Barriers and missed opportunities in breast and cervical cancer screening among women aged 50 and over, New York City, 2002.
Breast and cervical cancer screening both are routinely recommended for women. However, data are sparse on factors associated with joint screening behaviors. Our objective to describe the factors associated with receiving both, one, or neither screening test among women aged > or = 50. Using data from the New York City Community Health Survey (NYC CHS), we compared the characteristics of women > age 50 (n = 2059) who missed (1) a Pap smear only, (2) mammography only, or (3) both screening procedures with the characteristics of women who received both tests. Analyses were performed using multiple logistic regression. Seventy-three percent of women had both screening tests, 6.7% needed a Pap smear only, 10% missed mammography only, and 10% missed both tests. After multiple logistic regression, missing a Pap smear only was more likely among women > 70 years compared with younger women and among women from Queens than from Manhattan. Missing mammography only was more common among women not reporting a personal doctor than among those with a doctor and among uninsured women relative to the privately insured. Missing both tests was more common among women > 74 years, current smokers compared with never smokers, women without a personal doctor, and the uninsured. This was less common among women from the Bronx than women from Manhattan and among racial/ethnic minorities compared with non-Hispanic white women. The predictors of each screening outcome appear to be qualitatively different. Changes in provider practices and targeted education may improve Pap smear screening rates, whereas policy initiatives and increased access for the uninsured may raise mammography rates. To achieve optimal preventive care, coscreening should be considered.


Use of a stair-step compensatory gain nutritional regimen to program the onset of puberty in beef heifers.
It was hypothesized that metabolic programming of processes underlying puberty can be shifted temporally through the use of a stair-step compensatory growth model such that puberty is optimally timed to occur at 11 to 12 mo of age. Forty crossbred beef heifers were weaned at approximately 3.5 mo of age and, after a 2-wk acclimation period, were assigned randomly to 1 of 4 nutritional groups: 1) low control (LC), restricted feed intake of a forage-based diet to promote BW gain of 0.5 kg/d until 14 mo of age, 2) high control (HC), controlled feed intake of a high-concentrate diet to promote BW gain of 1 kg/d until 14 mo of age, 3) stair-step 1 (SS-1), ad libitum feed intake of a high-concentrate diet until 6.5 mo of age followed by restricted access to a high-forage diet to promote BW gain of 0.35 kg/d until 9 mo of age, ad libitum feed intake of a high-concentrate diet until 11.5 mo of age, and restricted intake of a high-forage diet to promote BW gain of 0.35 kg/d until 14 mo of age, and 4) stair-step 2 (SS-2), reverse sequence of SS-1, beginning with restricted access to a high-forage diet. Body weight (every 2 wk) and circulating concentrations of leptin (monthly) were determined throughout the experiment. Concentrations of progesterone in blood samples collected twice weekly beginning at 8 mo of age were used to determine pubertal status. Body weight gain followed a pattern similar to that proposed in our experimental design. Circulating concentrations of leptin increased following distinct elevations in BW but decreased abruptly after feed intake restriction. Survival analysis indicated that the percentage of pubertal heifers in the LC group was lower (P < 0.05) than all other groups throughout the experiment. Although heifers in SS-1 were nutritionally restricted between 6.5 and 9 mo of age, the proportion pubertal by 12 mo of age did not differ (P = 0.36) from that of the HC group, with 80% and 70% pubertal in SS-1 and HC, respectively. In contrast, the proportion of heifers pubertal by 12 mo of age in the SS-2 group (40%) was lower (P < 0.05) than both HC and SS-1. However, by 14 mo of age, 90% of heifers in the SS-2 group had also attained puberty compared to only 40% of the LC group. In summary, these data provide evidence that changes in the nutritional and metabolic status during the early juvenile period can program the onset of puberty that occurs months later, allowing optimal timing of sexual maturation in replacement beef heifers.


The transcription factor Ap-1 regulates monkey 20α-hydroxysteroid dehydrogenase promoter activity in CHO cells.
Monkey 20α-hydroxysteroid dehydrogenase (20α-HSD) is a catabolic enzyme responsible for converting progesterone into biologically inactive 20α-hydroxyprogesterone, thereby playing a key role in the estrous cycle or pregnancy and allowing ovulation and parturition to occur in most mammalian animals. Monkey 20α-HSD was highly abundant in ovarian and placental tissues during the pre-ovulation and pre-parturition phase and was primarily localized in the syncytiotrophoblast of the placenta. In this study, we focused on the molecular characterization of the monkey 20α-HSD promoter region by conducting reporter assays in Chinese hamster ovary (CHO) K1 cells. A reporter assay using constructs of various lengths of the 5'-flanking region (-890-Luc, -513-Luc, -306-Luc, -273-Luc, and -70-Luc) revealed that a region corresponding to the activator protein 1 (Ap-1) located between -281 and -274 bp was essential for the transcriptional activity. Absence of the Ap-1 site in -273-Luc dramatically decreased the transcription levels to the control levels. When the reporter constructs were co-transfected with Ap-1 (Jun) and specificity protein (Sp-1) genes, the transcription activities of the constructs increased with the exception of -273 and -70, while that of the double construct was reduced compared to that of Ap-1 alone. Furthermore, mutational analysis demonstrated that a putative Ap-1 site played an important role in the expression of the reporter gene. These findings were confirmed by EMSA examining the interactions of the protein Ap-1 in a nuclear extract from CHO-K1 cells and the expression levels of the Ap-1 transcription factor in pre-parturition placenta and CHO-K1 cells. Although mut-1 and mut-2 of Ap-1 bound with nuclear extracts from CHO-K1 cells, the transcriptional activity of mut-3 was almost completely suppressed. Our results indicate that the Ap-1 site (-281 → -274) (5'-TGTCTCAT-3') plays a crucial role in the activation of the monkey 20α-HSD gene. Thus, we demonstrated that monkey 20α-HSD promoter activity is regulated by the transcription factor Ap-1 in CHO-K1 cells.


Sustainable oil palm trunk fibre based activated carbon for the adsorption of methylene blue.
Activated carbon (AC) is becoming the limelight due to its widespread application as an adsorbent for wastewater treatment, gases, and catalysis. However, its high consumption and price have drawn more attention to the sustainable use of natural resources as precursor for AC production. This study focuses on synthesising AC from two types of oil palm trunk (OPT) fibres, a significant agricultural waste products produced by Malaysia's thriving palm oil industries. The BET surface area of about 2057.9 m2 g-1 was achieved by chemical activation with phosphoric acid (H3PO4). The efficiency of the synthesised AC was critically analysed based on the adsorption experiments with methylene blue (MB) by varying several parameters (dosage of adsorbent, pH, initial dye concentration, and temperature of the solution) to elucidate the adsorption mechanism(s). A maximum adsorption capacity of 320.4 mg g-1 at 50 °C was achieved, and the Temkin (r2 = 0.98, 0.95, 0.95) and Langmuir (r2 = 0.94, 0.93, 0.95) isotherm models fitted the adsorption process better than the Freundlich (r2 = 0.95, 0.90, 0.86) model. Besides, the pseudo-second-order model (r2 > 0.90) best described the adsorption process, favouring chemisorption over physisorption. Thermodynamics showed MB adsorption on AC was spontaneous except at the highest dye concentration. It was exothermic at lower dye concentrations (50 and 100 mg L-1) and endothermic at higher ones (300, 500, and 700 mg L-1). In a nutshell, this study reveals that OPT fibre is a promising precursor for synthesising highly porous AC for the adsorption of MB dye.


Estimation of pollen and seed production of common ragweed in France.
Common ragweed (Ambrosia artemisiifolia L.) is an invasive weed of field crops and human-disturbed habitats in Europe. As well as in its natural range (North America), common ragweed is a threat to human health due to its abundant allergenic pollen release. Most studies have been focused on airborne pollen monitoring, but to date, no data have been available on precise individual plant pollen and seed production related to plant traits growing in natural environment and on their corresponding source of variation. The aim of this study was to evaluate pollen and seed production of common ragweed plants in several populations in France. Seasonal pollen production per plant ranged from 100 million to 3 billion and seed production from 346 to 6,114, depending on plant size and habitat. Common ragweed plants developing in field crops produced more pollens and seeds than those growing in other habitats. Pollen and seed production was closely related to plant volume and biomass, thus providing a means of estimating potential pollen and seed production in given target areas. Such biological data could be integrated into population management strategies or into airborne pollen modelling.


Metastasis-related methyltransferase 1 (Merm1) represses the methyltransferase activity of Dnmt3a and facilitates RNA polymerase I transcriptional elongation.
Stimulatory regulators for DNA methyltransferase activity, such as Dnmt3L and some Dnmt3b isoforms, affect DNA methylation patterns, thereby maintaining gene body methylation and maternal methylation imprinting, as well as the methylation landscape of pluripotent cells. Here we show that metastasis-related methyltransferase 1 (Merm1), a protein deleted in individuals with Williams-Beuren syndrome, acts as a repressive regulator of Dnmt3a. Merm1 interacts with Dnmt3a and represses its methyltransferase activity with the requirement of the binding motif for S-adenosyl-L-methionine. Functional analysis of gene regulation revealed that Merm1 is capable of maintaining hypomethylated rRNA gene bodies and co-localizes with RNA polymerase I in the nucleolus. Dnmt3a recruits Merm1, and in return, Merm1 ensures the binding of Dnmt3a to hypomethylated gene bodies. Such interplay between Dnmt3a and Merm1 facilitates transcriptional elongation by RNA polymerase I. Our findings reveal a repressive factor for Dnmt3a and uncover a molecular mechanism underlying transcriptional elongation of rRNA genes.


Regulatory T cells and immune regulation of allergic diseases: roles of IL-10 and TGF-β.
The prevalence of allergic diseases has significantly increased in industrialized countries. Allergen-specific immunotherapy (AIT) remains as the only curative treatment. The knowledge about the mechanisms underlying healthy immune responses to allergens, the development of allergic reactions and restoration of appropriate immune responses to allergens has significantly improved over the last decades. It is now well-accepted that the generation and maintenance of functional allergen-specific regulatory T (Treg) cells and regulatory B (Breg) cells are essential for healthy immune responses to environmental proteins and successful AIT. Treg cells comprise different subsets of T cells with suppressive capacity, which control the development and maintenance of allergic diseases by various ways of action. Molecular mechanisms of generation of Treg cells, the identification of novel immunological organs, where this might occur in vivo, such as tonsils, and related epigenetic mechanisms are starting to be deciphered. The key role played by the suppressor cytokines interleukin (IL)-10 and transforming growth factor (TGF)-β produced by functional Treg cells during the generation of immune tolerance to allergens is now well established. Treg and Breg cells together have a role in suppression of IgE and induction of IgG4 isotype allergen-specific antibodies particularly mediated by IL-10. Other cell types such as subsets of dendritic cells, NK-T cells and natural killer cells producing high levels of IL-10 may also contribute to the generation of healthy immune responses to allergens. In conclusion, better understanding of the immune regulatory mechanisms operating at different stages of allergic diseases will significantly help the development of better diagnostic and predictive biomarkers and therapeutic interventions.


Video-assisted radical thoracoscopic and laparoscopic surgery for esophageal carcinoma.
Esophageal cancer is a common malignancy, for which surgery is the most effective treatment. Compared with traditional surgery, video-assisted thoracoscopic and laparoscopy minimally invasive surgery enables less trauma, better visibility, reduced bleeding and postoperative pain, and lower incidence of surgical complications through a minimally invasive, safe, and highly cost-effective approach in favor of early rehabilitation after surgery. Therefore, the promotion and application of this surgical approach will undoubtedly benefit the majority of patients with esophageal cancer. We have performed video-assisted thoracoscopic and laparoscopy minimally invasive surgery for more than 150 patients in our hospital to date, and have carried out a series of studies in this regard. As the video shows, this approach is safe and reliable with minimal injury and bleeding.


Cohesin and recombination proteins influence the G1-to-S transition in azygotic meiosis in Schizosaccharomyces pombe.
To determine whether recombination and/or sister-chromatid cohesion affect the timing of meiotic prophase events, the horsetail stage and S phase were analyzed in Schizosaccharomyces pombe strains carrying mutations in the cohesin genes rec8 or rec11, the linear element gene rec10, the pairing gene meu13, the double-strand-break formation genes rec6, rec7, rec12, rec14, rec15, and mde2, and the recombination gene dmc1. The double-mutant strains rec8 rec11 and rec8 rec12 were also assayed. Most of the single and both double mutants showed advancement of bulk DNA synthesis, start of nuclear movement (horsetail stage), and meiotic divisions by up to 2 hr. Only mde2 and dmc1 deletion strains showed wild-type timing. Contrasting behavior was observed for rec8 deletions (delayed by 1 hr) compared to a rec8 point mutation (advanced by 1 hr). An hypothesis for the role of cohesin and recombination proteins in the control of the G(1)-to-S transition is proposed. Finally, differences between azygotic meiosis and two other types of fission yeast meiosis (zygotic and pat1-114 meiosis) are discussed with respect to possible control steps in meiotic G(1).


Unconventional pharmacology of a neuronal nicotinic receptor mutated in the channel domain.
The putative channel-forming MII domains of the nicotinic, gamma-aminobutyric acid type A, and glycine receptors contain a highly conserved leucine residue. Mutation of this hydrophobic amino acid in the neuronal nicotinic receptor alpha 7 (Leu-247), reconstituted in Xenopus oocytes, modifies the ionic response to acetylcholine and alters desensitization. Furthermore, the Leu----Thr (L247T) mutant has two conducting states (46 pS and 80 pS), in contrast with the wild-type (WT) receptor, which has only one (45 pS). We now show that this mutant possesses a rather paradoxical pharmacology: antagonists of the WT receptor such as dihydro-beta-erythroidin, hexamethonium, or (+)-tubocurarine elicit ionic currents when applied to the L247T alpha 7 mutant and these responses are blocked by alpha-bungarotoxin. Furthermore, prolonged application of acetylcholine causes desensitization in the WT but leads to a potentiation of the responses to acetylcholine or dihydro-beta-erythroidin in the mutant. These data are consistent with a scheme in which mutation of Leu-247 renders a desensitized state in the WT channel a conducting state. They also strengthen the proposal that, in the WT, some competitive antagonists may stabilize desensitized states. Finally, these observations may shed light on properties of other ion channels, in particular the glutamate receptors, which display multiple conductance levels associated with various pharmacological agents.


Enhanced cyanide biodegradation by immobilized crude extract of Rhodococcus UKMP-5M.
The capability of the crude extract of Rhodococcus UKMP-5M was enhanced by adopting the technology of immobilization. Among the matrices screened to encapsulate the crude extract, gellan gum emerged as the most suitable immobilization material, exceeding the activity of cyanide-degrading enzyme by 61% and 361% in comparison to alginate carrier and non-immobilized crude extract, respectively. Improved bead mechanical strength which supported higher biocatalyst activity by 63% was observed when concentration of gellan gum, concentration of calcium chloride, number of beads and bead size were optimized. The immobilized crude extract demonstrated higher tolerance towards broad range of pH (5-10) and temperature (30°C-40°C), superior cyanide-degrading activity over time and improved storage stability by maintaining 76% of its initial activity after 30 days at 4°C. Furthermore, repeated use of the gellan gum beads up to 20 batches without substantial loss in the catalytic activity was documented in the present study, indicating that the durability of the beads and the stability of the enzyme are both above adequate. Collectively, the findings reported here revealed that the utilization of the encapsulated crude extract of Rhodococcus UKMP-5M can be considered as a novel attempt to develop an environmentally favourable and financially viable method in cyanide biodegradation.


Quantitative and spatio-temporal features of protein aggregation in Escherichia coli and consequences on protein quality control and cellular ageing.
The aggregation of proteins as a result of intrinsic or environmental stress may be cytoprotective, but is also linked to pathophysiological states and cellular ageing. We analysed the principles of aggregate formation and the cellular strategies to cope with aggregates in Escherichia coli using fluorescence microscopy of thermolabile reporters, EM tomography and mathematical modelling. Misfolded proteins deposited at the cell poles lead to selective re-localization of the DnaK/DnaJ/ClpB disaggregating chaperones, but not of GroEL and Lon to these sites. Polar aggregation of cytosolic proteins is mainly driven by nucleoid occlusion and not by an active targeting mechanism. Accordingly, cytosolic aggregation can be efficiently re-targeted to alternative sites such as the inner membrane in the presence of site-specific aggregation seeds. Polar positioning of aggregates allows for asymmetric inheritance of damaged proteins, resulting in higher growth rates of damage-free daughter cells. In contrast, symmetric damage inheritance of randomly distributed aggregates at the inner membrane abrogates this rejuvenation process, indicating that asymmetric deposition of protein aggregates is important for increasing the fitness of bacterial cell populations.


Myocardial Viability: Survival Mechanisms and Molecular Imaging Targets in Acute and Chronic Ischemia.
Myocardial responses to acute ischemia/reperfusion and to chronic ischemic conditions have been studied extensively at all levels of organization. These include subcellular (eg, mitochondria in vitro); intact, large animal models (eg, swine with chronic coronary stenosis); as well as human subjects. Investigations in humans have used positron emission tomographic metabolic and myocardial blood flow measurements, assessment of gene expression and anatomic description of myocardium obtained at the time of coronary artery revascularization, ventricular assist device placement, or heart transplantation. A multitude of genetic, molecular, and metabolic pathways have been identified, which may promote either myocyte survival or death or, most interestingly, both. Many of these potential mediators in both acute ischemia/reperfusion and adaptations to chronic ischemic conditions involve the mitochondria, which play a central role in cellular energy production and homeostasis. The present review is focused on operative survival mechanisms and potential myocardial viability molecular imaging targets in acute and chronic ischemia, especially those which impact mitochondrial function.


Mitochondrial DNA sequence polymorphism, VO2max, and response to endurance training.
Mitochondrial DNA sequence variation was determined in 46 sedentary young adult males who took part in ergocycle endurance training programs in two laboratories to assess whether mitochondrial DNA variants were associated with individual differences in maximal oxygen uptake (VO2max) and its response to training. VO2max was obtained from a progressive ergocycle test to exhaustion. White blood cell mitochondrial DNA was characterized with the restriction fragment length polymorphism (RFLP) technique using 22 restriction enzymes and human mitochondrial DNA as a probe for hybridization. Multiple mitochondrial DNA variants were detected with 15 of the enzymes. Some subjects exhibited many RFLPs, while others showed no variation. These RFLPs (morphs) were generated by base substitutions located in gene regions coding for mitochondrial proteins as well as in the noncoding regions. Carriers of three mitochondrial DNA morphs, two in the subunit 5 of the NADH dehydrogenase gene and one in the tRNA for threonine, had a VO2max (ml.kg-1.min-1) in the untrained state significantly higher than noncarriers, while carriers of one mitochondrial DNA morph in subunit 2 of NADH dehydrogenase had a lower initial VO2max. Endurance training increased VO2max by a mean of 0.51 of O2, with individual differences ranging from gains of 0.06 to 1.03. After adjustment for training site and initial VO2max, a lower response was observed for three carriers of a variant in subunit 5 of the NADH dehydrogenase detected with HincII (mean gain of 0.28 I; P less than 0.05). These results suggest that sequence variation in mitochondrial DNA may contribute to individual difference in VO2max and its response to training.


Effects of topical H-7 on outflow facility, intraocular pressure, and corneal thickness in monkeys.
To determine if low concentrations of H-7 (1-[5-isoquinoline sulfonyl]-2-methyl piperazine) topically applied to the eye increases outflow facility and decreases intraocular pressure (IOP) without affecting the cornea in monkeys, and to evaluate if the effect of H-7 on IOP is pressure dependent. Single or multiple doses of 5% H-7 or vehicle (20 micro L) were administered topically to opposite eyes of normal monkeys. A single dose of 2% H-7 or vehicle (50 micro L) was administered to the glaucomatous eye of monkeys with laser-induced unilateral glaucoma, with vehicle on day 1 and H-7 on day 2. In normotensive eyes, 1 dose of 5% H-7 maximally decreased IOP by a mean +/- SEM of 2.5 +/- 1.0 mm Hg (-16.7% +/- 5.5%) at 3 hours. Higher baseline IOP and repeated dosing were associated with greater IOP reduction. Outflow facility was increased, but central corneal thickness was not affected. In glaucomatous eyes, 1 dose of 2% H-7 maximally decreased IOP by a mean +/- SEM of 5.8 +/- 0.6 mm Hg (-16.9% +/- 1.6%) at 2 hours. Five percent H-7 increases outflow facility and decreases IOP, but does not affect corneal thickness. Multiple doses of H-7 induce greater reduction of IOP than a single dose. The effect of H-7 on IOP may be pressure dependent. Clinical Relevance Multiple topical treatments with low doses of H-7 or analogues may substantially reduce outflow resistance in the hypertensive eye without meaningfully affecting the cornea.


Importance of Inclusion of Pregnant and Breastfeeding Women in COVID-19 Therapeutic Trials.
Investigators are employing unprecedented innovation in the design of clinical trials to rapidly and rigorously assess potentially promising therapies for coronavirus disease 2019 (COVID-19); this is in stark contrast to the continued near-universal regressive practice of exclusion of pregnant and breastfeeding women from these trials. The few trials that allow their inclusion focus on postexposure prophylaxis or outpatient treatment of milder disease, limiting the options available to pregnant women with severe COVID-19 to compassionate use of remdesivir, or off-label drug use of hydroxychloroquine or other therapies. These restrictions were put in place despite experience with these drugs in pregnant women. In this Viewpoint, we call attention to the need and urgency to engage pregnant women in COVID-19 treatment trials now in order to develop data-driven recommendations regarding the risks and benefits of therapies in this unique but not uncommon population.


Quantitation of bacteria in cerebrospinal fluid and blood of children with meningitis and its diagnostic significance.
Cerebrospinal fluid (CSF) specimens from pediatric patients with meningitis were examined for their concentration of microbes and the relationship of this count to the bacteremia levels, microscopy results, and polymorphonuclear leukocyte concentration. A total of 2,031 consecutive CSF specimens were analyzed, of which 63 (3.1%) were positive by culture from the same number of patients. We observed that 85% of the total CSF specimens positive for Haemophilus influenzae type b, Streptococcus agalactiae, Streptococcus pneumoniae, and Neisseria meningitidis had counts in excess of 10(3) CFU/ml, with 56% of the specimens exceeding 10(5) CFU/ml. A correlation existed between the number of organisms present in the CSF and blood. For example, from a total of 22 patients who had counts of H. influenzae greater than 10(3) CFU/ml in the CSF, 16 or 73% had levels of bacteremia greater than 10(3) CFU/ml. It was also noted that the bacterial concentration had a profound effect on the sensitivity of microscopy. The percentage of positive results increased from 25% with less than or equal to 10(3) CFU/ml to 60% in the range of greater than 10(3) to 10(5) CFU/ml and to 97% at concentrations of greater than 10(5) CFU/ml. Furthermore, a significant correlation (P less than 0.01) was noted between the concentration of bacteria in the CSF and the number of polymorphonuclear leukocytes observed on microscopy.


A standardized test for cataplexy.
This study developed a standardized procedure for provoking cataplexy, which facilitated observation of the physiologic changes occurring with cataplexy. Data were obtained from narcoleptic patients recruited from a sleep disorder center. Patients were asked to describe the nature and frequency of cataplexy, as well as their typical emotional triggers. Referring clinicians were asked to assess the likelihood, frequency, and severity of the patients' cataplexy. Nine patients with multiple sleep latency test (MSLT)-confirmed narcolepsy were included in this study. The subjects were then instructed to view a humorous videotape while monitored with video-polysomnography including EEG, EMG, and EOG. In the event of a spell, quadriceps reflexes were tested. The data were examined to determine the occurrence of cataplexy in response to a standardized stimuli. Cataplexy was successfully provoked in five patients (four women and one man). Areflexia of the quadriceps muscle was the most sensitive marker of a cataplectic event. EMG tone was mildly reduced in three patients with no other remarkable changes on polysomnography. The narcoleptic patients' responses to the humorous videotapes and other stimuli varied tremendously. This pilot study demostrates the feasibility of a standardized procedure for provoking cataplexy, which permits further study of these phenomena. Furthermore, a cataplexy test has considerable potential as a diagnostic tool, especially in situations where an MSLT is impractical.


[Endovascular treatment of descending aorta trauma].
Mortality of traumatic aortic lesions is over 80%. A group of those who survive, develop a chronic pseudo aneurism, usually asymptomatic, that is detected during imaging studies. Since conventional surgical treatment of traumatic aortic lesions has a great mortality, endovascular treatment has been used as an alternative treatment in the last decade. To report our experience with endovascular treatment of traumatic aortic lesions. Report of seven patients aged 22 to 65 years, with traumatic aortic lesions. Under general anesthesia an endovascular prosthesis was inserted through the femoral artery. No complications were observed in the postoperative period, and after a follow up ranging from 4 to 40 months, no endoleaks or other complications have been detected. Endovascular treatment of traumatic aortic lesions has good immediate and midterm results.


Anti-HMGCR myopathy may resemble limb-girdle muscular dystrophy.
To determine the prevalence and clinical features of anti-HMGCR myopathy among patients with presumed limb-girdle muscular dystrophy (LGMD) in whom genetic testing has failed to elucidate causative mutations. Patients with presumed LGMD and unrevealing genetic testing were selected based on a few clinico-pathologic features and tested for anti-HMGCR autoantibodies (n = 11). These clinico-pathologic features are peak creatine kinase (CK) greater than 1,000 IU/L and at least 3 of the following features: (1) limb-girdle pattern of weakness, (2) selective involvement of posterior thigh on clinical examination or muscle imaging, (3) dystrophic changes on muscle biopsy, and (4) no family history of muscular dystrophy. Six patients tested positive for anti-HMGCR autoantibodies. In 4, there was a presymptomatic phase, lasting as long as 10 years, characterized by elevated CK levels without weakness. Muscle biopsies revealed variable degrees of a dystrophic pathology without prominent inflammation. In an independent cohort of patients with anti-HMGCR myopathy, 17 of 51 (∼33%) patients were initially presumed to have a form of LGMD based on clinico-pathologic features but were ultimately found to have anti-HMGCR myopathy. Most of these patients responded favorably to immunomodulatory therapies, evidenced by reduction of CK levels and improved strength. Anti-HMGCR myopathy can resemble LGMD. Diagnosis of patients with a LGMD-like presentation of anti-HMGCR myopathy is critical because these patients may respond favorably to immunotherapy, especially those with shorter disease duration.


Significance of biopterin induction in rats with postburn Staphylococcus aureus sepsis.
It has been demonstrated that biopterin, an essential cofactor of nitric oxide synthase (NOS), plays an important role in the pathogenesis of endotoxin-induced shock, yet its biological significance in gram-positive sepsis remains unclear. In this study, we adopted a rat model of postburn Staphylococcus aureus sepsis to investigate the potential role of biopterin in the pathogenesis of gram-positive sepsis. Wistar rats were inflicted with a 20% total body surface area (TBSA) full-thickness scald injury followed by S. aureus challenge, and then guanosine triphosphate-cyclohydrolase I (GTP-CHI) mRNA expression and biopterin levels in liver, kidneys, lungs, and heart were determined. We found that after S. aureus challenge, GTP-CHI gene expressions and biopterin levels were markedly upregulated in various tissues. Meanwhile, multiple organ dysfunction was induced by S. aureus challenge. It was shown that cardiac GTP-CHI mRNA expression and renal BH(4) levels were positively correlated with MB isoenzyme of creatine kinase (CK-MB) and creatinine (r = 0.892, P = 0.0012 and r = 0.9423, P = 0.0015, respectively). These results suggested that thermal injury combined with S. aureus challenge could induce de novo biosynthesis of biopterin, which might play a role in the development of multiple organ dysfunction syndrome secondary to postburn sepsis.


Identification of an IFN-gamma responsive region in an intron of the invariant chain gene.
The mechanism by which IFN-gamma up-regulates invariant chain mRNA in antigen-presenting cells has been under intensive investigation. This study shows that in murine monocytic cells the transcriptional up-regulation mediated by the invariant chain (Ii) upstream enhancer only accounts for part of the induction of Ii mRNA by IFN-gamma. We have identified an intronic region in the murine Ii gene that contributes to the transcriptional up-regulation by IFN-gamma. The region has S (H), X/X2 and Y boxes similar to those in MHC class II promoters and the Ii upstream enhancer. Mutations at the putative S, X and Y boxes have abolished the ability of the region to mediate Ii up-regulation by IFN-gamma. Consistent with the functions of these boxes, our findings reveal that the up-regulation of Ii transcription by IFN-gamma mediated by the intronic region is dependent on the induction of class II transactivator by IFN-gamma.


Electro-enhanced removal of copper ions from aqueous solutions by capacitive deionization.
This study was performed to determine the feasibility of electrosorptive removal of copper ions from aqueous solutions using a capacitive deionization process. The electrosorptive potential of copper ions was determined using cyclic voltammetry measurements, and copper electrodeposition could be suppressed at a voltage less than 0.8 V. Importantly, the experimental results demonstrated a significant enhancement of electrosorption capability of copper ions using the activated carbon electrodes under electro-assistance, associated with electrical double-layer charging. At 0.8 V, the equilibrium electrosorption capacity was enhanced to 24.57 mg/g based on the Langmuir model, and the electrosorption constant rate was increased to 0.038 min(-1) simulated by a first-order kinetics model. Moreover, the activated carbon electrode showed great regeneration performance for the removal of low level copper ions. Additional experiments regarding electrosorption selectivity were performed in the presence of sodium chloride, natural organic matter, or dissolved silica. Copper ions that were preferentially electroadsorbed on the electrode surface can be effectively removed in a competitive environment. Therefore, the electrosorption process using activated carbon electrodes can be recommended to treat copper solutions at low concentrations for wastewater treatment and water purification.


Molecular modeling of interfacial layer-by-layer assembly towards functionalized capsule materials.
Encapsulated nanomaterials, such as polymer-coated nanoemulsions, have highly tunable properties leading to versatile applications. A current lack of understanding of the fundamentals governing the choice of "capsule" materials (polyelectrolyte + surfactant) and its ensuing performance effectively precludes their widespread use. Computational methods can start to redress this by discovering molecule-scale attributes that significantly control the design of capsule materials tuned to fit desired properties. We use molecular dynamics (MD) to carry out the layer-by-layer (LbL) assembly of six unique polyelectrolyte bilayer systems at a surfactant-mediated interface, modeling early-stage capsule synthesis. Monolayer thickness is related to layer density and polyelectrolyte/surfactant interaction energy through polyelectrolyte molecular weight and radius of gyration, respectively, yielding a simple relationship between absorption kinetics and layer structure. For the second monolayer, faster absorption kinetics are observed for pairings of polyelectrolytes with similarly sized functional groups. Surfactants with a more delocalized charge on the head-group catalyze the build-up of ions at the interface, resulting in faster absorption kinetics and greater confinement of the encapsulated material but leading to thicker, less uniform bilayers. These relationships between capsule building block molecules and nanomaterial capsule properties provide a foundation for property prediction and rational design of optimized multi-functional capsule materials.


Boron-Doped Diamond/GaN Heterojunction-The Influence of the Low-Temperature Deposition.
We report a method of growing a boron-doped diamond film by plasma-assisted chemical vapour deposition utilizing a pre-treatment of GaN substrate to give a high density of nucleation. CVD diamond was deposited on GaN substrate grown epitaxially via the molecular-beam epitaxy process. To obtain a continuous diamond film with the presence of well-developed grains, the GaN substrates are exposed to hydrogen plasma prior to deposition. The diamond/GaN heterojunction was deposited in methane ratio, chamber pressure, temperature, and microwave power at 1%, 50 Torr, 500 °C, and 1100 W, respectively. Two samples with different doping were prepared 2000 ppm and 7000 [B/C] in the gas phase. SEM and AFM analyses revealed the presence of well-developed grains with an average size of 100 nm. The epitaxial GaN substrate-induced preferential formation of (111)-facetted diamond was revealed by AFM and XRD. After the deposition process, the signal of the GaN substrate is still visible in Raman spectroscopy (showing three main GaN bands located at 565, 640 and 735 cm-1) as well as in typical XRD patterns. Analysis of the current-voltage characteristics as a function of temperature yielded activation energy equal to 93.8 meV.


The greater trochanter located in the acetabulum in a girl with developmental dysplasia of the hip: an unusual complication after redislocation.
Unstable closed reduction often leads to unsatisfied function. Abnormal force transmission after unstable closed reduction can cause pain, episodes of instability and restriction of range of movement. There is a limited number of literature data which suggests overgrown greater trochanteric located in the acetabulum as a false femoral head without any functional deterioration. In this article, we reported a five-year-old girl with developmental dysplasia of the left hip redislocated following closed reduction. After five-years of follow-up, overgrown greater trochanter was located in the left acetabulum and it unexpectedly resulted in a satisfied function. The unforeseen overgrown greater trochanteric as a false femoral head may lead to a satisfactory function at five-years after reduction. However, long-term follow is required, as its role in early-onset degenerative osteoarthritis remains inconclusive.


Influence of a relaxing incision on suture tension in Bassini's and McVay's repairs.
Suture tension levels measured during 151 inguinal herniorrhaphies in 135 men were higher initially and after a standard relaxing incision in 78 McVay's as compared with 73 Bassini's repairs. The difference, as well as the effect of the relaxing incision on tension, was greater in the middle. In 77 indirect repairs, before relaxation suture tension differed in 51 Bassini's and 26 McVay's procedures only in the midzone. However, with a relaxing incision, the former had much less tension. Similar results were obtained in 74 direct hernias, but better relaxation was seen in 52 McVay's repairs than with their indirect counterparts. These findings were confirmed when 42 McVay's and 37 Bassini's operations on equally (moderate) sized defects were compared. Thus, the complete repair (McVay's operation), with closure of the femoral canal and a deeper, more posterior suturing than in Bassini's operation, is associated with more tension. Use of a relaxing incision is obviously indicated. Further follow-up of our cases may substantiate that the level of suture tension at the time of operation correlates with the risk of recurrence.


Outcomes After Respiratory Extracorporeal Life Support in Teens and Young Adults: An Extracorporeal Life Support Organization Registry Analysis.
A recent study from Germany found that survival after respiratory extracorporeal life support (ECLS) was lower among patients 10-20 years old than 20-30 years old. The objective of this study was to compare survival between teenage and young adult patients who receive respiratory ECLS. Retrospective cohort study. Extracorporeal Life Support Organization registry, an international prospective quality improvement database. All patients ages 16-30 years cannulated for respiratory indications from 1990 to 2020 were included. Patients were divided into two groups, teens (16-19 yr old) and young adults (20-30 yr old). None. Primary outcome was survival to discharge. Variables were considered for the multivariate logistic regression model if there was both a statistically significant difference (p ≤ 0.05) and a clinically meaningful absolute difference between the groups. A total of 5,751 patients were included, of whom 1,653 (29%) were teens and 4,098 (71%) were young adults. Survival to discharge was higher in young adults than teens, 69% versus 63% (p < 0.001). Severity of illness was higher among teens; however, survival within each stratum defined by Pao2/Fio2 ratio was higher in young adults than in teens. Use of venoarterial ECLS was higher in teens than in young adults, 15% versus 7%, respectively. Teens were more likely to receive high-frequency oscillatory ventilation and this therapy was associated with a longer time from admission to ECLS initiation. After adjusting for variables that differ significantly between the groups, the odds ratio for survival in young adults compared with teens was 1.14 (95% CI, 1.004-1.3). In this large multicenter retrospective study, mortality was higher in teens than in young adults who received respiratory ECLS. This difference persisted after adjusting for multiple variables and the mechanism underlying these findings remains unclear.


The Swansea RRHiME track: a new curriculum model for embedding rural and remote healthcare into undergraduate medicine programmes.
This article was migrated. The article was marked as recommended. Many medical programmes around the world seek to provide experiences for their students in rural and remote health, community and primary care, with a view to encouraging future doctors to practice in under resourced and under-doctored areas of the world. New schools (and satellites of existing schools) have been established in rural and remote areas with a view to recruiting students from those areas who will go on to practice there. In these new schools, and in more traditional programmes, the primary curriculum models in use are either short placements in selected areas (including overseas electives) or immersive longitudinal clerkships, typically in a primary/community setting. A wealth of evidence exists of the success of these approaches, however, for many schools, the curriculum is more fixed and there are limited opportunities for introducing what can be seen as more radical change. In this paper, we describe a new approach to curriculum design offered by the Graduate Entry Medicine (GEM) programme at Swansea University Medical School which provides a selected group of students within the cohort with a range of opportunities in rural and remote health embedded within the existing curriculum. The Rural and Remote Health in Medical Education (RRHiME) track has been positively evaluated for 7 years and is transferable to a range of curricula and contexts. The longitudinal evaluation has demonstrated that students experience a prolonged engagement in rural health environments and/or focused on rural and remote health issues, not in terms of spending time in one context but in obtaining a variety of perspectives about, and deepening their understanding of, the issues, challenges and opportunities encountered in rural and remote settings.


[Coordinating breathing and swallowing following laryngectomy].
Integrated study of respiration and deglutition includes 48 healthy examinees and 22 patients after laryngectomy. Laryngectomy changes the relationship between breathing and swallowing. In healthy subjects 70.68 per cent of swallows occurs during the expiratory phase and more than 80 per cent are followed by expiration. In the patients after laryngectomy 58.01 per cent of swallows coincide with the end of the expiration end the beginning of the inspiration and near 80 per cent of swallows are followed by inspiration. Laryngectomy eliminates necessity for specific coordination of breathing and swallowing and makes possible manifestation of the central neural control.


Neurochemical and behavioural effects of acute and chronic memantine administration in rats: Further support for NMDA as a new pharmacological target for the treatment of depression?
A growing body of evidence has pointed to the NMDA receptor antagonists as a potential therapeutic target for the treatment of major depression. The present study was aimed to evaluate behavioural and molecular effects of the acute and chronic treatment with memantine and imipramine in rats. To this aim, rats were acutely or chronically for 14 days once a day treated with memantine (5, 10 and 20 mg/kg) and imipramine (10, 20 and 30 mg/kg) and then subjected to the forced swimming and open-field tests. The acute treatment with memantine at all doses and imipramine at doses (20 and 30 mg/kg) reduced immobility time of rats compared to the saline group (p < 0.05), without affecting spontaneous locomotor activity and chronic treatment with memantine and imipramine, at all doses tested, reduced immobility time of rats compared to the saline group (p < 0.05), without affecting spontaneous locomotor activity. Brain-derived neurotrophic factor (BDNF) hippocampal levels were assessed in imipramine- and memantine-treated rats by ELISA sandwich assay. Interesting enough, acute administration, but not chronic administration of memantine at higher dose (20 mg/kg) increased BDNF protein levels in the rat hippocampus (p < 0.05). Finally, these findings further support the hypothesis that NMDA receptor could be a new pharmacological target for the treatment of depression.


Canine antibody response to Blastomyces dermatitidis WI-1 antigen.
To assess whether dogs with blastomycosis produce antibodies against the WI-1 and A-antigens of Blastomyces dermatitidis and whether the antibodies are useful in serodiagnosis. 359 serum samples obtained from 245 dogs. 233 samples from 122 dogs with blastomycosis, and 1 sample each from 24 dogs with suspected blastomycosis, 51 control dogs without infection, and 48 healthy dogs from an enzootic region were obtained. Antibodies against WI-1 antigen were detected by radioimmunoassay (RIA). Serum samples were tested in parallel for antibodies against the A-antigen of B dermatitidis by commercial agar-gel immunodiffusion (AGID) in a reference laboratory. Antibodies were detected in 92% of infected dogs by RIA and in 41 % by AGID. For 29 serum samples that were obtained 11 to 1,545 days after diagnosis, antibodies were detected in 92% of samples by RIA and 7% by AGID. For 93 serial serum samples from 29 dogs with blastomycosis, the mean anti-WI-1 titer was 1:18,761 at the time of diagnosis, and decreased to a mean of 1:1,338 by 210 days after treatment was initiated. Of 24 dogs with suspected infection, antibodies were detected in 67% by RIA and 33% by AGID. Control dogs without blastomycosis had no detectable antibodies in either assay. Thus, sensitivity was 92% for RIA and 41 % for AGID, and specificity was 100% for both tests. Anti-WI-1 antibodies are readily detected by RIA in dogs with blastomycosis. Titers become high, decline during treatment, and persist for months. Anti-A antibodies are sometimes detected with AGID, but these decrease quickly.


Concentrations of an activator protein for sphingolipid hydrolysis in liver and brain samples from patients with lysosomal storage diseases.
The hydrolysis of sphingolipids by lysosomal enzymes requires the presence of additional proteins, which have been called activator proteins. The number of activator proteins, their specificity, exact mechanism of action, and response to a storage process all remain to be determined. In this study, antibodies to an activator protein known to bind sphingolipids and activate the enzymatic hydrolysis of GM1 ganglioside and sulfatide were used to estimate the concentration of this activator protein in small samples of liver and brain from patients with lysosomal storage diseases. By using rocket immunoelectrophoresis, the concentration of cross-reacting material (CRM) was determined. Control livers had an average of 0.95 +/- 0.18 (mean +/- 1 SD) microgram CRM/mg protein in the extracts, and control brains had an average of 0.25 +/- 0.14 microgram CRM/mg protein. Extremely high levels of CRM were found in extracts of livers from patients with type 1 GM1 gangliosidosis (15.1 and 16.9), and type A Niemann-Pick disease (10.7). Extracts of brain samples revealed a large amount of CRM in type 1 GM1 gangliosidosis (14.8), Tay-Sachs disease (5.3 and 8.7), and Sandhoff disease (13.5). Significantly elevated CRM was also measured in brain samples from patients with type 2 GM1 gangliosidosis, type A Niemann-Pick disease, metachromatic leukodystrophy, and Krabbe disease. The highest levels are found in those genetic diseases where the lipids stored, primarily or secondarily to the genetic defect, bind to this activator protein. This activator protein may have an important function in regulating intralysosomal lipid catabolism, and changes in its concentration in certain genetic diseases may be the cause of clinical, biochemical, and pathological heterogeneity found in the patients.


Babesia microti, human babesiosis, and Borrelia burgdorferi in Connecticut.
Babesia microti was isolated from a white-footed mouse (Peromyscus leucopus) that was captured in southeastern Connecticut in 1988, when the first human case of babesiosis acquired in Connecticut was recognized. To date, 13 cases of babesiosis have been reported in Connecticut, the largest number of human cases reported on the mainland United States. Two of nine patients quiried remembered a prior tick bite. Since Babesia parasites are known to be vectored only by ticks, we surmise that 12 of these infections were acquired via tick bites; 1 was obtained by blood transfusion (the patient was 46 years of age) from an endemically infected donor. The ages of the patients with tick-acquired babesiosis ranged from 61 to 95 years. Two patients died with active infections, and one patient died from chronic obstructive pulmonary disease soon after treatment with clindamycin and quinine. Indirect fluorescent-antibody titers of blood samples drawn at the time of hospitalization for 11 patients and at the time of active infection for 1 asymptomatic person ranged from 1:1,024 to 1:4,096. Five of eight patients with babesiosis also had significant immunoglobulin G or immunoglobulin M titers (1:640 to 1:5,120) to Borrelia burgdorferi. B. microti was isolated in Syrian hamsters inoculated with blood from 7 of 12 patients tested and was also isolated from mice captured in six towns. The peridomestic nature of the disease was demonstrated by isolating the parasite from white-footed mice captured in or near the yards of eight different patients. Of 59 mice tested, 27 were positive and 25 were coinfected with B. burgdorferi. The isolation of B. microti from a white-footed mouse captured in north-central Connecticut (West Hartford), away from the focus of human infections in southeastern Connecticut, suggests that this pathogen may spread into other areas where Ixodes dammini, the tick vector, becomes established.


Arsenic trioxide induces p53-dependent apoptotic signals in myeloma cells with SiRNA-silenced p53: MAP kinase pathway is preferentially activated in cells expressing inactivated p53.
Mutations in p53 are the most common genetic abnormality in cancers. Arsenic trioxide (ATO) is an effective chemotherapeutic agent for the treatment of acute promyelocytic leukemia (APL) and is being tested in phase II studies in various types of cancers. We have shown that ATO is a potent inducer of apoptosis in multiple myeloma cells, engaging primarily the intrinsic apoptotic pathway in cells expressing w.t. p53 and the extrinsic apoptotic pathway in cells expressing mutant p53. To further establish the differential apoptotic signals of ATO in relation to p53 functional status we studied the activation of the intrinsic and the extrinsic apoptotic pathways in IM9 myeloma cells expressing w.t. p53 following silencing of p53 and p21 with the corresponding SiRNAs-GFP constructs. In untransfected cells or in cells transfected with GFP-empty vector construct we observed weak apoptosis concomitant with mild depolarization of mitochondrial membrane, depletion of reduced glutathione and release of cytochrome c. Following silencing of p53 or p21 we observed extensive apoptosis concomitant with extensive depolarization of mitochondrial membrane and depletion of reduced glutathione. We also observed in these cells activation of the extrinsic apoptotic pathway through upregulation of APO2/TRAIL and APO2/TRAIL-R2, activation of caspase 8, degradation of FLIP-L and release of apoptosis inducing factors from mitochondria, instead of cytochrome c. In addition, we observed marked activation of the MAP kinase pathway and dephosphorylation of Akt in p53 or p21 silenced cells. Hence, silencing of p53 or p21 in IM9 myeloma cells results in diversion of apoptosis to the extrinsic pathway and sensitization of myeloma cells to ATO.


[Characteristics of pregnancies obtained by in vitro fertilization].
193 patients had 212 cycles induced for in vitro fertilisation between May 1983 and May 1984. 20 pregnancies of which 10 are still in progress were obtained with 6 spontaneous abortions. There were 2 so-called biochemical pregnancies and 3 extra-uterine pregnancies. The figure of 17% pregnancies where embryos were replaced totals less than 10% if one considers those pregnancies that really carry on. The number of extra-uterine pregnancies is disturbing. Finally, 2 multiple pregnancies continued, one of them being a quadruple pregnancy. The authors have made a special study to see the parameters of the conditions under which the pregnancies were obtained and the prognosis for such pregnancies.


Novel usage of 2-BTSO2CF2H for metal-free electrophilic difluoroalkanethiolation of indoles.
The electrophilic difluoromethylthiolation of indoles with 2-BTSO2CF2H is developed. In the presence of (EtO)2P(O)H and TMSCl, the reaction proceeded under mild conditions to give products in modest to high yields. This is a new application of 2-BTSO2CF2H for electrophilic difluoromethylthiolation.


[Olive oil: influence and benefits on some pathologies].
The olive tree has been one of the agriculture bases in Mediterranean countries with a great economic and social significance. The oil derivative from it fruit can be classified in different kinds according with their quality, being the highest exponent the so-called pure olive oil that contribute in unquestionable benefits for the maintenance of health, illness prevention as well as a better evolution when the illness is present. There are some studies that prove these benefits in pathologies like cancer specially breast and stomach cancer (colon, endometrium and ovary cancer too). Gastrointestinal pathology like peptic ulcer, cholelithiasis and gastric mobility. Rheumatoid arthritis decreasing it development risk and improving it evolution. Diabetes mellitus increasing insulin sensibility and decreasing blood pressure and atherogenic lipoprotein.


Endoscopic removal of esthesioneuroblastoma.
Esthesioneuroblastoma is a rare tumor of neural crest origin that arises in the nasal cavity. There is still no consensus on the optimal treatment for this neoplasm, and the literature contains very few accounts of endoscopic excision in these cases. We described a case report of 12-year-old girl with esthesioneuroblastoma that was confined to the nasal cavity and paranasal sinuses, with no orbital or intracranial extension. The tumor was removed via intranasal endoscopic approach and radiotherapy was administered postoperatively. The patient is currently being followed, and there has been no recurrence in 24 months after surgery.


Perspectives and practices associated with consumer-directed care in Australia: Synergies and tensions in supporting planning and delivery of home care for older people with dementia.
This study used a qualitative, cross-sectional design to address a gap in understanding the perspectives and practices of care planners and case managers in supporting consumer- directed care (CDC) for community dwelling people living with dementia. Semi-structured telephone interviews were conducted with a convenience sample of n = 16 planners and managers from seven providers of the Australian home care packages (HCP) program in NSW (Australia). All interviewees described the aspirations of supporting choice within CDC as synergistic with their values and with person-centred care. Some described new flexibilities within the more open-ended planning conversations enabled by CDC. However, most acknowledged their capacity to enable choice for clients with dementia was limited by the capped care budgets, as well as the skills and time needed to support choice and decision- making. Organisational practice changes associated with the shift to a market-based system were also perceived as limiting the capacity to support choices. Reducing centralised systems, increasing individual budgets and improving staff capacity to support decision-making by people with dementia may help to improve this situation. However, results suggest a deeper need to re-evaluate whether the CDC model is the most appropriate for supporting the rising numbers of people with dementia to age well in place.


Single brain death examination is equivalent to dual brain death examinations.
Although the new Practice Parameters for brain death support a single examination, there is paucity of data comparing its impact to dual brain death (DBD) examinations. We reviewed all brain deaths in our hospital over a 39-month period and compared the optional single brain death (SBD) exam requiring an apnea and a mandatory confirmatory blood flow test to the DBD for organ function at the time of death, rate of donation, and cost. Thirty-six patients had a SBD and 59 DBD exams, without any of them regaining neurological functioning. There was no difference in serum electrolytes (except for higher Na(+) and Cl(-) in the SBD group), blood urea nitrogen, creatinine, blood gases, incidence of diabetes insipidus, apnea completion, consent for donation, and organs recovered and transplanted. During the second BD exam, 35% of patients with DBD were on higher dose of vasopressors, but had lower systolic blood pressure (P = 0.046). For DBD patients, the mean interval between the two exams was 14.4 h, which contributed to a higher cost of $43,707.67 compared to SBD. There was a trend for increased consent rates (adjusted for age, race, and type of exam) when patients were declared by the neurointensivist service following a strict family approach protocol (P = 0.06). SBD exam is easier, faster to perform, with no brain function recovery and leads to similar donation rates, equivalent or better organ function status at the time of BD and lower cost than conventional DBD exams.


Circadian rhythmicity in heart rate and duration of cardiac cycle (P-P interval) in donor and recipient cardiac tissue of heart homograft patients.
Chronobiologic analyses of data collected during one or more continuous 72-hr spans from 3 heart-transplant patients adhering at diurnal activity (0700-2230) and nocturnal rest (2230-0700) reveal statistically significant circadian rhythmicity in the P-P time interval of recipients (P-P)R and the donor (P-P)D, as well as in the reciprocal measure of the latter, the heart rate. The circadian acrophase for (P-P)D and (P-P)R differ slightly (the 95% confidence arcs overlap). For the group, the acrophases for (P-P)D and heart rate at 0344 (2056 to 0528) and 1656 (0940 to 2100) agree in anti-phase, as expected. For 1 patient studied during 3 separate occasions -1,5 and 12 months post-transplant--the period of the rhythm for the (P-P)R time interval progressively elongated from 23.7 hr (1 month post-transplant) to 26.1 hour (5 months post-transplant) and finally to 32.3 hr (12 months post-transplant and 4 months prior to death) while the (P-P)D remained around 24.0 hr (range 23.8 to 24.6 hr). Change in the rhythm's period in (P-P)R may reflect events associated with rejection, continuing necrosis of cardiac tissue and/or medications, among others.


First examination of varying health outcomes of the chronically homeless according to Housing First configuration.
To determine whether two Housing First configurations (scattered site [SS] versus congregated site [CS]) are associated with different health-related outcomes. This ecological study employed a longitudinal, quantitative design to compare the outcomes from 63 individuals (SS: n=37; CS: n=26) in Sydney, Australia, over 12 months. Both configurations showed similar improvements in quality of life and psychological distress. While recent use of substances remained stable across the two configurations over time, a marginally greater increase in the proportion of CS individuals injecting more than weekly was found. For health service utilisation, CS participants had notably higher service utilisation rates for mental health specialists and the emergency department for mental health reasons at follow-up than SS participants. Preliminary evidence of differential injecting and health service utilisation outcomes between configurations emerged within this small-scale study over the 12-month period. Implications for public health: Given the rapid expansion of both SS and CS Housing First configurations across Western countries and the indications from this initial study that outcomes may differ according to configuration, there remains a need for robust evaluative evidence on the efficacy of various supported housing models on long-term individual outcomes.


Anticancer and antimicrobial metallopharmaceutical agents based on palladium, gold, and silver N-heterocyclic carbene complexes.
Complete synthetic, structural, and biomedical studies of two Pd complexes as well as Au and Ag complexes of 1-benzyl-3-tert-butylimidazol-2-ylidene are reported. Specifically, trans-[1-benzyl-3-tert-butylimidazol-2-ylidene]Pd(pyridine)Cl2 (1a) was synthesized from the reaction of 1-benzyl-3-tert-butylimidazolium chloride (1) with PdCl2 in the presence of K2CO3 as a base. The other palladium complex, [1-benzyl-3-tert-butylimidazol-2-ylidene]2PdCl2 (1b), and a gold complex, [1-benzyl-3-tert-butylimidazol-2-ylidene]AuCl (1c), were synthesized by following a transmetallation route from the silver complex, [1-benzyl-3-tert-butylimidazol-2-ylidene]AgCl (1d), by treatment with (COD)PdCl2 and (SMe2)AuCl, respectively. The silver complex 1d in turn was synthesized by the reaction of 1 with Ag2O. The molecular structures of 1a-d have been determined by X-ray diffraction studies. Biomedical studies revealed that, while the palladium complexes 1a and 1b displayed potent anticancer activity, the gold (1c) and silver (1d) complexes exhibited significant antimicrobial properties. Specifically, 1b showed strong antiproliferative activity against three types of human tumor cells, namely, cervical cancer (HeLa), breast cancer (MCF-7), and colon adenocarcinoma (HCT 116), in culture. The antiproliferative activity of 1b was found to be considerably stronger than that of cisplatin. The 1b complex inhibited tumor cell proliferation by arresting the cell cycle progression at the G2 phase, preventing the mitotic entry of the cell. We present evidence suggesting that the treated cells underwent programmed cell death through a p53-dependent pathway. Though both the gold (1c) and silver (1d) complexes showed antimicrobial activity toward Bacillus subtilis, 1c was found to be ca. 2 times more potent than 1d.


Steroidogenesis in porcine atretic follicles: loss of aromatase activity in isolated granulosa and theca.
To evaluate the mechanisms involved in the reduction of estrogen concentrations in porcine follicular fluid during atresia, nonatretic and atretic follicles ranging from 4 to 7 mm in diameter were selected. Follicular fluid estrogen concentrations were 7-16-fold less in the atretic follicles. Isolated granulosa cells from atretic follicles demonstrated a significant reduction in aromatase activity and in follicle-stimulating hormone (FSH)-induced progesterone production in vitro compared to granulosa cells from nonatretic follicles. Isolated theca from atretic follicles also demonstrated a reduction in estrogen production. However, androgen concentrations were equivalent in the follicular fluid of atretic and nonatretic follicles, and theca from atretic follicles maintained testosterone and androstenedione production in vitro. The loss of thecal aromatase activity with atresia is not secondary to a reduction in FSH responsiveness, since FSH did not increase thecal progesterone production in vitro. Cell degeneration also does not account for the reduction in thecal estrogen production, since both androgen output in vitro and follicular fluid androgen concentrations were maintained. These data thus demonstrate that a mechanism other than reduced FSH responsiveness must account for the selective loss of thecal aromatase activity in this stage of atresia.


[Current views on migraine and anti-migraine preparations].
On the basis of comprehensive experimental and clinical research the authors defined a variety of migraine-related mechanisms and schemes of migraine-correction by drugs, which should be both of the vascular- and general-actions to ensure an effective medication.


[Initial stages of interaction of temperate phage 04 with Pseudomonas aeruginosa cells].
The first steps of the interaction of the temperate pilus-dependent phage 04 with susceptible and 04-lysogenic cells of Pseudomonas aeruginosa were investigated. The 04-lysogenic cells retained their ability to adsorb viral particles on the pili. However, after the translocation to the cell surface, the bacteriophage failed to infect the immune microorganism. It is assumed that was modified the surface of 04-immune cells due to lysogenic conversion, and this modification presented the terminal tail fibers of viral particles interacting from with the outer membrane of P. aeruginosa cells.


Cost-effectiveness analyses of self-harm strategies aimed at reducing the mortality of pesticide self-poisonings in Sri Lanka: a study protocol.
An estimated 803,900 people worldwide died as a result of self-harm in 2012. The deliberate ingestion of pesticides has been identified as the method most frequently used to commit fatal self-harm globally. In Sri Lanka, it is estimated that up to 60% of all suicides are committed using this method. The aim of the present study is to assess the cost-effectiveness of an ongoing safe storage intervention currently taking place in a rural Sri Lankan district and to model the cost-effectiveness of implementing the safe storage intervention as well as four potential interventions (legislative, medical management, follow-up contact and mobile phone contact) on a national level. Study design for all the strategies is a cost-effectiveness analysis. A governmental perspective is adopted. The time horizon for tracking the associated costs and health outcomes of the safe storage intervention on district level runs over 3 years. The time horizon is extended to 5 years when modelling a full national roll-out of the respective interventions. The discounting of costs and health outcomes are undertaken at the recommended real rate of 3%. Threshold analyses of the modelled strategies are employed to assess the strategies potential for cost-effectiveness, running scenarios with health outcome improvements ranging from 1% to 100%. Sensitivity analyses are also performed. The main outcome measures of the safe storage intervention are incremental cost-effectiveness ratios. Ethical approval was granted for the safe storage project from the University of Peradeniya, Sri Lanka, in March of 2008. An amendment for the present study was granted from Rajarata University of Sri Lanka in November of 2013. Findings will be disseminated to public and private stakeholders in local and national government in Sri Lanka as well as the wider academic audience through peer-reviewed publications and international conferences. The safe storage cluster trial is registered with the Clinical Trials, ref: NCT1146496 (http://clinicaltrialsfeeds.org/clinical-trials/show/NCT1146496).


Towards hyperpolarized (13)C-succinate imaging of brain cancer.
We describe a novel (13)C enriched precursor molecule, sodium 1-(13)C acetylenedicarboxylate, which after hydrogenation by PASADENA (Parahydrogen and Synthesis Allows Dramatically Enhanced Nuclear Alignment) under controlled experimental conditions, becomes hyperpolarized (13)C sodium succinate. Fast in vivo 3D FIESTA MR imaging demonstrated that, following carotid arterial injection, the hyperpolarized (13)C-succinate appeared in the head and cerebral circulation of normal and tumor-bearing rats. At this time, no in vivo hyperpolarized signal has been localized to normal brain or brain tumor. On the other hand, ex vivo samples of brain harvested from rats bearing a 9L brain tumor, 1 h or more following in vivo carotid injection of hyperpolarized (13)C sodium succinate, contained significant concentrations of the injected substrate, (13)C sodium succinate, together with (13)C maleate and succinate metabolites 1-(13)C-glutamate, 5-(13)C-glutamate, 1-(13)C-glutamine and 5-(13)C-glutamine. The (13)C substrates and products were below the limits of NMR detection in ex vivo samples of normal brain consistent with an intact blood-brain barrier. These ex vivo results indicate that hyperpolarized (13)C sodium succinate may become a useful tool for rapid in vivo identification of brain tumors, providing novel biomarkers in (13)C MR spectral-spatial images.


Renal Safety of Multimodal Brain Imaging Followed by Endovascular Therapy.
Contrast-enhanced noninvasive angiography and perfusion imaging are recommended to identify eligible patients for endovascular therapy (EVT) in extended time windows (>6 hours or wake-up). If eligible, additional intraarterial contrast exposure will occur during EVT. We aimed to study the renal safety in the DEFUSE 3 (Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke) population, selected with contrast-enhanced multimodal Imaging and randomized to EVT versus medical management. In the randomized DEFUSE 3 trial population, we compared changes in serum creatinine between baseline (before randomization) and 24 hours later. The primary outcome was the relative change in creatinine level between baseline and 24 hours in the EVT versus medical arm. The secondary outcome was a comparison between computed tomography (CT) versus magnetic resonance imaging selection in the EVT arm. The safety outcome was a comparison of the proportion of patients with criteria for contrast-associated kidney injury in the EVT versus medical arm and a comparison between CT versus magnetic resonance imaging selection in the EVT arm. In the DEFUSE 3 population (n=182, age 69±13, 51% female), mean creatinine decreased from a baseline of 0.98±0.33 mg/dL to 0.88±0.28 mg/dL at 24 hours (P<0.001). There was no difference in change between treatment groups: relative to baseline, there was a 6.3% reduction in the EVT group versus 9.2% in the medical group, P=0.294. Absolute decrease -0.08±0.18 in EVT versus -0.12±0.18 in medical, P=0.135; Among patients treated with EVT, there was no difference in 24-hour creatinine level changes between patients who were selected with CT angiography/CT perfusion (-0.08±0.18) versus magnetic resonance imaging (-0.07±0.19), P=0.808 or 6.8% reduction versus 4.8%, P=0.696. In the EVT arm, contrast-associated kidney injury was encountered in 4 out of 91 (4.4%) versus 2/90 (2.2%) in the medical arm P=0.682. In the EVT arm, contrast-associated kidney injury was evenly distributed between magnetic resonance imaging (1/22, 4.6%) versus CT 3 out of 69 (4.4%), P=1.0. Perfusion imaging before EVT was not associated with evidence of decline in renal function. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02586415.


Elevated amyloidoses of human IAPP and amyloid beta by lipopolysaccharide and their mitigation by carbon quantum dots.
Type 2 diabetes (T2D) and Alzheimer's disease (AD) represent two most prevalent amyloid diseases with a significant global burden. Pathologically, T2D and AD are characterized by the presence of amyloid plaques consisting primarily of toxic human islet amyloid polypeptide (IAPP) and amyloid beta (Aβ). It has been recently revealed that the gut microbiome plays key functions in the pathological progression of neurological disorders through the production of bacterial endotoxins, such as lipopolysaccharide (LPS). In this study, we examined the catalytic effects of LPS on IAPP and Aβ amyloidoses, and further demonstrated their mitigation with zero-dimensional carbon quantum dots (CQDs). Whereas LPS displayed preferred binding with the N-terminus of IAPP and the central hydrophobic core and C-terminus of Aβ, CQDs exhibited propensities for the amyloidogenic and C-terminus regions of IAPP and the N-terminus of Aβ, accordingly. The inhibitory effect of CQDs was verified by an embryonic zebrafish model exposed to the peptides and LPS, where impaired embryonic hatching was rescued and production of reactive oxygen species in the organism was suppressed by the nanomaterial. This study revealed a robust synergy between LPS and amyloid peptides in toxicity induction, and implicated CQDs as a potential therapeutic against the pathologies of T2D and AD.


Evidence-based concepts and procedures for bonded inlays and onlays. Part II. Guidelines for cavity preparation and restoration fabrication.
The second part of this article series presents an evidence-based update of clinical protocols and procedures for cavity preparation and restoration selection for bonded inlays and onlays. More than ever, tissue conservation dictates preparation concepts, even though some minimal dimensions still have to be considered for all restorative materials. In cases of severe bruxism or tooth fragilization, CAD/CAM composite resins or pressed CAD/CAM lithium disilicate glass ceramics are often recommended, although this choice relies mainly on scarce in vitro research as there is still a lack of medium- to long-term clinical evidence. The decision about whether or not to cover a cusp can only be made after a multifactorial analysis, which includes cavity dimensions and the resulting tooth biomechanical status, as well as occlusal and esthetic factors. The clinical impact of the modern treatment concepts that were outlined in the previous article - Dual Bonding (DB)/Immediate Dentin Sealing (IDS), Cavity Design Optimization (CDO), and Cervical Margins Relocation (CMR) - are described in detail in this article and discussed in light of existing clinical and scientific evidence for simpler, more predictable, and more durable results. Despite the wide choice of restorative materials (composite resin or ceramic) and techniques (classical or CAD/CAM), the cavity for an indirect restoration should meet five objective criteria before the impression.


Chondroitin sulfate proteoglycans inhibit the migration and differentiation of oligodendrocyte precursor cells and its counteractive interaction with laminin.
Cerebral white matter injury (WMI) is a recognized problem in premature infants, particularly in those with very low birth weights. Although the survival rate of premature infants has notably increased due to the advancement of modern medical treatments, their likelihood of developmental disability is higher than infants with an average birth weight. It has been previously reported that oligodendrocyte precursor cells (OPCs) are selectively vulnerable to WMI in premature infants. Following brain injury, glial scars may develop within the white matter. Their main constituent is chondroitin sulphate proteoglycans (CSPGs), revealing a potential association between CSPGs and OPCs. In the present study rat OPCs were cultured in vitro, and the effect of CSPGs on the proliferation, migration and differentiation of OPCs was determined. It was revealed that CSPGs did not affect proliferation, but they did inhibit the migration and differentiation of OPCs. It was also identified that the inhibitory effect of CSPGs was counteracted by laminin. Factor analysis revealed that CSPGs and laminin served interactive roles in OPC differentiation. The effect of CSPGs on OPCs was associated with the downregulation of β1-integrin, indicating that CSPGs potentially competitively inhibit the β1-integrin signaling pathway. Collectively, these results suggest that CSPGs serve a role as inhibitors of OPC differentiation and migration, as well as indicating an interaction between CSPGs and laminin. The present study has revealed a potential novel therapeutic target for WMI in premature infants, and identified β1-integrin signaling as a pathological mechanism for dysfunctional myelination in white matter.


Treatment of posttraumatic syringomyelia.
This paper presents results of a prospective study for patients undergoing surgery for posttraumatic syringomyelia between 1991 and 2010. A group of 137 patients with posttraumatic syringomyelia were evaluated (mean age 45 ± 13 years, mean follow-up 51 ± 51 months) with pre- and postoperative MRI and clinical examinations presenting in this period and followed prospectively by outpatient visits and questionnaires. Surgery was recommended for symptomatic patients with a progressive course. Short-term results were determined within 3 months of surgery, whereas long-term outcomes in terms of clinical recurrences were studied with Kaplan-Meier statistics. Three groups were distinguished according to the type of trauma: Group A, patients with spinal trauma but without cord injury (ASIA E, n = 37); Group B, patients with an incomplete cord injury (ASIA C or D, n = 55); and Group C, patients with complete loss of motor function or a complete cord injury (ASIA A or B, n = 45). Overall, 61 patients with progressive symptoms underwent 71 operations. Of these operations, 61 consisted of arachnolysis, untethering, and duraplasty at the trauma level (that is, decompression), while 4 ASIA A patients underwent a cordectomy. The remaining procedures consisted of placement of a thecoperitoneal shunt, 2 opiate pump placements, and 2 anterior and 1 posterior cervical decompression and fusion. Seventy-six patients were not treated surgically due to lack of neurological progression or refusal of an operation. Neurological symptoms remained stable for 10 years in 84% of the patients for whom surgery was not recommended due to lack of neurological progression. In contrast, 60% of those who declined recommended surgery had neurological progression within 5 years. For patients presenting with neurological progression, outcome was better with decompression. Postoperatively, 61% demonstrated a reduction of syrinx size. Although neurological symptoms generally remained unchanged after surgery, 47% of affected patients reported a postoperative improvement of their pain syndrome. After 3 months, 51% considered their postoperative status improved and 41% considered it unchanged. In the long-term, favorable results were obtained for Groups A and C with rates for neurological deterioration of 6% and 14% after 5 years, respectively. In Group B, this rate was considerably higher at 39%, because arachnolysis and untethering to preserve residual cord function could not be fully achieved in all patients. Cordectomy led to neurological improvement and syrinx collapse in all 4 patients. The technique of decompression with arachnolysis, untethering, and duraplasty at the level of the underlying trauma provides good long-term results for patients with progressive neurological symptoms following ASIA A, B and E injuries. Treatment of patients with posttraumatic syringomyelia after spinal cord injuries with preserved motor functions (ASIA C and D) remains a major challenge. Future studies will have to establish whether thecoperitoneal shunts would be a superior alternative for this subgroup.


Differential regulation of the stability of cyclic AMP-dependent protein kinase messenger RNA in normal versus neoplastic mouse lung epithelial cells.
Neoplastic mouse lung epithelial cells contain greatly diminished activity, protein, and mRNA for the type I isozyme of cyclic AMP-dependent protein kinase (PKA I), while expression of the type II isozyme (PKA II) is similar to that of normal lung cells. A time course of PKA mRNA content in transcriptionally inhibited cells indicated that most PKA mRNAs are more stable in the neoplastic E9 cell line than in related nontumorigenic C10 cells. To address the basis of this differential stability, we treated both cell lines with cycloheximide, an inhibitor of protein synthesis, in the presence or absence of the transcriptional inhibitor, 5,6-dichloro-1-b-ribofuranosyl-benzimidazole (DRB). The rate of PKA II regulatory subunit alpha mRNA decay in the presence of DRB was unaffected by cycloheximide treatment in E9 cells but decreased upon the addition of cycloheximide to DRB-treated C10 cells. The combination of these two agents markedly destabilized PKA II mRNAs (PKA catalytic subunit alpha and PKA II regulatory subunit alpha) relative to DRB treatment alone in neoplastic E9 cells, causing them to decay at a rate equal to that in C10 cells. PKA II mRNA may be specifically stabilized by a protein with a relatively short half-life in neoplastic E9 cells. These results suggest the involvement of tumor-specific factor(s) in the regulation of PKA mRNA stability, a potential mechanism for conferring the observed differential responsiveness of normal and neoplastic lung cells to cyclic AMP.


CheY3 of Borrelia burgdorferi is the key response regulator essential for chemotaxis and forms a long-lived phosphorylated intermediate.
Spirochetes have a unique cell structure: These bacteria have internal periplasmic flagella subterminally attached at each cell end. How spirochetes coordinate the rotation of the periplasmic flagella for chemotaxis is poorly understood. In other bacteria, modulation of flagellar rotation is essential for chemotaxis, and phosphorylation-dephosphorylation of the response regulator CheY plays a key role in regulating this rotary motion. The genome of the Lyme disease spirochete Borrelia burgdorferi contains multiple homologues of chemotaxis genes, including three copies of cheY, referred to as cheY1, cheY2, and cheY3. To investigate the function of these genes, we targeted them separately or in combination by allelic exchange mutagenesis. Whereas wild-type cells ran, paused (flexed), and reversed, cells of all single, double, and triple mutants that contained an inactivated cheY3 gene constantly ran. Capillary tube chemotaxis assays indicated that only those strains with a mutation in cheY3 were deficient in chemotaxis, and cheY3 complementation restored chemotactic ability. In vitro phosphorylation assays indicated that CheY3 was more efficiently phosphorylated by CheA2 than by CheA1, and the CheY3-P intermediate generated was considerably more stable than the CheY-P proteins found in most other bacteria. The results point toward CheY3 being the key response regulator essential for chemotaxis in B. burgdorferi. In addition, the stability of CheY3-P may be critical for coordination of the rotation of the periplasmic flagella.


The changing epidemiology of myocardial infarction in Olmsted County, Minnesota, 1995-2012.
Contemporary data on the epidemiology of myocardial infarction in the population are limited and derived primarily from cohorts of hospitalized myocardial infarction patients. We assessed temporal trends in incident and recurrent myocardial infarction, with further partitioning of the rates into prehospital deaths and hospitalized events, in a geographically defined community. All myocardial infarction events recorded among Olmsted County, Minnesota residents aged 25 years and older from 1995-2012, including prehospital deaths, were classified into incident and recurrent. Standardized rates were calculated and temporal trends compared. Altogether, 5258 myocardial infarctions occurred, including 1448 (27.5%) recurrences; 430 (8.2%) prehospital deaths were recorded. Among hospitalized events, recurrent myocardial infarction was associated with greater mortality risk than incident myocardial infarction (age-, sex-, and year-adjusted hazard ratio, 1.49; 95% confidence interval, 1.37-1.61). Although the overall rate of myocardial infarction declined over time (average annual percent change, -3.3), the magnitude of the decline varied widely. Incident hospitalized myocardial infarction rate fell 2.7%/y, compared with decreases of 1.5%/y in recurrent hospitalized myocardial infarction, 14.1%/y in prehospital fatal incident myocardial infarction, and 12.3%/y in prehospital fatal recurrent myocardial infarction (all P for diverging trends < .05). These trends resulted in an increasing proportion of recurrences among hospitalized myocardial infarctions (25.3% in 1995-2000, 26.8% in 2001-2006, and 29.0% in 2007-2012, Ptrend = .02). Over the past 18 years, a heterogeneous decline in myocardial infarction rates occurred in Olmsted County, resulting in transitions from incident to recurrent events and from prehospital deaths to hospitalized myocardial infarctions. Recurrent myocardial infarction confers a worse prognosis, thereby stressing the need to optimize prevention strategies in the population.


Androgens and puberty.
Puberty is associated with an increasing production of androgenic steroids. Adrenal androgen formation, termed adrenarche, may precede gonadal testosterone synthesis. Both adrenal and gonadal androgens exert their biological effects via the androgen receptor, a nuclear transcription factor modulating a specific transcription regulation of largely unknown genes. During puberty, virilizing actions such as genital enlargement and sexual hair growth can be distinguished from anabolic action such as the gain in muscle strength and general changes in body composition. Furthermore, androgens play a major role in the initiation and maintenance of spermatogenesis. Thus, different androgenic steroids play an important role in the process of puberty. The control of their biosynthesis, their possible differential action on the molecular level, as well as the different target organs in males and females are discussed.


Co-release of noradrenaline and dopamine in the cerebral cortex elicited by single train and repeated train stimulation of the locus coeruleus.
Previous studies by our group suggest that extracellular dopamine (DA) and noradrenaline (NA) may be co-released from noradrenergic nerve terminals in the cerebral cortex. We recently demonstrated that the concomitant release of DA and NA could be elicited in the cerebral cortex by electrical stimulation of the locus coeruleus (LC). This study analyses the effect of both single train and repeated electrical stimulation of LC on NA and DA release in the medial prefrontal cortex (mPFC), occipital cortex (Occ), and caudate nucleus. To rule out possible stressful effects of electrical stimulation, experiments were performed on chloral hydrate anaesthetised rats. Twenty min electrical stimulation of the LC, with burst type pattern of pulses, increased NA and DA both in the mPFC and in the Occ. NA in both cortices and DA in the mPFC returned to baseline within 20 min after the end of the stimulation period, while DA in the Occ reached a maximum increase during 20 min post-stimulation and remained higher than baseline values at 220 min post-stimulation. Local perfusion with tetrodotoxin (TTX, 10 microM) markedly reduced baseline NA and DA in the mPFC and Occ and totally suppressed the effect of electrical stimulation in both areas. A sequence of five 20 min stimulations at 20 min intervals were delivered to the LC. Each stimulus increased NA to the same extent and duration as the first stimulus, whereas DA remained elevated at the time next stimulus was delivered, so that baseline DA progressively increased in the mPFC and Occ to reach about 130 and 200% the initial level, respectively. In the presence of the NA transport (NAT) blocker desipramine (DMI, 100 microM), multiple LC stimulation still increased extracellular NA and DA levels. Electrical stimulation of the LC increased NA levels in the homolateral caudate nucleus, but failed to modify DA level. The results confirm and extend that LC stimulation induces a concomitant release of DA and NA in the mPFC and Occ. The different time-course of LC-induced elevation of DA and NA suggests that their co-release may be differentially controlled.


Issues in the development of an item bank.
To describe and illustrate 2 issues involved in the development of an item bank that can be used to improve measurement across settings and over time. Secondary (psychometric) analysis of data collected on existing quality of life (QOL) instruments. Five cancer clinics in hospital settings in various parts of the United States; 523 solo or group practices in 3 major US cities; and an inpatient rehabilitation hospital in a large metropolitan area. Illustration 1: 399 persons being treated for or having a history of cancer, 170 persons being treated for human immunodeficiency virus (HIV), 328 persons with stroke assessed during and after acute rehabilitation, and 433 persons being treated for multiple sclerosis. Illustration 2: 1714 persons with cancer and/or HIV participating in a large-scale multisite study, 3429 persons with prevalent treatable chronic health conditions, and 125 persons with stage IV metastatic breast cancer. Not applicable. QOL as measured by 10 different instruments. The illustrations show that (1). core items, which functioned similarly across 4 diagnostic groups, can be identified and used to construct instruments measuring physical function that are tailored to each of these groups, and (2). items from 3 separate datasets can be linked to create a dataset that can serve as an initial pain item bank. The methodology exists to develop item banks to develop better measures of QOL.


Tetra-2,3-pyrazinoporphyrazines with externally appended pyridine rings. 15. Effects of the pyridyl substituents and fused exocyclic rings on the UV-visible spectroscopic properties of Mg(II)-porphyrazines: a combined experimental and DFT/TDDFT study.
Two new Mg(II) porphyrazine macrocycles, the octakis(2-pyridyl)porphyrazinato-magnesium(II), [Py8PzMg(H2O)], and the tetrakis-[6,7-di(2-pyridyl)quinoxalino]porphyrazinato-magnesium(II), [Py8QxPzMg(H2O)], were prepared by Mg-template macrocyclization processes, and their general physicochemical properties were examined. The previously reported porphyrazine analog, the tetrakis-2,3-[5,6-di(2-pyridyl)-pyrazino]porphyrazinato-magnesium(II), [Py8PyzPzMg(H2O)], has been also considered in the present work. The UV-visible solution spectra in nonaqueous solvents of this triad of externally octapyridinated Mg(II) complexes exhibit the usual profile observed for phthalocyanine and porphyrazine macrocycles, with intense absorptions in the Soret (300-450 nm) and Q band (600-800 nm) regions. It is observed that the Q band maximum sensibly shifts toward the red with peak values at 635 → 658 → 759 nm along the series [Py8PzMg(H2O)], [Py8PyzPzMg(H2O)], and [Py8QxPzMg(H2O)], as the extension of the macrocycle π-system increases. TDDFT calculations of the electronic absorption spectra were performed for the related water-free model compounds [Py8PzMg], [Py8PyzPzMg], and [Py8QxPzMg] to provide an interpretation of the UV-visible spectral changes occurring upon introduction of the pyrazine and quinoxaline rings at the periphery of the Pz macrocycle. To discriminate the electronic effects of the fused exocyclic rings from those of the appended 2-pyridyl rings, the UV-visible spectra of [PzMg] and [PyzPzMg] were also theoretically investigated. The theoretical results prove to agree very well with the experimental data, providing an accurate description of the UV-visible spectra. The observed spectral changes are interpreted on the basis of the electronic structure changes occurring along the series.


Simulation-based assessment of anesthesiology residents' competence: development and implementation of the Canadian National Anesthesiology Simulation Curriculum (CanNASC).
The specialty of anesthesiology will soon adopt the Competence By Design (CBD) approach to residency education developed by the Royal College of Physicians and Surgeons of Canada (RCPSC). A foundational component of CBD is frequent and contextualized assessment of trainees. In 2013, the RCPSC Anesthesiology Specialty Committee assembled a group of simulation educators, representing each of the 17 Canadian anesthesiology residency programs, to form the Canadian National Anesthesiology Simulation Curriculum (CanNASC) Task Force. The goals were to develop, implement, and evaluate a set of consensus-driven standardized mannequin-based simulation scenarios that every trainee must complete satisfactorily prior to completion of anesthesiology residency and certification. Curriculum development followed Kern's principles and was accomplished via monthly teleconferences and annual face-to-face meetings. The development and implementation processes included the following key elements: 1) Curriculum needs assessment: 368 of 958 invitees (38.4%) responded to a national survey resulting in 64 suggested scenario topics. Use of a modified Delphi technique resulted in seven important and technically feasible scenarios. 2) Scenario development: All scenarios have learning objectives from the National Curriculum for Canadian Anesthesiology Residency. Standardized scenario templates were created, and the content was refined and piloted. 3) Assessment: A validated Global Rating Scale (GRS) is the primary assessment tool, informed by using scenario-specific checklists (created via a modified Delphi technique) and the Anesthesia Non-Technical Skills GRS. 4) Implementation: Standardized implementation guidelines, pre-brief/debrief documents, and rater training videos, guide, and commentary were generated. National implementation of the scenarios and program evaluation is currently underway. It is highly feasible to achieve specialty-based consensus on the elements of a national simulation-based curriculum. Our process could be adapted by any specialty interested in implementing a simulation-based curriculum incorporating competency-based assessment on a national scale.


Transradial catheterization may decrease the radial artery luminal diameter and impair the vasodilatation response in the access site at late term: an observational study.
The present study aimed to evaluate the late-term changes in radial artery luminal diameter (RAD) and vasodilatation response following transradial catheterization (TRC). TRC-inducing trauma to radial artery intima may trigger chronic phase vascular changes and lead to anatomical and functional impairment. There is controversial data whether the impairment persists or repairs later. Fifty-six consecutive patients undergoing TRC were enrolled prospectively. Baseline RAD, flow-mediated dilatation (FMD) and nitroglycerin-mediated dilatation (NMD) of the radial artery at the access site were measured before TRC by high-resolution ultrasound. Six months later; RAD, FMD and NMD were measured again at the same access site. RAD at the sixth month was reduced compared with pre-procedural measurements (2.85 ± 0.44 versus 2.74 ± 0.42 mm, p = 0.0001).The average FMD decreased to 5.66 ± 5.87 %, which was significantly lower than the observed pre-procedural FMD (9.45 ± 5.01 %) 6 months after TRC (p = 0.0001). Likewise, the average NMD at the sixth month was reduced compared with pre-procedural NMD (9.52 ± 6.77 versus 6.64 ± 6.51 %, p = 0.018). Logistic regression analysis indicated that pre-procedural radial artery diameter to sheath size ratio was the independent predictor of NMD reduction (95 % confidence interval, β = -9.74, p = 0.024). TRC may lead to a significant luminal diameter reduction and impairment of vasodilatation response in the radial artery at late term.


Estimating subgroup effects using the propensity score method: a practical application in outcomes research.
Our aim was to demonstrate the feasibility of the univariate and generalized propensity score (PS) method in subgroup analysis of outcomes research. First, to estimate subgroup effects, we tested the performance of 2 different PS methods, using Monte Carlo simulations: (1) the univariate PS with additional adjustment on the subgroup; and (2) the generalized PS, estimated by crossing the treatment options with a subgroup variable. The subgroup effects were estimated in a linear regression model using the 2 PS adjustments. We further explored whether the subgroup variable should be included in the univariate PS. Second, the 2 methods were compared using data from a large effectiveness study on psychotherapy in personality disorders. Using these data we tested the differences between short-term and long-term treatment, with the severity of patients' problems defining the subgroups of interest. The Monte Carlo simulations showed minor differences between both PS methods, with the bias and mean squared error overall marginally lower for the generalized PS. When considering the univariate PS, the subgroup variable can be excluded from the PS estimation and only adjusted for in the outcome equation. When applied to the psychotherapy data, the univariate and generalized PS estimations gave similar results. The results support the use of the generalized PS as a feasible method, compared with the univariate PS, to find certain subgroup effects in nonrandomized outcomes research.