Dairy products consumption and risk of type 2 diabetes: systematic review and dose-response meta-analysis.
The consumption of dairy products may influence the risk of type 2 diabetes mellitus (T2DM), but inconsistent findings have been reported. Moreover, large variation in the types of dairy intake has not yet been fully explored. We conducted a systematic review and meta-analysis to clarify the dose-response association of dairy products intake and T2DM risk. We searched PubMed, EMBASE and Scopus for studies of dairy products intake and T2DM risk published up to the end of October 2012. Random-effects models were used to estimate summary relative risk (RR) statistics. Dose-response relations were evaluated using data from different dairy products in each study. We included 14 articles of cohort studies that reported RR estimates and 95% confidence intervals (95% CIs) of T2DM with dairy products intake. We found an inverse linear association of consumption of total dairy products (13 studies), low-fat dairy products (8 studies), cheese (7 studies) and yogurt (7 studies) and risk of T2DM. The pooled RRs were 0.94 (95% CI 0.91-0.97) and 0.88 (0.84-0.93) for 200 g/day total and low-fat dairy consumption, respectively. The pooled RRs were 0.80 (0.69-0.93) and 0.91 (0.82-1.00) for 30 g/d cheese and 50 g/d yogurt consumption, respectively. We also found a nonlinear association of total and low-fat dairy intake and T2DM risk, and the inverse association appeared to be strongest within 200 g/d intake. A modest increase in daily intake of dairy products such as low fat dairy, cheese and yogurt may contribute to the prevention of T2DM, which needs confirmation in randomized controlled trials.


Cellular signaling underlying atrial tachycardia remodeling of L-type calcium current.
Atrial tachycardia (AT) downregulates L-type Ca(2+) current (I(CaL)) and causes atrial fibrillation-promoting electric remodeling. This study assessed potential underlying signal transduction. Cultured adult canine atrial cardiomyocytes were paced at 0, 1, or 3 Hz (P0, P1, P3) for up to 24 hours. Cellular tachypacing (P3) mimicked effects of in vivo AT: decreased I(CaL) and transient outward current (I(to)), unchanged I(CaT), I(Kr), and I(Ks), and reduced action potential duration (APD). I(CaL) was unchanged in P3 at 2 and 8 hours but decreased by 55+/-6% at 24 hours. Tachypacing caused Ca(2+)(i) accumulation in P3 cells at 2 to 8 hours, but, by 24 hours, Ca(2+)i returned to baseline. Ca(v)1.2 mRNA expression was not altered at 2 hours but decreased significantly at 8 and 24 hours (32+/-4% and 48+/-4%, respectively) and protein expression was decreased (47+/-8%) at 24 hours only. Suppressing Ca(2+)(i) increases during tachypacing with the I(CaL) blocker nimodipine or the Ca(2+) chelator BAPTA-AM prevented I(CaL) downregulation. Calcineurin activity increased in P3 at 2 and 8 hours, respectively, returning to baseline at 24 hours. Nuclear factor of activated T cells (NFAT) nuclear translocation was enhanced in P3 cells. Ca(2+)-dependent signaling was probed with inhibitors of Ca(2+)/calmodulin (W-7), calcineurin (FK-506), and NFAT (INCA6): each prevented I(CaL) downregulation. Significant APD reductions ( approximately 30%) at 24 hours in P3 cells were prevented by nimodipine, BAPTA-AM, W-7, or FK-506. Thus, rapid atrial cardiomyocyte activation causes Ca(2+) loading, which activates the Ca(2+)-dependent calmodulin-calcineurin-NFAT system to cause transcriptional downregulation of I(CaL), restoring Ca(2+)i to normal at the cost of APD reduction. These studies elucidate for the first time the molecular feedback mechanisms underlying arrhythmogenic AT remodeling.


Prevalence of non-motor symptoms in young-onset versus late-onset Parkinson's disease.
Non-motor symptoms (NMS) of Parkinson's disease (PD) have only recently been increasingly recognized for their impact on a patient's quality of life. In this study, we applied the validated, comprehensive self-completed NMS questionnaire for PD (NMS Quest) to 101 patients with young-onset PD (onset between 21 and 45 years, YOPD) and 107 patients with late-onset PD (onset of PD ≥ 55 years, LOPD). The mean total NMS (NMSQ-T) was 11.9 ± 6.0 (range: 0 to of a maximum of 26) in LOPD and 7.7 ± 5.8 (range: 0 to of a maximum of 26) in YOPD (p < 0.05). Compared to YOPD, dribbling of saliva, loss of taste/smell, nocturia, forgetfulness, loss of interest, hallucinations, lack of concentration, anxiety, change in libido and difficulty in sexual activities, were significantly more prevalent in LOPD. The only NMS more prevalent in YOPD were restless legs and sweating, although such findings might be associated with drug effects. Among the nine NMS Quest domains, in both LOPD and YOPD patients the three most prevalent domains were depression/anxiety, urinary and sexual. Also, in both groups, hallucinations/delusions had the lowest frequency. In the multivariate linear regression model, the Hoehn and Yahr (HY) stage of the disease and activities of daily living scores in YOPD patients, while only the HY stage in LOPD patients appeared to be statistically significant predictors of increasing number of NMS. In contrast to a previous suggestion that YOPD patients might have an increased risk for NMS, we found a higher prevalence of NMS in LOPD patients than in those with YOPD.


Experimental assessment of the performance of vitreous cutters with fluids with different rheological properties.
To assess the influence of rheological properties of an artificial vitreous (AV) on the performance of double-blade (DB) and single-blade (SB) guillotine vitreous cutters, with 23-, 25-, and 27-gauge (G) probes. We evaluate the aspiration flow rate, using an optical method, based on image processing. Experiments are conducted using ten viscoelastic vitreous phantoms, with different properties that are measured with rheological tests. Aspiration rate strongly varies with fluid properties. Regardless of cutter geometry and operational conditions, the flow rate significantly decreases as vitreous viscosity and elasticity increase. All tested vitreous probes are very sensitive to changes in fluid rheology. SB cutters produce smaller flow rates compared with DB ones of the same caliber; however, they are less sensitive to fluid properties at low aspiration pressures. The use of vitreous substitutes for test performance guarantees comparability between flow rate results achieved with different vitrectomy systems operating in different media. This outcome is further confirmed by the low values of estimated flow rate relative errors.


Correlation of cyclin D1 and cyclin D3 overexpression with the loss of PTEN expression in endometrial carcinoma.
Cyclins D1 and D3 play key roles in cell cycle progression. The downregulation of cyclin D3 was associated with phosphatase and tensin homolog deleted on chromosome ten-(PTEN)-induced cell cycle arrest. We attempted to determine whether cyclin D1 and D3 overexpression is correlated with PTEN inactivation in endometrioid endometrial cancer (EEC). The expression of PTEN, cyclin D1, and cyclin D3 were determined by immunohistochemical analysis in 105 EEC specimens. Forty-three percent of the EEC demonstrated loss of PTEN expression. Cyclin D3 was overexpressed in only 18% of the EEC specimens and was not associated with tumor grade. Cyclin D1 was overexpressed in 64% of the specimens and was more common in moderate or high-grade tumors (P = 0.002 and P = 0.02, respectively). The overexpression of cyclin D3 was not correlated with loss of PTEN in the EEC. The overexpression of cyclin D1 was much higher in grade 1 tumors with negative PTEN than tumors with positive PTEN expression (67% vs 26%). The overexpression of cyclin D3 was neither frequent nor correlated with the loss of PTEN expression. The overexpression of cyclin D1 was higher in the low-grade tumors with negative PTEN expression than tumors with positive PTEN expression. Overexpression of cyclin D1 is frequent in moderate or high-grade EECs and likely results from multiple mechanisms.


[Molecular pathology and the problem of bodily integrity].
The paper is devoted to general and special (local) problems in pathology. The author lays particular stress on the fact that, despite the achievements of molecular biology, a solution of many principal problems of pathogenesis of various diseases in man, regularities of his adaptation to diverse environmental factors, etc., can be achieved only by a synthetic insight into the whole complex of factual material seen from the standpoint of the organism as an integrated system functioning on the basis of general regulatory mechanisms, many elements of which remain still unknown. Establishing of the latter is one of the most important and most complicated present-day challenges of biology and medicine.


Biochemical phenotyping unravels novel metabolic abnormalities and potential biomarkers associated with treatment of GLUT1 deficiency with ketogenic diet.
Global metabolomic profiling offers novel opportunities for the discovery of biomarkers and for the elucidation of pathogenic mechanisms that might lead to the development of novel therapies. GLUT1 deficiency syndrome (GLUT1-DS) is an inborn error of metabolism due to reduced function of glucose transporter type 1. Clinical presentation of GLUT1-DS is heterogeneous and the disorder mirrors patients with epilepsy, movement disorders, or any paroxysmal events or unexplained neurological manifestation triggered by exercise or fasting. The diagnostic biochemical hallmark of the disease is a reduced cerebrospinal fluid (CSF)/blood glucose ratio and the only available treatment is ketogenic diet. This study aimed at advancing our understanding of the biochemical perturbations in GLUT1-DS pathogenesis through biochemical phenotyping and the treatment of GLUT1-DS with a ketogenic diet. Metabolomic analysis of three CSF samples from GLUT1-DS patients not on ketogenic diet was feasible inasmuch as CSF sampling was used for diagnosis before to start with ketogenic diet. The analysis of plasma and urine samples obtained from GLUT1-DS patients treated with a ketogenic diet showed alterations in lipid and amino acid profiles. While subtle, these were consistent findings across the patients with GLUT1-DS on ketogenic diet, suggesting impacts on mitochondrial physiology. Moreover, low levels of free carnitine were present suggesting its consumption in GLUT1-DS on ketogenic diet. 3-hydroxybutyrate, 3-hydroxybutyrylcarnitine, 3-methyladipate, and N-acetylglycine were identified as potential biomarkers of GLUT1-DS on ketogenic diet. This is the first study to identify CSF, plasma, and urine metabolites associated with GLUT1-DS, as well as biochemical changes impacted by a ketogenic diet. Potential biomarkers and metabolic insights deserve further investigation.


Systemic anti-cancer treatment in malignant ovarian germ cell tumours (MOGCTs): current management and promising approaches.
Malignant ovarian germ cell tumours (MOGCTs) are rare. Unlike epithelial ovarian cancer, MOGCTs typically occur in girls and young women. Fertility-sparing surgery and platinum-based chemotherapy remain the standard of care, providing high chance of cure at all stages. Given the lack of high-quality studies in this field, current practice guidelines recommend chemotherapy regimens adopted in testicular germ cell tumours. However, platinum-resistant/refractory MOGCTs retain a worse prognosis in comparison with their male counterpart. Herein, we focus on current systemic anti-cancer treatment options in MOGCTs and promising approaches. Future studies enrolling exclusively female participants or germ cell tumour trials allowing participation of MOGCT patients are strongly recommended in order to improve evidence on existing management and develop novel strategies.


Fascial Graft Repair of Wide Bilateral Cleft Lip Deformity.
Wide bilateral cleft lip deformity reconstruction represents a special difficulty as it affects the lip, nose, and maxillary segments making single-stage reconstruction sometimes unobtainable. Many surgical and nonsurgical techniques have been prescribed to facilitate the definitive repair. Although some of these techniques proved to be useful, they have their inherent limitations and add another treatment step with all its possible complications and costs. The authors present a new method to address muscle layer repair in 1-stage procedure. It entails using fascial graft obtained from the temporalis muscle fascia or fascia lata, to reconstruct orbicularis oris lip muscle. Seven patients of wide bilateral cleft lip deformity (mean 17 mm) with a mean age of 4.4 months were subjected to single-stage lip reconstruction. After measuring the defect between both lateral muscle segments in front of the premaxilla intraoperatively ensuring that direct muscle repair could not be obtained, a fascial graft was harvested and sutured to both muscle edges. The authors found that, regardless the defect size or premaxilla protrusion, all wide clefts could be reconstructed satisfactorily in 1 stage procedure. No serious postoperative complications have been encountered in the lip or donor areas. Early follow-up reporting of the patients revealed stable repair. However more follow-up is still needed to assess late sequelae. In conclusion, fascial graft muscle repair of wide bilateral cleft lip deformity enables early 1-stage lip reconstruction without tension. The added donor morbidity is minimal and well tolerated.


Changes in endocrine circadian rhythms as markers of physiological and pathological brain aging.
We studied the circadian rhythm of plasma melatonin, growth hormone (GH), prolactin (PRL), adrenocorticotropic hormone (ACTH), and cortisol in 52 mentally healthy old subjects, 35 old demented patients, and 22 clinically healthy young controls. When compared to young controls, the circadian profile of plasma melatonin of old subjects, both demented or not, was clearly flattened, particularly during the night. The selective impairment of nocturnal melatonin secretion was significantly related to both the age and the severity of mental impairment (Mini Mental State Examination [MMSE] score). The PRL and GH circadian profiles were similar in the three groups during the day, but a significant lowering of the values recorded during the night occurred with aging. The impairment of the nocturnal secretion was related to the subjects' age and, for the GH secretory pattern only, also to the MMSE score. The ACTH circadian profile was similar in the three groups studied, even when old subjects exhibited higher ACTH levels throughout the 24 h cycle, compared to young controls. Significantly higher cortisol values at evening- and nighttime occurred in elderly subjects and particularly in the demented group. Both the mean levels and the nadir values of plasma cortisol were positively related to age and negatively to MMSE score. In order to verify the sensitivity of the hypothalamo-pituitary-adrenal (HPA) axis to the steroid feedback, the circadian profile of plasma cortisol was evaluated also after dexamethasone (DXM) administration (1 mg at 23:00 h); the sensitivity of the HPA axis was significantly impaired in old subjects and particularly in the demented ones. These findings suggest that the neuroendocrine alterations already present in physiological aging, due to both anatomical damages and unbalanced central neurotransmitters, are enhanced in senile dementia.


Shifts in the care for patients presenting in primary care with anxiety; stepped collaborative care parameters from more than a decade.
The mental health burden on primary care is substantial and increasing. Anxiety is a major contributor. Stepped collaborative care (SCC) is implemented worldwide to improve patient outcomes, but long term real-world evaluations of SCC do not exist. Using routinely used electronic medical records from more than a decade, we investigated changes in anxiety prevalences, whether physicians made distinction between non-severe and severe anxiety, and whether these groups were referred and treated differently, both non-pharmacologically and pharmacologically. Retrospective assessment of anxiety care parameters recorded by 54 general practitioners between 2003 and 2014, in the electronic medical records of a dynamic population of 49,841-69,413 primary care patients. Substantial shifts in anxiety care parameters have occurred. The prevalence of anxiety symptoms doubled to 0.9% and of anxiety disorders almost tripled to 1.1%. Use of ICPC codes seemed comprehensive and use of instruments to support in anxiety level differentiation increased to 13% of anxiety symptom and 7% of anxiety disorder patients in 2014. Minimal interventions were used more frequently, especially for anxiety symptoms (OR 21 [95% CI 5.1-85]). The antidepressant prescription rates decreased significantly for anxiety symptoms (OR 0.5 [95% CI 0.4-0.8]) and anxiety disorders (OR 0.6 [95% CI 0.4-0.8]). More patients were referred to psychologists and psychiatrists. We found shifts in anxiety care parameters that follow the principles of SCC. Future primary care research should comprehensively assess the use of the SCC range of therapeutic options, tailored to patients with all different anxiety severity levels.


Canada lynx use of burned areas: Conservation implications of changing fire regimes.
A fundamental problem in ecology is forecasting how species will react to major disturbances. As the climate warms, large, frequent, and severe fires are restructuring forested landscapes at large spatial scales, with unknown impacts on imperilled predators. We use the United States federally Threatened Canada lynx as a case study to examine how predators navigate recent large burns, with particular focus on habitat features and the spatial configuration (e.g., distance to edge) that enabled lynx use of these transformed landscapes. We coupled GPS location data of lynx in Washington in an area with several recent large fires and a number of GIS layers of habitat data to develop models of lynx habitat selection in recent burns. Random Forest habitat models showed lynx-selected islands of forest skipped by large fires, residual vegetation, and areas where some trees survived to use newly burned areas. Lynx used burned areas as early as 1 year postfire, which is much earlier than the 2-4 decades postfire previously thought for this predator. These findings are encouraging for predator persistence in the face of fires, but increasingly severe fires or management that reduces postfire residual trees or slow regeneration will likely jeopardize lynx and other predators. Fire management should change to ensure heterogeneity is retained within the footprint of large fires to enable viable predator populations as fire regimes worsen with climate change.


Immune suppression induced by Actinobacillus actinomycetemcomitans: effects on immunoglobulin production by human B cells.
Actinobacillus actinomycetemcomitans produces an immunosuppressive factor (ISF) which has been shown to suppress mitogen- and antigen-induced DNA, RNA, and protein synthesis in human T lymphocytes. In this study, we examined purified A. actinomycetemcomitans ISF for its ability to alter immunoglobulin production by human B cells. The ISF caused a dose-dependent inhibition of pokeweed mitogen (PWM)-induced immunoglobulin G (IgG) and IgM production. Preexposure to ISF was not required to achieve maximal inhibition of immunoglobulin synthesis, as previously observed for its effect on T-cell activation. Nevertheless, the ISF appeared to act by irreversibly affecting the early stages of cell activation. While PWM-induced immunoglobulin production is under the influence of T-regulatory circuits, it appears that the ISF interacts directly with B cells. First, ISF failed to alter either the synthesis of interleukin-2 (IL-2) or the expression of IL-2 receptors on T cells. Second, experiments in which individual purified populations of cells were exposed to ISF, washed, and placed back into tissue culture indicated that when all cells (i.e., T cells, B cells, and monocytes) were exposed to ISF, significant suppression was observed. However, when only one cell population was treated with ISF, suppression of both IgG and IgM synthesis was observed only when the B-cell-enriched population was exposed to ISF. These results in conjunction with our earlier findings suggest that the ISF functions via the activation of a regulatory subpopulation of B lymphocytes, which in turn either directly or indirectly (via suppressor T cells) downregulate both B- and T-cell responsiveness. Furthermore, it is hypothesized that patients who harbor A. actinomycetemcomitans could suffer from local or systemic immune suppression. This suppression may enhance the pathogenicity of A. actinomycetemcomitans itself or that of some other opportunistic organism.


Address and message sequences for the nociceptin receptor: a structure-activity study of nociceptin-(1-13)-peptide amide.
Nociceptin (NC) and some of its fragments as well as nociceptin-(1-13)-peptide amide [NC- (1-13)-NH2] and a series of its analogues were prepared and tested in the mouse vas deferens in an attempt to identify the sequences involved in the activation (message) and in the binding (address) of nociceptin to its receptor. The NC receptor that inhibits the electrically evoked twitches of the mouse vas deferens was demonstrated to be distinct from the delta opioid receptor, since naloxone and Dmt-Tic-OH (a selective delta opioid receptor antagonist) block the delta opioid receptor but have no effect on the nociceptin receptor. Results from structure-activity experiments suggest that (a) the entire sequence of NC may not be required for full biological activities, since NC(1-13)-NH2 is as active as NC; (b) fragments of NC have however to be amidated as in NC(1-13)-NH2 in order to be protected from degradation by proteases; (c) cationic residues (as Arg8,12, Lys9,13) appear to play a functional role, since their replacement with Ala in the sequence of NC(1-13)-NH2 leads to inactivity; (d) the N-terminal tetrapeptide Phe-Gly-Gly-Phe is essential for activity: its full length and flexibility appear to be required for NC receptor activation and/or occupation; (e) Phe4 and not Phe1 appears to be the residue involved in receptor activation, since the replacement of Phe1 with Leu has no effect, while that of Phe4 leads to inactivity. Results summarized in this paper indicate that the structural requirements of NC for occupation and activation of its receptor are different from that of opioids, particularly delta agonists.


Determinants of early antibody responses to COVID-19 mRNA vaccines in a cohort of exposed and naïve healthcare workers.
Two doses of mRNA vaccination have shown >94% efficacy at preventing COVID-19 mostly in naïve adults, but it is not clear if the second dose is needed to maximize effectiveness in those previously exposed to SARS-CoV-2 and what other factors affect responsiveness. We measured IgA, IgG and IgM levels against SARS-CoV-2 spike (S) and nucleocapsid (N) antigens from the wild-type and S from the Alpha, Beta and Gamma variants of concern, after BNT162b2 (Pfizer/BioNTech) or mRNA-1273 (Moderna) vaccination in a cohort of health care workers (N=578). Neutralizing capacity and antibody avidity were evaluated. Data were analyzed in relation to COVID-19 history, comorbidities, vaccine doses, brand and adverse events. Vaccination induced robust IgA and IgG levels against all S antigens. Neutralization capacity and S IgA and IgG levels were higher in mRNA-1273 vaccinees, previously SARS-CoV-2 exposed, particularly if symptomatic, and in those experiencing systemic adverse effects (p<0·05). A second dose in pre-exposed did not increase antibody levels. Smoking and comorbidities were associated with 43% (95% CI, 19-59) and 45% (95% CI, 63-18) lower neutralization, respectively, and 35% (95% CI, 3-57%) and 55% (95% CI, 33-70%) lower antibody levels, respectively. Among fully vaccinated, 6·3% breakthroughs were detected up to 189 days post-vaccination. Among pre-exposed non-vaccinated, 90% were IgG seropositive more than 300 days post-infection. Our data support administering a single-dose in pre-exposed healthy individuals as primary vaccination. However, heterogeneity of responses suggests that personalized recommendations may be necessary depending on COVID-19 history and life-style. Higher mRNA-1273 immunogenicity would be beneficial for those expected to respond worse to vaccination and in face of variants that escape immunity such as Omicron. Persistence of antibody levels in pre-exposed unvaccinated indicates maintenance of immunity up to one year. This work was supported by Institut de Salut Global de Barcelona (ISGlobal) internal funds, in-kind contributions from Hospital Clínic de Barcelona, the Fundació Privada Daniel Bravo Andreu, and European Institute of Innovation and Technology (EIT) Health (grant number 20877), supported by the European Institute of Innovation and Technology, a body of the European Union receiving support from the H2020 Research and Innovation Programme. We acknowledge support from the Spanish Ministry of Science and Innovation and State Research Agency through the "Centro de Excelencia Severo Ochoa 2019-2023" Program (CEX2018-000806-S), and support from the Generalitat de Catalunya through the CERCA Program. L. I. work was supported by PID2019-110810RB-I00 grant from the Spanish Ministry of Science & Innovation. Development of SARS-CoV-2 reagents was partially supported by the National Institute of Allergy and Infectious Diseases Centers of Excellence for Influenza Research and Surveillance (contract number HHSN272201400008C). The funders had no role in study design, data collection and analysis, the decision to publish, or the preparation of the manuscript.


Transcriptome divergence during leaf development in two contrasting switchgrass (Panicum virgatum L.) cultivars.
The genetics and responses to biotic stressors of tetraploid switchgrass (Panicum virgatum L.) lowland cultivar 'Kanlow' and upland cultivar Summer are distinct and can be exploited for trait improvement. In general, there is a paucity of data on the basal differences in transcription across tissue developmental times for switchgrass cultivars. Here, the changes in basal and temporal expression of genes related to leaf functions were evaluated for greenhouse grown 'Kanlow', and 'Summer' plants. Three biological replicates of the 4th leaf pooled from 15 plants per replicate were harvested at regular intervals beginning from leaf emergence through senescence. Increases and decreases in leaf chlorophyll and N content were similar for both cultivars. Likewise, multidimensional scaling (MDS) analysis indicated both cultivar-independent and cultivar-specific gene expression. Cultivar-independent genes and gene-networks included those associated with leaf function, such as growth/senescence, carbon/nitrogen assimilation, photosynthesis, chlorophyll biosynthesis, and chlorophyll degradation. However, many genes encoding nucleotide-binding leucine rich repeat (NB-LRRs) proteins and wall-bound kinases associated with detecting and responding to environmental signals were differentially expressed. Several of these belonged to unique cultivar-specific gene co-expression networks. Analysis of genomic resequencing data provided several examples of NB-LRRs genes that were not expressed and/or apparently absent in the genomes of Summer plants. It is plausible that cultivar (ecotype)-specific genes and gene-networks could be one of the drivers for the documented differences in responses to leaf-borne pathogens between these two cultivars. Incorporating broad resistance to plant pathogens in elite switchgrass germplasm could improve sustainability of biomass production under low-input conditions.


It matters how and when you ask: self-reported race/ethnicity of incoming law students.
The high-stakes nature of law school testing and admissions puts a premium on the student data presented to admissions committees, such as essays, academic and work history, and student background characteristics including race/ethnicity. 4,472 law school-bound students self-identified their race/ethnicity using (a) a mutually exclusive "choose one" format during registration for the law school admissions test, and (b) an elaborated "check-all-that-apply" format as part of a national survey administered during the first weeks at their chosen law school. Student multiraciality that was masked by the first assessment was associated with self-reported ethnic identity, discrimination experience, intergroup contact, race-related attitudes, academic performance, and trait ratings, as compared to monoracial majority students. A different profile of findings was observed across these constructs when multiracial students were compared to monoracial majority students, to monoracial minority students, and within group. These correlates also predicted the likelihood of changing identification across the two assessment contexts. These findings support the continued study of specific combinations of multiracial groups, fluidity of multiracial identities, and context effects that influence race/ethnicity self-categorizations.


Recent trends in the process of stratification.
Using the 14 annual cross-sections from the General Social Survey, we specify a "basic model" of attainment and describe the year-by-year fluctuations in its parameters. The results are partially consistent with theories describing the gradual growth of universalistic patterns of stratification and mobility. Under a linear model of educational achievement, we find that the direct effects of race are weakening and the returns to class-based advantages are declining in tandem. The contours of the socioeconomic "gender gap" are also changing in important ways, with the male intercept declining at a rapid pace and the female term registering small and insignificant year-by-year gains. At the same time, the returns to experience and schooling are increasing for men, whereas the corresponding returns for women have remained stable over the 15-year period. This pattern of interaction effects implies that the size of the gender gap varies over time and across different population groups.


[Effect of lidocaine administration mode on decreasing injection pain caused by propofol].
Pain is a well known complication of propofol injection. Many methods are described to reduce it but often empirical ways are used. In this study we attempt to determine the effects of premixing propofol with lidocaine or to preinjecting lidocaine in a hand vein in combination with using a tourniquet before we applicated propofol. Our study shows that both ways are able to reduce the injection pain but premixing with lidocaine 0.05% is less effective than giving a bolus of lidocaine before the propofol injection.


Structural elucidation of cisoid and transoid cyclization pathways of a sesquiterpene synthase using 2-fluorofarnesyl diphosphates.
Sesquiterpene skeletal complexity in nature originates from the enzyme-catalyzed ionization of (trans,trans)-farnesyl diphosphate (FPP) (1a) and subsequent cyclization along either 2,3-transoid or 2,3-cisoid farnesyl cation pathways. Tobacco 5-epi-aristolochene synthase (TEAS), a transoid synthase, produces cisoid products as a component of its minor product spectrum. To investigate the cryptic cisoid cyclization pathway in TEAS, we employed (cis,trans)-FPP (1b) as an alternative substrate. Strikingly, TEAS was catalytically robust in the enzymatic conversion of (cis,trans)-FPP (1b) to exclusively (>/=99.5%) cisoid products. Further, crystallographic characterization of wild-type TEAS and a catalytically promiscuous mutant (M4 TEAS) with 2-fluoro analogues of both all-trans FPP (1a) and (cis,trans)-FPP (1b) revealed binding modes consistent with preorganization of the farnesyl chain. These results provide a structural glimpse into both cisoid and transoid cyclization pathways efficiently templated by a single enzyme active site, consistent with the recently elucidated stereochemistry of the cisoid products. Further, computational studies using density functional theory calculations reveal concerted, highly asynchronous cyclization pathways leading to the major cisoid cyclization products. The implications of these discoveries for expanded sesquiterpene diversity in nature are discussed.


Heredity and pituitary response to exercise-related stress in trained men.
To evaluate the role of heredity in the pituitary responses to exercise-related stress, serum ACTH, beta-endorphin, cortisol, GH, and PRL responses to a thirty-minute treadmill exercise at individual anaerobic threshold were evaluated in nine pairs of male monozygotic twin athletes. Hormone evaluations were performed before (-30, -15, 0 pre) and after exercise (0 post, + 15, + 30, + 45, + 60, and + 90 min). The intraclass correlation coefficient (expression of within-pair resemblance) was computed for each hormone before and after exercise as area under curves (AUC), absolute values, and percentage of variation, respectively. The exercise-related stress condition induced a significant increase for all evaluated hormones before (anticipatory response) and/or after exercise. As new data, we observed: 1) A significant within-pair resemblance for exercise-related GH and PRL increase (AUCs and/or absolute values), and for the percentage of variation of cortisol, and 2) the lack of significant resemblance for the observed increase of ACTH, cortisol and absolute beta-endorphin serum concentration. This first co-twin control study supports the hypothesis that, in trained men, there are probably different relative roles for the influence of genetic factors on the pituitary hormones involved in physiological adaptation to exercise-related stress. Furthermore, our findings justify further investigations into this topic.


Design of an efficient medium for heterologous protein production in Yarrowia lipolytica: case of human interferon alpha 2b.
The non conventional yeast Yarrowia lipolytica has aroused a strong industrial interest for heterologous protein production. However most of the studies describing recombinant protein production by this yeast rely on the use of complex media, such media are not convenient for large scale production particularly for products intended for pharmaceutical applications. In addition medium composition can also affect the production yield. Hence it is necessary to design an efficient medium for therapeutic protein expression by this host. Five different media, including four minimal media and a complex medium, were assessed in shake flasks for the production of human interferon alpha 2b (hIFN α2b) by Y. lipolytica under the control of POX2 promoter inducible with oleic acid. The chemically defined medium SM4 formulated by Invitrogen for Pichia pastoris growth was the most suitable. Using statistical experimental design this medium was further optimized. The selected minimal medium consisting in SM4 supplemented with 10 mg/l FeCl₃, 1 g/l glutamate, 5 ml/l PTM1 (Pichia Trace Metals) solution and a vitamin solution composed of myo-inositol, thiamin and biotin was called GNY medium. Compared to shake flask, bioreactor culture in GNY medium resulted in 416-fold increase of hIFN α2b production and 2-fold increase of the biological activity. Furthermore, SM4 enrichment with 5 ml/l PTM1 solution contributed to protect hIFN α2b against the degradation by the 28 kDa protease identified by zymography gel in culture supernatant. The screening of the inhibitory effect of the trace elements present in PTM1 solution on the activity of this protease was achieved using a Box-Behnken design. Statistical data analysis showed that FeCl₃ and MnSO₄ had the most inhibitory effect. We have designed an efficient medium for large scale production of heterologous proteins by Y. lipolytica. The optimized medium GNY is suitable for the production of hIFN α2b with the advantage that no complex nitrogen sources with non-defined composition were required.


[Biochemistry of the development cycle of Triatoma infestans (vinchuca). X. Hemolymph lipoproteins of females].
A lipoprotein of high density (HDL) and three of very high density (VHDL-I, VHDL-f and VHDL-II) were separated by ultracentrifugation from T. infestans female hemolymph. Lipids were mainly transported by HDL, whereas VHDL-II presented the highest protein content. In all the lipoproteins, 1,2 and 1,3-diacylglycerols, triacylglycerols, free fatty acids, cholesterol, cholesterol esters and hydrocarbons, were present. Phosphatidylcholine and phosphatidylethanolamine were also identified. The main lipids were represented by phospholipids, 1,2 and 1,3-diacylglycerols and hydrocarbons. All lipoproteins were delipidated to study the corresponding apolipoproteins. They were examined by SDS-polyacrylamide gel electrophoresis in the presence of 2-mercaptoethanol. Apo-HDL was separated into four intense polypeptide bands of approximate MW 19,000; 45,000; 86,000 and 200,000. Apo-VHDL-I was fractionated into three polypeptide bands--a major one of MW 18,500 and two minor ones of 28,000 and 45,000. The apolipoproteins belonging to VHDL-f that only appeared in females, were separated into 10 bands; the major ones corresponded to MW of 58,000, 86,000 and 160,000. In these apolipoproteins, the specimens of 58,000 and 160,000 showed positive carbohydrate reaction. Yet, in the apo-VHDL-II the most intense protein subunits primarily corresponded to bands of MW 160,000 and 86,000. Apparently, the four lipoproteins would share two polypeptide chains.


The Stat3-activating Tyk2 V678F mutant does not up-regulate signaling through the type I interferon receptor but confers ligand hypersensitivity to a homodimeric receptor.
Tyk2 is a Jak family member involved in cytokine signaling through heterodimeric-type receptors. Here, we analyzed the impact of the Val(678)-to-Phe substitution on Tyk2 functioning. This mutation is homologous to the Jak2 Val(617)-to-Phe mutation, implicated in myeloproliferative disorders. We studied ligand-independent and ligand-dependent Jak/Stat signaling in cells expressing Tyk2 V678F. Moreover, the effect of Tyk2 V678F was monitored in the context of the native heterodimeric interferon alpha receptor and in the context of a homodimeric receptor chimera, EpoR/R1, containing the ectodomain of the erythropoietin receptor. We show that Tyk2 V678F has increased catalytic potential in vivo and in vitro and more so when it is anchored to the homodimeric receptor. Tyk2 V678F leads to constitutive Stat3 phosphorylation but has no notable effect on the canonical interferon alpha-induced signaling. However, if anchored to the homodimeric EpoR/R1, the mutant confers to the cell increased sensitivity to erythropoietin. Thus, despite the catalytic gain of function of Tyk2 V678F, the effect on ligand-induced signaling is manifest only when two mutant enzymes are juxtaposed via the homodimeric receptor.


The orphan nuclear receptor SHP inhibits agonist-dependent transcriptional activity of estrogen receptors ERalpha and ERbeta.
SHP (short heterodimer partner) is an unusual orphan nuclear receptor that contains a putative ligand-binding domain but lacks a conserved DNA-binding domain. Although no conventional receptor function has yet been identified, SHP has been proposed to act as a negative regulator of nuclear receptor signaling pathways, because it interacts with and inhibits DNA binding and transcriptional activity of various nonsteroid receptors, including thyroid hormone and retinoid receptors. We show here that SHP interacts directly with agonist-bound estrogen receptors, ERalpha and ERbeta, and inhibits ER-mediated transcriptional activation. SHP specifically targets the ligand-regulated activation domain AF-2 and competes for binding of coactivators such as TIF2. Thus, SHP may represent a new category of negative coregulators for ligand-activated nuclear receptors. SHP mRNA is widely expressed in rat tissues including certain estrogen target tissues, and subcellular localization studies demonstrate that SHP is a nuclear protein, suggesting a biological significance of the SHP interactions with ERs. Taken together, these results identify ERs as novel SHP targets and suggest that competition for coactivator-binding is a novel mechanism by which SHP may inhibit nuclear receptor activation.


The relationship sabotage scale: an evaluation of factor analyses and constructive validity.
Some individuals are no longer entering romantic relationships, others move through relationships too quickly searching for "the one" and making quick assessments of their romantic partners, while others stay in their relationships but "check out" or do not work on their issues. These are conclusions from two studies: (1) an interview with psychologists who specialise in relationship therapy, and (2) an analysis of individuals' lived experiences of relationships. The concept of relationship sabotage can explain these phenomena. However, presently, there is no instrument to conceptualise and empirically measure how people continue to employ self-defeating attitudes and behaviors in (and out) of relationships to impede success, or withdraw effort, and justify failure. A series of three studies (involving a total of 1365 English speaking individuals of diverse gender orientation, sexual orientation, and cultural background, with relationship sabotage experience) were conceptualized for the current project to fill the need for scale development and to build empirical evidence on the topic of self-sabotage in romantic relationships. The scale was developed over two studies using exploratory factor analysis and one-congeneric model analyses. The third study, using confirmatory factor analysis, confirmed the final structure for the Relationship Sabotage Scale (RSS), which contains 12 items and three factors: defensiveness, trust difficulty, and lack of relationship skills. Constructive validity analyses were also conducted. The RSS is a brief scale that provides conclusive information about individual patterns in relationships. Findings using this scale can offer explanations regarding the reasons that individuals engage in destructive behaviours from one relationship to the next. Investigations should continue to test a model for sabotage in romantic relationships using the developed scale and other factors such as relationship diferences and insecure attachment. More specifically, this measure can be used to understand mediator constructs of relational outcomes within the attachment framework to explain relationship dissolution and work towards relationship maintenance.


International consultation by United States nurses.
Two sets of data were used in this exploratory/descriptive study of U.S. nurses who have engaged in international consultation during the past 7 years. The first set consisted of the responses to a 12-page questionnaire which was completed by 93 informants, while the second set consisted of the content analysis of 25 interviews. Findings included a demographic profile of the consultant, information about the client, type of advice given, motivation for engaging in international consultation, and ways in which advice was adapted to make it culturally relevant and effective in its context.


Unsupervised iterative detection of land mines in highly cluttered environments.
An unsupervised iterative scheme is proposed for land mine detection in heavily cluttered scenes. This scheme is based on iterating hybrid multispectral filters that consist of a decorrelating linear transform coupled with a nonlinear morphological detector. Detections extracted from the first pass are used to improve results in subsequent iterations. The procedure stops after a predetermined number of iterations. The proposed scheme addresses several weaknesses associated with previous adaptations of morphological approaches to land mine detection. Improvement in detection performance, robustness with respect to clutter inhomogeneities, a completely unsupervised operation, and computational efficiency are the main highlights of the method. Experimental results reveal excellent performance.


The community medicine-primary care connection.
Community medicine is defined as an academic discipline, the practice of which addresses the identification and solution of health problems in population groups and emphasizes such disciplines as epidemiology and biostatistics and behavioral and management sciences in relation to their bearing on problems of health care delivery and environmental health. The essential components of a community-based system of medical care are highlighted. The place of primary care in that system is discussed and the contributions that community medicine can make toward enhancing primary care within the community-based system of medical care are outlined.


A Simple Representation of Three-Dimensional Molecular Structure.
Statistical and machine learning approaches predict drug-to-target relationships from 2D small-molecule topology patterns. One might expect 3D information to improve these calculations. Here we apply the logic of the extended connectivity fingerprint (ECFP) to develop a rapid, alignment-invariant 3D representation of molecular conformers, the extended three-dimensional fingerprint (E3FP). By integrating E3FP with the similarity ensemble approach (SEA), we achieve higher precision-recall performance relative to SEA with ECFP on ChEMBL20 and equivalent receiver operating characteristic performance. We identify classes of molecules for which E3FP is a better predictor of similarity in bioactivity than is ECFP. Finally, we report novel drug-to-target binding predictions inaccessible by 2D fingerprints and confirm three of them experimentally with ligand efficiencies from 0.442-0.637 kcal/mol/heavy atom.


Penumbral Rescue by normobaric O = O administration in patients with ischemic stroke and target mismatch proFile (PROOF): Study protocol of a phase IIb trial.
Oxygen is essential for cellular energy metabolism. Neurons are particularly vulnerable to hypoxia. Increasing oxygen supply shortly after stroke onset could preserve the ischemic penumbra until revascularization occurs. PROOF investigates the use of normobaric oxygen (NBO) therapy within 6 h of symptom onset/notice for brain-protective bridging until endovascular revascularization of acute intracranial anterior-circulation occlusion. Randomized (1:1), standard treatment-controlled, open-label, blinded endpoint, multicenter adaptive phase IIb trial. Primary outcome is ischemic core growth (mL) from baseline to 24 h (intention-to-treat analysis). Secondary efficacy outcomes include change in NIHSS from baseline to 24 h, mRS at 90 days, cognitive and emotional function, and quality of life. Safety outcomes include mortality, intracranial hemorrhage, and respiratory failure. Exploratory analyses of imaging and blood biomarkers will be conducted. Using an adaptive design with interim analysis at 80 patients per arm, up to 456 participants (228 per arm) would be needed for 80% power (one-sided alpha 0.05) to detect a mean reduction of ischemic core growth by 6.68 mL, assuming 21.4 mL standard deviation. By enrolling endovascular thrombectomy candidates in an early time window, the trial replicates insights from preclinical studies in which NBO showed beneficial effects, namely early initiation of near 100% inspired oxygen during short temporary ischemia. Primary outcome assessment at 24 h on follow-up imaging reduces variability due to withdrawal of care and early clinical confounders such as delayed extubation and aspiration pneumonia. ClinicalTrials.gov: NCT03500939; EudraCT: 2017-001355-31.


Early Birds by Light at Night: Effects of Light Color and Intensity on Daily Activity Patterns in Blue Tits.
Artificial light at night disturbs the daily rhythms of many organisms. To what extent this disturbance depends on the intensity and spectral composition of light remain obscure. Here, we measured daily activity patterns of captive blue tits ( Cyanistes caeruleus) exposed to similar intensities of green, red, or white light at night. Birds advanced their onset of activity in the morning under all light colors but more under red and white light than under green light. Offset of activity was slightly delayed in all light colors. The total activity over a 24-h period did not change but birds moved a part of their daily activity into the night. Since the effect of red and white lights are comparable, we tested the influence of light intensity in a follow-up experiment, where we compared the activity of the birds under different intensities of green and white light only. While in the higher range of intensities, the effects of white and green light were comparable; at lower intensities, green light had a less disturbing effect as compared with white light on daily rhythms in blue tits. Our results show that the extent of this disturbance can be mitigated by modulating the spectral characteristics and intensity of outdoor lighting, which is now feasible through the use of LED lighting.


Towards improved HIV-microbicide activity through the co-encapsulation of NRTI drugs in biocompatible metal organic framework nanocarriers.
The efficacy of the routinely used anti-HIV (Human Immunodeficiency Virus) therapy based on nucleoside reverse transcriptase inhibitors (NRTIs) is limited by the poor cellular uptake of the active triphosphorylated metabolites and the low efficiency of intracellular phosphorylation of their prodrugs. Nanoparticles of iron(iii) polycarboxylate Metal-Organic Frameworks (nanoMOFs) are promising drug nanocarriers. In this study, two active triphosphorylated NRTIs, azidothymidine triphosphate (AZT-Tp) and lamivudine triphosphate (3TC-Tp), were successfully co-encapsulated into the biocompatible mesoporous iron(iii) trimesate MIL-100(Fe) nanoMOF in order to improve anti-HIV therapies. The drug loaded nanoMOFs could be stored for up to 2-months and reconstituted after freeze drying, retaining similar physicochemical properties. Their antiretroviral activity was evidenced in vitro on monocyte-derived macrophages experimentally infected with HIV, making these co-encapsulated nanosystems excellent HIV-microbicide candidates.


In situ lobular carcinoma of the breast.
Nineteen patients who did not have mastectomy for in situ lobular carcinoma that was diagnosed by excisional biopsy were followed up for a period of seven to 21 years. In two patients, infiltrating carcinoma developed; each had mastectomies. They were followed up for 20 and 21 years. A third patient who previously had a mastectomy for infiltrating lobular carcinoma and who was being followed up for in situ lobular carcinoma in the contralateral breast died of metastatic disease. The remaining patients were found to be free of disease. These data support the concept that a small percentage (11%) of in situ lesions will progress to invasive tumors. Although mastectomy would seem to be the most prudent course, prolonged disease-free intervals were seen in patients who did not have mastectomy, suggesting close observation to be an alternative approach to this problem.


Correlation between efficacy endpoints in patients with advanced biliary tract cancer treated by systemic second-line therapies: Analysis of aggregated data from a systematic literature review.
Overall response rate (ORR) and progression-free survival (PFS) are commonly used as endpoints for phase II trials. However, the ultimate goal is to bring survival benefit for the patients. We aimed to assess the correlation between ORR, median PFS and overall survival (OS) using aggregated data from a systematic review of second-line systemic therapies in advanced biliary tract cancer (BTC) patients. Clinical trials were identified using Medline database. Studies only enrolling patients with gallbladder cancer were not included. Searches were last updated on April 2020. Eligible studies reported OS, PFS and/or ORR data for BTC patients receiving second-line systemic chemotherapy. Pearson weighted correlation was estimated between OS and ORR and between median OS and PFS. Seventeen studies (N = 912 patients) were selected. There was a strong correlation between median OS/ORR in the overall analysis (r = 0.85; P < 0.0001), both for trials with chemotherapy (r = 0.90; P=0.0152) and targeted therapy (r = 0.84; P = 0.0006). In contrast, the correlation between median OS/PFS, albeit significant in the overall analysis (r = 0.80; P < 0.0001), remained significant only for targeted therapies in the sensitivity analysis (r = 0.83; P = 0.0009). ORR seems to be a more interesting intermediate endpoint in BTC in second line for both chemotherapy and targeted therapies, while PFS may be relevant only for targeted therapy trials. Further well-designed studies for surrogacy evaluation should be performed to confirm this observation.


Immobilization of glutaminase enzyme from Hypocria jecorina on polyacrylic acid: preparation and biochemical characterization.
L-glutaminase enzyme produced from Hypocrea jecorina pure culture and polyacrylic acid (PAA) in the presence (Cu2+) ions were composed the ternary complex at pH 7. The properties of free and immobilized enzyme were defined. The effect of various factors such as pH, temperature, heat, and storage stability on immobilized enzyme were investigated. The properties of immobilized enzyme were investigated and compared to those of free enzyme. Optimum pH and temperature of both enzyme were determined to be 8.0 and 50°C, respectively. Kinetic parameters of the immobilized enzyme (Km and Vmax values) were also determined as 0.38 mM of the Km and 10.9 U/L of the Vmax. No drastic change was observed in the Km and Vmax values. Thermal and storage stability experiments were carried out. The thermal stability studies indicated that the immobilization process tends to stabilize the enzyme.


Assessment of quantitative computed tomographic cerebral perfusion imaging with H2(15)O positron emission tomography.
Assessment of quantitative cerebral blood flow on a conventional fast CT machine without the use of specialized equipment may be valuable in the investigation of acute stroke and head injury. We aimed to compare a single slice CT perfusion sequence with H2(15)O positron emission tomography using the sagittal sinus as an input function, a method that avoids unnecessary orbital irradiation. Eight patients were studied, two patients with gliomas, and six with arteriovenous malformations. The dynamic CT perfusion sequence was performed by acquiring the same 10 mm slice 10 times over 30 sec during a 50 ml bolus of intravenous contrast medium given at a rate of 7.5 ml sec-1 using a power injector. The CT perfusion studies were completed without complication. Co-registration was sub-optimal in one patient. Overall the correlation between the two methodologies was encouraging with an average r2 value of 0.524 for individual analyses. When two patients with high flow arteriovenous malformations were excluded the average r2 value increased to 0.640. The results of this CT perfusion methodology are encouraging. Having shown its feasibility, further studies in conditions with lower rates of cerebral blood flow are warranted.


Organic Nitrate Additive for High-Rate and Large-Capacity Lithium Metal Anode in Carbonate Electrolyte.
Lithium nitrate has been widely used to improve the interfacial stability of Li metal anode in ether electrolyte. However, the low solubility limits its application in carbonate electrolytes for high-voltage Li metal batteries. Herein, nitrated polycaprolactone (PCL-ONO2 ), which is prepared via the acylation of polycaprolactone diol (PCL-diol) followed by the grafting of nitrate group, has been proposed as an electrolyte additive to introduce high-concentration NO3 - into carbonate electrolytes for the first time. The theoretical calculations and X-ray photoelectron spectroscopy depth profiling demonstrate that the PCL-ONO2 additive preferentially reacts with Li metal and in situ constructs a stable dual-layered solid electrolyte interphase film, presenting an inner nitride-rich layer and an outer flexible PCL-based layer on the surface of Li metal anode. As a result, the Li metal anode delivers an impressive long-term cycling performance over 1400 h at an elevated area capacity of 10.0 mAh cm-2 and an ultrahigh current density of 10.0 mA cm-2 in the Li symmetrical cells. Moreover, the PCL-ONO2 additive enables the full cells constructed by coupling high-loading LiFePO4 (20.0 mg cm-2 ) or LiNi0.5 Co0.2 Mn0.3 (16.5 mg cm-2 ) cathode and thin Li metal anode (≈50 µm) to demonstrate greatly improved cycling stability and rate capability.


[Ketoconazole in the control of arterial hypertension in Cushing's syndrome].
To determine the usefulness of ketoconazole for the control of arterial hypertension (AH) in Cushing syndrome (CS) as temporary treatment. Fifteen cases of CS were collected (eleven cases of Cushing disease, two cases of ectopic secretion of ACTH, one case of adrenal adenoma, and one case of adrenal carcinoma). The clinical characteristics as well as laboratory data of patients with AH and the response to therapy were studied. Six patients (40%) had AH. A significant difference was observed of an older age, a higher frequency of association with diabetes mellitus and a higher 24 hour free urine cortisol (FUC) for patients with AH compared with non hypertensive patients. Ketoconazole was efficient for controlling AH in five cases, and in all of them the return to normal levels of 24 hour FUC was achieved. A failure of AH control under treatment with ketoconazole occurred in the only case of adrenal carcinoma. There was no significant secondary adverse reaction to ketoconazole. Ketoconazole is an efficient drug for the control of AH in CS and is well tolerated. In our series, the return to normal levels of FUC was associated with control of AH.


Interventions to prevent and treat corticosteroid-induced osteoporosis and prevent osteoporotic fractures in Duchenne muscular dystrophy.
Corticosteroid treatment is considered the 'gold standard' for Duchenne muscular dystrophy (DMD); however, it is also known to induce osteoporosis and thus increase the risk of vertebral fragility fractures. Good practice in the care of those with DMD requires prevention of these adverse effects. Treatments to increase bone mineral density include bisphosphonates and vitamin D and calcium supplements, and in adolescents with pubertal delay, testosterone. Bone health management is an important part of lifelong care for patients with DMD. To assess the effects of interventions to prevent or treat osteoporosis in children and adults with DMD taking long-term corticosteroids; to assess the effects of these interventions on the frequency of vertebral fragility fractures and long-bone fractures, and on quality of life; and to assess adverse events. On 12 September 2016, we searched the Cochrane Neuromuscular Specialised Register, CENTRAL, MEDLINE, Embase, and CINAHL Plus to identify potentially eligible trials. We also searched the Web of Science ISI Proceedings (2001 to September 2016) and three clinical trials registries to identify unpublished studies and ongoing trials. We contacted correspondence authors of the included studies in the review to obtain information on unpublished studies or work in progress. We considered for inclusion in the review randomised controlled trials (RCTs) and quasi-RCTs involving any bone health intervention for corticosteroid-induced osteoporosis and fragility fractures in children, adolescents, and adults with a confirmed diagnosis of DMD. The interventions might have included oral and intravenous bisphosphonates, vitamin D supplements, calcium supplements, dietary calcium, testosterone, and weight-bearing activity. Two review authors independently assessed reports and selected potential studies for inclusion, following standard Cochrane methodology. We contacted study authors to obtain further information for clarification on published work, unpublished studies, and work in progress. We identified 18 potential studies, of which two, currently reported only as abstracts, met the inclusion criteria for this review. Too little information was available for us to present full results or adequately assess risk of bias. The participants were children aged five to 15 years with DMD, ambulant and non-ambulant. The interventions were risedronate versus no treatment in one trial (13 participants) and whole-body vibration versus a placebo device in the second (21 participants). Both studies reported improved bone mineral density with the active treatments, with no improvement in the control groups, but the abstracts did not compare treatment and control conditions. All children tolerated whole-body vibration treatment. No study provided information on adverse events. Two studies are ongoing: one investigating whole-body vibration, the other investigating zoledronic acid. We know of no high-quality evidence from RCTs to guide use of treatments to prevent or treat corticosteroid-induced osteoporosis and reduce the risk of fragility fractures in children and adults with DMD; only limited results from two trials reported in abstracts were available. We await formal trial reports. Findings from two ongoing relevant studies and two trials, for which only abstracts are available, will be important in future updates of this review.


Vasopressin and oxytocin secretion in chronically hyposmolar rats.
Neurohypophysial secretion of vasopressin (AVP) and oxytocin (OT) was studied in rats maintained under hyposmolar conditions for 10-24 days. Graded intravenous infusions of hypertonic saline solutions had no consistent effect on plasma AVP and OT levels until plasma sodium concentration ([Na+]) exceeded 130 mM, after which levels of both hormones increased as an exponential function of plasma [Na+]. Detectable increases in plasma AVP and OT began at significantly lower plasma [Na+] in hyposmolar rats than in normosmolar control rats (10.8 mM lower for AVP and 18.4 mM lower for OT). AVP and OT secretion in hyposmolar rats was also markedly blunted in response to nonosmotic stimuli, including acute and chronic hypovolemia and systemic administration of cholecystokinin. Cessation of 1-desamino-8-D-arginine vasopressin-induced antidiuresis resulted in an appropriately rapid correction of plasma [Na+] to normal levels within 24 h. Consequently, although chronic hyposmolarity caused a moderate downward resetting of the osmotic thresholds for AVP and OT secretion, it did not cause sustained deficits in osmoregulation. These results suggest that osmoreceptor activity is regulated to maintain extracellular fluid and plasma osmolality within narrow absolute ranges rather than responding to relative changes in osmolality.


Screening-engineered field-effect solar cells.
Photovoltaics (PV) are a promising source of clean renewable energy, but current technologies face a cost-to-efficiency trade-off that has slowed widespread implementation. We have developed a PV architecture-screening-engineered field-effect photovoltaics (SFPV)-that in principle enables fabrication of low-cost, high efficiency PV from virtually any semiconductor, including the promising but hard-to-dope metal oxides, sulfides, and phosphides. Prototype SFPV devices have been constructed and are found to operate successfully in accord with model predictions.


Reasons for hospitalisation in youth with type 1 diabetes, 2010-2019.
To determine the incidence of hospitalisation for all diagnoses among Australian youth with type 1 diabetes. We linked Australians aged under 20 years with type 1 diabetes on the National Diabetes Services Scheme (n = 45,685) to hospital admission data from 2010 to 2019. We determined relative risks (RR) of hospitalisation among those with type 1 diabetes in the states of Victoria and Queensland (n = 21,898) compared to the general population for 2010-2017 using Poisson regression. Australian youth with type 1 diabetes had increased risk for almost all reasons for hospitalisation compared to the general population, especially infections such as anogenital herpesviral infections (RR 54.83, 95% CI 33.21-90.53), and mental health disorders including personality disorders (RR 9.70, 95% CI 8.02-11.72). Among those with type 1 diabetes, over 60% of hospitalisations were directly related to diabetes, almost half of which were for ketoacidosis. Approximately 15% of ketoacidosis admissions occurred within 3 months of diabetes diagnosis. One quarter of those with admissions for ketoacidosis were readmitted for ketoacidosis within 12 months. Residence in areas of high socio-economic disadvantage was an independent risk factor for admission and readmission for ketoacidosis. Youth with type 1 diabetes are susceptible to a wide range of complications. Clinicians should consider screening and prevention for conditions such as infections and mental health disorders. Targeted support and education around glycaemic management should be considered in those at high risk for ketoacidosis admission including those living in areas of high socio-economic disadvantage.


Methylenendioxyamphetamine produces serotonin nerve terminal loss and diminished behavioural and neurochemical responses to the antidepressant fluoxetine.
The effect of prior exposure to methylenedioxyamphetamine (MDA) on behavioural and neurochemical responses to fluoxetine were assessed in a rat model of antidepressant action. MDA (7.5 mg/kg, i.p.) was administered to rats twice daily for 4 consecutive days, and 4 weeks later the behavioural effect of fluoxetine (5 or 20 mg/kg; i.p. x 3) was examined in the modified rat forced-swimming test. In addition, the ability of fluoxetine to reduce serotonin (5-HT) metabolism was measured as an index of its efficacy in inhibiting 5-HT reuptake in vivo. In vehicle-treated rats, fluoxetine (5 and 20 mg/kg) produced a characteristic increase in swimming behaviour in the forced-swimming test. In contrast, fluoxetine-induced swimming was markedly attenuated in MDA-treated rats. MDA pretreatment resulted in 5-HT nerve terminal degeneration, indicated by reduced 5-HT and 5-HIAA concentrations in the frontal cortex, amygdala and hippocampus, and reduced [3H]paroxetine binding in the frontal cortex. In vehicle-treated rats, fluoxetine (5 and 20 mg/kg) decreased 5-HT metabolism (5-HIAA : 5-HT ratio) in the frontal cortex, amygdala and hippocampus. MDA pretreatment attenuated the ability of fluoxetine to reduce 5-HT metabolism in all brain regions examined. These findings are the first to demonstrate that prior exposure to the methylenedioxy-substituted amphetamine MDA results in diminished responsiveness to the antidepressant fluoxetine.


Linear DNA low efficiency transfection by liposome can be improved by the use of cationic lipid as charge neutralizer.
A plasmid expressing the beta-galactosidase enzyme was used to transfect Vero cells in order to evaluate the efficiency of a liposome-mediated transfection by circular and linear DNA. The results obtained showed a low rate of transfection by linear DNA:liposome complexes. To explore whether the structure of the complexes was interfering with the transfection, atomic force microscopy (AFM) was used. It has confirmed the difference between the linear and circular condensates: whereas the circular DNA:liposome complexes presented compact spherical or cylindrical structures of about 100-800 nm, the linear DNA showed pearl necklace-like structures, with pearls varying from 250 to 400 nm. On the basis of the theory proposed by Kuhn et al. (1999), low concentrations of cationic amphihile were used to neutralize or reverse the DNA charge in order to improve the transfection efficiency of the linear DNA. Using this method, we were able to obtain the expression of the transgene without an associated toxicity observed with the linear DNA liposome delivery.


Surgery of the parathyroid glands.
Surgical procedures involving the parathyroid glands pose special problems. Careful attention to preoperative rehydration, control of hypercalcemia, and evaluation of renal function are mandatory. Intraoperative management is usually uncomplicated. Severe hypocalcemia may complicate the postoperative period, especially if severe bone disease is present.


Hydroxyl functionalized polytriazole-co-polyoxadiazole as substrates for forward osmosis membranes.
Hydroxyl functionalized polytriazole-co-polyoxadiazole (PTA-POD) copolymers have been synthesized and cast as promising highly thermally stable, chemically resistant, and antiorganic/biological fouling porous substrates for the fabrication of thin-film composite (TFC) forward osmosis (FO) membranes. The roles of PTA/POD ratios in the membrane substrates, TFC layers, and FO membrane performance have been investigated. This study demonstrates that the substrate fabricated from the copolymer containing 40 mol % PTA is optimal for the TFC membranes. Compared to the POD-TFC membrane, the 40 mol % PTA-TFC membrane exhibits a remarkable decrease in structural parameter (S) of more than 3.3 times. In addition, the 40 mol % PTA-TFC membrane is characterized by high water fluxes of 24.9 LMH and 47.2 LMH using 1 M NaCl as the draw solution and DI water as the feed under FO and pressure retarded osmosis (PRO) modes, respectively. Compared to a polysulfone (PSU) supported TFC-FO membrane under similar fabrication conditions, the 40% mol PTA-TFC membrane shows better FO performance and enhanced antifouling properties on the support (lower protein binding propensity and improved bacterial inhibition). Moreover, the performance of the 40 mol % PTA supported TFC-FO membrane can be improved to 37.5 LMH (FO mode)/78.4 LMH (PRO mode) and potentially higher by optimizing the support morphology, the TFC formation, and the post-treatment process. Hence, the use of newly developed hydroxyl functionalized polytriazole-co-polyoxadiazole copolymers may open up a new class of material for FO processes.


Oxidative stress and mitochondrial functions in the intestinal Caco-2/15 cell line.
Although mitochondrial dysfunction and oxidative stress are central mechanisms in various pathological conditions, they have not been extensively studied in the gastrointestinal tract, which is known to be constantly exposed to luminal oxidants from ingested foods. Key among these is the simultaneous consumption of iron salts and ascorbic acid, which can cause oxidative damage to biomolecules. The objective of the present work was to evaluate how iron-ascorbate (FE/ASC)-mediated lipid peroxidation affects mitochondrion functioning in Caco-2/15 cells. Our results show that treatment of Caco-2/15 cells with FE/ASC (0.2 mM/2 mM) (1) increased malondialdehyde levels assessed by HPLC; (2) reduced ATP production noted by luminescence assay; (3) provoked dysregulation of mitochondrial calcium homeostasis as evidenced by confocal fluorescence microscopy; (4) upregulated the protein expression of cytochrome C and apoptotic inducing factor, indicating exaggerated apoptosis; (5) affected mitochondrial respiratory chain complexes I, II, III and IV; (6) elicited mtDNA lesions as illustrated by the raised levels of 8-OHdG; (7) lowered DNA glycosylase, one of the first lines of defense against 8-OHdG mutagenicity; and (8) altered the gene expression and protein mass of mitochondrial transcription factors (mtTFA, mtTFB1, mtTFB2) without any effects on RNA Polymerase. The presence of the powerful antioxidant BHT (50 microM) prevented the occurrence of oxidative stress and most of the mitochondrial abnormalities. Collectively, our findings indicate that acute exposure of Caco-2/15 cells to FE/ASC-catalyzed peroxidation produces harmful effects on mitochondrial functions and DNA integrity, which are abrogated by the powerful exogenous BHT antioxidant. Functional derangements of mitochondria may have implications in oxidative stress-related disorders such as inflammatory bowel diseases.


Increasing the uptake of prevention of mother-to-child transmission of HIV services in a resource-limited setting.
As in other resource limited settings, the Ministry of Health in Zambia is challenged to make affordable and acceptable PMTCT interventions accessible and available. With a 14.3% HIV prevalence, the MOH estimates over one million people are HIV positive in Zambia. Approximately 500,000 children are born annually in Zambia and 40,000 acquire the infection vertically each year if no intervention is offered. This study sought to review uptake of prevention of mother-to-child (PMTCT) services in a resource-limited setting following the introduction of context-specific interventions. Interventions to improve PMTCT uptake were introduced into 38 sites providing PMTCT services in Zambia in July 2005. Baseline and follow up service data were collected on a monthly basis through September 2008. Data was checked for internal and external consistency using logic built into databases used for data management. Data audits were conducted to determine accuracy and reliability. Trends were analyzed pre- and post- intervention. Uptake among pregnant women increased across the 13 quarters (39 months) of observation, particularly in the case of acceptance of counseling and HIV testing from 45% to 90% (p value = 0.00) in the first year and 99% by year 3 (p value = 0.00). Receipt of complete course of antiretroviral (ARV) prophylaxis increased from 29% to 66% (p = 0.00) in the first year and 97% by year 3 (p value = 0.00). There was also significant improvement in the percentage of HIV positive pregnant women referred for clinical care. Uptake of PMTCT services in resource-limited settings can be improved by utilizing innovative alternatives to mitigate the effects of human resource shortage such as by providing technical assistance and mentorship beyond regular training courses, integrating PMTCT services into existing maternal and child health structures, addressing information gaps, mobilizing traditional and opinion leaders and building strong relationships with the government. These health system based approaches provide a sustainable improvement in the capacity and uptake of services.


Editorial Perspective: Longitudinal research in autism - introducing the concept of 'chronogeneity'.
Autism Spectrum Disorder (ASD or autism) is a heterogeneous neurodevelopmental disorder. We are now at a critical juncture in autism research where we have the knowledge base and expertise to begin to think about studies that view heterogeneity, not as 'statistical noise' that can be 'accounted for' using data-reduction techniques (such as group trajectories), but rather as 'informative variance' that can help form a more precise and dynamic picture of autism. In this Editorial we coin a new term and introduce the concept of 'chronogeneity' for the study of autism heterogeneity in relation to the dimension of time (chrono). Using examples of ongoing research and analytical advances we build the case for the potential utility of the concept of 'chronogeneity' and argue that a refined approach to the longitudinal investigation of autism (and other neurodevelopmental disorders) may move us closer to more precise and adaptive models of care for the children and youth affected by these disorders.


Targeting the mesenchymal subtype in glioblastoma and other cancers via inhibition of diacylglycerol kinase alpha.
The mesenchymal phenotype in glioblastoma (GBM) and other cancers drives aggressiveness and treatment resistance, leading to therapeutic failure and recurrence of disease. Currently, there is no successful treatment option available against the mesenchymal phenotype. We classified patient-derived GBM stem cell lines into 3 subtypes: proneural, mesenchymal, and other/classical. Each subtype's response to the inhibition of diacylglycerol kinase alpha (DGKα) was compared both in vitro and in vivo. RhoA activation, liposome binding, immunoblot, and kinase assays were utilized to elucidate the novel link between DGKα and geranylgeranyltransferase I (GGTase I). Here we show that inhibition of DGKα with a small-molecule inhibitor, ritanserin, or RNA interference preferentially targets the mesenchymal subtype of GBM. We show that the mesenchymal phenotype creates the sensitivity to DGKα inhibition; shifting GBM cells from the proneural to the mesenchymal subtype increases ritanserin activity, with similar effects in epithelial-mesenchymal transition models of lung and pancreatic carcinoma. This enhanced sensitivity of mesenchymal cancer cells to ritanserin is through inhibition of GGTase I and downstream mediators previously associated with the mesenchymal cancer phenotype, including RhoA and nuclear factor-kappaB. DGKα inhibition is synergistic with both radiation and imatinib, a drug preferentially affecting proneural GBM. Our findings demonstrate that a DGKα-GGTase I pathway can be targeted to combat the treatment-resistant mesenchymal cancer phenotype. Combining therapies with greater activity against each GBM subtype may represent a viable therapeutic option against GBM.


Incretin Hormones: Pathophysiological Risk Factors and Potential Targets for Type 2 Diabetes.
Type 2 diabetes (T2D) is a multifaceted metabolic disorder associated with distinctive pathophysiological disturbances. One of the pathophysiological risk factors observed in T2D is dysregulation of the incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). Both hormones stimulate insulin secretion by acting postprandially on pancreatic β-cell receptors. Oral glucose administration stimulates increased insulin secretion in comparison with isoglycemic intravenous glucose administration, a phenomenon known as the incretin effect. While the evidence for incretin defects in individuals with T2D is growing, the etiology behind this attenuated incretin effect in T2D is not clearly understood. Given their central role in T2D pathophysiology, incretins are promising targets for T2D therapeutics. The present review synthesizes the recent attempts to explain the biological importance of incretin hormones and explore potential pharmacological approaches that target the incretins.


Tumor necrosis factor-alpha induces functionally active hyaluronan-adhesive CD44 by activating sialidase through p38 mitogen-activated protein kinase in lipopolysaccharide-stimulated human monocytic cells.
Interaction of CD44, an adhesion molecule, with its ligand, hyaluronan (HA), in monocytic cells plays a critical role in cell migration, inflammation, and immune responses. Most cell types express CD44 but do not bind HA. The biological functions of CD44 have been attributed to the generation of the functionally active, HA-adhesive form of this molecule. Although lipopolysaccharide (LPS) and cytokines induce HA-adhesive CD44, the molecular mechanism underlying this process remains unknown. In this study, we show that LPS-induced CD44-mediated HA (CD44-HA) binding in monocytes is regulated by endogenously produced tumor necrosis factor (TNF)-alpha and IL-10. Furthermore, p38 mitogen-activated protein kinase (MAPK) activation was required for LPS- and TNF-alpha-induced, but not IL-10-induced, CD44-HA-binding in normal monocytes. To dissect the signaling pathways regulating CD44-HA binding independently of cross-regulatory IL-10-mediated effects, IL-10-refractory promonocytic THP-1 cells were employed. LPS-induced CD44-HA binding in THP-1 cells was regulated by endogenously produced TNF-alpha. Our results also suggest that lysosomal sialidase activation may be required for the acquisition of the HA-binding form of CD44 in LPS- and TNF-alpha-stimulated monocytic cells. Studies conducted to understand the role of MAPKs in the induction of sialidase activity revealed that LPS-induced sialidase activity was dependent on p42/44 MAPK-mediated TNF-alpha production. Blocking TNF-alpha production by PD98059, a p42/44 inhibitor, significantly reduced the LPS-induced sialidase activity and CD44-HA binding. Subsequently, TNF-alpha-mediated p38 MAPK activation induced sialidase activity and CD44-HA binding. Taken together, our results suggest that TNF-alpha-induced p38 MAPK activation may regulate the induction of functionally active HA-binding form of CD44 by activating sialidase in LPS-stimulated human monocytic cells.


Forsythia suspensa extract attenuates corticosterone-induced growth inhibition, oxidative injury, and immune depression in broilers.
Forsythia suspensa extract (FSE) has been demonstrated to attenuate physiological stress induced by high temperature or high stocking density. This experiment was conducted with 144 male Arbor Acre broilers (1-d-old, weighing 42.7 ± 1.7 g) to determine the effects of FSE on performance, nutrient digestibility, antioxidant activities, serum metabolites, and immune parameters for birds treated with corticosterone (CS). The birds were randomly allotted to 1 of 4 treatments in a 2 × 2 factorial arrangement that included FSE supplementation (0 or 100 mg/kg) and CS administration (0 or 20 mg/kg of diet for 7 consecutive days starting on d 14). The feeding program consisted of a starter diet from d 1 to 21 and a finisher diet from d 22 to 42. Corticosterone administration decreased (P < 0.01) ADG and impaired (P < 0.01) feed conversion ratio in both phases and overall, which were alleviated (P < 0.01) by dietary FSE supplementation in the finisher phase and overall. At d 21, CS administration caused decreases (P < 0.05) in the apparent digestibility of energy, relative weight of bursa and thymus, total antioxidant capacity, superoxide dismutase (SOD) activity, and antibody titers to Newcastle disease virus (NDV); however, serum malondialdehyde and uric acid were increased. All of these changes were attenuated (P < 0.05) by dietary FSE supplementation. At d 42, FSE supplementation improved (P < 0.05) the apparent digestibility of DM and CP, relative weights of bursa, SOD activity, and antibody titers to NDV, which were impaired by CS administration. Interactions (P < 0.05) were noted between CS and FSE for ADG and feed conversion ratio in the finisher phase and overall, as well as total antioxidant capacity, SOD activity, uric acid, and antibody titers to NDV at d 21, as well as relative weights of thymus at d 42. In conclusion, dietary FSE supplementation enhanced nutrient digestibility and performance of broiler possibly by reducing oxidative stress and immune depression challenged by CS.


Facile synthesis of silver alkynide cluster and coordination polymers using picolinic acid as a co-ligand.
We describe five 1D-coordination polymers and two discrete silver clusters consisting of alkynides and picolinic carboxylates as co-ligands. In some cases, DMSO or EtOH further solvated the structural motifs. Utilising the sterically demanding tri-isopropylsilyl acetylene afforded a tridecanuclear cluster that possessed an unprecedented core with a silver center surrounded by six octahedrally arranged silver atoms.


Add-on Antiplatelet Effects of Eicosapentaenoic Acid With Tailored Dose Setting in Patients on Dual Antiplatelet Therapy.
The aim of this study was to investigate the antiplatelet effects of eicosapentaenoic acid (EPA) at a sufficient dose following coronary stent implantation. Thirty-one patients on dual antiplatelet therapy with aspirin and clopidogrel were treated with highly purified EPA-E (Epadel®) for 12 weeks. Based on our previous study, patients with a high baseline EPA/arachidonic acid (AA) ratio (≥ 0.37; n = 11) were given a standard dose (1800 mg daily) of EPA-E, whereas those with a low EPA/AA ratio (< 0.37; n = 20) were given a high dose (2700 mg daily) to reach the target value of > 0.92. Platelet function was then evaluated with agonist-induced aggregation using light transmittance aggregometry and VerifyNow®. After EPA-E treatment, the EPA/AA ratio significantly increased from 0.28 to 1.31 (P < 0.001). Collagen (1, 2, and 4 μg/mL)-induced maximal platelet aggregation (MPA) was significantly suppressed after EPA-E administration (from 28.0 to 24.0, P = 0.033; from 44.0 to 40.0, P = 0.016; from 60.0 to 56.0, P = 0.010; respectively). However, there were no changes in MPA induced by adenosine diphosphate and AA and in P2Y12 reaction units (PRU) and aspirin reaction units. After EPA-E treatment, PRU was significantly suppressed in 8 patients showing high on-treatment platelet reactivity (HTPR) (baseline 305; 266-321 versus on-treatment 256; 233-261, P = 0.012), but not in those without HTPR (201; 156-220 versus 183; 159-233, P = 0.212). In conclusion, EPA treatment at a sufficient dose suppressed platelet aggregation and showed possible add-on effects in patients with clopidogrel hyporesponsiveness.


Vertical transmission of dengue viruses by mosquitoes of the Aedes scutellaris group.
Seventeen strains of mosquitoes belonging to 12 species in the Aedes scutellaris subgroup were tested for an ability to transmit one or more dengue virus serotype(s) vertically. Strains of virus employed for dengue types 1, 2, 3, and 4 were from Fiji, Bangkok, Burma, and Medan, respectively. After parental females were infected by intrathoracic inoculation, F1 larval and pupal progeny were tested for the presence of virus by inoculating aliquots of triturated suspensions into Toxorhynchites amboinensis mosquitoes. Dengue type 1 was transmitted vertically by 11 strains of mosquitoes representing 8 species with the highest filial infection rates observed for Ae. cooki (1.2%). Vertical transmission of the other dengue virus serotypes was observed for fewer species of mosquitoes, however the filial infection rates of those demonstrating vertical transmission were between 1%-2% for types 2 and 3, and about 0.5% for type 4. Tests with the progeny of individual Ae. cooki and Ae. polynesiensis infected with dengue virus types 1 and 3, respectively, showed that approximately greater than or equal to 50% of the parental females transmitted virus to their progeny. Highest filial infection rates were 6.7% for Ae. cooki and 4.6% for Ae. polynesiensis.


Antitumor effects of thalidomide analogs in human prostate cancer xenografts implanted in immunodeficient mice.
Thalidomide has demonstrated clinical activity in various malignancies including androgen-independent prostate cancer. The development of novel thalidomide analogs with better activity/toxicity profiles is an ongoing research effort. Our laboratory previously reported the in vitro antiangiogenic activity of the N-substituted thalidomide analog CPS11 and the tetrafluorinated analogs CPS45 and CPS49. The current study evaluated the therapeutic potential of these analogs in the treatment of prostate cancer in vivo. Severely combined immunodeficient mice bearing s.c. human prostate cancer (PC3 or 22Rv1) xenografts were treated with the analogs at their maximum tolerated doses. Tumors were then excised and processed for ELISA and CD31 immunostaining to determine the levels of various angiogenic factors and microvessel density (MVD), respectively. CPS11, CPS45, and CPS49 induced prominent and modest growth inhibition in PC3 and 22Rv1 tumors, respectively. Thalidomide had no effect on tumor growth in either xenograft. Vascular endothelial growth factor and basic fibroblast growth factor levels were not significantly altered by any of the thalidomide analogs or thalidomide in both PC3 and 22Rv1 tumors. CPS45, CPS49, and thalidomide significantly reduced PC3 tumor platelet-derived growth factor (PDGF)-AA levels by 58-82% (P < 0.05). Interestingly, treatment with the analogs and thalidomide resulted in differential down-regulation (>/=1.5-fold) of genes encoding PDGF and PDGF receptor isoforms as determined by DNA microarray analysis. Intratumoral MVD of 22Rv1 xenografts was significantly decreased by CPS45 and CPS49. CPS49 also reduced MVD in PC3 xenografts. Thalidomide analogs CPS11 and 49 are promising anti-cancer agents. PDGF signaling pathway may be a potential target for these thalidomide analogs. Detailed microarray and functional analyses are under way with the aim of elucidating the molecular mechanism(s) of action of these thalidomide analogs.


Psychosocial work factors, blood pressure and psychological strain in male bus operators.
The research aim was to predict the bus operators' blood pressure (BP) and psychological strain using a combination of the Job-Demand Control (JDC) and Effort-Reward Imbalance (ERI) models. The study was conducted with a sample of 139 bus operators in the city of Bogotá (Colombia), who answered a questionnaire that included the Job Content Questionnaire (JCQ), the ERI Questionnaire, and the General Health Questionnaire (GHQ). Four consecutive BP readings taken in the workplace were averaged to calculate an estimation of the bus operators' BP. By conducting multiple linear regressions it was found that, taken together, JDC and ERI models explain 10% (F(11,139)=2,502; p=0.00) of systolic BP variance, and 34% (F(6,139)=8,638; p=0.00) of psychological strain variance. These results suggest that the JDC and ERI predictors provide complementary information which increases the probability of accurately model the bus operators' health.


Profiling physicochemical changes within catalyst bodies during preparation: new insights from invasive and noninvasive microspectroscopic studies.
Cylindrical or spherical catalyst bodies with sizes ranging from tens of micrometers to a few millimeters have a wide variety of industrial applications. They are crucial in the oil refining industry and in the manufacture of bulk and fine chemicals. Their stability, activity, and selectivity are largely dependent on their preparation; thus, achieving the optimum catalyst requires a perfect understanding of the physicochemical processes occurring in a catalyst body during its synthesis. The ultimate goal of the catalyst researcher is to visualize these physicochemical processes as the catalyst is being prepared and without interfering with the system. In order to understand this chemistry and improve catalyst design, researchers need better, less invasive tools to observe this chemistry as it occurs, from the first stages in contact with a precursor all the way through its synthesis. In this Account, we provide an overview of the recent advances in the development of space- and time-resolved spectroscopic methods, from invasive techniques to noninvasive ones, to image the physicochemical processes taking place during the preparation of catalyst bodies. Although several preparation methods are available to produce catalyst bodies, the most common method used in industry is the incipient wetness impregnation. It is the most common method used in industry because it is simple and cost-effective. This method consists of three main steps each of which has an important role in the design of a catalytic material: pore volume impregnation, drying, and thermal treatment. During the impregnation step, the interface between the support surface and the precursor of the active phase at the solid-liquid interface is where the critical synthetic chemistry occurs. Gas-solid and solid-solid interfaces are critical during the drying and thermal treatment steps. Because of the length scale of these catalyst bodies, the interfacial chemistry that occurs during preparation is space-dependent. Different processes occurring in the core or in the outer rim of the catalytic solid are enhanced by several factors, such as the impregnation solution pH, the metal ion concentration, the presence of organic additives, and the temperature gradients inside the body. Invasive methods for studying the molecular nature of the metal-ion species during the preparation of catalyst bodies include Raman, UV-vis-NIR, and IR microspectroscopies. Noninvasive techniques include magnetic resonance imaging (MRI). Synchrotron-based techniques such as tomographic energy dispersive diffraction imaging (TEDDI) and X-ray microtomography for noninvasive characterization are also evaluated.


Chronic sensitivity of white sturgeon (Acipenser transmontanus) and rainbow trout (Oncorhynchus mykiss) to cadmium, copper, lead, or zinc in laboratory water-only exposures.
Chronic toxicity of cadmium, copper, lead, or zinc to white sturgeon (Acipenser transmontanus) and rainbow trout (Oncorhynchus mykiss) was evaluated in water-only exposures started with newly hatched larvae or approximately 1-mo-old juveniles. The 20% effect concentration (EC20) for cadmium from the sturgeon tests was higher than the EC20 from the trout tests, whereas the EC20 for copper, lead, or zinc for the sturgeon were lower than those EC20s for the trout. When the EC20s from the present study were included in compiled toxicity databases for all freshwater species, species mean chronic value for white sturgeon was in a relatively low percentile of the species sensitivity distribution for copper (9th percentile) and in the middle percentile for cadmium (55th percentile), zinc (40th percentile), or lead (50th percentile). However, the species mean chronic value for rainbow trout was in a high percentile for copper, lead, and zinc (∼68th-82nd percentile), but in a low percentile for cadmium (23rd percentile). The trout EC20s for each of the 4 metals and the sturgeon EC20s for cadmium or lead were above US Environmental Protection Agency chronic ambient water quality criteria (AWQC) or Washington State chronic water quality standards (WQS), whereas the sturgeon EC20s for copper or zinc were approximately equal to or below the chronic AWQC and WQS. In addition, acute 50% effect concentrations (EC50s) for copper obtained in the first 4 d of the chronic sturgeon test were below the final acute value used to derive acute AWQC and below acute WQS for copper.


[Successful treatment of refractory peripheral T-cell lymphoma by allogeneic peripheral blood stem cell transplantation].
A 40-year-old man was admitted to our hospital suffering from abdominal pain. He revealed marked splenomegaly, lymphadenopathy and pancytopenia. Lymph node biopsy showed diffuse proliferation of medium to large atypical lymphoid cells. Immunohistochemically the cells were positive for T-cell markers. He was diagnosed as having peripheral T cell lymphoma (PTCL) with involvement of the spleen and bone marrow. Because of refractoriness to combination chemotherapies and splenic irradiation, we performed allogeneic peripheral blood stem cell transplantation from an HLA-identical sister. Conditioning was consisted of conventional doses of total body irradiation and cyclophosphamide, and GVHD prophylaxis was performed with cyclosporine and methotrexate. After the patient developed grade III graft-versus-host disease, his splenomegaly improved dramatically. Although the effectiveness of allogeneic hematopoietic cell transplantation in the treatment of malignant lymphoma is controversial, we should consider this as a second-line therapy to refractory subsets of PTCL.


Understanding treatment decisions for Hodgkin lymphoma: a qualitative study.
Hodgkin lymphoma (HL) affects older and younger patients and includes multiple options for initial treatment. We sought to examine the decision processes of practicing oncologists caring for patients with newly diagnosed HL. Through semi-structured interviews, we explored their perspectives about treatment decisions. We completed thematic analysis using the Anderson Behavioral Model of Health Services framework to identify factors associated with initial decisions. We completed 22 interviews, grouping findings into contextual factors, individual characteristics, and physician preferences. Paternalism was widely cited, along with collaboration between community and academic colleagues. Participants used sequential therapy but not geriatric assessment in care for older patients. Physicians had varied responses about use of frontline brentuximab vedotin (Bv)-based therapy based on perceptions about benefit versus toxicity. Our work suggests a need to further understand the heterogeneity of clinical practices, especially in the post-approval setting of new therapies.


Comparison of biomechanical stability of osteosynthesis materials in long bone fractures.
Aim To calculate stress and deformation under the force of pressure and bending in the dynamic compression plate (DCP), locking compression plate (LCP), selfdynamisable internal fixator (SIF) and locked intramedullary nail (LIN) in the models of juvidur, beef tibia bone (cadaver) and software of bone model simulator. Methods Juvidur and bone models were used for the experimental study, static tests were performed with SHIMADZU AGS-X tester. CATIA software was used to create a 3D model for the SCA simulator, while software ANSYS to calculate the tension and deformation for compressive and bending forces. Stress and deformation analysis was performed with the use of Finite Element Analysis (FEA). Results Weight coefficients of research methods were different (juvidur=0.3; cadaver=0.5; SCA Simuator=0.2), and weight coefficients of the force of pressure Kp =0.5 and bending forces in one plane K1 =0.25 and K2 =0.25 in another plane, the overall result on the dilatation of DCP, LCP, LIN and SIF on juvidur and veal cadaver models showed that the first ranking was the LIN with a rank coefficient KU-LIN = 0.0603, followed by the IFM with KU-IFM = 0.0621, DCP with KU-DCP = 0.0826 and LCP with KU-LCP = 0.2264. Conclusion Dilatation size did not exceed 0.2264 mm, hence the implants fulfilled biomechanical conditions for the internal stabilization of bone fractures. Prevalence goes to the locked intramedullar nailing and Mitković internal fixator in the treatment of diaphyseal, transversal, comminuted fractures in relation to DCP and LCP.