposes that once males became capable of maintaining high status and reproductive access beyond their peak physical condition, selection favored the extension of maximum life span in males. Because the relevant genes were not on the Y chromosome, life span increased in females as well. However, the female reproductive span was constrained by the depletion of viable oocytes, which resulted in menopause.


Medical futility in end-of-life care: report of the Council on Ethical and Judicial Affairs.
Use of life-sustaining or invasive interventions in patients in a persistent vegetative state or who are terminally ill may only prolong the dying process. What constitutes futile intervention remains a point of controversy in the medical literature and in clinical practice. In clinical practice, controversy arises when the patient or proxy and the physician have discrepant values or goals of care. Since definitions of futile care are value laden, universal consensus on futile care is unlikely to be achieved. Rather, the American Medical Association Council on Ethical and Judicial Affairs recommends a process-based approach to futility determinations. The process includes at least 4 steps aimed at deliberation and resolution including all involved parties, 2 steps aimed at securing alternatives in the case of irreconcilable differences, and a final step aimed at closure when all alternatives have been exhausted. The approach is placed in the context of the circumstances in which futility claims are made, the difficulties of defining medical futility, and a discussion of how best to implement a policy on futility.


Currents through the fusion pore that forms during exocytosis of a secretory vesicle.
Exocytosis, or the fusion of cytoplasmic vesicles with the cell membrane, occurs in nearly all eukaryotic cells, but its mechanism is not understood. Morphological and electrophysiological studies have suggested that membrane fusion begins with the formation of a 'fusion pore', a narrow channel across the closely adjacent membranes of vesicle and cell that forms the first connection of the vesicle lumen with the cell exterior and later dilates to allow release of vesicle contents. We used the patch clamp technique to study exocytosis of single giant secretory vesicles in mast cells of beige mice. The first opening of the fusion pore was found to generate a brief current transient, whose size and direction indicated an initial pore conductance of about 230 pS and a lumen-positive vesicle membrane potential. In time-resolved a.c. admittance measurements, the pore conductance was found to increase to much larger values within milliseconds, as if the pore dilated soon after opening. We conclude that the earliest fusion event may be the formation of a structure similar to an ion channel. Its conductance is of the same order of magnitude as that of a single gap junction channel, the only other known channel that spans two membranes.


Evaluation of antifungal volatile compounds on the basis of the elongation rate of a single hypha.
A novel method is proposed for the evaluation of the activity of an antifungal agent administered as a gas. This system is composed of a batch-flow type reaction vessel, a gas flow system, and a microscopic observation system. The agar plate was prepared on the ceiling of the reaction vessel, and the mycelium of a fungus (Aspergillus niger or Rhizoctonia solani) was inoculated onto it. After preincubation at 25 degrees C for 24 h, the reaction vessel was connected to the gas flow system. An appropriate hypha was selected, and its elongation rate was measured. Then a sample holder containing an antifungal compound was inserted into the reaction vessel from the side hole to saturate the atmosphere inside with its vapor. The retardation or inhibition of the hypha elongation was observed on a television monitor and recorded on a video tape recorder. The antifungal compound was then removed, and the reaction vessel was flushed with air. If the hypha lived, it began to elongate again. By this method, antifungal activity of seven odor compounds could be evaluated quantitatively within several hours.


Downregulation of Cdc2/CDK1 kinase activity induces the synthesis of noninfectious human papillomavirus type 31b virions in organotypic tissues exposed to benzo[a]pyrene.
Epidemiological studies suggest that human papillomavirus (HPV)-infected women who smoke face an increased risk for developing cervical cancer. We have previously reported that exposure of HPV-positive organotypic cultures to benzo[a]pyrene (BaP), a major carcinogen in cigarette smoke, resulted in enhanced viral titers. Since BaP is known to deregulate multiple pathways of cellular proliferation, enhanced virion synthesis could result from carcinogen/host cell interaction. Here, we report that BaP-mediated upregulation of virus synthesis is correlated to an altered balance between cell cycle-specific cyclin-dependent kinase (CDK) activity profile compared with controls. Specifically, BaP treatment increased accumulation of hyperphosphorylated retinoblastoma protein (pRb) which coincided with increased cdc2/CDK1 kinase activity, but which further conflicted with the simultaneous upregulation of CDK inhibitors p16(INK4) and p27(KIP1), which normally mediate pRb hypophosphorylation. In contrast, p21(WAF1) and p53 levels remained unchanged. Under these conditions, CDK6 and CDK2 kinase activities were decreased, whereas CDK4 kinase activity remained unchanged. The addition of purvalanol A, a specific inhibitor of CDK1 kinase, to BaP-treated cultures, resulted in the production of noninfectious HPV type 31b (HPV31b) particles. In contrast, infectivity of control virus was unaffected by purvalanol A treatment. BaP targeting of CDK1 occurred independently of HPV status, since BaP treatment also increased CDK1 activity in tissues derived from primary keratinocytes. Our data indicate that HPV31b virions synthesized in the presence of BaP were dependent on BaP-mediated alteration in CDK1 kinase activity for maintaining their infectivity.


Diseased dogs isoamylases in clinically normal and diseased dogs.
Isoamylases in normal canine sera were separated on cellulose acetate membranes using a discontinuous buffer system without EDTA. Four peaks of amylase activity were present in 17 of 24 sera. Normal values were established. The majority of activity was present in Peak 4 (cathodal isoamylase). Tissue extracts of pancreas, duodenum, kidney, lung, testis, spleen and uterus-ovaries contained Peak 4 isoamylase. Liver and salivary gland lacked all isoamylase activity. Pancreas contained Peak 3 in addition to Peak 4 isoamylase. A tissue origin for Peaks 1 and 2 was not identified. An overall lack of resolution resulted from the inclusion of EDTA in the electrophoresis buffer system. This may account for previous findings suggesting that pancreatic amylase is not present in normal canine serum. An increase in the Peak 3 isoamylase was present in dogs with pancreatitis while dogs with pancreatic atrophy had a decrease in all isoamylases. Total amylase activity was significantly (p < 0.05) decreased in dogs with pancreatic atrophy.


Progress on understanding spatial and temporal variability of PM(2.5) and its components in the Detroit Exposure and Aerosol Research Study (DEARS).
The Detroit Exposure and Aerosol Research Study (DEARS) measured personal exposures, ambient, residential indoor and residential outdoor concentrations of select PM2.5 aerosol components (SO4, NO3, Fe, Si, Ca, K, Mn, Pb, Zn, EC and OC) over a three year period (2004-2007). These events represented approximately 190 calendar days of monitoring which was performed in seven residential neighborhoods throughout Wayne County, MI. The selection of neighborhoods and participants for study inclusion was based upon an a priori hypothesis that each neighborhood represented a potentially distinct air quality scenario being influenced by both regional as well as local pollution sources. Daily (24 h integrated) measurement data were used to evaluate the spatial and temporal PM2.5 compositional variability of the personal, indoor and outdoor spatial settings as they related to a central ambient monitoring site (Allen Park). Many of the PM2.5 components were observed to have spatially different outdoor mass concentrations in matched neighborhood by neighborhood comparisons, with sulfate, OC, and NO3 being noted exceptions. Coefficient of divergence (COD) comparisons involving outdoor measures for Ca, Si, Fe, Zn, Pb, and EC revealed significant spatial variability. While concentrations of most components were lower indoors as compared to outdoor measures, K and Si indoor concentrations often reflected aerosol enrichment (indoor/outdoor ratios ≥ 1.2). Even when personal exposures were adjusted for day to day changes in ambient concentrations, certain components (Ca, Fe, Mn, Zn, among others) revealed a high degree of location-specific spatial variability suggesting the influences of personal activities and/or local source influences on total personal PM2.5 exposures. As a whole, findings indicate that reliance on a central ambient monitor as a surrogate for total personal and potentially even residential outdoor estimates of PM2.5 aerosol composition may provide an undesirable degree of exposure uncertainty for health-based risk estimates. The focus of this paper is on the spatial variability and uncertainty in using a central monitoring site to estimate exposures. Additional information concerning the DEARS can be found at http://www.epa.gov/DEARS/.


A Nickel Anchored Covalent Organic Framework as Unimolecular Metallaphotocatalyst for Visible Light Driver C-P Bond Coupling Reaction.
The urgent need to develop a sustainable and environmentally friendly method for synthesizing organophosphine compounds is underscored by their extensive applications in organic synthesis, coordination chemistry, medicinal chemistry, and photoelectric materials. Metalated covalent organic frameworks (MCOFs), which seamlessly integrate the inherent photo properties of COF with the catalytic capabilities of metal ions, offer an optimal material for efficient transformation of organics sustainably. In this study, we introduce a simple COF with nickel anchorages (Bpy-COF-NiCl2) as a unimolecular metallaphotocatalytic system for effective C-P bond formation. This heterogeneous photocatalyst exhibits superior catalytic performance, achieving yields of up to 95%, and demonstrates broad substrate tolerance and functional group reactivity. Notably, the metallaphotocatalytic system has demonstrated the capability to process aryl bromides to produce the desired product, a feat not previously reported. Finally, the production and reusability test at the gram scale attests to its superior practicality for designing future organic cross-coupling reactions.


Dioxin exposure blocks lactation through a direct effect on mammary epithelial cells mediated by the aryl hydrocarbon receptor repressor.
In mammals, lactation is a rich source of nutrients and antibodies for newborn animals. However, millions of mothers each year experience an inability to breastfeed. Exposure to several environmental toxicants, including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), has been strongly implicated in impaired mammary differentiation and lactation. TCDD and related polyhalogenated aromatic hydrocarbons are widespread industrial pollutants that activate the aryl hydrocarbon receptor (AHR). Despite many epidemiological and animal studies, the molecular mechanism through which AHR signaling blocks lactation remains unclear. We employed in vitro models of mammary differentiation to recapitulate lactogenesis in the presence of toxicants. We demonstrate AHR agonists directly block milk production in isolated mammary epithelial cells. Moreover, we define a novel role for the aryl hydrocarbon receptor repressor (AHRR) in mediating this response. Our mechanistic studies suggest AHRR is sufficient to block transcription of the milk gene β-casein. As TCDD is a prevalent environmental pollutant that affects women worldwide, our results have important public health implications for newborn nutrition.


[Pharmacological role of isatin, an endogenous MAO inhibitor].
Isatin (indole-2,3-dione) has been found in mammalian tissues as one of major components of tribulin, a postulated endogenous marker of stress and anxiety. I previously identified isatin as an endogenous inhibitor of monoamine oxidase (MAO) in the human urine and the brain of stroke-prone spontaneously hypertensive rats (SHRSP) using GC-MS. A single dose of isatin significantly increased norepinephrine (NE) and 5-hydroxytryptamine (5-HT) concentrations measured 2 h later in the various brain regions of normotensive Wistar Kyoto rats (WKY). Striatal acetylcholine (ACh) and dopamine (DA) levels significantly increased 2 h after the administration of isatin. Perfused through a microdialysis probe, isatin also produced a significant and concentration-dependent increase in the ACh and DA concentration in the perfusate from the rat striatum. In the patients with Parkinson's disease, urinary isatin concentrations tended to increase according to the severity of disease, as classified by the Hoehn and Yahr criteria. Isatin significantly increased striatal DA levels in a rat model of Parkinson's disease. Isatin may play a role in the regulation of the brain levels of ACh and DA. Furthermore, isatin has a wide spectrum of biological properties: (a) a marker of stress and anxiety, (b) an inhibitor of a number of enzymes, (c) an anti-seizure agent, (d) an inhibitor of benzodiazepin receptors and ANP binding to its receptors.


Salinomycin's potential to eliminate glioblastoma stem cells and treat glioblastoma multiforme (Review).
Glioblastoma multiforme (GBM) is the most common and deadliest form of primary brain tumor. Despite treatment with surgery, radiotherapy, and chemotherapy with the drug temozolomide, the expected survival after diagnosis remains low. The median survival is only 14.6 months and the two-year survival is a mere 30%. One reason for this is the heterogeneity of GBM including the presence of glioblastoma cancer stem cells (GSCs). GSCs are a subset of cells with the unique ability to proliferate, differentiate, and create tumors. GSCs are resistant to chemotherapy and radiation and thought to play an important role in recurrence. In order to effectively treat GBM, a drug must be identified that can kill GSCs. The ionophore salinomycin has been shown to kill cancer stem cells and is therefore a promising future treatment for GBM. This study focuses on salinomycin's potential to treat GBM including its ability to reduce the CSC population, its toxicity to normal brain cells, its mechanism of action, and its potential for combination treatment.


A mutational analysis of the vaccinia virus B5R protein.
A mutational analysis of the vaccinia virus (VV) B5R protein is presented. This protein is related to the regulators of complement activation (RCA) superfamily, has four short consensus repeats (SCRs) that are typical of this superfamily and is present on extracellular enveloped virus (EEV) particles. Here we have constructed VV mutants in which the cytoplasmic tail (CT) of the B5R protein is progressively truncated, and domains of the B5R protein [the SCR (short consensus repeat) domains, the transmembrane anchor region or the CT] are substituted by corresponding domains from the VV haemagglutinin (HA), another EEV protein. Analysis of these mutant viruses showed that loss of the B5R CT did not affect the formation of intracellular enveloped virus (IEV), actin tails, EEV or virus plaque size. However, if the SCR domains of the B5R protein were replaced by the corresponding region of the HA, the virus plaque size was diminished, the formation of actin tails was decreased severely and the titre of infectious EEV released from cells was reduced approximately 25-fold compared to wild-type virus and 5-fold compared to a virus lacking the entire B5R gene. Thus the linkage of HA to the B5R transmembrane and CT is deleterious for the formation and release of EEV and for cell-to-cell virus spread. In contrast, deletion or substitution of the B5R CT did not affect virus replication, although the amount of cell surface B5R was reduced compared to control.


PEG-appended beta-(1-->3)-D-glucan schizophyllan to deliver antisense-oligonucleotides with avoiding lysosomal degradation.
Schizophyllan is a natural beta-(1-->3)-d-glucan existing as a triple helix in water and as a single chain in dimethylsulfoxide (DMSO). As we already reported, when a homo-polynucleotide [e.g., poly(dA) or poly(C)] is added to the schizophyllan/DMSO solution and subsequently DMSO is exchanged for water, the single chain of schizophyllan forms a complex with the polynucleotide. One of the potential applications for this novel complex is an antisense-oligonucleotide (AS ODN) carrier. The present paper describes a modification technique that enabled us to introduce PEG only to the side chain of schizophyllan. This technique consisted of periodate oxidation of the glucose side chain and subsequent reaction between methoxypolyethylene glycol amine and the formyl terminate, followed by reduction with NaBH4. Subsequently, we made a complex from PEG-appended schizophyllan and an AS ODN sequence, and carried out an in vitro antisense assay, administrating the AS ODN complex to depress A375 c-myb mRNA of A375 melanoma cell lines. The PEG-SPG/AS ODN complex showed more enhanced antisnese effect than naked AS ODN dose, i.e., the same level as that of RGD-appended SPG. Here, the RGD system has been shown one on the most effective AS ODN carrier (Science 261 (1993) 1004-1012). When we added nigericin to the assay system, the antisense effect was not affected in the PEG-SPG system, on the other hand, it was almost eliminated in the RGD system. Nigericin is well known to interrupt transport from endosome to lysosome. Therefore, the difference between the PEG and RGD complexes indicates that, in the PEG system, AS ODN was able to escape from lysosomal degradation. The present work has thus proposed a new strategy to delivery AS ODN using schizophyllan as a new carrier.


Vaccine vial monitor availability and use in low- and middle-income countries: A systematic review.
The vaccine vial monitor (VVM) registers cumulative heat exposure on vaccines over time. As low- and lower-middle-income countries transition beyond support from the Global Alliance for Vaccines and Immunization (Gavi), they will assume full responsibility for vaccine financing and procurement. It is unclear to what extent countries transitioning out of Gavi support will continue to include VVMs on their vaccines. This paper aims to systematically review evidence on VVM availability and use in low- and middle-income countries to document factors behind global access to and country demand for VVMs. Such results could help identify actions needed to ensure continued use of VVMs in countries that transition out of Gavi support. We performed a systematic review of electronic databases, reference lists, and grey literature in English and French languages with publication dates from 2005 onwards. The studies included were analyzed for the following outcomes: (1) availability and deployment of VVM-labeled vaccines; (2) VVM practices and perceptions in the immunization system; (3) vaccine introduction and decision-making processes; (4) Gavi graduation and vaccine program sustainability. The study found that VVM availability and use was affected by multiple sourcing of vaccines and the extent to which VVM was included in the vaccine specification in the tendering documents when procuring vaccines. Knowledge about VVM and its impact on the EPI program was found to be high among health workers as well as decision-makers. However, the study also found that weak capacity in key national institutions such as NRA and NPA might impact on demand for VVM. As countries take decisions regarding the adoption of new vaccines, factors such as disease burden and vaccine price may assume greater importance than vaccine characteristics and presentation. Finally, the study found that countries rely largely on the advice and recommendations from technical partners such as WHO and PAHO. The study concludes that global access to and country demand for VVM are dependent on policy statements and recommendations about VVM by key policy institutions such as WHO and UNICEF. The study also concludes that despite Gavi-eligible countries having access to VVM-labeled vaccines, inclusion is often below 100%. Weak institutional capacity in key national agencies such as NRA and NPA seems to be a contributing factor, while other factors include the procurement of clear national policies on the inclusion of VVM on vaccines, along with the capacity to enforce the policy. Finally, the study concludes that knowledge about VVM and its impact on vaccine program efficiency, safety, and cost is critical for transitioning countries' continuous demand for VVM.


Development of a risk-prediction model for primary aldosteronism in veterans with hypertension.
Rates of screening for primary aldosteronism in patients who meet the criteria are exceedingly low (1%-3%). To help clinicians prioritize screening in patients most likely to benefit, we developed a risk-prediction model. Using national Veterans Health Administration data, we identified patients who met the criteria for primary aldosteronism screening between 2000 and 2019. We performed multivariable logistic regression to identify characteristics associated with positive primary aldosteronism testing before generating a risk-scoring system based on the coefficients (0< β < 0.5 = 1 pt, 0.5 ≤ β < 1 = 2 pts, 1 ≤ β < 1.5 = 3 pts) and then tested the system performance using an internal validation cohort. We identified 502,190 patients who met primary aldosteronism screening criteria, of whom 1.6% were screened and 15% tested positive. Based on the regression model, we generated a risk-scoring system based on a total of 9 possible points in which age under 50, absence of smoking history, and resistant hypertension each scored 1 point; elevated serum sodium 2 points; and hypokalemia 3 points. Rates of positive screening increased with risk score, with 5.6% to 6.7% of those scoring 0 points testing positive; 7.9% to 9.0% 1 point; 8.6% to 10% 2 points; 13% to 14% 3 points; 21% 4 points; 22% to 38% 5 points; 27% to 38% 6 points; 42% to 49% 7 points; and 50% to 51% ≥8 points. In hypertensive patients who meet the criteria for primary aldosteronism screening, rates of positive screening range from 5.6% to 51%. Use of our risk-predication model incorporating these factors can identify patients most likely to benefit from testing.


Brief Report: Seroprevalence of Pertussis Infection in HIV-Infected Adults in the United States.
Pertussis is a resurgent infection that can cause significant morbidity among adults. CD4 T cells are necessary for its clearance, but pertussis studies in HIV-infected adults are limited to case reports. We analyzed stored serum samples from 299 HIV-infected adults to determine the seroprevalence of pertussis among this population. We found that 4.3% of subjects had serologic evidence of recent pertussis infection, and annual incidence of pertussis infection among subjects not vaccinated against pertussis in the last 5 years was 10.5%-17.5%. Prospective studies are needed to define the clinical presentation of pertussis in HIV-infected adults and to optimize vaccination strategies.


Gridifying phylogeny and medical applications on the volunteer computing platform XtremWeb-CH.
XtremWeb-CH (XWCH) is a volunteer computing middleware that makes it easy for scientists and industrials to deploy and execute their parallel and distributed applications on a public-resource computing infrastructure. XWCH supports various high performance applications, including those having large storage and communication requirements. Two high performance applications were ported and deployed on an XWCH platform. The first one is the Phylip package of programs that is employed for inferring phylogenies (evolutionary trees). It is the most widely distributed phylogeny package and has been used to build the largest number of published trees. Some modules of Phylip are CPU time consuming; their sequential version cannot be applied to a large number of sequences. The second application ported on XWCH is a medical application used to generate temporal dynamic neuronal maps. The application,named NeuroWeb,is used to better understand the connectivity and activity of neurons. NeuroWeb is a data and CPU intensive application. This paper describes the different components of an XWCH platform and the lessons learned from gridifying Phylip and NeuroWeb. It also details the new features and extensions, which are being added to XWCH in order to support new types of applications.


Motivation of adult female patients seeking orthodontic treatment: an application of Q-methodology.
Motivation is the impetus for patients to seek orthodontic treatment, affecting adherence, treatment outcomes, and satisfaction. The aim of this study was to assess the motivation of adult female patients seeking orthodontic treatment, and classify the patients according to their motivations. This study used Q-methodology as the main tool. Q-samples were collected and categorized (35 items). Forty-two adult female patients were interviewed before treatment as the P-sample, and their responses were categorized into the Q-methodology grid. Participants were asked to rank-order a set of 35 statements (Q-sample) from "agree most" to "disagree most" (Q-sorting). The finished Q-grids were analyzed using PQ method 2.35. Four main factors were identified based on how adult female patients ranked statements: factor 1, patients who focus on their self-perception of their appearance; factor 2, patients who are concerned about the esthetics and function of their teeth; factor 3, patients who are easily influenced by others; factor 4, patients who want to improve their confidence and avoid negative thoughts caused by their teeth. The remaining patients who had other views did not match any of the above four groups. The motivations of adult female patients seeking orthodontic treatment are complex. This study found that most adult female patients fell into one of four typical factor groups. Our findings may improve the adherence of adult female patients by developing a more ideal treatment program.


FlyBase: the Drosophila database.
FlyBase is a database of genetic and molecular data concerning Drosophila. FlyBase is maintained as a relational database (in Sybase). The scope of FlyBase includes: genes, alleles (and phenotypes), aberrations, pointers to sequence data, clones, stock lists, Drosophila workers and bibliographic references. FlyBase is also available on CD-ROM for Macintosh systems (Encyclopaedia of Drosophila).


Conformational Changes That Coordinate the Activity of BamA and BamD Allowing β-Barrel Assembly.
Most integral outer membrane proteins (OMPs) of Gram-negative bacteria, such as Escherichia coli, assume a β-barrel structure. The β-barrel assembly machine (Bam), a five-member complex composed of β-barrel OMP BamA and four associated lipoproteins, BamB, BamC, BamD, and BamE, folds and inserts OMPs into the outer membrane. The two essential proteins BamA and BamD interact to stabilize two subcomplexes, BamAB and BamCDE, and genetic and structural evidence suggests that interactions between BamA and BamD occur via an electrostatic interaction between a conserved aspartate residue in a periplasmic domain of BamA and a conserved arginine in BamD. In this work, we characterize charge-change mutations at these key BamA and BamD residues and nearby charged residues in BamA with respect to OMP assembly and Bam complex stability. We show that Bam complex stability does not correlate with function, that BamA and BamD must adopt at least two active conformational states during OMP assembly, and that these charged residues are not required for function. Rather, these charged residues are important for coordinating the activities of BamA and BamD to allow efficient OMP assembly. We present a model of OMP assembly wherein recognition and binding of unfolded OMP substrate by BamA and BamD induce a signaling interaction between the two proteins, causing conformational changes necessary for the assembly reaction to proceed. By analogy to signal sequence recognition by SecYEG, we believe these BamA-BamD interactions ensure that both substrate and complex are competent for OMP assembly before the assembly reaction commences.IMPORTANCE Conformational changes in the proteins of the β-barrel assembly machine (Bam complex) are associated with the folding and assembly of outer membrane proteins (OMPs) in Gram-negative bacteria. We show that electrostatic interactions between the two essential proteins BamA and BamD coordinate conformational changes upon binding of unfolded substrate that allow the assembly reaction to proceed. Mutations affecting this interaction are lethal not because they destabilize the Bam complex but rather because they disrupt this coordination. Our model of BamA-BamD interactions regulating conformation in response to proper substrate interaction is reminiscent of conformational changes the secretory (Sec) machinery undergoes after signal sequence recognition that ensure protein quality control.


Microgravity decreases c-fos induction and serum response element activity.
Several studies have shown that altered gravity conditions influence mammalian cell growth and differentiation. The molecular mechanisms underlying these effects, however, remain relatively obscure. In this paper we show that microgravity reached in a sounding rocket strongly decreases epidermal growth factor (EGF)-induced expression of the proto-oncogenes c-fos and c-jun, which are both implicated in the regulation of proliferation and differentiation. Decreased activity of the serum response element (SRE), present in the c-fos promoter-enhancer region, is probably responsible for the decrease in EGF-induced c-fos expression. In addition, we show that gravity alterations differentially modulate distinctive signal transduction pathways, indicating that gravity-dependent modulations of mammalian cell proliferation are unlikely to be caused by a nonspecific stress response of the cell.


Seroprevalence of antibodies to Encephalitozoon cuniculi in domestic rabbits in Nigeria.
Serum samples from 237 randomized rabbits from the five ecological zones of Nigeria, i.e. Northwest (NW), Northeast (NE), Southeast (SE), Southwest (SW) and Northcentral (NC), were evaluated for the presence of antibodies to Encephalitozoon cuniculi by the indirect immunofluorescent antibodies test. A titre of 10 or more was taken as positive. Thirty-nine (16.5%) of the 237 samples were positive with 11, 10, 8, 6 and 4 seropositive rabbits occurring in the NW, NE, SE, SW and NC zones of Nigeria, respectively. Age, sex, live mass and access to grass as a feed supplement were not statistically (P > 0.05) associated with seropositivity, but cage type (single-versus multi-rabbit type), contact with free-range rats and previous illness were strongly (P < 0.05) associated with it. The practice of selling unscreened and untreated 5 to 10-week-old weaners to prospective buyers as foundation stock, use of multi-rabbit communal cages, occasional release of rabbits in runs and contact with free-range house rats should be discouraged. Regular prophylactic and curative treatments, occasional serological screening to remove carriers, and the practice of a high level of hygiene in rabbit colonies are effective control measures.


Fluorometric method for determining the efficiency of spun-glass air filtration media.
The procedures and equipment needed to measure filtration efficiency by means of fluorescent aerosols are described. The filtration efficiency of individual lots of spun-glass air filtration medium or of entire air filtration systems employing such media was determined. Data relating to the comparative evaluation of spun-glass filter media by means of the fluorometric method described, as well as by conventional biological procedures, are presented.


Examining the Role of Quality of Institutionalized Healthcare on Maternal Mortality in the Dominican Republic.
The main study objective was to determine the extent to which the quality of institutionalized healthcare, sociodemographic factors of obstetric patients, and institutional factors affect maternal mortality in the Dominican Republic. COM-Poisson distribution and the Pearson correlation coefficient were used to determine the relationship of predictor factors (i.e., hospital bed rate, vaginal birth rate, teenage mother birth rate, single mother birth rate, unemployment rate, infant mortality rate, and sex of child rate) in influencing maternal mortality rate. The factors hospital bed rate, teenage mother birth rate, and unemployment rate were not correlated with maternal mortality. Maternal mortality increased as vaginal birth rates and infant death rates increased whereas it decreased as single mother birth rates increased. Further research to explore alternate response variables, such as maternal near-misses or severe maternal morbidity is warranted. Additionally, the link found between infant death and maternal mortality presents an opportunity for collaboration among medical specialists to develop multi-faceted solutions to combat adverse maternal and infant health outcomes in the DR.


GDF15(MIC1) H6D Polymorphism Does Not Influence Cardiovascular Disease in a Latin American Population with Rheumatoid Arthritis.
Rheumatoid arthritis (RA) is the most common autoimmune arthropathy worldwide. The increased prevalence of cardiovascular disease (CVD) in RA is not fully explained by classic risk factors. The aim of this study was to determine the influence of rs1058587 SNP within GDF15(MIC1) gene on the risk of CVD in a Colombian RA population. This was a cross-sectional analytical study in which 310 consecutive Colombian patients with RA and 228 age- and sex-matched controls were included and assessed for variables associated with CVD. The mixed cluster methodology based on multivariate descriptive methods such as principal components analysis and multiple correspondence analyses and regression tree (CART) predictive model were performed. Of the 310 patients, 87.4% were women and CVD was reported in 69.5%. Significant differences concerning GDF15 polymorphism were not observed between patients and controls. Mean arterial pressure, current smoking, and some clusters were significantly associated with CVD. GDF15 (rs1058587) does not influence the development of CVD in the population studied.


Using the ecological framework to identify barriers and enablers to implementing Namaste Care in Canada's long-term care system.
Higher acuity of care at the time of admission to long-term care (LTC) is resulting in a shorter period to time of death, yet most LTC homes in Canada do not have formalized approaches to palliative care. Namaste Care is a palliative care approach specifically tailored to persons with advanced cognitive impairment who are living in LTC. The purpose of this study was to employ the ecological framework to identify barriers and enablers to an implementation of Namaste Care. Six group interviews were conducted with families, unlicensed staff, and licensed staff at two Canadian LTC homes that were planning to implement Namaste Care. None of the interviewees had prior experience implementing Namaste Care. The resulting qualitative data were analyzed using a template organizing approach. We found that the strongest implementation enablers were positive perceptions of need for the program, benefits of the program, and fit within a resident-centred or palliative approach to care. Barriers included a generally low resource base for LTC, the need to adjust highly developed routines to accommodate the program, and reliance on a casual work force. We conclude that within the Canadian LTC system, positive perceptions of Namaste Care are tempered by concerns about organizational capacity to support new programming.


[Artificial ventilation of lungs in wounded patients and patients with severe mechanical injuries].
Artificial ventilation of the lungs with positive pressure at the end of respiration and inverse ratio of the respiratory phases was used in patients with wounds and grave mechanical injuries involving acute injuries to the lungs. Negative effect of positive pressure at the end of respiration on gas exchange, hemodynamics, and biomechanics of the lungs was confirmed and therefore this method is not recommended for such patients. Artificial ventilation of the lungs with inverse ratio of the respiratory phases improved gas exchange and biomechanical properties of the lungs, reduced the negative effect of forced ventilation on hemodynamics, and decreased the incidence of complications.


A quantitative method for assessing smoke associated molecular damage in lung cancers.
While tobacco exposure is the cause of the vast majority of lung cancers, an important percentage arise in lifetime never smokers. Documenting the precise extent of tobacco induced molecular changes may be of importance. Also, the contribution of environmental tobacco smoke (ETS) is difficult to assess. We developed and validated a quantitative method to assess the extent of tobacco related molecular damage by combing the most characteristic changes associated with tobacco smoke, the tumor mutation burden (TMB) and type of molecular changes present in lung cancers. Using maximum entropy (MaxEnt) as a classifier, we developed a F score. F score values >0 were considered to show evidence of tobacco related molecular damage, while values ≤0 were considered to lack evidence of tobacco related molecular damage. Compared to the stated patient tobacco exposure histories, the F scores had sensitivity, specificity and accuracy values of 85-87%. Using this method, we analyzed public data sets of lung adenocarcinoma (LUAD), lung squamous cell (LUSC) and small cell lung cancer (SCLC). Less than 10% of LUSCs and SCLCs had negative F scores, while 27% to 35% of LUADs had positive scores. The F score showed a highly significant downward trend when LUADs were subdivided into the following categories: ever, reformed ≤15 years, reformed >15 years and never smokers. Most of the examined bronchial carcinoids (a lung cancer type not associated with smoke exposure) had negative F scores. In addition, most LUADs with EGFR mutations had negative F scores, while almost all with KRAS mutations had positive scores. We have established and validated a quantitative assay that will be of use in assessing the presence and degree of smoke associated molecular damage in lung cancers arising in ever and never smokers.


Lack of accuracy of ventilatory indexes in predicting extubation success in children submitted to mechanical ventilation.
Between 10% and 20% of children submitted to mechanical ventilation in the pediatric intensive care unit present extubation failure. Several ventilatory indexes have been proposed to predict extubation failure. The aim of this study was to analyze the accuracy of these indices in predicting successful extubation in children and to evaluate these variables according to the age of the patient and the specific disease. A prospective observational study including all children submitted to mechanical ventilation in a Brazilian referral pediatric intensive care unit was conducted between August 2007 and August 2008. The tidal volume, maximal negative inspiratory pressure, rapid shallow breathing index and other ventilatory indexes were measured before extubation. These variables were analyzed according to the extubation outcome (success or failure) as well as age and specific disease (post cardiac surgery and acute viral bronchiolitis). A total of 100 patients were included (median age of 2.1 years old). Extubation failure was observed in 13% and was associated with lower weight (10.3+8.1 Kg vs. 5.5+2.4 Kg; p=0.01). We also evaluated the relationship between extubation failure and the main cause indicating mechanical ventilation: children who had received cardiac surgery (n=17) presented an extubation failure rate of 29.4% with a relative risk of 4.6 (1.2-17.2) when compared to children with acute viral bronchiolitis (n=47, extubation failure rate of 6.4%). The maximal inspiratory pressure was the only physiologic variable independently associated with the outcome. However, this variable showed a wide dispersion and lack of accuracy for predicting extubation success (sensitivity of 82% and specificity of 55% for a cut point of -37.5 cmH2O predicting successful extubation). The same wide dispersion was observed with other ventilatory indexes. The indexes for predicting extubation success in children submitted to mechanical ventilation are not accurate; they vary widely depending on age, main disease and other clinical aspects. New formulas including clinical variables should be developed for better prediction of extubation success in children submitted to mechanical ventilation.


Vaccine efficacy and iron deficiency: an intertwined pair?
Vaccines are the most effective measure to prevent deaths and illness from infectious diseases. Nevertheless, the efficacy of several paediatric vaccines is lower in low-income and middle-income countries (LMICs), where mortality from vaccine-preventable infections remains high. Vaccine efficacy can also be decreased in adults in the context of some common comorbidities. Identifying and correcting the specific causes of impaired vaccine efficacy is of substantial value to global health. Iron deficiency is the most common micronutrient deficiency worldwide, affecting more than 2 billion people, and its prevalence in LMICs could increase as food security is threatened by the COVID-19 pandemic. In this Viewpoint, we highlight evidence showing that iron deficiency limits adaptive immunity and responses to vaccines, representing an under-appreciated additional disadvantage to iron deficient populations. We propose a framework for urgent detailed studies of iron-vaccine interactions to investigate and clarify the issue. This framework includes retrospective analysis of newly available datasets derived from trials of COVID-19 and other vaccines, and prospective testing of whether nutritional iron interventions, commonly used worldwide to combat anaemia, improve vaccine performance.