Effect of SLCO1B1 polymorphism on induction of CYP3A4 by rifampicin.
Rifampicin (rifampin) is a potent inducer of cytochrome P450 (CYP) 3A4. It was recently identified as a substrate of the polymorphic organic anion transporting polypeptide 1B1 (OATP1B1) expressed on the sinusoidal membrane of human hepatocytes. The present study aimed to investigate the possible association of single nucleotide polymorphisms (SNP) in the SLCO1B1 gene encoding for OATP1B1 with the inducing effect of rifampicin on hepatic CYP3A4. A total of 38 healthy volunteers who had participated in drug interaction studies with rifampicin were genotyped for the g. - 11187G > A and c.521T > C SNPs in SLCO1B1, c.3435C > T SNP in ABCB1 and g.6986A > G SNP in CYP3A5. The plasma concentration of 4beta-hydroxycholesterol, an endogenous marker of CYP3A4 activity, was measured before and after administration of 600 mg rifampicin once daily for 9-11 days. Treatment with rifampicin significantly increased the mean +/- SD plasma concentration of 4beta-hydroxycholesterol from 55.2 +/- 17.9 ng/ml to 120.9 +/- 32.0 ng/ml (P < 0.001). A large intersubject variability existed in the induction of CYP3A4 by rifampicin, but no associations were observed between the variability in induction and any of the polymorphisms studied. These data suggest that SLCO1B1 polymorphism does not affect the extent of induction of hepatic CYP3A4 by rifampicin, probably because other uptake transporters, such as OATP1B3, can compensate for reduced uptake of rifampicin by OATP1B1. However, the present study had sufficient power to detect only a considerably smaller rifampicin-induced increase in 4beta-hydroxycholesterol in carriers of the SLCO1B1 c.521C allele compared to subjects with the reference genotype.


Self-initiated smoking cessation among high school students.
The purpose of this study was to examine psychosocial predictors of self-initiated smoking cessation among high school students. Students from nine high schools were pretested using a questionnaire which assessed smoking behavior, beliefs about positive and negative consequences of smoking, moral attitudes toward smoking, normative expectations about smoking, rebelliousness, peer smoking and parent smoking. Smokers identified at pretest were reexamined three months and fifteen months later. Three variables, moral attitudes, peer smoking and positive beliefs about smoking significantly discriminated continuing smokers from quitters at the three-month posttest. Three different variables, negative beliefs about smoking, parental smoking and rebelliousness significantly discriminated between those who quit and later relapsed and those who quit and maintained their non-smoking status at the 15 month posttest. Smoking characteristics at pretest failed to discriminate either those who would quit or those who would maintain their non-smoking status. Results support the development of public information programs which encourage early cessation of smoking which feature the development of appropriate attitudes and beliefs and which foster social support.


Genetic approach to insight into the immunobiology of human dendritic cells and identification of CD84-H1, a novel CD84 homologue.
To better understand the immunobiology of dendritic cells (DCs), we took the expressed sequence tag (EST) approach to describe their transcript profile and discovered novel genes. ESTs (n = 25,668) were generated from monocyte-derived DCs, and 15,863 ESTs (61.8%) represented unique genes in GenBank. Integration of ESTs allowed for the generation of a profile of 4,367 known genes and identification of > 100 novel genes. HLA-DR invariant chain p33, cathepsin D, HLA-DR alpha chain, beta2-microglobulin, HLA-DP beta chain, CD11a, and mannose receptor were in the top 30 transcripts, and 451 known genes were potentially associated with the immunobiology of DCs. This transcript profile was consistent with the unique antigen-presenting capacity of DCs and provided invaluable information to better understand the immunobiology of DCs. On the basis of the EST database, a full-length novel gene was identified that exhibited close homology with CD84; it was designated CD84-H1. The full-length cDNA of CD84-H1 contained an open reading frame of 870 bp encoding a type I transmembrane protein of 289 amino acids. Consistent with the structural feature of the CD2 family, the predicted 270-amino acid mature protein of CD84-H1 contained two extracellular immunoglobulin-like domains that shared homology with CD2 family members, e.g., CD84, Ly-9, CD48, and signaling lymphocyte activation molecule. Its intracellular domain was short and contained no putative signaling structure. Northern blot analysis revealed that CD84-H1 expression was predominantly restricted in hematopoietic tissues. Reverse transcription-PCR analysis showed that it was widely expressed in the immune cells, including monocytes, DCs, B cells, and T cells. These data indicate that CD84-H1 may be relevant to immune responses.


Effects of testosterone on the metabolism of folate coenzymes in the rat.
1. The effects of castration and testosterone treatment on enzymic activities involved in folate coenzyme metabolism in the liver and in accessory sex organs of male adult rats were studied. 2. In the liver of castrated rats the concentration of 10-formyltetrahydrofolate (10-HCO-H(4)folate) synthetase and tetrahydrofolate (H(4)folate) dehydrogenase were significantly decreased whereas that of 5,10-methylenetetrahydrofolate dehydrogenase increased; the treatment with five doses of testosterone caused a return to normal values of these activities. 3. In the prostate of castrated rats a pronounced decrease in H(4)folate dehydrogenase, serine hydroxymethyltransferase and 10-HCO-H(4)folate synthetase activities was observed. The administration of testosterone restored the enzymic activities to normal values. 4. In the seminal vesicles of castrated rats only 10-HCO-H(4)folate synthetase was markedly depressed; testosterone treatment not only restored activity to normal values but raised it to higher than normal values. The slight changes observed in other enzymic activities also returned to normal values with the hormone treatment. 5. These results are discussed in relation to a possible control mechanism of folate metabolism by testosterone.


Genome-wide Association Study of Creativity Reveals Genetic Overlap With Psychiatric Disorders, Risk Tolerance, and Risky Behaviors.
Creativity represents one of the most important and partially heritable human characteristics, yet little is known about its genetic basis. Epidemiological studies reveal associations between creativity and psychiatric disorders as well as multiple personality and behavioral traits. To test whether creativity and these disorders or traits share genetic basis, we performed genome-wide association studies (GWAS) followed by polygenic risk score (PRS) analyses. Two cohorts of Han Chinese subjects (4,834 individuals in total) aged 18-45 were recruited for creativity measurement using typical performance test. After exclusion of the outliers with significantly deviated creativity scores and low-quality genotyping results, 4,664 participants were proceeded for GWAS. We conducted PRS analyses using both the classical pruning and thresholding (P+T) method and the LDpred method. The extent of polygenic risk was estimated through linear regression adjusting for the top 3 genotyping principal components. R2 was used as a measurement of the explained variance. PRS analyses demonstrated significantly positive genetic overlap, respectively, between creativity with schizophrenia ((P+T) method: R2(max) ~ .196%, P = .00245; LDpred method: R2(max) ~ .226%, P = .00114), depression ((P+T) method: R2(max) ~ .178%, P = .00389; LDpred method: R2(max) ~ .093%, P = .03675), general risk tolerance ((P+T) method: R2(max) ~ .177%, P = .00399; LDpred method: R2(max) ~ .305%, P = .00016), and risky behaviors ((P+T) method: R2(max) ~ .187%, P = .00307; LDpred method: R2(max) ~ .155%, P = .00715). Our results suggest that human creativity is probably a polygenic trait affected by numerous variations with tiny effects. Genetic variations that predispose to psychiatric disorders and risky behaviors may underlie part of the genetic basis of creativity, confirming the epidemiological associations between creativity and these traits.


The short-term results of internal carotid reconstructions by absorbable suture material.
Analysis was made of the results of 11 internal carotid reconstructions using polydioxanone (PDS) sutures 6 months after intervention performed in 10 patients. All operations on the carotid bifurcation were accomplished using 5/0 PDS continuous suture. Nine eversion carotid endarterectomies and 2 internal carotid reconstructions were performed for Kinkiking. There were no neurologic complications, thromboses, bleedings or repeated operations after interventions on the brachiocephalic arteries. Six months later the patients were examined under ambulatory conditions and were provided color duplex scanning (CDS) of the reconstructed area. Measurements were made of the diameter of the common carotid artery (CCA) right beneath the anastomosis between the CCA and the internal carotid artery (ICA), of the maximal diameter of the anastomosis between the CCA and the ICA, and of the size of the proximal ICA segment right the anastomosis. During the 6-month period following surgical intervention, all 10 patients did not demonstrate any ischemic attacks (TIA) or strokes. No cases of anastomotic aneurysms were recorded. After 9 reconstructions no ICA restenoses were marked. In one case, restenosis accounted for 40% because of atherosclerosis progression and after one operation there developed asymptomatic thrombosis of the ICA. The study has demonstrated that the use of PBS absorbable suture for autoarterial ICA reconstruction provides for anastomosis integrity minimally over the period as long as 6 months.


Diagnostic SNPs reveal widespread introgressive hybridization between introduced bighead and silver carp in the Mississippi River Basin.
Hybridization among conspecifics in native and introduced habitats has important implications for biological invasions in new ecosystems. Bighead (Hypophthalmichthys nobilis) and silver carp (H. molitrix) are genetically isolated and occur in sympatry within their native range. Following their introduction to North America, however, introgressant hybrids have been reported throughout their expanded range within the Mississippi River Basin (MRB). The extent of introgression, both spatially and generationally, is largely unknown. Therefore, we examined mixed-species populations from across the MRB to characterize the extent of interspecific gene flow. We assayed 2798 individuals from nine locations with a suite of species-diagnostic SNPs (57 nuclear and one mitochondrial). Forty-four per cent (n = 1244) of individuals displayed hybrid genotypes. Moreover, the composition of hybrid genotypes varied among locations and represented complex hybrid swarms with multiple generations of gene flow. Introgressive hybrids were identified from all locations, were bidirectional and followed a bimodal distribution consisting primarily of parental or parental-like genotypes and phenotypes. All described hybrid categories were present among individuals from 1999 to 2008, with parents and later-generation backcrosses representing the largest proportion of individuals among years. Our mitochondrial SNP (COII), tested on a subset of 730 individuals, revealed a silver carp maternal bias in 13 of 21 (62%) F1 hybrids, in all silver carp backcrosses, and maintained throughout many of the bighead carp backcrosses. The application of this suite of diagnostic markers and the spatial coverage permits a deeper examination of the complexity in hybrid swarms between two invasive, introduced species.


[Consumption of licit and illicit drugs in students and the factors of protection and risk].
The aims of the investigation were identify the population that consumes licit and illicit drugs among students of sixth primary, from municipal urban schools of Chiguayante, know the levels of risks and identify risks factors and protection. Descriptive, transversal, correlate study. The instrument applied to 301 students was the Dusy Abreviado. The variables were subjected to a statistic descriptive -- comparative analysis through the test of Chi -- Cuadrado de Pearson and ANOVA. There was 60% of the consumers of licit drugs, that began consumption between 8 and 11 years. The prevalence of use of tobacco and alcohol was 18.7% and 16.3% respectively. The 85% of men showed inclination to the consumption, from which 69% is between 11 and 12 years old. There are mainly abusers of licit drugs. The behaviours associated to the personal risk factor were the most relevant, the ones of protection were mainly associated with the micro-social protective factor. All subjects were submitted to different levels of risk.


Metformin Prevents Cocaine Sensitization: Involvement of Adenosine Monophosphate-Activated Protein Kinase Trafficking between Subcellular Compartments in the Corticostriatal Reward Circuit.
Repeated cocaine exposure produces an enhanced locomotor response (sensitization) paralleled by biological adaptations in the brain. Previous studies demonstrated region-specific responsivity of adenosine monophosphate-activated protein kinase (AMPK) to repeated cocaine exposure. AMPK maintains cellular energy homeostasis at the organismal and cellular levels. Here, our objective was to quantify changes in phosphorylated (active) and total AMPK in the cytosol and synaptosome of the medial prefrontal cortex, nucleus accumbens, and dorsal striatum following acute or sensitizing cocaine injections. Brain region and cellular compartment selective changes in AMPK and pAMPK were found with some differences associated with acute withdrawal versus ongoing cocaine treatment. Our additional goal was to determine the behavioral and molecular effects of pretreatment with the indirect AMPK activator metformin. Metformin potentiated the locomotor activating effects of acute cocaine but blocked the development of sensitization. Sex differences largely obscured any protein-level treatment group effects, although pAMPK in the NAc shell cytosol was surprisingly reduced by metformin in rats receiving repeated cocaine. The rationale for these studies was to inform our understanding of AMPK activation dynamics in subcellular compartments and provide additional support for repurposing metformin for treating cocaine use disorder.


Molecular identification and characterization of novel human and mouse concentrative Na+-nucleoside cotransporter proteins (hCNT3 and mCNT3) broadly selective for purine and pyrimidine nucleosides (system cib).
The human concentrative (Na(+)-linked) plasma membrane transport proteins hCNT1 and hCNT2 are selective for pyrimidine nucleosides (system cit) and purine nucleosides (system cif), respectively. Both have homologs in other mammalian species and belong to a gene family (CNT) that also includes hfCNT, a newly identified broad specificity pyrimidine and purine Na(+)-nucleoside symporter (system cib) from the ancient marine vertebrate, the Pacific hagfish (Eptatretus stouti). We now report the cDNA cloning and characterization of cib homologs of hfCNT from human mammary gland, differentiated human myeloid HL-60 cells, and mouse liver. The 691- and 703-residue human and mouse proteins, designated hCNT3 and mCNT3, respectively, were 79% identical in amino acid sequence and contained 13 putative transmembrane helices. hCNT3 was 48, 47, and 57% identical to hCNT1, hCNT2, and hfCNT, respectively. When produced in Xenopus oocytes, both proteins exhibited Na(+)-dependent cib-type functional activities. hCNT3 was electrogenic, and a sigmoidal dependence of uridine influx on Na(+) concentration indicated a Na(+):uridine coupling ratio of at least 2:1 for both hCNT3 and mCNT3 (cf 1:1 for hCNT1/2). Phorbol myristate acetate-induced differentiation of HL-60 cells led to the parallel appearance of cib-type activity and hCNT3 mRNA. Tissues containing hCNT3 transcripts included pancreas, bone marrow, trachea, mammary gland, liver, prostate, and regions of intestine, brain, and heart. The hCNT3 gene mapped to chromosome 9q22.2 and included an upstream phorbol myristate acetate response element.


Asymmetric hydrogenation approaches to valuable, acyclic 1,3-hydroxymethyl chirons.
An iridium carbene oxazoline complex was used to catalyze hydrogenations of trisubstituted alkenes to give terminal and internal 1,3-hydroxymethyl chirons. The products are accessible in all possible stereoisomeric forms. These hydrogenations do not require strongly coordinating functionalities on the substrate, and in some key cases, catalyst- rather than substrate-controlled stereoselectivities are observed. It is hypothesized that these reactions would not be feasible using iridium or rhodium diphosphine complexes.


Seizure-induced hippocampal damage in the mature and immature brain.
Neurologists caring for patients who have experienced a first seizure or who are at increased risk of seizures are concerned with two questions. First, at what point do seizures lesion the brain and create the conditions for unprovoked, recurrent seizures, i.e. epilepsy. And second, seizure-induced changes can be prevented pharmacologically following an initial prolonged seizure, or prophylactically in individuals deemed at high risk of epilepsy? The number, duration and severity of seizures each influence the likelihood that an individual will experience chronic seizure-induced brain damage. However, the thresholds for deleterious seizure-induced sequelae are not well understood. Will repeated brief seizures produce similar changes as a single prolonged seizure? Do permanent alterations of neuronal function result from a single brief seizure? How long can neurons resist damage caused by prolonged seizures? These are all questions of immediate clinical significance. The anatomical, synaptic and functional consequences of seizures have been most extensively studied in the hippocampus, an epileptogenic structure that plays a central role in the generation of temporal lobe seizures. In this review, we will discuss the spectrum of known hippocampal alterations in epilepsy and highlight mechanisms through which neuronal and synaptic changes accrue. In addition to discussing the effects of prolonged seizures on the hippocampus, we will also review current data regarding the effects of repeated brief seizures as well as the effect of a single brief seizure. We will also discuss the relevance of development and gender on the manifestations of seizure-induced damage, in order to begin to stratify the risk of seizure sequelae to different human populations depending on age, and - to a lesser extent - on gender. The decision whether to treat, and how to treat seizures, results from an understanding of the immediate and long-term risks to the patient of either recurrent seizures, or of seizure-induced brain damage. Paradigmatic to this type of decision is the assessment of febrile seizures, a common occurrence in childhood. Current clinical and laboratory data indicate that simple febrile seizures do not result in long-term brain injury. However, novel laboratory findings indicate that even "benign" febrile seizures may produce subtle long-term changes in neuronal behavior - such as altered synaptic function. The improved understanding of the mechanism producing these long term effects is a necessary first step in the development of neuroprotective treatments that can be applied either in the acute setting at the time of an initial prolonged seizure, or prophylactically in individuals most likely to high risk of developing epilepsy.


Risk Factors for Postoperative Urinary Tract Infections Following Anterior Lumbar Interbody Fusion.
Although risk factors contributing to UTI have been studied in posterior approaches to lumbar fusion, there is a lack of literature on factors contributing to UTI in anterior lumbar interbody fusion (ALIF). Our purpose was to identify preoperative independent risk factors for postoperative urinary tract infection (UTI) following anterior lumbar interbody fusion (ALIF) so that surgeons may be able to initiate preventative measures and minimize the risk of UTI-related morbidity following ALIF. The American College of Surgeons-National Surgical Quality Improvement Program database was queried to identify 10 232 patients who had undergone ALIF from 2005 to 2016; 144 patients (1.41%) developed a postoperative UTI while 10 088 patients (98.59%) did not. Univariate analyses were conducted to compare the 2 cohorts' demographics and preoperative comorbidities. Multivariate logistic regression models were then utilized to identify significant predictors of postoperative UTI following ALIF while controlling for differences seen in univariate analyses. Age ≥ 60 years (P = .022), female sex (P < .001), alcohol use (P = .014), open wound or wound infections (P = .019), and steroid use (P = .046) were independent risk factors for postoperative UTI. Longer operative times were also independent predictors for developing UTI: 120 minutes ≤ x < 180 minutes (P = .050), 180 minutes ≤ x < 240 minutes (P = .025), and ≥ 240 minutes (P = .001). Postoperative UTI independently increased the risk for pneumonia, blood transfusions, sepsis, thromboembolic events, and extended length of stay as well. Age ≥ 60 years, female sex, alcohol use, steroid use, and open wound or wound infections independently increased the risk for UTI following ALIF. Future work analyzing the efficacy of tapering alcohol and steroid use preoperatively and reducing procedural time with the aim of lowering UTI risk is warranted. Preoperative wound care is strongly encouraged to decrease UTI risk. III.


The development of the Rhinosinusitis Disability Index.
Assessment of patient perception of disability and outcomes from treatment has become an integral part of medical care. General quality-of-life measurement tools have led to the development of disease-specific quality instruments. Conventional methods for evaluating nasal-sinus disease are inadequate to assess the impact of these disorders on everyday life. Therefore, using methods that are well established and validated for creating instruments, the Rhinosinusitis Disability. Index was created to evaluate the self-perceived impact of disease-specific head and neck disorders. The development of the preliminary and final versions (30 items) of the Rhinosinusitis Disability Index is described. Content-related validity using Cronbach's alpha measurement and construct-related validity were accomplished. A comparison of the responses between patients with and without documented nasal or sinus disease was used to verify that the Rhinosinusitis Disability Index is a valid measuring instrument for patients with sinus disease, and test-retest validity reveals reliability over time.


Temperature-dependent properties of silver-poly(methylmethacrylate) nanocomposites synthesized by in-situ technique.
Ag/PMMA nanocomposites were successfully synthesized by in-situ technique. Transmission electron microscopy (TEM) images show that the particles are spherical in shape and their sizes are dependent on temperature. The smallest particle achieved high stability as indicated from Zeta sizer analysis. The red shift of surface plasmon resonance (SPR) indicated the increases of particle sizes. X-ray diffraction (XRD) patterns exhibit a two-phase (crystalline and amorphous) structure of Ag/PMMA nanocomposites. The complexation of Ag/PMMA nanocomposites was confirmed using Raman spectroscopy. Fourier transform infrared spectroscopy spectra confirmed that the bonding was dominantly influenced by the PMMA and DMF solution. Finally, thermogravimetric analysis (TGA) results indicate that the total weight loss increases as the temperature increases.


[Elucidation of functionally active domains in molecules of protective antigen bacillus anthracis's toxin].
Limited proteolysis has established that the protective antigen (PA) molecule consists of four functional-active domains. So, the shielding domain borrows an area in the linear structure of the PA molecule with NH2 of the end up to Lys 166 and plays a conducting role in the proteolytic activation of PA. The associative domain, engaging in the area Arg 167-Met266, plays a key role in the interaction with LF or EF at self-assembly toxic complexes LT or ET. The stabilizing domain borrows in the linear structure of the PA molecule are with Gly351 up to Met434. On the one hand, this area promotes formation with LF conformationally steady toxic complex's, and, on the other, takes a direct participation in the formation of a hydrophobic channel by which the molecule LF or EF enters the target cell. The receptor domain, representing a COOH-terminal area, starting from Leu663 amino acid, begins to interact with specific receptors on the macrophages and thus delivers the toxic complex to the target cell. It has been found that in the molecule of lethal factor there are 3 functionally active domains located in the linear structure of the molecule as follows: the associative domain borrows an area from Lys39 up to Met242, stabilizing and effector domains occupy areas from Leu517 to Lys614 and from that point to Lys COOH-terminal amino acid.


Case Reports of Transdermal Fentanyl Patch Administration Difficulties in Cancer Patients with Excess Sweating.
(Case 1) A 45-year-old male was diagnosed with prostate cancer. Treatment was administered using bicalutamide and leuprorelin acetate, while a transdermal fentanyl (TDF) was applied for pain relief. However, TDF continued to peel off owing to excessive sweating, even when reinforced by a protective layer. As such, TDF was discontinued and pain control was initiated using other medicines. Sweating occurred irregularly because of hot flashes, approximately four to five times per day. (Case 2) A 37-year-old male was diagnosed with a malignant thymoma and sacral metastasis. For analgesic control, etodolac tablets, carbamazepine tablets, and TDF were administered. Subsequently, the dose of the TDF was gradually increased, but the analgesic effect was low; thus, fentanyl blood concentration was measured. The measurements showed that even higher TDF doses did not increase fentanyl blood levels. During this period, full body sweating began to occur to a large extent due to unknown causes, and it was thought that the absorption of fentanyl decreased. When using a TDF, it is necessary to monitor patients for any sweating during treatment, while also considering changes in medication in some cases. This should promote the maintenance and improvement of the quality of life of the affected patients.


The nuclear import factor p10 regulates the functional size of the nuclear pore complex during oogenesis.
Previtellogenic, stage-1 Xenopus oocytes produce mainly 5S and tRNA, whereas vitellogenic oocytes, stages 2-6, synthesize predominantly 18S and 28S rRNA. Using nucleoplasmin-coated gold as a transport substrate, it was determined that the shift in synthesis from small to large RNAs during oogenesis is accompanied by an increase in both the rates of signal-mediated nuclear import and the functional size of nuclear pores. It was observed that, despite the reduction in transport capacity, gold still accumulated at the cytoplasmic surface of the pores in stage-1 oocytes. This suggested that transport in these cells is limited by translocation factors, rather than by cytoplasmic binding factors. Analysis of extracts prepared from stage-1 and vitellogenic oocytes revealed that the transport factor p10 is more abundant in stage-1 cells. Microinjection of purified p10 into stage-2 oocytes reduced the nuclear import of large gold particles to the level observed in stage-1 cells. It is concluded that p10 can modulate transport through the pores by regulating the functional size of the central transporter element.


Care Coordination Strategies and Barriers during Medication Safety Incidents: a Qualitative, Cognitive Task Analysis.
Medication errors are prevalent in healthcare institutions worldwide, often arising from difficulties in care coordination among primary care providers, specialists, and pharmacists. Greater knowledge about care coordination surrounding medication safety incidents can inform efforts to improve patient safety. To identify strategies that hospital and outpatient healthcare professionals (HCPs) use, and barriers encountered, when they coordinate care during a medication safety incident involving an adverse drug reaction, drug-drug interaction, or drug-renal concern. We asked HCPs to complete a form whenever they encountered these incidents and intervened to prevent or mitigate patient harm. We stratified incidents across HCP roles and incident categories to conduct follow-up cognitive task analysis interviews with HCPs. We invited all physicians and pharmacists working in inpatient or outpatient care at a tertiary Veterans Affairs Medical Center. We examined 24 incidents: 12 from physicians and 12 from pharmacists, with a total of 8 incidents per category. Interviews were transcribed and analyzed via a two-stage inductive, qualitative analysis. In stage 1, we analyzed each incident to identify decision requirements. In stage 2, we analyzed results across incidents to identify emergent themes. Most incidents (19, 79%) were from outpatient care. HCPs relied on four main strategies to coordinate care: cognitive decentering; collaborative decision-making; back-up behaviors; and contingency planning. HCPs encountered four main barriers: role ambiguity and constraints, breakdowns (e.g., delays) in care, challenges related to the electronic health record, and factors that increased coordination complexity. Each strategy and barrier occurred across all incident categories and HCP groups. Pharmacists went to extra effort to ensure safety plans were implemented. Similar strategies and barriers were evident across HCP groups and incident types. Strategies for enhancing patient safety may be strengthened by deliberate organizational support. Some barriers could be addressed by improving work systems.


Progression of retinitis pigmentosa on static perimetry, optical coherence tomography, and fundus autofluorescence.
In retinitis pigmentosa (RP), photoreceptor degeneration leads to progressive visual field loss and visual impairment. Several therapeutic trials are ongoing aiming to establish effective treatments. Although functional evaluations are commonly used in clinical trials, residual ellipsoid zone (EZ) measurement on optical coherence tomography has been shown to be more sensitive to detect disease progression. Establishment of sensitive outcome measurement is essential to develop new therapeutic strategies. In the current study, we evaluated the progression rates of the disease in 76 eyes of 76 patients with RP, using the residual EZ length, ring-shaped macular hyperautofluorescent (AF), and visual field. Decrease rates measured by the residual EZ area and by the hyper-AF ring area were strongly positively correlated (P < 0.0001, r = 0.71). The reduction rates of the residual EZ length and hyper-AF ring radius were constant regardless of their baseline measurements. Faster annual reduction rates of the hyper-AF ring area or radius were significantly correlated with faster visual field progression (P = 0.03, r = 0.25 and P = 0.004, r = 0.33, respectively). These findings support the usage of morphological measurements such as EZ or hyper-AF ring measurements as outcome measurement for future clinical trials for RP.


COVID-19 infection in former living kidney donors.
The COVID-19 pandemic brought living donor kidney transplant programs across the United States to a near halt in March 2020. As programs have begun to reopen, potential donor candidates often inquire about their risk of a COVID-19 infection and its potential impact on kidney function after donation. To address their concerns, we surveyed 1740 former live kidney donors at four transplant centers located in New York and Michigan. Of these, 839 (48.2%) donors responded, their mean age was 46 ± 12.5 years, 543 (65%) were females, and 611 (73%) were white. Ninety-two donors (11%) had symptoms suggestive of a COVID-19 infection with fever (48%) and fatigue (43%) being the most common. Among those with symptoms, 42 donors underwent testing and 16 tested positive. Testing was more common among donors with private insurance, and a positive test result was more common among young black donors. Only one donor surveyed required hospitalization and none required dialysis. Fourteen donors have recovered completely and two partially. Our survey highlights that a COVID-19 infection in former donors results in a mild disease with good recovery. These data will be useful for transplant programs to counsel living donors who are considering kidney donation during this pandemic.


[Daily living functionality in elderly adults].
to evaluate the daily living activities in elderly adults and to determine the factors related to disability. cross-sectional and analytic study with convenience samples. both sex, without cognitive diseases. socio-demographics, functionality for daily living basic activities (DLBA), functionality for daily living instrumental activities (DLIA): Katz Scale, Lawton and Brody Index. descriptive statistics and odds ratio (OR) with 95 % confidence intervals. a hundred elderly adults, 60 % females and 40 % males. Mean age 69.71 ± 7.01 years. Functionality for DLBA: normal 26 %, very slightly disabled 33 %, slightly disabled 17 %, moderately disabled 23%, severely disabled 1 %. Functionality for DLIA: independent 8 %, moderately dependent 71 %, dependent 21 %. Associated factors for basic dependence: age > 74 years. Associated factors for instrumental dependence: unmarried. the frequency of basic dependence was different from that reported by other authors. The frequency of instrumental dependence was greater than earlier regional studies. More studies are need to arrive at better conclusions.


Non-dopaminergic Alterations in Depression-Like FSL Rats in Experimental Parkinsonism and L-DOPA Responses.
Depression is a common comorbid condition in Parkinson's disease (PD). Patients with depression have a two-fold increased risk to develop PD. Further, depression symptoms often precede motor symptoms in PD and are frequent at all stages of the disease. However, the influence of a depressive state on the responses to antiparkinson treatments is largely unknown. In this study, the genetically inbred depression-like flinders sensitive line (FSL) rats and control flinders resistant line (FRL) rats were studied in models of experimental parkinsonism. FSL rats showed a potentiated tremorgenic response to tacrine, a cholinesterase inhibitor used experimentally to induce 6 Hz resting tremor reminiscent of parkinsonian tremor. We also studied rats lesioned with 6-OHDA to induce hemiparkinsonism. No baseline differences in dopaminergic response to acute apomorphine or L-DOPA was found. However, following chronic treatment with L-DOPA, FRL rats developed sensitization of turning and abnormal involuntary movements (AIMs); these effects were counteracted by the anti-dyskinetic 5-HT1 A agonist/D2 partial agonist sarizotan. In contrast, FSL rats did not develop sensitization of turning and only minor AIMs in response to L-DOPA treatment. The roles of several non-dopamine systems underlying this discrepancy were studied. Unexpectedly, no differences of opioid neuropeptides or serotonin markers were found between FRL and FSL rats. The marked behavioral difference between the FRL and FSL rats was paralleled with the striatal expression of the established marker, c-fos, but also the GABAergic transporter (vGAT), and a hitherto unknown marker, tamalin, that is known to regulate mGluR5 receptor function and postsynaptic organization. This study demonstrates that behavioral and transcriptional responses of non-dopaminergic systems to experimental parkinsonism and L-DOPA are modified in a genetic rat model of depression.


A high-affinity cytosol binding protein for 1 alpha,25-dihydroxycholecalciferol in the uterus of Japanese quail.
Cytosol fractions prepared from the uterine mucosa of egg-laying Japanese Quail were analysed for binding of the metabolites of cholecalciferol. When the uterus was incubated at 37 degrees C with various radioactive metabolites of cholecalciferol, the nuclear fraction incorporated only 1 alpha,25-dihydroxy[3H]cholecalciferol. When the uterus was incubated at 0 degree C with 1 alpha,25-dihydroxy[3H]cholecalciferol, most of the radioactivity was found in the cytosol. Translocation of 1 alpha,25-dihydroxy[3H]cholecalciferol from the cytosol to the nucleus was temperature-dependent. The addition of 100-fold excess amounts of unlabelled 1 alpha-25-dihydroxycholecalciferol significantly diminished the nuclear binding of 1 alpha,25-dihydroxy[3H]cholecalciferol. The cytosol fraction contained a 3.5 S macromolecule that specifically binds 1 alpha,25-dihydroxy[3H]cholecalciferol. The dissociation constant was 0.39 nM and the maximal binding was 55 fmol/mg of protein. These results strongly suggest that the uterus in egg-laying birds is a target organ or 1 alpha,25-dihydroxycholecalciferol.


Identifying patients with obsessive-compulsive disorder using whole-brain anatomy.
Structural neuroimaging studies have reported a variety of brain alterations between groups of obsessive-compulsive disorder (OCD) patients and healthy controls. However, the large heterogeneity in discrete anatomical measures that exists among patients prevents a clear discrimination of single patients from healthy subjects. This reduces the potential clinical applicability of structural neuroimaging studies. In the present study we assessed the feasibility of identifying OCD patients on the basis of whole-brain anatomical alterations. Whole-brain magnetic resonance images were collected from two consecutive samples of OCD outpatients (n=72 and n=30), and control subjects (n=72 and n=30). We computed the whole-brain (voxel-wise) pattern of structural difference between OCD patients and control subjects at the group level. A single expression value of this difference pattern was calculated for each subject, expressing their degree of 'OCD-like' anatomical alteration. Accuracy of patient classification based on these expression values was assessed using two validation approaches. Firstly, using a cross-validation method, we obtained a high classification accuracy (average of the sensitivity and specificity indices) of 93.1%. In a second assessment, which classified new groups of OCD patients and control subjects, overall accuracy was lower at 76.6%. Individual expression values for OCD patients were significantly correlated with overall symptom severity as measured by the Y-BOCS scale. Our results suggest that OCD patients can be identified on the basis of whole-brain structural alterations, although the accuracy of our approach may be limited by the inherent variability of psychiatric populations. Nevertheless, the anatomical characterization of individual patients may ultimately provide the psychiatrist with relevant biological information.


Prevalence and correlates of non-disclosure of maternal HIV status to male partners: a national survey in Kenya.
Prevention of mother-to-child HIV transmission (PMTCT) programs usually test pregnant women for HIV without involving their partners. Non-disclosure of maternal HIV status to male partners may deter utilization of PMTCT interventions since partners play a pivotal role in decision-making within the home including access to and utilization of health services. Mothers attending routine 6-week and 9-month infant immunizations were enrolled at 141 maternal and child health (MCH) clinics across Kenya from June-December 2013. The current analysis was restricted to mothers with known HIV status who had a current partner. Multivariate logistic regression models adjusted for marital status, relationship length and partner attendance at antenatal care (ANC) were used to determine correlates of HIV non-disclosure among HIV-uninfected and HIV-infected mothers, separately, and to evaluate the relationship of non-disclosure with uptake of PMTCT interventions. All analyses accounted for facility-level clustering, RESULTS: Overall, 2522 mothers (86% of total study population) met inclusion criteria, 420 (17%) were HIV-infected. Non-disclosure of HIV results to partners was higher among HIV-infected than HIV-uninfected women (13% versus 3% respectively, p < 0.001). HIV-uninfected mothers were more likely to not disclose their HIV status to male partners if they were unmarried (adjusted odds ratio [aOR] = 3.79, 95% CI: 1.56-9.19, p = 0.004), had low (≤KSH 5000) income (aOR = 1.85, 95% CI: 1.00-3.14, p = 0.050), experienced intimate partner violence (aOR = 3.65, 95% CI: 1.84-7.21, p < 0.001) and if their partner did not attend ANC (aOR = 4.12, 95% CI: 1.89-8.95, p < 0.001). Among HIV-infected women, non-disclosure to male partners was less likely if women had salaried employment (aOR = 0.42, 95%CI: 0.18-0.96, p = 0.039) and each increasing year of relationship length was associated with decreased likelihood of non-disclosure (aOR = 0.90, 95% CI: 0.82-0.98, p = 0.015 for each year increase). HIV-infected women who did not disclose their HIV status to partners were less likely to uptake CD4 testing (aOR = 0.32, 95% CI: 0.15-0.69, p = 0.004), to use antiretrovirals (ARVs) during labor (OR = 0.38, 95% CI 0.15-0.97, p = 0.042), or give their infants ARVs (OR = 0.08, 95% CI 0.02-0.31, p < 0.001). HIV-infected women were less likely to disclose their status to partners than HIV-uninfected women. Non-disclosure was associated with lower use of PMTCT services. Facilitating maternal disclosure to male partners may enhance PMTCT uptake.


A method for recording the respiratory and hatching movements of the chick embryo.
1. An artificial air space was made in the narrow end of the pipped egg by separating the shell membranes from the shell. The respiratory and hatching movements of the embryo set up pressure changes within the artificial air space and these were recorded up until the moment when the chick emerged from the shell. 3. Random movements appeared to be inhibited during the period of hatching. 4. The ways in which the presence of the artificial air space might affect the embryo have been discussed.


Mating behavior, population growth, and the operational sex ratio: a periodic two-sex model approach.
We present a new approach to modeling two-sex populations, using periodic, nonlinear two-sex matrix models. The models project the population growth rate, the population structure, and any ratio of interest (e.g., operational sex ratio). The periodic formulation permits inclusion of highly seasonal behavioral events. A periodic product of the seasonal matrices describes annual population dynamics. The model is nonlinear because mating probability depends on the structure of the population. To study how the vital rates influence population growth rate, population structure, and operational sex ratio, we used sensitivity analysis of frequency-dependent nonlinear models. In nonlinear two-sex models the vital rates affect growth rate directly and also indirectly through effects on the population structure. The indirect effects can sometimes overwhelm the direct effects and are revealed only by nonlinear analysis. We find that the sensitivity of the population growth rate to female survival is negative for the emperor penguin, a species with highly seasonal breeding behavior. This result could not occur in linear models because changes in population structure have no effect on per capita reproduction. Our approach is applicable to ecological and evolutionary studies of any species in which males and females interact in a seasonal environment.


Esophageal moniliasis: a new radiographic presentation.
A previously unreported manifestation of esophageal moniliasis is described. Two patients with acquired immunodeficiency syndrome and Kaposi's sarcoma presented with solitary esophageal ulcers. Endoscopic biopsy confirmed the clinical diagnosis of esophageal moniliasis. The clinical and radiographic features of esophageal moniliasis are described.


Exercise-related death in subjects with coexistent hypertrophic cardiomyopathy and coronary artery disease. Case reports.
Autopsy findings in 3 White men who died suddenly during or after exercise are described. Two were well conditioned marathon runners who had recently completed a 90 km ultramarathon, while the third was active in sports other than running. At autopsy all had significant coronary artery disease (CAD) involving the left anterior descending and right coronary arteries and macroscopic or histological features diagnostic of hypertrophic cardiomyopathy (HCM). Although CAD and HCM are well-established causes of sudden death in athletes, the combination is uncommon. The absence of symptoms prior to death in 2 of the subjects indicates that the possibility of antemortem diagnosis (particularly of HCM) was unlikely.


Mean and variance of greenness and pregnancy outcomes in Tel Aviv during 2000-14: longitudinal and cross-sectional approaches.
Natural environments may have beneficial impacts on pregnancy outcomes. However, longitudinal evidence is limited and the associations with variance in surrounding greenness is unknown. Our objective was to evaluate these associations among 73 221 live births in Tel Aviv, Israel. Longitudinal exposure to mean of greenness during pregnancy and trimesters were calculated using satellite-based Moderate Resolution Imaging Spectroradiometer (MODIS) Normalised Difference Vegetation Index (NDVI) data. In addition, exposure to mean and variation of NDVI from high-resolution satellite and percentage of tree cover [Vegetation Continuous Fields (VCF)] at 300-m buffer were evaluated in a cross-sectional approach. Generalized linear models were used to estimate the crude and adjusted associations. We explore the possible mediating role of ambient exposures and distance to 'outdoor gyms' located in parks. Crude beneficial associations between exposure to higher mean NDVI during pregnancy and pregnancy outcomes were observed [for birthweight, 3rd/1st tertile exposure increased the mean by 25.5 g, 95% confidence intervals (CIs): 15.4, 35.5] and decreased the odds of low birthweight, small for gestational age, preterm deliveries (PTD) and very PTD. Adjustment for individual and neighbourhood-level markers of socio-economic status (SES) attenuated all the associations. Strongest associations were observed during the first and second trimesters. Cross-sectional associations for mean greenness were similar with narrower CIs, and associations with NDVI were stronger than with tree cover and stronger for mean compared with variance of greenness. Associations were consistent for term births, different buffer sizes and for further adjustment to maternal education. Stronger associations were observed for lowest SES. Distance to 'outdoor gyms' and variance of greenness had the largest estimates of mediation. This study adds to the limited information on when exposure to greenness is most beneficial, on the association with variance of greenness and the possible pathways. These observations require confirmation in other populations.


As-projective-as-possible bias correction for illumination estimation algorithms.
Illumination estimation is the key routine in a camera's onboard auto-white-balance (AWB) function. Illumination estimation algorithms estimate the color of the scene's illumination from an image in the form of an R, G, B vector in the sensor's raw-RGB color space. While learning-based methods have demonstrated impressive performance for illumination estimation, cameras still rely on simple statistical-based algorithms that are less accurate but capable of executing quickly on the camera's hardware. An effective strategy to improve the accuracy of these fast statistical-based algorithms is to apply a post-estimate bias-correction function to transform the estimated R, G, B vector such that it lies closer to the correct solution. Recent work by Finlayson [Interface Focus8, 20180008 (2018)2042-889810.1098/rsfs.2018.0008] showed that a bias-correction function can be formulated as a projective transform because the magnitude of the R, G, B illumination vector does not matter to the AWB procedure. This paper builds on this finding and shows that further improvements can be obtained by using an as-projective-as-possible (APAP) projective transform that locally adapts the projective transform to the input R, G, B vector. We demonstrate the effectiveness of the proposed APAP bias correction on several well-known statistical illumination estimation methods. We also describe a fast lookup method that allows the APAP transform to be performed with only a few lookup operations.


Biochemical features of mtDNA 14484 (ND6/M64V) point mutation associated with Leber's hereditary optic neuropathy.
We report the effect on complex I function of the 14484 Leber's hereditary optic neuropathy (LHON) mutation affecting the ND6 subunit gene. The same gene was also reported to carry another mutation, at position 14459, associated with the LHON/dystonia phenotype that induces a reduction of complex I-specific activity and increases the sensitivity to the product decylubiquinol. Given the proximity of both mutations in the ND6 gene, we tested the specific activity of complex I and its sensitivity to myxothiazol and nonylbenzoquinol, both inhibitors at the ubiquinol product site, in platelet submitochondrial particles from nine 14484 homoplasmic individuals, 8 Italians with Caucasian mtDNA haplogroup J (adjunctive 4216 and 13708 mutations), and 1 Tunisian with an African mtDNA haplogroup. The specific activity of complex I was not affected by the 14484 mutation, but the sensitivity to both inhibitors was significantly increased compared with control subjects regardless of the presence of haplogroup J polymorphisms. Analysis of 70 different amino acid sequences of the ND6 subunit indicated that the 14484 mutation affects an amino acid belonging to its most conserved region, which shows local similarities with cytochrome b regions interacting with ubiquinone or ubiquinol in complex III. Our results suggest that both 14484 and 14459 mutations may affect amino acids forming the interaction site of ubiquinol product, and the 14484 mutation produces a biochemical defect resembling in part that already reported for the common 11778/ND4 LHON mutation.


The role of exogenous p53 and E6 oncoproteins in in vitro transformation by bovine papillomavirus type 4 (BPV-4): significance of the absence of an E6 ORF in the BPV-4 genome.
Bovine papillomavirus type 4 (BPV-4) does not possess an E6 ORF. The E6 oncoprotein of human papillomavirus (HPV) binds and degrades the tumour suppressor protein p53, thus contributing to tumour progression. Since BPV-4 lacks E6, it is unknown how the virus evades the tumour suppressor properties of p53 in the induction of tumours of the gastrointestinal tract. Mutations in the p53 gene have been detected both in papillomas and carcinomas, suggesting that p53 dysfunction plays a part in these neoplasias. BPV-4 can transform primary foetal bovine cells (PalFs) in cooperation with an activated ras gene, but the transformed cells are neither immortal nor tumorigenic. Co-transfection with the HPV-16 E6 (16E6) ORF confers immortality but not tumorigenicity. To investigate the role of p53 in BPV-4 cell transformation in vitro, we transfected PalFs and p53-null mouse fibroblasts with BPV-4 DNA in combinations with ras, 16E6 ORF and mutant (V143A) p53 cDNA. Transfection of PalFs with BPV-4 DNA, ras and mutant p53 led to cell immortalization, indicating that 16E6 and mutant p53 are functionally equivalent in conferring immortality. However, co-transfection of PalFs with BPV-4 DNA, ras, and both mutant p53 cDNA and 16E6 ORF resulted in cells which were fully transformed to tumorigenicity. In p53-null mouse fibroblasts, BPV-4 DNA induced transformation by itself, but the transformed cells were incapable of suspension growth. The co-transfection of BPV-4 DNA with 16E6 ORF produced many more transformed colonies and the cells were capable of growing in suspension. In this system, therefore, 16E6 confers anchorage-independence to BPV-4-transformed cells in a p53-independent fashion.


In vitro targeting of Polo-like kinase 1 in bladder carcinoma: comparative effects of four potent inhibitors.
Despite the improvements in neoadjuvant chemotherapy, the outcome of patients with advanced bladder cancer has changed very little over the past 30 years. In the present study we tested and compared the in vitro antitumor activities of four different inhibitors of Polo-like kinase 1 (PLK1) (BI 2536, BI 6727, GW843682X, and GSK461364), against 3 bladder carcinoma cell lines RT4, 5637 and T24. The impact on radiosensitivity and drug interactions in simultaneous treatments with cisplatin, methotrexate, and doxorubicin were also investigated. Our results showed that PLK1 inhibition prevented cell proliferation and clonogenicity, causing significant inhibition of invasion of tumor cells, though modest differences were observed between drugs. Moreover, all PLK1 inhibitors induced G 2/M arrest, with the subsequent induction of death in all 3 cell lines. Drug interactions studies showed auspicious results for all PLK1 inhibitors when combined with the commonly used cisplatin and methotrexate, though combinations with doxorubicin showed mostly antagonistic effects. Comparably, the four PLK1 inhibitors efficiently sensitized cells to ionizing radiation. Our findings demonstrate that irrespective of the inhibitor used, the pharmacological inhibition of PLK1 constrains bladder cancer growth and dissemination, providing new opportunities for future therapeutic intervention. However, further laboratorial and pre-clinical tests are still needed to corroborate the usefulness of using them in combination with other commonly used chemotherapeutic drugs.


High affinity fucose binding of Pseudomonas aeruginosa lectin PA-IIL: 1.0 A resolution crystal structure of the complex combined with thermodynamics and computational chemistry approaches.
PA-IIL is a fucose-binding lectin from Pseudomonas aeruginosa that is closely related to the virulence factors of the bacterium. Previous structural studies have revealed a new carbohydrate-binding mode with direct involvement of two calcium ions (Mitchell E, Houles C, Sudakevitz D, Wimmerova M, Gautier C, Perez S, Wu AM, Gilboa-Garber N, Imberty A. Structural basis for selective recognition of oligosaccharides from cystic fibrosis patients by the lectin PA-IIL of Pseudomonas aeruginosa. Nat Struct Biol 2002;9:918-921). A combination of thermodynamic, structural, and computational methods has been used to study the basis of the high affinity for the monosaccharide ligand. A titration microcalorimetry study indicated that the high affinity is enthalpy driven. The crystal structure of the tetrameric PA-IIL in complex with fucose and calcium was refined to 1.0 A resolution and, in combination with modeling, allowed a proposal to be made for the hydrogen-bond network in the binding site. Calculations of partial charges using ab initio computational chemistry methods indicated that extensive delocalization of charges between the calcium ions, the side chains of the protein-binding site and the carbohydrate ligand is responsible for the high enthalpy of binding and therefore for the unusually high affinity observed for this unique mode of carbohydrate recognition.


Development of small molecule Hsp90 inhibitors: utilizing both forward and reverse chemical genomics for drug identification.
Heat shock protein 90 (Hsp90) is a molecular chaperone whose association is required for stability and function of multiple mutated, chimeric, and over-expressed signaling proteins that promote cancer cell growth and/or survival. Hsp90 client proteins include mutated p53, Bcr-Abl, Raf-1, Akt, HER2/Neu (ErbB2), and HIF-1alpha. Hsp90 inhibitors, by interacting specifically with a single molecular target, cause the destabilization and eventual degradation of Hsp90 client proteins, and they have also shown promising anti-tumor activity in preclinical model systems. One Hsp90 inhibitor, 17-AAG, is currently in Phase I clinical trial. Hsp90 inhibitors are unique in that, although they are directed towards a specific molecular target, they simultaneously inhibit multiple signaling pathways on which cancer cells depend for growth and survival. Benzoquinone ansamycin binding to Hsp90 led to the identification of radicicol as an additional Hsp90 inhibitor. Additional target-based screening uncovered novobiocin as a third structurally distinct small molecule with Hsp90 inhibitory properties. Use of novobiocin, in turn, led to identification of a previously uncharacterized C-terminal ATP binding site in the chaperone. Small molecule inhibitors of Hsp90 have been very useful in understanding Hsp90 biology and in validating this protein as a molecular target for anti-cancer drug development.


Crystal structure and cell surface anchorage sites of laminin alpha1LG4-5.
The laminin G-like (LG) domains of laminin-111, a glycoprotein widely expressed during embryogenesis, provide cell anchoring and receptor binding sites that are involved in basement membrane assembly and cell signaling. We now report the crystal structure of the laminin alpha1LG4-5 domains and provide a mutational analysis of heparin, alpha-dystroglycan, and galactosylsulfatide binding. The two domains of alpha1LG4-5 are arranged in a V-shaped fashion similar to that observed with laminin alpha2 LG4-5 but with a substantially different interdomain angle. Recombinant alpha1LG4-5 binding to heparin, alpha-dystroglycan, and sulfatides was dependent upon both shared and unique contributions from basic residues distributed in several clusters on the surface of LG4. For heparin, the greatest contribution was detected from two clusters, 2719RKR and 2791KRK. Binding to alpha-dystroglycan was particularly dependent on basic residues within 2719RKR, 2831RAR, and 2858KDR. Binding to galactosylsulfatide was most affected by mutations in 2831RAR and 2766KGRTK but not in 2719RKR. The combined analysis of structure and activities reveal differences in LG domain interactions that should enable dissection of biological roles of different laminin ligands.


Pediatric do-not-attempt-resuscitation orders and public schools: a national assessment of policies and laws.
Some children living with life-shortening medical conditions may wish to attend school without the threat of having resuscitation attempted in the event of cardiopulmonary arrest on the school premises. Despite recent attention to in-school do-not-attempt-resuscitation (DNAR) orders, no assessment of state laws or school policies has yet been made. We therefore sought to survey a national sample of prominent school districts and situate their policies in the context of relevant state laws. Most (80%) school districts sampled did not have policies, regulations, or protocols for dealing with student DNARs. A similar majority (76%) either would not honor student DNARs or were uncertain about whether they could. Frequent contradictions between school policies and state laws also exist. Consequently, children living with life-shortening conditions who have DNARs may not have these orders honored if cardiopulmonary arrest were to occur on school premises. Coordinated efforts are needed to harmonize school district, state, and federal approaches in order to support children and families' right to have important medical decisions honored.


Tipping the scales: obese children and child safety seats.
To shed light on the extent to which childhood obesity affects the types of appropriate child safety seats for young children, by providing an estimate of the number of US children whose weight renders them unable to use safely the majority of child safety seat types currently available. The types of appropriate child safety seats were assessed by using National Highway Traffic Safety Administration 2005 Child Safety Seat Ease of Use Ratings. Estimates of the numbers of children weighing above the maximal weight for those child safety seats were calculated by using the tabulations of growth curves based on National Health and Nutrition Examination Survey 1999 to 2000 data that were assembled by the National Center for Health Statistics and the US Census for the year 2000. A total of 283,305 children 1 to 6 years of age would have a difficult (if not impossible) time finding a safe child safety seat because of their age and weight. The vast majority of these children are 3 years of age and weigh >40 lb (182,661 children). For these children, there are currently only 4 child safety seat types available, each of which costs between $240 and $270. This study determined that there is limited availability of child safety seat types for the ever-increasing number of obese young children. There are substantial numbers of children who weigh more than the upper weight limit for most currently available child safety seats. While we await reductions in the childhood obesity epidemic, options for maximizing the protection of obese children in automobiles must be identified.


A Primer on RECIST 1.1 for Oncologic Imaging in Clinical Drug Trials.
Drug discovery and approval in oncology is mediated by the use of imaging to evaluate drug efficacy in clinical trials. Imaging is performed while patients receive therapy to evaluate their response to treatment. Response criteria, specifically Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1), are standardized and can be used at different time points to classify response into the categories of complete response, partial response, stable disease, or disease progression. At the trial level, categorical responses for all patients are summated into image-based trial endpoints. These outcome measures, including objective response rate (ORR) and progression-free survival (PFS), are characteristics that can be derived from imaging and can be used as surrogates for overall survival (OS). Similar to OS, ORR and PFS describe the efficacy of a drug. U.S. Food and Drug Administration (FDA) regulatory approval requires therapies to demonstrate direct evidence of clinical benefit, such as improved OS. However, multiple programs have been created to expedite drug approval for life-threatening illnesses, including advanced cancer. ORR and PFS have been accepted by the FDA as adequate predictors of OS on which to base drug approval decisions, thus substantially shortening the time and cost of drug development (1). Use of imaging surrogate markers for drug approval has become increasingly common, accounting for more than 90% of approvals through the Accelerated Approval Program and allowing for use of many therapies which have altered the course of cancer. Keywords: Oncology, Tumor Response RSNA, 2021.


Pharmacological control of the mevalonate pathway: effect on arterial smooth muscle cell proliferation.
The mevalonate (MVA) pathway is involved in cell proliferation. We investigated drugs acting at different enzymatic steps on rat aorta smooth muscle cell (SMC) proliferation. Competitive inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase (0.1-10 microM) dose-dependently decreased (up to 90%) SMC proliferation. This effect was prevented by 100 microM MVA, 10 microM all-trans farnesol (F-OH) and 5 microM all-trans geranylgeraniol (GG-OH), precursors of protein prenyl groups, but not by 2-cis GG-OH, precursor of dolichols, squalene and ubiquinone. The same inhibitory effect was obtained with 6-fluoromevalonate (1-50 microM), an inhibitor of MVA-pyrophosphate decarboxylase. Partial recovery of cell proliferation was possible by all-trans F-OH and all-trans GG-OH, but not MVA. Squalestatin 1 (1-25 microM), a potent squalene synthase inhibitor, blocked cholesterol synthesis and slightly inhibited (21% decrease) SMC proliferation only at the highest tested concentration. NB-598 (1-10 microM), a potent squalene epoxidase inhibitor, blocked cholesterol synthesis without affecting SMC proliferation. Finally, the benzodiazepine peptidomimetic BZA-5B (10-100 microM), a specific inhibitor of protein farnesyltransferase, time- and dose-dependently decreased SMC proliferation (up to 62%) after 9 days. This effect of BZA-5B was prevented by MVA and all-trans GG-OH, but not by all-trans F-OH. SMC proliferation was not affected by the closely related compound BZA-7B, which does not inhibit protein farnesyltransferase. Altogether, these findings focus the role of the MVA pathway in cell proliferation and call attention to the involvement of specific isoprenoid metabolites, probably through farnesylated and geranylgeranylated proteins, in the control of this cellular event.


Increased risk of advanced prostate cancer associated with MnSOD Ala-9-Val gene polymorphism.
We aimed to investigate the association between manganese superoxide dismutase (MnSOD) Ala-9-Val gene polymorphism and the initiation and/or progression of prostate cancer (PCa) as well as to evaluate its potential interactions with advanced age and smoking status. MnSOD Ala-9-Val gene polymorphism was carried out in 134 (mean age 64.1±7.48) PCa patients and 159 (mean age 62.5±7.53) healthy controls with serum prostate specific antigen (PSA) levels (<4 ng/ml) and normal digital rectal examination (DRE) findings in this prospectively designed study. PCa patients were classified as low stage disease (T1 or T2 and N0M0 stages) and high stage disease (T3 or T4 and N0M0 or N1 or M1 stages). Genotypes for MnSOD Ala-9-Val gene polymorphism were identified by using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFPL). Despite lack of association between different genotypes of MnSOD Ala-9-Val gene polymorphism and the presence of PCa, patients with Ala/Ala genotype were at an increased risk of high stage disease compared with those with the Val/Val genotype [odds ratio (OR), 3.77; 95% CI, 1.30-10.94; P=0.012]. However, no significant difference was observed in the distribution of each genotype among PCa patients, with respect to tumor grade. On the other hand, smoking status and aging did not seem to change the association between genotypes and PCa risk. Ala/Ala genotype of MnSOD polymorphism may have an effect on adverse features of PCa such as high stage disease.


Epilepsy after neuroimaging normalization in a woman with tacrolimus-related posterior reversible encephalopathy syndrome.
Posterior reversible encephalopathy syndrome (PRES) is known to occur after solid organ transplantation, and is caused by immunosuppressive agents such as tacrolimus. PRES onset usually occurs within the first 2months after liver transplantation. Clinical findings include seizures, headache, focal neurological deficits, visual disturbances, and altered mental status. These are associated with characteristic imaging features of subcortical white matter lesions on brain MRI. Atypical localizations of this posterior leukoencephalopathy have been reported. Expeditious recognition of the syndrome may lead to a complete recovery. Abnormalities of EEG during follow-up might be associated with unfavorable seizure outcome, even when neuroimaging changes resolve. We report a case of late-onset PRES with atypical localization following liver transplantation. The patient developed epilepsy despite resolution of MRI lesions at 8 months of follow-up. EEG was a prognostic factor of seizure persistence, suggesting an incomplete recovery of brain lesions in contrast to neuroimaging findings.


Ezetimibe inhibits hepatic Niemann-Pick C1-Like 1 to facilitate macrophage reverse cholesterol transport in mice.
Controversies have arisen from recent mouse studies about the essential role of biliary sterol secretion in reverse cholesterol transport (RCT). The objective of this study was to examine the role of biliary cholesterol secretion in modulating macrophage RCT in Niemann-Pick C1-Like 1 (NPC1L1) liver only (L1(LivOnly)) mice, an animal model that is defective in both biliary sterol secretion and intestinal sterol absorption, and determine whether NPC1L1 inhibitor ezetimibe facilitates macrophage RCT by inhibiting hepatic NPC1L1. L1(LivOnly) mice were generated by crossing NPC1L1 knockout (L1-KO) mice with transgenic mice overexpressing human NPC1L1 specifically in liver. Macrophage-to-feces RCT was assayed in L1-KO and L1(LivOnly) mice injected intraperitoneally with [(3)H]-cholesterol-labeled peritoneal macrophages isolated from C57BL/6 mice. Inhibition of biliary sterol secretion by hepatic overexpression of NPC1L1 substantially reduced transport of [(3)H]-cholesterol from primary peritoneal macrophages to the neutral sterol fraction in bile and feces in L1(LivOnly) mice without affecting tracer excretion in the bile acid fraction. Ezetimibe treatment for 2 weeks completely restored both biliary and fecal excretion of [(3)H]-tracer in the neutral sterol fraction in L1(LivOnly) mice. High-density lipoprotein kinetic studies showed that L1(LivOnly) mice compared with L1-KO mice had a significantly reduced fractional catabolic rate without altered hepatic and intestinal uptake of high-density lipoprotein-cholesterol ether. In mice lacking intestinal cholesterol absorption, macrophage-to-feces RCT depends on efficient biliary sterol secretion, and ezetimibe promotes macrophage RCT by inhibiting hepatic NPC1L1 function.


Understanding the Perspective of Youths on Undergoing Metabolic Monitoring While on Second-Generation Antipsychotics: Challenges, Insight, and Implications.
Introduction: Prescription of second-generation antipsychotics (SGAs) in youths is rapidly increasing globally, despite the potential for significant adverse effects and long-term health consequences. A known adverse reaction resulting from SGAs is metabolic syndrome (MS). Youths exposed to antipsychotics are at higher risk than adults for adverse drug reactions, including adverse events such as MS (with weight gain as the most significant adverse outcome) and other long-term endocrinological abnormalities. This study aimed to explore the experiences of young patients on factors impacting barriers to metabolic monitoring of SGAs and the strategies to address those barriers thereby providing further guidance on policy and service delivery. Methods: Semi-structured interviews were conducted with patients (youths who were prescribed SGAs) who attended Child and Youth Mental Health Services. The interviews focused on barriers to monitoring and strategies to enhance rates of monitoring that could be customized across study sites. Results: Young patients revealed that none of them had any concerns or objections to receiving anthropometric metabolic measurements. However, they seemed concerned to undergo blood tests as part of the metabolic monitoring process. Specifically, youths cited their fear of the needles as barrier to undergo the required blood tests. Youths have also reported that their dislike to healthy foods and exercise being the most common challenge they face while trying to engage in a healthy lifestyle to manage the SGAs resulted weight gain. Conclusion: Prescribers are recommended to actively engage young patients about the expected SGAs-induced adverse effects, the importance of conducting metabolic monitoring, and how to prevent and minimize the expected adverse effects from the start of initiating SGAs. This could be a vital step toward a successful treatment as the insight of youths into the details of the chosen treatment can play a significant role into treatment adherence and recovery.


Quantification of global intervertebral torques during gait: comparison between two subjects with different scoliosis severities.
The internal forces in the human body in motion could provide valuable information for the evaluation and follow-up of subjects with musculo-skeletal pathologies, such as scoliosis, but are still difficult to accurately measure. In this context, the objective of this study is to quantify the global intervertebral torques along the spine during walking, in order to compare the dynamical behavior between two subjects with different scoliosis severities. Practically, two patients, both with left lumbar adolescent idiopathic scoliosis (lumbar Cobb angles: 40 degrees), but with different apical axial rotations (20 degrees and 30 degrees) and different thoracic Cobb angles (20 degrees and 30 degrees), walked on a treadmill at 4 km/h. The acquisition system included optokinetic sensors (reflective markers), recording the 3D-joint coordinates, and a treadmill equipped with strain gauges, measuring the external forces independently applied to both feet. The global intervertebral torques were computed using an inverse dynamic model of the human body in 3D. As results, significant differences of the subject kinematics and ground reaction forces were recorded, which lead to different internal torque behavior in magnitude, maxima and minima when normalized to the subject mass. In conclusion in this preliminary study, different dynamical behavior was found between two subjects with different scoliosis severities, suggesting that the scoliosis severity could be affected by abnormal internal torques along the spine during gait (different than in the standing posture), which could lead to a supplementary asymmetric growth modulation of the vertebrae and the further progression of the scoliotic deformities in the framework of the Hueter-Volkman principle. Finally, this is a pilot study and the results will inform future studies and biomechanical modeling.


Impact of Safinamide on Patient-Reported Outcomes in Parkinson's Disease.
Parkinson's disease (PD) is a chronic and progressive neurodegenerative condition due to the degeneration of nigral dopaminergic cells. Both motor and non-motor symptoms (NMS) of PD produce a marked impairment in PD patients' quality of life (QoL), but contrary to motor features, NMS do not improve with dopamine replacement. Novel therapeutic interventions for PD have successfully controlled most motor manifestations of PD, but the management of NMS is still challenging. Since NMS have a negative impact on the QoL of PD patients, researchers are currently looking for drugs that can modulate the activity of neurotransmitter systems other than dopamine in the hope that can alleviate NMS in PD. Among the recently approved drugs for patients experiencing fluctuations in motor symptoms, safinamide stands out as an effective add-on therapy to levodopa. Safinamide is a monoamine oxidase type-B inhibitor (MAOB-I), with proven efficacy in reducing motor fluctuations. Its distinctive mechanism of action impacts dopaminergic pathways via MAOB inhibition and glutamatergic pathways by blocking sodium and calcium channels. Findings from Phase III clinical trials, meta-analysis, post-hoc analysis, and real-life experiences indicate that safinamide benefits motor symptoms such as tremor, bradykinesia, rigidity, and gait. Additionally, it shows promise for improving NMS like fatigue, pain, mood, and sleep disturbances in patients with PD. In this article, the authors explore the impact of safinamide on patient-reported outcomes in PD. A thorough search was conducted on PubMed focusing on studies published between 2018 and 2023 in English. The inclusion criteria encompassed clinical trials, randomized controlled trials, systematic reviews, meta-analyses, and reviews. The search strategy revolved around the implementation of MeSH terms related to safinamide and its impact on the quality of life in PD. Our data strongly support the improving effect on QoL, reducing the disabling NMS reported in patients with PD.


Paeoniflorin ameliorates Adriamycin-induced nephrotic syndrome through the PPARγ/ANGPTL4 pathway in vivo and vitro.
Paeoniflorin (PF), an effective composition that is extracted from Radix Paeoniae Alba, plays a role in protecting against various kidney diseases. However, the mechanism of PF on nephrotic syndrome (NS) remains unclear. The aim of this study was to investigate the protective role of PF on Adriamycin (ADR)-induced NS in vivo and vitro as well as its potential mechanism. In animal study, PF significantly decreased the levels of 24-h urine protein, blood urea nitrogen, serum creatinine, total cholesterol and triglycerides in NS rats, but increased the total protein and albumin levels. Hematoxylin-eosin (HE) staining revealed that the kidney lesion was resolved upon PF treatment. After treatment with PF, the morphology and number of podocytes in renal tissue were restored to normal. PF increased expression of synaptopodin and decreased expression of desmin, demonstrating a protective effect in podocyte injury. Further studies revealed that PF upregulated Peroxisome proliferator-activated receptor gamma (PPARγ) and restrained Angiopointin-like 4 (ANGPTL4) in kidney tissue. In vitro study, PF reduced Caspase3 and Bax and increased Bcl-2, indicating that the apoptosis rate of podocytes induced by ADR was reduced by PF. Furthermore, PF ameliorated podocyte injury by upregulating synaptopodin and reducing desmin. In accordance with animal study, PF downregulated ANGPTL4 by activating PPARγ. However, the therapeutic effects of PF were reversed by GW9662 (PPARγ inhibitor), likely by suppressing ANGPTL4 degradation. In general, these results demonstrate that PF has a good therapeutic effect on NS by activating PPARγ and subsequently inhibiting ANGPTL4.


Unbalanced bidirectional causal association between thyroid cancer and ER-positive breast cancer: should we recommend screening for thyroid cancer in breast cancer patients?
The association between breast cancer (BC) and thyroid cancer (TC) has been studied in several epidemiological studies. However, the underlying causal relationship between them is not yet clear. The data from the latest large-sample genome-wide association studies (GWAS) of BC and TC were searched in the public GWAS database. The BC GWAS data included estrogen receptor (ER)-positive and negative subgroups. Two-way two-sample Mendelian Randomization (MR) was used to explore the potential causal relationship between BC and TC. Inverse variance weighting (IVW) and the MR-Egger method were used to combine the estimation of each single nucleotide variation (previous single nucleotide polymorphism). BC was taken as the result, and the effect of TC exposure was analyzed. Then, the effect of BC exposure on the result of TC was analyzed. Both IVW and MR-Egger results indicated that gene-driven thyroid cancer does not cause estrogen receptor-positive breast cancer and is a protective factor (β = -1.203, SE = 4.663*10-4, P = 0.010). However, gene-driven estrogen receptor-positive breast cancer can lead to the development of thyroid cancer (β = 0.516, SE = 0.220, P = 0.019). From the perspective of gene drive, people with TC are less likely to have ER-positive BC. In contrast, people with ER-positive BC are more likely to have TC. Therefore, it is recommended that patients with BC be screened regularly for TC.


Melatonin mediates mucosal immune cells, microbial metabolism, and rhythm crosstalk: A therapeutic target to reduce intestinal inflammation.
Nowadays, melatonin, previously considered only as a pharmaceutical product for rhythm regulation and sleep aiding, has shown its potential as a co-adjuvant treatment in intestinal diseases, however, its mechanism is still not very clear. A firm connection between melatonin at a physiologically relevant concentration and the gut microbiota and inflammation has recently established. Herein, we summarize their crosstalk and focus on four novelties. First, how melatonin is synthesized and degraded in the gut and exerts potentially diverse phenotypic effects through its diverse metabolites. Second, how melatonin mediates the activation and proliferation of intestinal mucosal immune cells with paracrine and autocrine properties. By modulating T/B cells, mast cells, macrophages and dendritic cells, melatonin immunomodulatory involved in regulating T-cell differentiation, intervening T/B cell interaction and attenuating the production of pro-inflammatory factors, achieving its antioxidant action via specific receptors. Third, how melatonin exerts antimicrobial action and modulates microbial components, such as lipopolysaccharide, amyloid-β peptides via nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) or signal transducers and activators of transcription (STAT1) pathway to modulate intestinal immune function in immune-pineal axis. The last, how melatonin mediates the effect of intestinal bacterial activity signals on the body rhythm system through the NF-κB pathway and influences the mucosal epithelium oscillation via clock gene expression. These processes are achieved at mitochondrial and nuclear levels to control the host immune cell development. Considering unclear mechanisms and undiscovered actions of melatonin in gut-microbiome-immune axis, it's time to reveal them and provide new insight for the outlook of melatonin as a potential therapeutic target in the treatment and management of intestinal diseases.


Health literacy in people living with mental illness: A latent profile analysis.
Health literacy comprises cognitive and social skills that enable people to understand health information and maintain good health. Research examining the health literacy of people living with mental illness is scarce. The aim of the present study was to identify distinct subgroups of health literacy in individuals attending mental health treatment and determine if profiles and health literacy levels differ from other populations accessing healthcare services and on health characteristics. Participants (N = 325) were attending Neami National Australia services. Participants completed the multidimensional Health Literacy Questionnaire. Latent profile analysis was conducted to identify health literacy profiles. Participants reported lowest health literacy scores in appraising health information, navigating the healthcare system, and finding good health information. Three health literacy profiles were identified; low (20.4%), moderate (61.3%), and high (18.3%). Compared to the other populations (i.e. private hospital patients, men with prostate cancer, older individuals with diabetes, general population, people attending substance dependence treatment), the current sample tended to have lower health literacy scores. The findings highlight the need to increase overall health literacy and consider an individualised approach to enhance specific health literacy domains.


Spinal stimulation for motor rehabilitation immediately modulates nociceptive transmission.
Objective. Spinal cord injury (SCI) often results in debilitating movement impairments and neuropathic pain. Electrical stimulation of spinal neurons holds considerable promise both for enhancing neural transmission in weakened motor pathways and for reducing neural transmission in overactive nociceptive pathways. However, spinal stimulation paradigms currently under development for individuals living with SCI continue overwhelmingly to be developed in the context of motor rehabilitation alone. The objective of this study is to test the hypothesis that motor-targeted spinal stimulation simultaneously modulates spinal nociceptive transmission.Approach. We characterized the neuromodulatory actions of motor-targeted intraspinal microstimulation (ISMS) on the firing dynamics of large populations of discrete nociceptive specific and wide dynamic range (WDR) neurons. Neurons were accessed via dense microelectrode arrays implantedin vivointo lumbar enlargement of rats. Nociceptive and non-nociceptive cutaneous transmission was induced before, during, and after ISMS by mechanically probing the L5 dermatome.Main results. Our primary findings are that (a) sub-motor threshold ISMS delivered to spinal motor pools immediately modulates concurrent nociceptive transmission; (b) the magnitude of anti-nociceptive effects increases with longer durations of ISMS, including robust carryover effects; (c) the majority of all identified nociceptive-specific and WDR neurons exhibit firing rate reductions after only 10 min of ISMS; and (d) ISMS does not increase spinal responsiveness to non-nociceptive cutaneous transmission. These results lead to the conclusion that ISMS parameterized to enhance motor output results in an overall net decrease n spinal nociceptive transmission.Significance. These results suggest that ISMS may hold translational potential for neuropathic pain-related applications and that it may be uniquely suited to delivering multi-modal therapeutic benefits for individuals living with SCI.


A cluster randomized trial to assess the effect of clinical pathways for patients with stroke: results of the clinical pathways for effective and appropriate care study.
Clinical pathways (CPs) are used to improve the outcomes of acute stroke, but their use in stroke care is questionable, because the evidence on their effectiveness is still inconclusive. The objective of this study was to evaluate whether CPs improve the outcomes and the quality of care provided to patients after acute ischemic stroke. This was a multicentre cluster-randomized trial, in which 14 hospitals were randomized to the CP arm or to the non intervention/usual care (UC) arm. Healthcare workers in the CP arm received 3 days of training in quality improvement of CPs and in use of a standardized package including information on evidence-based key interventions and indicators. Healthcare workers in the usual-care arm followed their standard procedures. The teams in the CP arm developed their CPs over a 6-month period. The primary end point was mortality. Secondary end points were: use of diagnostic and therapeutic procedures, implementation of organized care, length of stay, re-admission and institutionalization rates after discharge, dependency levels, and complication rates. Compared with the patients in the UC arm, the patients in the CP arm had a significantly lower risk of mortality at 7 days (OR = 0.10; 95% CI 0.01 to 0.95) and significantly lower rates of adverse functional outcomes, expressed as the odds of not returning to pre-stroke functioning in their daily life (OR = 0.42; 95 CI 0.18 to 0.98). There was no significant effect on 30-day mortality. Compared with the UC arm, the hospital diagnostic and therapeutic procedures were performed more appropriately in the CP arm, and the evidence-based key interventions and organized care were more applied in the CP arm. CPs can significantly improve the outcomes of patients with ischemic patients with stroke, indicating better application of evidence-based key interventions and of diagnostic and therapeutic procedures. This study tested a new hypothesis and provided evidence on how CPs can work. ClinicalTrials.gov ID: [NCT00673491].


Influence on the osteogenic activity of the human bone marrow mesenchymal stem cells transfected by liposome-mediated recombinant plasmid pIRES-hBMP2-hVEGF165 in vitro.
Bone marrow mesenchymal stem cells (BMSCs) is an attractive option for use as seed cells in tissue engineering strategies. Bone morphogenetic proteins (BMPs) to be involved in the formation of various tissue types including bone, cartilage, tendon, and ligament. Vascular endothelial growth factor (VEGF) is a promising reagent for inducing angiogenesis. Constructed a coexpressing vector of human bone morphogenetic protein 2 (hBMP-2) and vascular endothelial growth factor 165 (hVEGF165). The vectors were transfected into proliferated BMSCs isolated from healthy adult bone marrow. The expression of hBMP-2 and hVEGF165 genes of BMSCs were assayed by Western-blot, and the level of alkaline phosphatase activities of BMSCs was determined by RT-PCR analysis of osteocalcin mRNA expression. The levels of collagen I by immunohistochemical staining were also determined.BMSCs transfected with reconstructed plasmid pIRES-hBMP-2-VEGF165 could secret a high level of BMP-2 and hVEGF165. The production of type I collagen, the activity of alkaline phosphatase, and the expression of osteocalcin mRNA were also significantly improved in the transfected BMSCs, compared with the control group.The exogenous hBMP-2 and hVEGF165 genes can be expressed constitutively in the transfected BMSCs, and the lineage-committed differentiation abilities of BMSCs containing combination of genes BMP-2 and VEGF165 are enhanced.


Hingeless arm for space robotics actuated through shape memory alloys.
Operating outside the spacecraft via remotely controlled structures is an important opportunity in different space applications. The research in this area is focused on designing robots that are sufficiently flexible to allow inspection in locations where access is difficult or impossible for astronauts, while minimizing weight and bulk.
The purpose of the research is to design a borescope for space applications with no hinges or other mechanisms, exploiting biomimetic design concepts. This is pursued by giving to the borescope a backbone exoskeleton provided by a continuous structure made of fibre reinforced composite material and using NiTi wires as tendons, taking advantage of their low weight and dimensions, which allow them to be embedded between the composite layers during the lamination process.
After a study of the state of the art of flexible structures, concentrated in the medical and robotic fields, the research work unfolded in two phases. In the first design phase, several composite layup solutions were considered and analysed using finite element models, leading to the definition of the borescope geometrical parameters and to an initial estimate of the displacements that can be achieved. In the second experimental phase, seven prototypes were produced and tested, with one or more wires, to validate the design and to search for a configuration that can be actuated in different directions.
The borescope prototypes resulted flexible enough to achieve an extended degree of bending and at the same time sufficiently rigid to allow complete rearm of the NiTi wires. The numerical and experimental study led to the definition of the design parameters, the number of wires, and the manufacturing technique to integrate NiTi actuators.


Specific binding of divalent metal ions to tetracycline and to the Tet repressor/tetracycline complex.
Tetracyclines coordinate metal(II) ions under physiological conditions forming chelate complexes with their ketoenolate moiety at rings B and C. These metal(II) complexes are the biologically relevant molecules conferring the antibiotic character of the drug by inhibiting ribosomal protein biosynthesis in prokaryotes. The Tet repressor, TetR, is the molecular switch for tetracycline resistance determinants in gram-negative bacteria. TetR controls transcription of a gene encoding the integral membrane protein TetA, which mediates active efflux of a tetracycline-metal(II) cation, [MeTc](+), by equimolar antiport with a proton. We evaluated distinct characteristics of the metal binding by crystal structure determination of TetR/[MeTc](+) complexes and of association equilibrium constants of [MeTc](+) and TetR/[MeTc](+) complexes. Various divalent metal ions bind to the same octahedral coordination site, defined by a histidine side chain of TetR, the tetracycline, and three water molecules. Whereas association constants for [MeTc](+) vary within 3 orders of magnitude, association of the [MeTc](+) cation to TetR is very similar for all measured divalent metals. Taking intracellular cation concentrations into account, it is evident that no other metal ion can compete with Mg(2+) for TetR/[MeTc](+) complex formation.


Transplacental transmission of Bluetongue virus serotype 8 in ewes in early and mid gestation.
The ability of Bluetongue virus serotype 8 (BTV-8) originating from the 2006 European outbreak to cross the ovine placenta during early and mid gestation was investigated in two separate experiments. In the first experiment, 16 ewes were infected with BTV-8 at 70-75 days gestation. The foetuses were collected at 18-19 days after infection (dpi). BTV-8 could be isolated from at least two organs of 19 out of 40 lambs and from 11 out of 16 infected ewes. In the second experiment, 20 BTV-8 infected ewes in early gestation (day 40-45) were euthanized at 10 days (10 ewes) or 30 days (10 ewes) after infection. The presence of BTV could be demonstrated in two foetuses from two ewes at 10 dpi and in 4 foetuses from four ewes at 30 dpi. The main pathological findings in the foetuses in mid gestation were meningo-encephalitis and vacuolation of the cerebrum. In the foetuses early at gestation, haemorrhages in various foetal tissues and necrosis and haemorrhages in the placentomes were found. These experiments demonstrate for the first time the presence of infectious BTV in lamb foetuses at different stages of gestation, combined with a difference in transmission rate depending on the gestation stage. The high transmission rate found at mid term gestation (69%) makes our model very suitable for further research into the mechanisms of transplacental transmission and for research into the reduction of this route of transmission through vaccination.


Analytic energy gradients for the coupled-cluster singles and doubles with perturbative triples method with the density-fitting approximation.
An efficient implementation of analytic gradients for the coupled-cluster singles and doubles with perturbative triples [CCSD(T)] method with the density-fitting (DF) approximation, denoted as DF-CCSD(T), is reported. For the molecules considered, the DF approach substantially accelerates conventional CCSD(T) analytic gradients due to the reduced input/output time and the acceleration of the so-called "gradient terms": formation of particle density matrices (PDMs), computation of the generalized Fock-matrix (GFM), solution of the Z-vector equation, formation of the effective PDMs and GFM, back-transformation of the PDMs and GFM, from the molecular orbital to the atomic orbital (AO) basis, and computation of gradients in the AO basis. For the largest member of the molecular test set considered (C6H14), the computational times for analytic gradients (with the correlation-consistent polarized valence triple-ζ basis set in serial) are 106.2 [CCSD(T)] and 49.8 [DF-CCSD(T)] h, a speedup of more than 2-fold. In the evaluation of gradient terms, the DF approach completely avoids the use of four-index two-electron integrals. Similar to our previous studies on DF-second-order Møller-Plesset perturbation theory and DF-CCSD gradients, our formalism employs 2- and 3-index two-particle density matrices (TPDMs) instead of 4-index TPDMs. Errors introduced by the DF approximation are negligible for equilibrium geometries and harmonic vibrational frequencies.


Angiographic findings and outcome in diabetic patients treated with thrombolytic therapy for acute myocardial infarction: the GUSTO-I experience.
This study sought to determine whether diabetes mellitus, in the setting of thrombolysis for acute myocardial infarction, affects 1) early infarct-related artery patency and reocclusion rates; and 2) global and regional ventricular function indexes. We also sought to assess whether angiographic or baseline clinical variables, or both, can account for the known excess mortality after myocardial infarction in the diabetic population. Mortality after acute myocardial infarction in patients with diabetes is approximately twice that of nondiabetic patients. It is uncertain whether this difference in mortality is due to a lower rate of successful thrombolysis, increased reocclusion after successful thrombolysis, greater ventricular injury or a more adverse angiographic or clinical profile in diabetic patients. Patency rates and global and regional left ventricular function were determined in patients enrolled in the GUSTO-I Angiographic Trial. Thirty-day mortality differences between those with and without diabetes were compared. The diabetic cohort had a significantly higher proportion of female and elderly patients, and they were more often hypertensive, came to the hospital later and had more congestive heart failure and a higher number of previous myocardial infarctions and bypass surgery procedures. Ninety-minute patency (Thrombolysis in Myocardial Infarction [TIMI] flow grade 3) rates in patients with and without diabetes were 40.3% and 37.6%, respectively (p = 0.7). Reocclusion rates were 9.2% vs. 5.3% (p = 0.17). Ejection fraction at 90 min after thrombolysis was similar in diabetic and nondiabetic patients ([mean +/- SEM] 6.10 +/- 1.6% vs. 60.1 +/- 0.7%, p = 0.7), as was regional ventricular function (number of abnormal chords: 19.1 +/- 2.0 vs. 17.5 +/- 0.8, p = 0.3; SD/chord: -2.3 +/- 0.2 vs. -2.4 +/- 0.1, p = 0.6). Diabetic patients had less compensatory hyperkinesia in the noninfarct zone (SD/ chord: 1.3 +/- 0.2 vs. 1.7 +/- 0.1, p < or = 0.01). No significant difference in ventricular function was noted at 5- to 7-day follow-up. The 30-day mortality rate was 11.3% in diabetic versus 5.9% in nondiabetic patients (p < or = 0.0001). After adjustment for clinical and angiographic variables, diabetes remained an independent determinant of 30-day mortality (p = 0.02). Early (90-min) infarct-related artery patency as well as regional and global ventricular function do not differ between patients with and without diabetes after thrombolytic therapy, except for reduced compensatory hyperkinesia in the noninfarct zone among patients with diabetes. Diabetes remained an independent determinant of 30-day mortality after correction for clinical and angiographic variables.


Is disgust prepared? A preliminary examination in young children.
Children may be prepared to associate adult disgust reactions with adult disgust elicitors. To test this, three-year olds (and adults) were presented with two images and an emotive vocalization. The images and vocalizations included stimuli adults found disgusting, fear-provoking, and sad. On one set of trials, the main dependent variable (DV) was time spent looking at each image and on a second set of repeat trials the DV was knowledge of image-sound matches. Fear and disgust vocalizations were both more effective at orienting a child's attention to adult fear and disgust images, than sad vocalizations. Parental disgust sensitivity was associated with this effect, moderated by explicit matching knowledge. Matching knowledge was poor in children and good in adults. These data suggest that in children, fear and disgust vocalizations may both promote attention to stimuli that adults find disgusting and/or fear-provoking, suggesting that "preparedness" may not be wholly emotion-specific.