Meta-analysis of perioperative immunotherapy in renal cell carcinoma: Available, but the jury is still out.
While surgical management of renal cell carcinoma (RCC) is curative for many patients, others may relapse and could benefit from adjuvant treatments. Immune checkpoint inhibitors (ICI) have been proposed as a potential adjuvant therapy for improving survival in these patients, but the benefit/risk ratio of ICI in the perioperative setting remains unclear. A systematic review and a meta-analysis of phase III trials of perioperative ICI (anti PD1/PD-L1 alone or in combination with anti-CTLA4 agents) in RCC was conducted. The analysis included results from 4 phase III trials, comprising 3,407 patients. ICI did not show a significant increase in disease-free survival (Hazard Ratio [HR] 0.85; 95% confidence interval [CI] 0.69-1.04; p: 0.11) or overall survival [OS] (HR 0.73; 95% CI 0.40-1.34; p: 0.31). High-grade adverse events were more frequent in the immunotherapy arm (OR 2.65; 95% CI 1.53-4.59; p: <0.001), and high-grade treatment-related adverse events were 8 times more frequent in the experimental arm (OR: 8.07; 95% CI: 3.14-20.75; p: <0.001). Subgroup analyses showed statistically significant differences favoring the experimental arm in females (HR: 0.71; 95 CI 0.55-0.92; p: 0.009), in sarcomatoid differentiation (HR: 0.60 95% CI 0.41-0.89; p: 0.01), and PD-L1 positive tumors (HR HR: 0.74; 95% CI 0.61-0.90; p: 0.003). No significant effect was found in patients according to age, type of nephrectomy (radical vs. partial), and stage (M1 without evidence of disease vs. M0 patients). Our comprehensive meta-analysis generally suggests that immunotherapy does not confer a survival advantage in the perioperative setting for RCC, with the exception of one positive study. While the overall results are not statistically significant, individual patient factors and other variables may play a role in determining who benefits from immunotherapy. Therefore, despite the mixed findings, immunotherapy may still be a viable treatment option for certain patients, and further studies are needed to determine which patient subgroups would be most likely to benefit.


Preparative isolation and purification of trans-3,5,4'-trihydroxystilbene-4'-O-beta-D-glucopyranoside and (+)catechin from Rheum tanguticum Maxim. ex Balf. using high-speed counter-current chromatography by stepwise elution and stepwise increasing the flow-rate of the mobile phase.
Preparative high-speed counter-current chromatography (HSCCC) was successfully used for isolation and purification of trans-3,5,4'-trihydroxystilbene-4'-O-beta-D-glucopyranoside (compound 1) and (+)catechin (compound 2) from Rheum tanguticum Maxim. ex Balf. by stepwise elution with a pair of two-phase solvent system composed of ethyl acetate-ethanol-water (25:1:25, v/v) and (5:1:5, v/v), and stepwise increasing the flow-rate of the mobile phase from 0.8 to 2.0 mlmin(-1) after 5 h. The preparative HSCCC separation was performed on 250 mg of crude extract yielding pure compound 1 (10.2 mg) and compound 2 (26.7 mg) all at purities of over 96% in a single run. The structures of the two compounds have been elucidated by means of spectroscopic methods including MS and 1H, 13C nuclear magnetic resonance spectroscopy.


Impact of inhibition of Qo site of mitochondrial complex III with myxothiazol on persistent sodium currents via superoxide and protein kinase C in rat hippocampal CA1 cells.
Inhibition of Qo site of mitochondrial complex III under hypoxia has received attention, but its downstream pathways remain unclear. We used Qo site inhibitor myxothiazol to mimic the inhibition of the Qo site of complex III and studied the effects of the inhibition of this site on persistent and transient sodium currents and neuron excitability in rat hippocampal CA1 cells. The results showed myxothiazol apparently increased persistent sodium currents but with a weak effect on transient sodium currents; the effect of myxothiazol on persistent sodium currents was blocked by protein kinase C inhibitor and superoxide scavengers, but not by hydrogen peroxide scavenger and hydroxyl radical formation inhibitor; myxothiazol could increase the activity of protein kinase C and neuron excitability. These results suggest that the inhibition of Qo site of mitochondrial complex III increases persistent sodium currents via superoxide production and protein kinase C activation.


Characterization of an epithelioid cell line derived from rat small intestine: demonstration of cytokeratin filaments.
A cell line (RIE-1) of epithelioid morphology was established from rat small intestine. RIE-1 cells possess the normal rat diploid number of chromosomes (42) up to at least passage 20. Both early (less than 10) and late (greater than 20) passage cells are non-tumourigenic and do not form colonies in soft agarose. RIE-1 cells bind two epithelial-specific monoclonal antibodies. In addition, the cells exhibit a network of cytoskeletal filaments which are labelled by an antiserum to keratin. These findings provide strong evidence for an epithelial origin of the RIE-1 cell line.


A High-Throughput Genome-Integrated Assay Reveals Spatial Dependencies Governing Tcf7l2 Binding.
Predicting where transcription factors bind in the genome from their in vitro DNA-binding affinity is confounded by the large number of possible interactions with nearby transcription factors. To characterize the in vivo binding logic for the Wnt effector Tcf7l2, we developed a high-throughput screening platform in which thousands of synthesized DNA phrases are inserted into a specific genomic locus, followed by measurement of Tcf7l2 binding by DamID. Using this platform at two genomic loci in mouse embryonic stem cells, we show that while the binding of Tcf7l2 closely follows the in vitro motif-binding strength and is influenced by local chromatin accessibility, it is also strongly affected by the surrounding 99 bp of sequence. Through controlled sequence perturbation, we show that Oct4 and Klf4 motifs promote Tcf7l2 binding, particularly in the adjacent ∼50 bp and oscillating with a 10.8-bp phasing relative to these cofactor motifs, which matches the turn of a DNA helix.


Bladder neck evaluation by perineal ultrasound before and after reconstructive surgery for pelvic organ prolapse.
To study the correlation between stress urinary incontinence (SUI) and the mobility and funneling of the bladder neck (BN) by observation of pre- and postoperative course by perineal ultrasound (PUS). We investigated 123 cases that underwent reconstructive surgery for pelvic organ prolapse (POP). We prospectively checked bladder neck mobility (BNM) during the Valsalva maneuver and funneling of the BN at rest by PUS. We defined the width multiplied by the depth of the funnel-like profile of the BN as the funneling index (FI). We checked BNM, FI, and the presence of SUI just before the operation, and we checked the postoperative course of BNM and SUI. When BNM was ≥10 mm before surgery, the odds ratio for accompanying SUI was 2.68 relative to BNM <10 mm (p = 0.031). When FI was ≥150 before surgery, the odds ratio for accompanying SUI was 4.12 relative to FI <150 (p = 0.004). Although postoperative BNM values were significantly improved immediately after surgery, they gradually increased within 2 years. Among the cases with preoperative SUI, the recurrence rate was significantly higher in the patients whose FI was <150 (p = 0.019). Our results yielded by PUS suggested that larger BNM and FI values were the causative factors of SUI. PUS may be beneficial for selecting a suitable surgical procedure for POP, and it may also be helpful for assessing surgical efficacy.


Growing up poor but doing well: Contextual factors that predict academic success.
This paper combines data on family, school, neighborhood, and city contexts with survey data from the Year 9 (n = 2,193) and Year 15 (n = 2, 236) Fragile Families and Child Wellbeing Study to study children in America's inner-cities who are "beating the odds". We identify children as beating the odds if they were born to families of low socio-economic status but scored above the state average in reading, vocabulary and math at age 9, and were academically on-track by age 15. We also examine if the influences of these contexts are developmentally nuanced. We find that living in two parent households where harsh parenting methods are absent (family context) and living in neighborhoods where two parent families predominate (neighborhood context) are protective factors that help children beat the odds. We also find that city-wide contexts of higher levels of religiosity and fewer single parent households contribute to children beating the odds, however, these macro predictors are weaker when compared with family/neighborhood contexts. We find that these contextual effects are indeed developmentally nuanced. We conclude with a discussion of some interventions and policies that could help increase the number of at-risk children who beat the odds.


Metabolomics driven analysis of Nigella sativa seeds identifies the impact of roasting on the chemical composition and immunomodulatory activity.
Nigella sativa L. seeds (NS) are known as one of the most traditional immunomodulatory and nutritive food additives. NS can, furthermore, be roasted to give curries, breads, and other dishes a smoky, nutty flavor. This study evaluated the effect of roasting NS on the metabolic profile and immunomodulatory activity. Non-targeted metabolomics analysis was conducted using several analytical platforms, including GC-MS and UPLC-MS. A total of 197 metabolites were identified, belonging to different classes such as saponins, alkaloids, flavonoids, and lipids. In vitro immunomodulatory activity on the differentiated monocytic cell line THP-1 was assessed, revealing that the roasted seeds showed significantly-decreased immunomodulatory activity. Furthermore, a molecular docking study, which was carried out against immunomodulation-related pathway protein (iNOS), revealed that compounds which showed the best binding scores were severely decreased by roasting. Conclusively, our results demonstrate that the roasting of NS results in severe losses in their bioactive metabolites and immunomodulatory activity.


Inhibition of the growth of a human nasopharyngeal carcinoma cell line by bFGF is mediated via FGFR-1.
The growth of CG-1 human nasopharyngeal carcinoma cell line and five of its randomly selected, single cell-derived subline cells is inhibited by bFGF in an autocrine and paracrine manner. In contrast, aFGF, which has a 55% homology in amino acid sequence with bFGF, stimulates cell growth. Basic FGF binds to specific cell surface high-affinity receptor sites with an apparent Kd of 105 pM. Of the two lines examined, the high-affinity binding sites for bFGF are calculated to be 1200 and 2600 per cell. The biological effect of bFGF is conveyed through its binding to the high-affinity receptor sites and the binding is dependent on the presence of cell surface heparin-like molecules, as treatment of cells with heparitinase or sodium chlorate abolishes high-affinity binding and growth inhibition. In contrast, similar treatment has no obvious effect on the growth-stimulatory effect of aFGF. Experimental results are also presented showing that the growth inhibition by bFGF is mediated through type I FGF receptors. These results suggest that bFGF and aFGF act via distinct receptor types to oppositely regulate the growth of CG-1 and subline cells.


Longitudinal myocardial deformation is selectively decreased after pediatric cardiac transplantation: a comparison of children 1 year after transplantation with normal subjects using velocity vector imaging.
The transplanted heart experiences numerous hemodynamic changes during and after cardiac transplantation. This study sought to evaluate the left ventricular myocardial mechanics in the pediatric heart transplant population using Velocity Vector Imaging (VVI). This study retrospectively evaluated 28 heart transplant recipients by echocardiography 12 months after transplantation. Echocardiograms from 28 age- and gender-matched subjects were used as a control group. Peak global longitudinal and circumferential left ventricular strain, systolic strain rate, and diastolic strain rate were obtained. Student's t tests were used to assess differences between the two groups (defined as p ≤ 0.05). The peak global left ventricular longitudinal strain was lower in the transplant group (17.21%) than in the control group (22.14%). The transplant and control groups did not differ significantly in terms of their peak global circumferential strain (20.28% vs. 20.79%, respectively). Similar results were observed for longitudinal and circumferential systolic and diastolic strain rates. The transplant patients showed statistically significant reductions in all peak global longitudinal measures compared with those of the control subjects. Circumferential myocardial deformation appears to be preserved in transplant recipients. This could suggest evidence of ischemia given the known myocardial fiber arrangement of longitudinal fibers toward the endocardial surface, which is also more distal in the coronary arterioles.


Determination of uptake kinetics and sampling rates for 56 organic micropollutants using "pharmaceutical" POCIS.
The literature increasingly reports sampling rates (Rs) for Polar Organic Chemical Integrative Samplers (POCIS) but the data obtained come from various calibration systems that are not always well-defined (agitation, temperature, measured micropollutant concentrations in water,…). In order to obtain accurate laboratory Rs for priority and emerging substances, POCIS need to be exposed in a robust and well-defined calibration system. Thus, we built a flow-through calibration system containing tap water spiked with 56 organic micropollutants (alkylphenols and phenols, hormones, pesticides, pharmaceuticals, UV filter). POCIS were immersed for up to 28 days. Tap water micropollutant concentrations and additional parameters (temperature, pH, conductivity, dissolved organic carbon, flow velocities) were kept constant and controlled throughout the calibration experiment. Based on the observed uptake kinetics, we distinguished four types of micropollutant accumulation patterns: curvilinear accumulation (30 molecules, group 1), accumulation with an inflexion point (13 molecules, group 2), random accumulation (eight molecules, group 3), and no or very low accumulation (five molecules, group 4). Rs was calculated for 43 out of 56 micropollutants (groups 1 and 2). Calculated Rs values ranged from 0.030 L/d to 0.398 L/d. POCIS can supply TWA concentrations for hormones, pesticides, several pharmaceuticals, a few alkylphenols, and the UV filter. Our Rs results are generally less than two fold-different (higher or lower depending on target molecule) to the literature data using the same type of calibration system or for micropollutants with log Kow>2.65. We found a quadratic correlation between Rs and log D for betablockers, herbicides and hormones.


The Clinical Usefulness of Sleep Studies in Children.
Sleep disordered breathing is common in children and has the potential to have a significant impact on cognition, activity and social interaction. The overnight in-laboratory polysomnography (PSG) continues to be the gold standard instrument for the investigation of sleep-disordered breathing in children. It has the ability to rule in or rule out the need for intervention for common conditions such as obstructive sleep apnoea, assess the role of sleep quality in children and adolescents with hypersomnolence, provide physiologic data in children with hypoventilation as may be seen in neuromuscular disease and assist in the assessment of children with structural airway and lung abnormalities. Polysomnography is valuable and the only reliable method to differentiate habitual snoring from many levels of sleep apnoea syndrome [1]. The American Academy of Paediatrics recommends that, in order to diagnose and manage OSA syndrome, all children should be screened for snoring and complex cases should be referred to a specialist. PSG is the diagnostic gold standard and adenotonsillectomy is the first line of treatment [2]. There is no evidence to support nap studies or ambulatory sleep studies in children [3]. With adequate staffing, expertise, and a child and family-friendly environment, children of any age can undergo a sleep study.


Comparative analysis of detection methods for congenital cytomegalovirus infection in a Guinea pig model.
To assess the validity of the guinea pig as a model for congenital cytomegalovirus (CMV) infection by comparing the effectiveness of detecting the virus by real-time polymerase chain reaction (PCR) in blood, urine, and saliva. Case-control study. Academic research. Eleven pregnant Hartley guinea pigs. Blood, urine, and saliva samples were collected from guinea pig pups delivered from pregnant dams inoculated with guinea pig CMV. These samples were then evaluated for the presence of guinea pig CMV by real-time PCR assuming 100% transmission. Thirty-one pups delivered from 9 inoculated pregnant dams and 8 uninfected control pups underwent testing for guinea pig CMV and for auditory brainstem response hearing loss. Repeated-measures analysis of variance demonstrated no statistically significantly lower weight for the infected pups compared with the noninfected control pups. Six infected pups demonstrated auditory brainstem response hearing loss. The sensitivity and specificity of the real-time PCR assay on saliva samples were 74.2% and 100.0%, respectively. The sensitivity of the real-time PCR on blood and urine samples was significantly lower than that on saliva samples. Real-time PCR assays of blood, urine, and saliva revealed that saliva samples show high sensitivity and specificity for detecting congenital CMV infection in guinea pigs. This finding is consistent with recent screening studies in human newborns. The guinea pig may be a good animal model in which to compare different diagnostic assays for congenital CMV infection.


Association between fasting plasma glucose and nonalcoholic fatty liver disease in a nonobese Chinese population with normal blood lipid levels: a prospective cohort study.
Fasting plasma glucose (FPG) is an easily quantifiable and inexpensive metabolic marker, which is often used to assess cardiovascular disease and diabetes. However, there have been limited studies on the association between FPG and nonalcoholic fatty liver disease (NAFLD) risk in nonobese people, especially in Chinese individuals. The purpose of this study was to investigate the association between FPG and NAFLD in nonobese Chinese people with normal blood lipid levels. In this prospective cohort study, 9767 nonobese participants with normal blood lipid levels without NAFLD were recruited and prospectively followed for 5 years. The Cox proportional hazard model was used to evaluate the risk factors of NAFLD. Moreover, a Cox model with cubic spline functions and smooth curve fitting (the cubic spline smoothing) were used to identify the nonlinear association between FPG and NAFLD. During the 5-year follow-up, 841 (8.61%) participants were diagnosed with NAFLD. The good functional results (without NAFLD) estimated by the Kaplan-Meier method for 1 year, 2 years, 3 years, 4 years, and 5 years were 98.84, 95.35, 91.67%, 87.57 and 74.86%, respectively. Additionally, through the Cox proportional hazard model, after adjusting for other covariates, there was an independent positive correlation between FPG and increased NAFLD risk (HR:1.21, 95% CI:1.15-1.28, P < 0.0001), and the NAFLD risk was incrementally higher with the rising FPG quartile. The nonlinear association between FPG and NAFLD was visualized by cubic spline smoothing technique. It was calculated that the inflection point of FPG was 5.54. When FPG ≤ 5.54, there was a positive correlation between FPG and the risk of NAFLD (HR:2.20, 95% CI:1.78-2.73, P < 0.0001). When FPG > 5.54, the risk of NAFLD increased by 50% (HR:1.10, 95% CI:1.02-1.18, P = 0.0159) compared with the left side of the inflection point and gradually leveled off. In a nonobese Chinese population with normal lipid levels, there is an independent nonlinear association between FPG and NAFLD, and the increase in FPG may indicate an increased risk of NAFLD. Additionally, this independent association is more obvious in the short stature population.


[Nasal neurinoma: communication of a case and clinicopathologic analysis].
The schwannomas are tumors arising from nervous tissue. It appears very rarely in the nose and paranasal sinuses. We report a case of a female whit nasal obstruction that presents a nasal neurinoma schwannoma.


The role of NMDA receptors in the slow neuronal degeneration of Parkinson's disease.
Parkinson's disease is a disorder, in which neurons of various neuronal systems degenerate. Furthermore, in such degenerating neurons, the cytoskeleton seems to be affected. In this respect, Parkinson's disease resembles Alzheimer's disease. Since it has been shown, that elevated levels of intracellular calcium can disrupt the cytoskeleton and that the stimulation of glutamate (NMDA) receptors can cause high intracellular concentrations of calcium, it has been suggested, that the stimulation of glutamate receptors plays a role in the slow degeneration in Alzheimer's and Parkinson's disease. In case of the degeneration of the dopaminergic nigrostriatal system in Parkinson's disease, neurons that contain calcium binding protein appear to be less vulnerable than the neurons that lack it, suggesting that calcium binding protein might protect these neurons from degeneration by preventing that cytosolic calcium concentrations increase excessively. And, since there is in the nigrostriatal system a glutamatergic afferent pathway (the prefrontonigral projection) and since dopaminergic nigrostriatal neurons contain postsynaptic NMDA receptors, glutamatergic excitation may play a role in the degeneration of the nigrostriatal system in Parkinson's disease. If so, it may be possible to protect the neurodegeneration of these dopaminergic neurons by NMDA receptor antagonists.


Effects of cholesterol on the divalent cation-mediated interactions of vesicles containing amino and choline phospholipids.
We have used assays of lipid probe mixing, contents mixing and contents leakage to monitor the divalent cation-mediated interactions between lipid vesicles containing phosphatidylserine (PS) as a minority component together with mixtures of phosphatidylethanolamine (PE), phosphatidylcholine (PC) or sphingomyelin, and cholesterol in varying proportions. The initial rates of calcium- and magnesium-induced lipid probe quenching between vesicles, which reflect primarily the rates of vesicle aggregation, are strongly reduced as progressively higher proportions of PC or sphingomyelin are incorporated into PE/PS vesicles. The initial rates of divalent cation-induced contents mixing and contents leakage for PE/PS vesicles are also strongly reduced when choline phospholipids are incorporated into the vesicles in even low molar proportions. Sphingomyelin has a more potent inhibitory effect on these processes than does PC at an equal level in the vesicle membranes. The inclusion of cholesterol in these vesicles, at levels up to 1:2 moles sterol/mole phospholipid, has little effect on the rates of calcium- or magnesium-induced vesicle aggregation. However, cholesterol significantly enhances the initial rates of vesicle contents mixing and contents leakage in the presence of divalent cations when the vesicles contain choline as well as amino phospholipids. This effect is substantial only when the level of cholesterol exceeds the level of choline phospholipids in the vesicles. These results may have significance for the fusion of certain cellular membranes in mammalian cells, whose cytoplasmic faces have lipid compositions very similar to those of the vesicles examined in this study.


Typology of end-of-life priorities in Saudi females: averaging analysis and Q-methodology.
Understanding culture-and sex-related end-of-life preferences is essential to provide quality end-of-life care. We have previously explored end-of-life choices in Saudi males and found important culture-related differences and that Q-methodology is useful in identifying intraculture, opinion-based groups. Here, we explore Saudi females' end-of-life choices. A volunteer sample of 68 females rank-ordered 47 opinion statements on end-of-life issues into a nine-category symmetrical distribution. The ranking scores of the statements were analyzed by averaging analysis and Q-methodology. The mean age of the females in the sample was 30.3 years (range, 19-55 years). Among them, 51% reported average religiosity, 78% reported very good health, 79% reported very good life quality, and 100% reported high-school education or more. The extreme five overall priorities were to be able to say the statement of faith, be at peace with God, die without having the body exposed, maintain dignity, and resolve all conflicts. The extreme five overall dis-priorities were to die in the hospital, die well dressed, be informed about impending death by family/friends rather than doctor, die at peak of life, and not know if one has a fatal illness. Q-methodology identified five opinion-based groups with qualitatively different characteristics: "physical and emotional privacy concerned, family caring" (younger, lower religiosity), "whole person" (higher religiosity), "pain and informational privacy concerned" (lower life quality), "decisional privacy concerned" (older, higher life quality), and "life quantity concerned, family dependent" (high life quality, low life satisfaction). Out of the extreme 14 priorities/dis-priorities for each group, 21%-50% were not represented among the extreme 20 priorities/dis-priorities for the entire sample. Consistent with the previously reported findings in Saudi males, transcendence and dying in the hospital were the extreme end-of-life priority and dis-priority, respectively, in Saudi females. Body modesty was a major overall concern; however, concerns about pain, various types of privacy, and life quantity were variably emphasized by the five opinion-based groups but masked by averaging analysis.


Efficacy of ixekizumab compared to etanercept and placebo in patients with moderate-to-severe plaque psoriasis and non-pustular palmoplantar involvement: results from three phase 3 trials (UNCOVER-1, UNCOVER-2 and UNCOVER-3).
Palmoplantar psoriasis has significant physical and emotional impact on patients and can be difficult to treat. To evaluate the efficacy of ixekizumab in the treatment of patients with moderate-to-severe plaque psoriasis and moderate-to-severe non-pustular palmoplantar involvement. In three phase 3, double-blind, placebo-controlled trials, patients with moderate-to-severe non-pustular plaque psoriasis [UNCOVER-1 (N = 1296), UNCOVER-2 (N = 1224), UNCOVER-3 (N = 1346)] were randomized to subcutaneous 80 mg ixekizumab every 2 or 4 weeks (Q2W, Q4W), after a 160-mg starting dose, or placebo through week 12. Additional UNCOVER-2 and UNCOVER-3 cohorts were randomized to 50 mg etanercept biweekly. Patients entering the open-label long-term extension (UNCOVER-3) received ixekizumab Q4W weeks 12-60. Moderate-to-severe palmoplantar involvement was defined as Palmoplantar Psoriasis Area and Severity Index (PPASI) ≥8. Twenty-eight percent of UNCOVER-1, UNCOVER-2 and UNCOVER-3 patients had baseline palmoplantar involvement (PPASI ≥0, n = 1092) and 9.1% (n = 350) had moderate-to-severe involvement, with mean baseline PPASI ~20, PASI ~24, and most (>60%) had static Physician's Global Assessment ≥4. Higher percentages of patients treated with ixekizumab vs. placebo or etanercept achieved PPASI 50 (approximately 80% vs. 32.9%, 67.8%; ixekizumab, placebo, etanercept, respectively) and PPASI 75 (approximately 70% vs. 18.8%, 44.1%; ixekizumab, placebo, etanercept, respectively) at week 12 (all P < 0.05). PPASI 100 was achieved by higher percentages of ixekizumab-treated patients vs. placebo (approximately 50% vs. 8.2%, P < 0.001) and ixekizumab Q2W-treated patients vs. etanercept (51.8% vs. 32.2%, P < 0.05). Outcomes were maintained or improved in patients continuing on ixekizumab Q4W through week 60. Differences between ixekizumab and placebo or etanercept were statistically significant as early as week 1. In a subpopulation analysis of patients from phase 3 trials with moderate-to-severe non-pustular palmoplantar involvement and moderate-to-severe plaque psoriasis, ixekizumab treatment resulted in greater and more rapid improvements than placebo and etanercept at week 12; improvements were sustained with continued treatment.


Deliberate metallic paint inhalation and cultural marginality: paint sniffing among acculturating central California youth.
Deliberate metallic paint inhalation, paint sniffing, has recently become the focus of community concern in central California, as numbers of recalcitrant young abusers have entered the overloaded Mental Health and Juvenile Justice systems. This study, based on an extension of psychological, sociological and anthropological explanations of inhalant abuse, describes the adolescent paint sniffer and proposes that a combination of interacting factors both differentiates him/her from other-drug abusing youth, and predisposes him/her to inhalant use. The experimental hypothesis was tested by a stepwise discriminant analysis performed on 50 subjects, equally divided into two groups, paint and other-drug. Six variables, in combination, were found to significantly differentiate the groups, and the derived function accounted for 56% of the between group differences. The following conclusions can be drawn from this investigation. Firstly, the adolescent paint sniffer is demonstrably and meaningfully different as discriminated by a combination of personal, familial and sociocultural variables. Secondly, these identified factors have predisposed the sniffer to abuse, and cannot be considered simply the consequence of said abuse. Finally, it can be concluded that the paint sniffer is a youth disengaged from the symbols and traditions of his/her culture of origin and concomitantly rejected by the majority culture. Inhalant intoxication provides a "cheap" and effective escape from his/her isolation. Recommendations for prevention, early intervention and treatment are addressed.


Early treatment of cold sores with topical ME-609 decreases the frequency of ulcerative lesions: a randomized, double-blind, placebo-controlled, patient-initiated clinical trial.
Prior pilot studies support the use of antiviral medications with topical corticosteroids for herpes simplex labialis (HSL). ME-609 (Xerese, Xerclear) is a combination of 5% acyclovir and 1% hydrocortisone developed for the topical treatment of HSL. The primary study end point was the prevention of ulcerative HSL lesions. In all, 2437 patients with a history of HSL were randomized to self-initiate treatment with ME-609, 5% acyclovir in ME-609 vehicle, or ME-609 vehicle (placebo) at the earliest sign of a cold sore recurrence. Cream was applied 5 times/d for 5 days. A total of 1443 patients experienced a recurrence and initiated treatment with ME-609 (n = 601), acyclovir (n = 610), or placebo (n = 232). Of patients receiving ME-609, 42% did not develop an ulcerative lesion compared with 35% of patients receiving acyclovir in ME-609 vehicle (P = .014) and 26% of patients receiving placebo (P < .0001). In patients with ulcerative lesions, healing times were reduced in the ME-609 and acyclovir groups compared with placebo (P < .01 for both). The cumulative lesion area for all lesions was reduced 50% in patients receiving ME-609 compared with the placebo group (P < .0001). There were no differences among groups in the number of patients with positive herpes simplex virus cultures. The side-effect profile was similar among treatments. The study did not contain a group treated with a topical corticosteroid alone. ME-609 prevented progression of cold sores to ulcerative lesions and significantly reduced the cumulative lesion area compared with acyclovir and placebo. ME-609 treatment offers additional therapeutic benefit compared with therapy with topical acyclovir alone.


Acid/base balance in fortified donor human milk: An experimental study.
Our goal was to quantify the pH and total acidity of human milk fortified with human milk fortifiers (HMFs), powder infant formulas, and protein additives. Commercial liquid HMFs and powder infant formulas were added to pasteurized pooled donor human milk in triplicate and stirred. The pH of unfortified and fortified human milk at 22, 24, 26, 27, 28, and 30 kcal/ounce (624, 680, 737, 765, 794, and 850 kcal/g, respectively) was determined using a pH meter. Phenolphthalein acidity at 24 and 30 kcal/ounce (680 and 850 kcal/g, respectively) was determined using diluted sodium hydroxide. The pH of unfortified human milk increased within the first hour (6.52 ± 0.06 vs 6.62 ± 0.05, P < 0.0001). Changes in pH largely correlated with caloric density; however, directional changes varied considerably between HMFs and powder infant formulas. Two liquid HMFs demonstrated modest reductions in pH with increasing caloric density whereas one liquid HMF alkalinized human milk with increasing caloric density (analysis of variance P < 0.0001). Phenolphthalein acidity was significantly higher for five HMFs and lower for one HMF at 30 kcal/ounce (850 kcal/g) but not 24 kcal/ounce (680 kcal/g). Powder infant formulas generally increased pH with increasing caloric density (analysis of variance P < 0.0001), but no differences in phenolphthalein acidity were noted. Changes in acid/base balancefor fortified human milk are variable and may be a consideration when selecting a fortifying agent for human milk.


Impact of Heat Stress on Blood, Production, and Physiological Indicators in Heat-Tolerant and Heat-Sensitive Dairy Cows.
Heat stress affects production and health in cows severely. Since it is difficult to define heat-tolerant animals, studies of response to heat stress are important for understanding dairy cows' health and production. However, information on the impact of heat stress on various indicators in heat-tolerant and heat-sensitive cows is sparse. This study aimed to investigate the effects of heat stress (HS) on blood, production, and physiological indicators in heat-tolerant and heat-sensitive cows. A total of 43 dairy cows were used from 9 May to 7 August 2021, under Temperature-Humidity Index (THI) measurements that ranged from 65.9 to 86.7. We identified cows that were tolerant or sensitive to HS based on the slope of the response of physiological and production traits against THI during the HS period by using a clustering method. After HS, serum glucose (Glu), cortisol (COR), 5-hydroxytryptamine (5-HT), and interleukin-6 (IL-6) levels of cows in the heat-tolerant group were lower than in the heat-sensitive group (p < 0.05). With THI as the predictor, the R2 for predicting respiration rate (RR) and body surface temperature (BT) in heat-tolerant cows was 0.15 and 0.16, respectively, whereas the R2 for predicting RR and BT in heat-sensitive cows was 0.19 and 0.18, respectively. There were low to moderate, positive correlations between RR, BT, and MY with THI, with Pearson correlation coefficients ranging from r = 0.11 to 0.4 in the heat-tolerant group, and from r = 0.24 to 0.43 in the heat-sensitive group. There was a low positive correlation between VT and THI, with a Spearman correlation coefficient of r = 0.07 in the heat-sensitive group. The heat-tolerant dairy cows had lower MY losses and had lower MY (p = 0.0007) in mixed models. Heat-tolerant cows with low-stress levels, through upregulating RR rapidly, increased their adaptability to thermal environments. They have better thermoregulation capability; the hypothalamic-pituitary-adrenal (HPA) axis regulated the thermoregulatory in animals by releasing a variety of neurotransmitters and hormones.


Regulation of the glutamine transporter SN1 by extracellular pH and intracellular sodium ions.
The glutamine transporter SN1 has recently been identified as one of the major glutamine transporters in hepatocytes and brain astrocytes. It appears to be the molecular correlate of system N amino acid transport. Two different transport mechanisms have been proposed for this transporter. These are an electroneutral mechanism, in which glutamine uptake is coupled to an exchange of 1Na+ and 1H+, or an electrogenic mechanism coupled to the exchange of 2Na+ against 1H+. This study was performed to solve these discrepancies and to investigate the reversibility of the transporter. When SN1 was expressed in Xenopus laevis oocytes, glutamine uptake was accompanied by a cotransport of 2-3 Na+ ions as determined by 22Na+ fluxes. However, at the same time a rapid release of intracellular Na+ was observed indicating an active exchange of Na+ ions. The driving force of the proton electrochemical gradient was equivalent to that of the sodium electrochemical gradient. Acidification of the extracellular medium caused the transporter to run in reverse and to release glutamine. Determination of accumulation ratios at different driving forces were in agreement with an electroneutral 1Na+-glutamine cotransport-1H+ antiport. Inward currents that were observed during glutamine uptake were much smaller than expected for a stoichiometric cotransport of charges. A slippage mode in the transporter mechanism and pH-regulated endogenous oocyte cation channels are likely to contribute to the observed currents.


Social cybersecurity: an emerging science.
With the rise of online platforms where individuals could gather and spread information came the rise of online cybercrimes aimed at taking advantage of not just single individuals but collectives. In response, researchers and practitioners began trying to understand this digital playground and the way in which individuals who were socially and digitally embedded could be manipulated. What is emerging is a new scientific and engineering discipline-social cybersecurity. This paper defines this emerging area, provides case examples of the research issues and types of tools needed, and lays out a program of research in this area.


Assessing the burden of viral co-infections in acute gastroenteritis in children: An eleven-year-long investigation.
Acute gastroenteritis is an important cause of childhood morbidity and mortality worldwide. A number of pathogens are responsible for human acute gastroenteritis. The recent introduction of syndromic assays for the diagnosis of enteric infections, including a wide panel of enteric pathogens, has unveiled the frequency of mixed infections. This study was carried out to assess the burden of viral co-infections and the genetic diversity of the viruses detected in children hospitalized with acute gastroenteritis in Italy. A total of 4161 stool samples collected from diarrheic children over 11 years, from January 2008 to December 2018, were investigated for the presence of four enteric viruses, i.e. group A rotavirus, norovirus, astrovirus and adenovirus. The samples were initially screened by either molecular or immunochromatographic assays and subsequently confirmed by Real-time PCR and sequence analyses. At least one viral agent was detected in 48.6 %of specimens. Rotavirus was the most prevalent virus (24.7 %) followed by norovirus (19.6 %), adenovirus (5.3 %) and astrovirus (3%). Co-infections were detected in 8.3 % of virus-positive patients, with common viral combination being rotavirus with norovirus (70.6 % of co-infections) or with astrovirus (9.6 %). A variety of viral genotypes was detected in co-infections and in single infections. Using Real-time PCR cycle thresholds as a proxy measure of fecal viral load, rotavirus was generally detected at higher levels in co-infected patients. Combining and deciphering measurable indicators of viral load and epidemiological information could be useful for an accurate interpretation of viral co-infections.


A developmental perspective on the cultural evolution of prosocial religious beliefs.
Norenzayan et al. argue that prosocial religion develops through cultural evolution. Surprisingly, they give little attention to developmental accounts of prosocial religious beliefs. A consideration of the developmental literature supports some, but not all, of the authors' conclusions.


Spontaneous regression of coronary artery obstructions: incidence in 313 consecutive repeat angiograms.
We studied the incidence of reversibility of coronary obstructions in a consecutive series of 313 patients with nonoperated coronary artery disease catheterized twice 3 to 118 (mean 38) months apart. Recanalization was observed in three patients and regression from an initial less than 100% obstruction in six patients. Progression in a different location occurred in six of the nine patients who demonstrated one recanalized or one regressive lesion. We conclude that true regression is an infrequent event in the natural history of medically treated patients with coronary artery disease; moreover, the pathophysiology and clinical relevance of angiographic regression remain poorly defined.


Dental caries in pre-school children: associations with social class, toothbrushing habit and consumption of sugars and sugar-containing foods. Further analysis of data from the National Diet and Nutrition Survey of children aged 1.5-4.5 years.
This project examined the relative significance of dietary sugars, toothbrushing frequency and social class as predictors of caries experience (caries vs. no caries) among 1,450 British pre-school children who took part in the National Diet and Nutrition Survey. This cross-sectional survey was based on a representative sample of children aged 1.5-4.5 years studied in 1992/3. Children were classified into four groups according to social class and toothbrushing habit. Diet/caries associations were examined for biscuits and cakes, sugar confectionery, chocolate confectionery and soft drinks, and the percentage of energy from non-milk extrinsic sugars, using data on amount and frequency of consumption from 4-day weighed dietary records. In stepwise logistic regressions, the strength of the association between social class and caries experience was twice that between toothbrushing and caries, and nearly three times that between sugar confectionery and caries (other dietary variables were not significant). The association of caries with sugar confectionery (both in amount and frequency) was only present among children whose teeth were brushed less than twice a day. Toothbrushing frequency appeared to have a stronger impact on caries prevention in non-manual compared with manual children. Household expenditure on confectionery was associated with caries only among children from the manual group. The findings suggest the hypothesis that regular brushing (twice a day) with a fluoride toothpaste may have greater impact on caries in young children than restricting sugary foods.


Bacteria associated with four species of Dacus (Diptera: Tephritidae) and their role in the nutrition of the larvae.
The bacteria associated with Dacus tryoni (Froggatt), Dacus jarvisi (Tryon), Dacus neohumeralis (Hardy) and Dacus cacuminatus (Hering) were examined. Bacteria were isolated from the surface of freshly-laid eggs, from within surface sterilised pupae, from heads and abdomens of wild and laboratory-maintained flies, and from decomposed fruits in which the wild larvae were feeding. A more diverse flora was associated with D. tryoni and D. jarvisi (15 and 14 species, respectively) than with D. neohumeralis and D. cacuminatus (9 and 6 species, respectively). Most of the bacteria belonged to the family Enterobacteriaceae and while there were similarities of bacterial associations between fly species there was no evidence of a strict symbiotic association of a particular bacterium or bacteria with each species of fly. The larvae of D. jarvisi were unable to develop normally in an artificial medium containing unhydrolysed protein and free of bacteria and on a medium containing casein and Serratia liquefaciens (isolated from the flies and shown to secrete protease) the larvae died. On the same casein medium containing Enterobacter cloacae (isolated from the flies and shown to be protease negative) the larvae developed normally. Larvae of D. tryoni and D. jarvisi were devoid of protease and cellulase activity, but contained some amylase activity. The significance of these results in terms of current hypotheses concerning symbioses between tephritids and bacteria is discussed.


Identification of an epitope derived from the cancer testis antigen HOM-TES-14/SCP1 and presented by dendritic cells to circulating CD4+ T cells.
Because of their frequent expression in a wide spectrum of malignant tumors but not in normal tissue except testis, cancer testis antigens are promising targets. However, except for HOM-TES-14/SCP1, their expression in malignant lymphomas is rare. SCP1 (synaptonemal complex protein 1) has been shown to elicit antibody responses in the autologous host, but no T-cell responses against HOM-TES-14/SCP1 have been reported. Using the SYFPEITHI algorithm, we selected peptides with a high binding affinity to major histocompatibility complex class 2 (MHC 2) molecules. The pentadecamer epitope p635-649 induced specific CD4+ T-cell responses that were shown to be restricted by HLA-DRB1*1401. The responses could be blocked by preincubation of T cells with anti-CD4 and antigen-presenting cells with anti-HLA-DR, respectively, proving the HLA-DR-restricted presentation of p635-649 and a CD4+ T-cell-mediated effector response. Responding CD4+ cells did not secrete interleukin-5 (IL-5), indicating that they belong to the T(H)1 subtype. The natural processing and presentation of p635-649 were demonstrated by pulsing autologous and allogeneic dendritic cells with a protein fragment covering p635-649. Thus, p635-649 is the first HOM-TES-14/SCP1-derived epitope to fulfill all prerequisites for use as a peptide vaccine in patients with HOM-TES-14/SCP1-expressing tumors, which is the case in two thirds of peripheral T-cell lymphomas.


Case Report: Refractory Shock due to Fulminant Dengue Myocarditis Treated with Venoarterial Extracorporeal Membrane Oxygenation: A Report of Four Cases.
Dengue disease is found worldwide and has been spreading exponentially in the past decades. Severe forms affect about 2% of patients, sometimes leading to organ failure. Recent studies have shown that fulminant dengue myocarditis is more common than previously thought, and fatal cases have been reported. The treatment of fulminant dengue myocarditis remains supportive and is very challenging in cases of cardiogenic shock. Here, we describe four cases presenting with fulminant dengue myocarditis treated with extracorporeal membrane oxygenation, among two survived.


Myelin basic protein gene expression in quaking, jimpy, and myelin synthesis-deficient mice.
Jimpy (jp), myelin synthesis-deficient (jpmsd), and quaking (qk) are mutations which affect myelination to different degrees in the mouse central nervous system (CNS). Total messenger RNA (mRNA) and myelin basic protein (MBP)-specific mRNA from brains of these three mutants have been analyzed by in vitro translation and immunoprecipitation with antibody to MBP. The results indicate that the three mutations do not affect the level of total MBP-specific mRNA in the CNS but do affect the relative proportions of the various MBP-related translation products encoded in vitro. In each case the proportions of 14K and 12K Mr MBP-related translation products are reduced and the proportions of 21.5K, 18.5K, and 17K Mr MBP-related translation products are increased relative to wild type. This effect is most pronounced in jp, less so in jpmsd, and least pronounced in qk animals. The MBP-related polypeptides that accumulate in vivo have also been analyzed in the three mutants by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) followed by immunoblotting with antibody to MBP. The levels of all the major MBP-related polypeptides that accumulate in vivo are reduced in all three mutations. The reduction is most pronounced in jp, less in jpmsd, and least pronounced in qk animals. These results indicate that the jp, jpmsd, and qk mutations exhibit qualitatively similar phenotypic effects on MBP gene expression but the magnitude of the effect is proportional to the extent of hypomyelination in each mutant.


Preliminary study for predicting better methotrexate efficacy in Japanese patients with rheumatoid arthritis.
Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by systemic inflammatory status, joint destruction, disability, and pain. Methotrexate (MTX) has been confirmed to reduce disease activity and delay or stabilize the development of bone erosions. However, major drawbacks are that patients show great interindividual variability in response to MTX and the unpredictable occurrence of side effects. A strategy for personalized MTX treatment to predict its efficacy and toxicity has not yet been determined. To establish personalized MTX therapy in Japanese patients with rheumatoid arthritis, we performed a preliminary study for predicting better methotrexate efficacy including single-nucleotide polymorphisms (SNPs) for MTX-related transporters/enzymes. Disease control status (good or poor) was judged by the number of Disease Activity Scores (DAS28) of <2 for 6-12 months. The response index R was calculated by the improved area under the curve (AUC) of the DAS28 score for 0-3 or 0-6 months by dividing the cumulative dose of MTX during 0-3 or 0-6 months, respectively. Genotyping of alleles of RFC1 80G > A, RFC1 -43 T > C, FPGS 1994G > A, GGH 401C > T, MTHFR 1298A > C, and TYMS 3'-UTR (-6/+6) was performed using the real-time PCR system. Seven of 21 patients were judged as good responders in terms of disease control, and the remainder as poor responders. For 0-3 months after starting MTX administration, the median cumulative dose and improved DAS28 AUC in the good and poor response groups were 96.0 mg and 25.4 and 118.0 mg and 23.4, respectively. For 0-6 months, the median cumulative dose and improved DAS28 AUC in the good and poor response groups were 192.0 mg and 51.0 and 214.0 mg and 47.6, respectively. Statistically significant differences between the 2 groups in the 0-6-month period were observed in DAS28 AUC improvement and index R. A slight tendency for a correlation between G/G genotypes and A allele genotypes in RFC1 80 genotypes was observed, although it did not reach statistical significance. This study suggested that aggressive RA treatment with MTX from the early period of administration is necessary to obtain a good response after 6 months, although no SNPs predicting a better treatment response to MTX were identified.


At 10-Year Minimum Follow-Up, One-Third of Patients Have Patellofemoral Arthritis After Isolated Medial Patellofemoral Ligament Reconstruction Using Gracilis Tendon Autograft.
To report the long-term clinical outcomes after isolated medial patellofemoral ligament reconstruction (MPFLr) to treat recurrent patellar instability. This was a single-center study of patients undergoing an isolated MPFLr between 2000 and 2011. All patients underwent reconstruction using hamstring autograft. The inclusion criteria were a minimum 10-year follow-up period and skeletally mature patients with more than 1 episode of patellar dislocation who underwent MPFLr without an associated bony procedure. A total of 54 knees were available for final analysis. The mean follow-up period was 12.3 years (range, 10-14 year). The mean age at surgery was 25 years. No patients had patellofemoral arthritis (PFA) prior to surgery. Preoperatively, the mean Caton-Deschamps index was 1.1 and the mean tibial tubercle-trochlear groove distance was 14.9 ± 2 mm (range, 7-17 mm). All patients had trochlear dysplasia according to the Dejour classification. At final follow-up, the mean Kujala score was 82.9 ± 15.3; mean International Knee Documentation Committee score, 78.3 ± 18.5; and mean Tegner score, 4.0 ± 1.7. Patients with an unsatisfactory outcome as determined by a Kujala score lower than 80 had a higher Caton-Deschamps index preoperatively and were more likely to be female patients; however, neither factor reached significance. Of the patients, 33 (66%) had no radiographic evidence of PFA whereas 15 (30%) had Iwano stage 1 and 2 had Iwano stage 2 (4%). At final follow-up, 4 patients (7.4%) had recurrent instability requiring revision surgery. Isolated MPFLr with gracilis tendon autograft in appropriately selected patients is an effective long-term treatment for recurrent patellofemoral instability with low rates of recurrence. One-third of patients exhibit radiographic evidence of PFA more than 10 years after isolated MPFLr. Level IV, case series.


Molecular mechanisms of eukaryotic translation fidelity and their associations with diseases.
Converting genetic information into functional proteins is a complex, multi-step process, with each step being tightly regulated to ensure the accuracy of translation, which is critical to cellular health. In recent years, advances in modern biotechnology, especially the development of cryo-electron microscopy and single-molecule techniques, have enabled a clearer understanding of the mechanisms of protein translation fidelity. Although there are many studies on the regulation of protein translation in prokaryotes, and the basic elements of translation are highly conserved in prokaryotes and eukaryotes, there are still great differences in the specific regulatory mechanisms. This review describes how eukaryotic ribosomes and translation factors regulate protein translation and ensure translation accuracy. However, a certain frequency of translation errors does occur in translation, so we describe diseases that arise when the rate of translation errors reaches or exceeds a threshold of cellular tolerance.


Accreditation of an old surgical technique for stress urinary incontinence: long-term outcomes of modified autologous fascial pubovaginal sling.
To evaluate long-term outcomes of modified autologous fascial pubovaginal sling (AFPVS) in women with stress urinary incontinence (SUI). To evaluate long-term outcomes of modified AFPVS, we retrospectively reviewed the medical records of our patients from 2004 to 2015. From 2 decades ago, we have made modifications to classic surgical technique to make it simpler and faster. 199 patients were contacted with mean age of 52 years. The mean follow-up period was 107 months. According to Revised Urinary Incontinence Scale (RUIS) questionnaire, overall success rate was 83.9%. In patients with positive history for SUI surgery, success rate was 73% compared to 87% in those without it. Body mass index was negatively associated with cure rate. We did not encounter any major complications and most of the issues were managed conservatively. Recurrence of SUI occurred in 6 patients (3.5%) after initial improvement. Modified AFPVS is an effective surgical technique for treatment of SUI with high and durable success rate. At the present time with concerns regarding the use of transvaginal synthetic mesh, there is increasing interest and request for modified traditional procedures. It is likely that AFPVS may become more popular in upcoming years.


Deconstructing 5-HT6 receptor effects on striatal circuit function.
Medium spiny neurons (MSNs) constitute 95% of neurons in the dorsal striatum subdivided into direct (striatonigral) and indirect (striatopallidal) pathways. Whereas D1 and D2 receptors and several neuropeptides, including dynorphin and enkephalin, are differentially expressed in these neurons, 5-hydroxytryptamine 6 receptors (5-HT6) are expressed in both pathways. Previous results demonstrate that concurrent 5-HT6 receptor overexpression in MSNs of both pathways in the dorsomedial striatum (DMS) interferes with instrumental learning and that 5-HT6 overexpression in the dorsolateral striatum (DLS) relieves rats from inflexible habitual behaviors. We hypothesized that 5-HT6 receptor-mediated co-activation of both pathways interferes with the differential activation/inhibition of direct/indirect pathways by dopamine. To test this idea, we cloned novel viral vectors to selectively overexpress 5-HT6 receptors in direct or indirect pathway MSNs to deconstruct their role in modulating instrumental learning and habitual responding. We found that increasing 5-HT6 receptor expression in either direct or indirect pathway MSNs of the posterior DMS selectively enhanced or impaired initial acquisition of a discrete instrumental learning task respectively, though all rats were ultimately able to learn the task. In a separate set of experiments, 5-HT6 receptor overexpression in indirect pathway MSNs of the DLS facilitated behavioral flexibility in rats overtrained on a repetitive pressing task using a variable interval schedule of reinforcement, during an omission contingency training session and subsequent probe testing. Together these findings further the notion that 5-HT6 signaling causes balanced activation of opposing MSN pathways by serotonin in sub-regions of the dorsal striatum allowing for more reflective modalities of behavior.


Genetic relationship and diversity among coconut (Cocos nucifera L.) accessions revealed through SCoT analysis.
Coconut (Cocos nucifera L.) is one of the important palms grown both as a homestead and plantation crop in countries and most island territories of tropical regions. Different DNA-based marker systems have been utilized to assess the extent of genetic diversity in coconut. Advances in genomics research have resulted in the development of novel gene-targeted markers. In the present study, we have used a simple and novel marker system, start codon targeted polymorphism (SCoT), for its evaluation as a potential marker system in coconut. SCoT markers were utilized for assessment of genetic diversity in 23 coconut accessions (10 talls and 13 dwarfs), representing different geographical regions. Out of 25 SCoT primers screened, 15 primers were selected for this study based on their consistent amplification patterns. A total of 102 scorable bands were produced by the 15 primers, 88 % of which were polymorphic. The scored data were used to construct a similarity matrix. The similarity coefficient values ranged between 0.37 and 0.91. These coefficients were utilized to construct a dendrogram using the unweighted pair group of arithmetic means (UPGMA). The extent of genetic diversity observed based on SCoT analysis of coconut accessions was comparable to earlier findings using other marker systems. Tall and dwarf coconut accessions were clearly demarcated, and in general, coconut accessions from the same geographical region clustered together. The results indicate the potential of SCoT markers to be utilized as molecular markers to detect DNA polymorphism in coconut accessions.


Effects of hypoxia on cerebral and muscle haemodynamics during knee extensions in healthy subjects.
A hypoxic model was used to investigate changes in localized cerebral and muscle haemodynamics during knee extension (KE) in healthy individuals. Thirty-one young healthy volunteers performed one set of KE until failure under hypoxia (14 % O(2)) or normoxia (21 % O(2)) at 50, 75 or 100 % of 1 repetition maximum, in random order, on three occasions. Prefrontal cerebral and vastus lateralis muscle oxygenation and blood volume (Cox, Mox, Cbv and Mbv, respectively) were recorded simultaneously by near-infrared spectroscopy. Hypoxia induced significant declines in Cox [-0.017 ± 0.016 optical density (OD) units] and Mox (-0.014 ± 0.026 OD units) and increases in Cbv (0.017 ± 0.027 OD units) and Mbv (0.016 ± 0.023 OD units) at rest. Hypoxia significantly reduced total work (TW) performed during KE at each exercise intensity. Cox, Cbv, Mox, and Mbv changes during KE did not differ between normoxia and hypoxia. Correlations between TW done and Cox changes under normoxia (r = 0.04, p = 0.182) and hypoxia (r = 0.05, p = 0.122) were not significant. However, TW was significantly correlated with Mox under both normoxia (R (2) = 0.24, p = 0.000) and hypoxia (R (2) = 0.15, p = 0.004). Since changes in Cox and Mox reflect alterations in the balance between oxygen delivery and extraction in these tissues, which, in the brain, is an index of neuronal activation, we conclude that: (1) limitation of KE performance was mediated peripherally under both normoxia and hypoxia, with no additional effect of hypoxia, and (2) because of the low common variance with Mox additional intramuscular factors likely play a role in limiting KE performance.


Treatment of ammonium-rich swine waste in modified porphyritic andesite fixed-bed anaerobic bioreactor.
In this study, a modified porphyritic andesite (WRS) was developed as ammonium adsorbent and bed material for the anaerobic digestion of ammonium-rich swine waste. The performance in bioreactors with modified WRS, natural WRS, calcium chloride and no additives was investigated. The bioreactor with modified WRS exhibited the best performance, with start-up time on the 7th day, methane yield of 359.71 ml/g-VS, and COD removal of 67.99% during all 44 days of the experiment at 35°C. The effective ammonium adsorption and essential ions dissociation for microorganisms by modified WRS, as well as the immobilization of microbial on the surface of the modified WRS play a great role on the high efficiency anaerobic digestion of ammonium-rich swine waste.


IκB kinase promotes Nrf2 ubiquitination and degradation by phosphorylating cylindromatosis, aggravating oxidative stress injury in obesity-related nephropathy.
Obesity-related nephropathy (ORN) has become one of the leading causes of end-stage renal disease and has tripled over the past decade. Previous studies have demonstrated that decreased reactive oxygen species production may contribute to improving ORN by ameliorating oxidative stress injury. Here, IκB kinase (IKK) was hypothesized to inactivate the deubiquitination activity of cylindromatosis (CYLD) by activating the phosphorylation of CYLD, thus promoting the ubiquitination of NF-E2-related factor 2 (Nrf2) and further aggravating oxidative stress injury of the kidney in ORN. This study was aimed to confirm this hypothesis. Haematoxylin and eosin (HE), periodic acid-Schiff (PAS) and Oil Red O staining were performed to assess histopathology. Dihydroethidium (DHE) staining and MDA, SOD, CAT, and GSH-PX assessments were performed to measure reactive oxygen species (ROS) production. Immunohistochemical (IHC) staining, qRT-PCR and/or western blotting were performed to assess the expression of related genes. JC-1 assays were used to measure the mitochondrial membrane potential (ΔΨm) of treated HK-2 cells. Co-immunoprecipitation experiments (Co-IP) were used to analyse the interaction between CYLD and Nrf2 in ORN. ORN in vivo and in vitro models were successfully constructed, and oxidative stress injury was detected in the model tissues and cells. Compared with the control groups, the phosphorylation level of CYLD increased while Nrf2 levels decreased in ORN model cells. An IKK inhibitor reduced lipid deposition, ROS production, CYLD phosphorylation levels and ΔΨm in vitro, which were reversed by knockdown of CYLD. Nrf2 directly bound to CYLD and was ubiquitinated in ORN cells. The proteasome inhibitor MG132 activated the Nrf2/ARE signalling pathway, thereby reversing the promoting effect of CYLD knockdown on oxidative stress. IKK inactivates the deubiquitination activity of CYLD by activating the phosphorylation of CYLD, thus promoting the ubiquitination of Nrf2 and further aggravating oxidative stress injury of the kidney in ORN. This observation provided a feasible basis for the treatment of kidney damage caused by ORN.


Rapid phosphorylation of cellular proteins during differentiation of neuroblastoma cells induced by recombinant human interferon-gamma.
Cells of two human neuroblastoma lines, GOTO and KP-N-RT-LN, differentiated in response to treatment with 1,000 IU/ml of recombinant human interferon-gamma (rIFN-gamma), but did not respond to rIFN-alpha 2 or IFN-beta. Treatment with rIFN-gamma rapidly increased the phosphorylation of several cell proteins; in particular, there was enhanced phosphorylation of a 61-kD protein within 1 min after treatment. This enhancement was not observed in variant sublines of GOTO cells, which did not differentiate when treated with rIFN-gamma. These findings suggest that when neuroblastoma cells are induced to differentiate by treatment with rIFN-gamma, phosphorylation of the 61-kD protein plays an important role.


Towards a robust out-of-the-box neural network model for genomic data.
The accurate prediction of biological features from genomic data is paramount for precision medicine and sustainable agriculture. For decades, neural network models have been widely popular in fields like computer vision, astrophysics and targeted marketing given their prediction accuracy and their robust performance under big data settings. Yet neural network models have not made a successful transition into the medical and biological world due to the ubiquitous characteristics of biological data such as modest sample sizes, sparsity, and extreme heterogeneity. Here, we investigate the robustness, generalization potential and prediction accuracy of widely used convolutional neural network and natural language processing models with a variety of heterogeneous genomic datasets. Mainly, recurrent neural network models outperform convolutional neural network models in terms of prediction accuracy, overfitting and transferability across the datasets under study. While the perspective of a robust out-of-the-box neural network model is out of reach, we identify certain model characteristics that translate well across datasets and could serve as a baseline model for translational researchers.


Transcriptional profiles of regulatory and virulence factors of Staphylococcus aureus of bovine origin: oxygen impact and strain-to-strain variations.
Staphylococcus aureus is responsible for a large panel of infections in humans and animals. In cows, S. aureus provokes chronic intramammary infections. Little information is available about the regulation of virulence factors in bovine isolates. Moreover, oxygenation, which is low in an inflamed mammary gland, could play an important role during the infectious process. We investigated the impact of oxygen on regulatory and virulence factors transcription for three S. aureus bovine isolates cultivated in CYPG medium into a fermentor under moderate oxygenation or low oxygenation. A selective panel of regulatory factors and virulence factors was studied through their mRNA profiles by real-time PCR according to growth phases and oxygenation. RNAIII, rot and sarR genes, for the regulatory factors, and asp23 and cflA genes, for the virulence factors, were strongly expressed, whatever the oxygenation and the strains. Under low oxygenation, whatever the strain, an enhanced expression of srr, clfA and spa genes was detected. Some regulators such as sae, sarA and sigB were differentially transcribed according to the strain and the oxygenation condition. This study sustains the complexity of S. aureus genes global regulation and suggests the coexistence of different pathways that can be activated depending on the strain and the oxygen availability.


Effect of light, oxygen and temperature on the stability of artepillin C and p-coumaric acid from Brazilian green propolis.
Brazilian Green Propolis (BGP) is an important bee product, which displays important biological activities, making it valuable in the international market. The major prenylated phenolic compound in BPG is (E)-artepillin C, along with its precursor (E)-p-coumaric acid, both contributing to the biological effects of BGP. Taking that into account, it was evaluated the effect of light, temperature and air oxygen in their content to establish the best storage and transport conditions for crude BGP and the pure compounds. For that, (E)-artepillin C and (E)-p-coumaric acid were initially submitted to degradation for five days under sunlight and high temperature (50 °C), furnishing three major (E)-Artepillin C isomers and one from (E)-p-coumaric acid. Then, it was developed and validated a Reverse Phase High Performance Liquid Chromatography (RP-HPLC) method for quantifying these compounds in crude BGP and in its extracts. In the stability studies, it was used a Full Factorial and Central Composite Design to establish the desirable storage conditions. (E)-Artepillin C, both pure and in BGP should be kept protected from light and storage below -2.5 °C. (E)-p-Coumaric acid can be stored at room temperature. Therefore, the best storage and transport conditions to keep the content of both compounds in BGP are protection from light at low temperatures.


Microscopic evaluation of vesicles shed by erythrocytes at elevated temperatures.
The images of human erythrocytes and vesicles were analyzed by a light microscopy system with spatial resolution of better than 90 nm. The samples were observed in an aqueous environment and required no freezing, dehydration, staining, shadowing, marking, or any other manipulation. Temperature elevation resulted in significant concentration increase of structurally transformed erythrocytes (echinocytes) and vesicles in the blood. The process of vesicle separation from spiculated erythrocytes was video recorded in real time. At a temperature of 37°C, mean vesicle concentrations and diameters were found to be 1.50 ± 0.35 × 10(6) vesicles per microliter and 0.365 ± 0.065 μm, respectively. The vesicle concentration increased approximately threefold as the temperature increased from 37 to 40°C. It was estimated that 80% of all vesicles found in the blood are smaller than 0.4 μm. Accurate account of vesicle numbers and dimensions suggest that 86% of the lost erythrocyte material is lost not by vesiculation but by another, as yet, unknown mechanism.


Differentiated thyroid carcinoma in sporadic and familial presentations of acromegaly: A case series.
In acromegaly, chronic growth hormone (GH) and insulin-like growth factor-1 (IGF-1) exacerbate comorbidities in multiple organs. Differentiated thyroid carcinoma (DTC) has been reported as being a comorbid condition in acromegaly. Acromegaly is usuallysporadic, but 5% of cases may be genetic. The most frequent inheritable form of acromegaly is related to germline mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene. Epidemiological data on the relationship between active acromegaly, its familial forms and DTC are sparse. We present the investigation of a FIPA family (familial isolated pituitary adenoma) with homogeneous acromegaly and 6 sporadic acromegaly patients with DTC. A study of 59 acromegaly patients assessed thyroid nodules on ultrasound and fine-needle aspiration biopsy following the ATA 2015 criteria. We diagnosed 7 differentiated thyroid carcinomas. Resected thyroid carcinoma tissues were stained using an anti-AIP antibody. Analysis of germline and tumor-derived DNA for variants in the AIP and MEN1 genes were performed in the FIPA kindred. We describe one FIPA patient and 6 sporadic acromegaly cases with DTC. The FIPA family (AIP mutation negative) consisted of two sisters, one of whom had a DTC with intermediate risk and incomplete structural response to therapy. In our study, DTC in sporadic acromegaly had a low recurrence rate (6/6), and excellent response to therapy (6/6). Immunohistochemistry for AIP showed similar or increased staining intensity in DTC versus normal thyroid tissue. In our cohort of sporadic and familial forms of acromegaly with DTC, AIP did not appear to influence thyroid cancer progression.


Confidential unit exclusion at the regional blood bank in Montes Claros - Fundação Hemominas.
This study aimed at analyzing the rate of self-exclusion at the Regional Blood Bank in Montes Claros. Data of self-excluding donors from August 2008 to August 2010 were analyzed. The following variables were considered: age, marital status, gender, ethnical background, blood group, Rh factor, number of donations, type of donation and serologic results. During the analyzed period, 34,778 individuals donated blood, 215 (0.62%) of which were self-excluded; 12% of donors did not answer, 6.3% ballots were spoilt and 13.6% of the responses were considered non-compliant. The profile of the donors was: male (81.9%), single (50.7%), aged between 19 and 29 years old (52.1%), Mulatto (48.3%), blood group O (32.1%) and positive Rh (32.1%). Most individuals were donating for the 2(nd)to 5(th) time (43.7%) and had negative serology (94.4%). It was not evident that self-excluding donors had higher rates of seropositivity.


Biodegradation of benazolin-ethyl by strain Methyloversatilis sp. cd-1 isolated from activated sludge.
Benazolin-ethyl has been used on a wide range of weeds present in various crops since 1964. Because benazolin-ethyl is a potential hazard to the environment and human health, it is important to remove this herbicide from the environment. However, to the best of our knowledge, no report is available in the literature regarding the microbial degradation of benazolin-ethyl by bacteria. In this study, one strain named cd-1, which is capable of degrading benazolin-ethyl, was isolated from benazolin-ethyl wastewater treatment pool. The isolate was identified as Methyloversatilis sp. according to its morphological, physiological, biochemical properties, and 16S rRNA gene sequences analysis. This strain utilizes benazolin-ethyl as the sole carbon source. and degrades 100 mg l⁻¹ benazolin-ethyl to non-detectable level within 48 h. Three metabolites were identified as benazolin, 7-chloro-3-methylbenzo[d]thiazol-2(3H)-one, and 2-chloro-6-(methyleneamino)benzenethiol based on the MS/MS and GC/MS analyses. The first step involved in the degradation of benazolin-ethyl was the cleavage of the ester bond to form benazolin. Benazolin was subsequently subjected to demethylation for decomposition into 7-chloro-3-methylbenzo[d]thiazol-2(3H)-one and methanol. The last step was to form 2-chloro-6-(methyleneamino)benzenethiol.


No significant level of inheritable interchromosomal aberrations in the progeny of bystander primary human fibroblast after alpha particle irradiation.
A major concern for bystander effects is the probability that normal healthy cells adjacent to the irradiated cells become genomically unstable and undergo further carcinogenesis after therapeutic irradiation or space mission where astronauts are exposed to low dose of heavy ions. Genomic instability is a hallmark of cancer cells. In the present study, two irradiation protocols were performed in order to ensure pure populations of bystander cells and the genomic instability in their progeny were investigated. After irradiation, chromosomal aberrations of cells were analyzed at designated time points using G2 phase premature chromosome condensation (G2-PCC) coupled with Giemsa staining and with multiplex fluorescent in situ hybridization (mFISH). Our Giemsa staining assay demonstrated that elevated yields of chromatid breaks were induced in the progeny of pure bystander primary fibroblasts up to 20 days after irradiation. MFISH assay showed no significant level of inheritable interchromosomal aberrations were induced in the progeny of the bystander cell groups, while the fractions of gross aberrations (chromatid breaks or chromosomal breaks) significantly increased in some bystander cell groups. These results suggest that genomic instability occurred in the progeny of the irradiation associated bystander normal fibroblasts exclude the inheritable interchromosomal aberration.


[The occurence of genetic trombophilic markers in patients evaluated for infertility].
To assess and compare the frequency of selected gene mutations of thrombophilic markers (FV Leiden, FII prothrombin G20210A and MTHFR C677T) in patients with primary and secondary infertility. Retrospective study. Institute of normal anatomy, Faculty of Medicine and Dentistry, Palacky University Olomouc. The study included 92 patients with primary infertility and 89 patients with secondary infertility. Indications for examination of these mutations were following: a positive family or personal history, a positive obstetrical history or a repeated failure of assisted reproduction treatment. According to our anticipation, women with the secondary infertility were significantly older(p < 0.0005) than those with primary infertility. No mutations of genes of examined thrombophilic markers (FV, FII and MTHFR), either alone or in combination, were found in only 8.7 % patients with primary infertility and in 5.6 % patients with secondary infertility. Significantly higher frequency of factor Leiden(p < 0.02) was observed in women with secondary infertility. There were no significant differences in the frequency of detected mutations of the remaining factors. Based on our findings we suggest that the assessment of selected gene mutations of thrombophilic markers should be a part of the diagnostic algorithm in patients with positive history for thrombophilic disorders.


Synthesis and Performance of Imide-Based Small Molecules Containing Carbazole Groups with AIE Properties.
Here, two novel naphthalimide derivatives SNI-Cz and SNI-DCz with AIE were designed and synthesized. The correctness of the two structures was characterized by NMR and HRMS. Their crystal structures, photophysical properties, electrochemical properties, thermal stabilities, fluorescence lifetime and yields have been characterized. Photoluminescence experiments revealed that SNI-DCz had superior properties due to the D-π-A-π-D structure and sliding away stacking of molecules. SNI-DCz exhibited weak fluorescence in pure DMF, with a significant AIE effect observed in the 40% water mixture and a sharp increase in fluorescence intensity was also observed. Cyclic voltammetry and thermogravimetric analysis indicated that SNI-DCz had good electron affinity and thermal stability. The excellent properties of SNI-DCz made it a promising emitter for optoelectronics.


Biomarkers of Endothelial Activation in Black South African HIV-Positive Subjects are Associated with Both High Viral Load and Low CD4 Counts.
The prevalence of cardiovascular death in the HIV-infected population is higher than in uninfected individuals. Growing evidence suggests that HIV infection itself is directly linked to endothelial activation and dysfunction. Therefore, the aim of this study was to investigate whether endothelial activation is present in African subjects with HIV infection and identify its possible determinants. Eighty HIV-infected treatment-naive cases, categorized into two groups based on CD4 count (38 subjects with CD4 count ≤350 cells/mm3 and 42 subjects with CD4 count >350 cells/mm3), were compared with 60 HIV-uninfected controls. A small subgroup of the HIV-infected participants (n = 13) were followed up for 18 months following initiation of antiretroviral therapy (ART). Anthropometric data, fasting lipid and glucose levels, viral load, and CD4 counts were measured as were serum levels of intercellular adhesion molecule-1 (ICAM-1), endothelial leukocyte adhesion molecule-1, vascular cell adhesion molecule-1 (VCAM-1), monocyte chemoattractant protein-1, von Willebrand factor (vWF), tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), and interleukin-8 (IL-8). The HIV-infected low CD4 group had higher levels of ICAM-1 (p < .05), VCAM-1 (p < .0005), TNF-α (p < .005), and vWF (p < .005), compared with the controls. In the HIV-infected cohort, VCAM-1 levels were negatively associated with CD4 counts (β = -0.474; p < .0005), whereas vWF levels were positively associated with viral load (β = 0.344; p < .01). Levels of ICAM-1 and VCAM-1 were reduced by ART (p < .05 vs. baseline for both), however, levels of IL-6, IL-8, and TNF-α increased (p < .005 vs. baseline for all). Endothelial activation and inflammation are evident in African ART-naive HIV-infected patients; the former is attenuated, and the latter is increased after 18 months of ART. In HIV-infected subjects, both immunological dysregulation and viral load are associated with biomarkers of endothelial activation.


Structure of the tear film during the blinking process.
The structure of the tear film was photographed immediately prior and subsequent to lid closure with a magnification factor of 140 X. Deformations of the tear film were observed in the form of "creasing", "wave motion" and also "fairly rough graininess" which point to a remarkably stable consistency of the lipid layer.


Meta-analysis of cortical thickness abnormalities in medication-free patients with major depressive disorder.
Alterations in cortical thickness have been identified in major depressive disorder (MDD), but findings have been variable and inconsistent. To date, no reliable tools have been available for the meta-analysis of surface-based morphometric (SBM) studies to effectively characterize what has been learned in previous studies, and drug treatments may have differentially impacted findings. We conducted a comprehensive meta-analysis of magnetic resonance imaging (MRI) studies that explored cortical thickness in medication-free patients with MDD, using a newly developed meta-analytic mask compatible with seed-based d mapping (SDM) meta-analytic software. We performed the meta-regression to explore the effects of demographics and clinical characteristics on variation in cortical thickness in MDD. Fifteen studies describing 529 patients and 586 healthy controls (HCs) were included. Medication-free patients with MDD, relative to HCs, showed a complex pattern of increased cortical thickness in some areas (posterior cingulate cortex, ventromedial prefrontal cortex, and anterior cingulate cortex) and decreased cortical thickness in others (gyrus rectus, orbital segment of the superior frontal gyrus, and middle temporal gyrus). Most findings in the whole sample analysis were confirmed in a meta-analysis of studies recruiting medication-naive patients. Using the new mask specifically developed for SBM studies, this SDM meta-analysis provides evidence for regional cortical thickness alterations in MDD, mainly involving increased cortical thickness in the default mode network and decreased cortical thickness in the orbitofrontal and temporal cortex.


Value and engagement: what can clinical trials learn from techniques used in not-for-profit marketing?
Marketing is a core business function in commercial companies but is also frequently used by not-for-profit organisations. Marketing focuses on understanding what people value to make choices about engaging with a product or service: a concept also key to understanding why people may choose to engage with a clinical trial. Understanding the needs and values of stakeholders, whether they are participants, staff at recruiting sites or policy-makers, is critical for a clinical trial to be a success. As many trials fail to recruit and retain participants, perhaps it is time for us to consider approaches from other disciplines. Though clinical trial teams may consider evidence- and non-evidence-based recruitment and retention strategies, this is rarely done in a systematic, streamlined way and is often in response to challenges once the trial has started. In this short commentary, we argue the need for a formal marketing approach to be applied to clinical trials, from the outset, as a potential prevention to recruitment and retention problems.


Prognostic significance of the novel nutrition-inflammation marker of lymphocyte-C-reactive protein ratio in patients with nasopharyngeal carcinoma receiving concurrent chemoradiotherapy.
Recent studies indicate that the novel lymphocyte-C-reactive protein ratio (LCR) is strongly associated with the survival of various tumors, but its prognostic value in nasopharyngeal carcinoma (NPC) is understudied. This study aimed to explore the relationship between LCR and overall survival (OS) in NPC and develop a predictive model. A total of 841 NPC patients who received concurrent chemoradiotherapy (CCRT) between January 2010 and December 2014 were retrospectively enrolled and randomly divided into a training cohort (n = 589) and a validation cohort (n = 252), and 122 patients between January 2015 and March 2015 were included as an additional validation cohort. Univariate and multivariate Cox analyses were performed to identify variables associated with OS and construct a predictive nomogram. The predictive accuracy of the nomogram was evaluated and independently validated. The LCR score differentiated NPC patients into two groups with distinct prognoses (HR = 0.53; 95% CI: 0.32-0.89, P = 0.014). Multivariate analysis showed that age, T stage, N stage, EBV-DNA status, and LCR score were independently associated with OS, and a predictive nomogram was developed. The nomogram had a good performance for the prediction of OS [C-index = 0.770 (95% CI: 0.675-0.864)]. and outperformed the traditional staging system [C-index = 0.589 (95% CI: 0.385-0.792)]. The results were internally and additionally validated using independent cohorts. The pretreatment LCR could independently predict the overall survival in NPC patients. A novel LCR-based prognostic model of an easy-to-use nomogram was established, and it outperformed the conventional staging system in terms of predictive power. Further external verification remains necessary.


A review of the barriers to using Patient-Reported Outcomes (PROs) and Patient-Reported Outcome Measures (PROMs) in routine cancer care.
Patient-reported outcomes (PROs) are direct reports from patients about the status of their health condition without amendment or interpretation by others. Patient-reported outcome measures (PROMs) are the tools used to measure PROs; they are usually validated questionnaires patients complete by self-assessing their health status. Whilst the benefits of using PROs and PROMs to guide real-time patient care are well established, they have not been adopted by many oncology institutions worldwide. This literature review aimed to examine the barriers associated with using PROs and PROMs in routine oncology care. A literature search was conducted across EMBASE, Medline and CINAHL databases. Studies detailing barriers to routine PRO use for real-time patient care were included; those focusing on PRO collection in the research setting were excluded. Of 1165 records captured, 14 studies informed this review. At the patient level, patient time, incapacity and difficulty using electronic devices to complete PROMs were prominent barriers. At the health professional level, major barriers included health professionals' lack of time and knowledge to meaningfully interpret and integrate PRO data into their clinical practice and the inability for PRO data to be acted upon. Prominent barriers at the service level included difficulties integrating PROs and PROMs into clinical workflows and inadequate information technology (IT) infrastructures for easy PRO collection. This review has outlined potential barriers to routine PRO use in the oncology setting. Such barriers should be considered when implementing PROs into routine clinical practice.


Intervention in free radical mediated hepatotoxicity and lipid peroxidation by indole-3-carbinol.
The cytoprotective effect of the natural dietary constituent indole-3-carbinol (I-3-C) on carbon tetrachloride (CCl4) mediated hepatotoxicity in mice was examined. I-3-C pretreatment by gavage 1 hr prior to intraperitoneal injection of CCl4 produced a 63% decrease in CCl4-mediated centrolobular necrosis and a related 60% decrease in plasma alanine aminotransferase activity (a marker of liver necrosis). Since the toxicological effects of CCl4 are mediated by radical species generated during reductive metabolism by cytochrome P-450, we examined the potential ability of I-3-C to scavenge reactive radicals. Three systems were used to evaluate the ability of I-3-C to intervene in free radical mediated lipid peroxidation. These systems consisted of the following: (1) phospholipid dissolved in chlorobenzene, with peroxidation initiated by the thermal and photo decomposition of azobisisobutyronitrile (AIBN); (2) sonicated phospholipid vesicles in phosphate buffer (pH 7.4), with peroxidation initiated by ferrous/ascorbate; and (3) mouse liver microsomes containing an NADPH-regenerating system, with peroxidation initiated with CCl4. Lipid peroxidation was measured in these three systems as thiobarbiturate-reacting material. In the AIBN and ferrous/ascorbate systems, I-3-C inhibited lipid peroxidation, with greater inhibition under conditions of low rates of free radical generation. I-3-C was not as effective an antioxidant as butylated hydroxytoluene (BHT) or tocopherol, but it inhibited peroxidation in a dose-response manner. I-3-C was most effective as a radical scavenger in the microsomal CCl4-initiated system by inhibiting lipid peroxidation in a dose-dependent fashion, with 50% inhibition at 35-40 microM I-3-C. This concentration is about one-third of the concentration of I-3-C achieved in liver after treatment of mice by gavage with 50 mg I-3-C/kg body weight. These data suggest that I-3-C may be a natural antioxidant in the human diet and, as such, may intervene in toxicological or carcinogenic processes that are mediated by radical mechanisms.


Prediction of retention times in comprehensive two-dimensional gas chromatography using thermodynamic models.
A method was developed to accurately predict both the primary and secondary retention times for a series of alkanes, ketones and alcohols in a flow-modulated GC×GC system. This was accomplished through the use of a three-parameter thermodynamic model where ΔH, ΔS, and ΔC(p) for an analyte's interaction with the stationary phases in both dimensions are known. Coupling this thermodynamic model with a time summation calculation it was possible to accurately predict both (1)t(r) and (2)t(r) for all analytes. The model was able to predict retention times regardless of the temperature ramp used, with an average error of only 0.64% for (1)t(r) and an average error of only 2.22% for (2)t(r). The model shows promise for the accurate prediction of retention times in GC×GC for a wide range of compounds and is able to utilize data collected from 1D experiments.


Performance of chemically modified plastic blood collection tubes.
The objective of this study was to compare newly-modified and aged chemoPET tubes, which contain no problematic surfactants, with commercially available serum blood collection tubes (BCTs) for use in analysis of cortisol, total triiodothyronine (TT3), total thyroxine (TT4), and routine clinical chemistry analytes in serum from apparently healthy volunteers and pooled quality control (QC) specimens. Blood specimens collected from 60 apparently healthy volunteers (18 males, 42 females) and pooled QC specimens poured into seven different BCTs were analyzed by a trained phlebotomist. Cortisol, TT3, and TT4 levels were measured on an Immulite 1000 instrument and routine chemistry tests were analyzed on a Siemens RxL instrument. The significance of differences between chemoPET and other BCT types compared to glass tubes were assessed by Student's paired t-test or repeated measures ANOVA or their non-parametric equivalents. The BCT-related biases (deviation from glass tubes) in analyte concentrations were compared with the current desirable allowable bias, derived from biological variation. Serum analyte concentrations in the different BCTs that exceeded their respective significant change limits were considered clinically significant. No statistically and/or clinically significant differences were noted in the analyte concentrations from serum specimens and pooled QC material when our newly modified and aged chemoPET tubes were compared to glass and other BCTs. The chemoPET tubes described here may be a suitable alternative to serum BCTs that contain problematic surfactants known to interfere with some clinical assays on the Immulite 1000 and RxL instruments.


Clinical management and hospital outcomes of acute coronary syndrome patients in Mexico: The Third National Registry of Acute Coronary Syndromes (RENASICA III).
To describe current management and clinical outcomes in patients hospitalized with an acute coronary syndrome (ACS) in Mexico. RENASICA III was a prospective multicenter registry of consecutive patients hospitalized with an ACS. Patients had objective evidence of ischemic heart disease; those with type II infarction or secondary ischemic were excluded. Study design conformed to current quality recommendations. A total of 123 investigators at 29 tertiary and 44 community hospitals enrolled 8296 patients with an ACS (4038 with non-ST-elevation myocardial infarction/unstable angina [NSTEMI/UA], 4258 with ST-elevation myocardial infarction [STEMI]). The majority were younger (62±12years) and 76.0% were male. On admission 80.5% had ischemic chest pain lasting >20min and clinical stability. Left ventricular dysfunction was more frequent in NSTEMI/UA than in those with STEMI (30.0% vs. 10.7%, p<0.0001). In STEMI 37.6% received thrombolysis and 15.0% primary PCI. PCI was performed in 39.6% of NSTEMI/UA (early strategy in 10.8%, urgent strategy in 3.0%). Overall hospital death rate was 6.4% (8.7% in STEMI vs. 3.9% in NSTEMI/UA, p<0.001). The strongest independent predictors of hospital mortality were cardiogenic shock (odds ratio 22.4, 95% confidence interval 18.3-27.3) and ventricular fibrillation (odds ratio 12.5, 95% confidence interval 9.3-16.7). The results from RENASICA III establish the urgent need to develop large-scale regional programs to improve adherence to guideline recommendations in ACS, including rates of pharmacological thrombolysis and increasing the ratio of PCI to thrombolysis.


Single-cell measurements and modelling reveal substantial organic carbon acquisition by Prochlorococcus.
Marine phytoplankton are responsible for about half of the photosynthesis on Earth. Many are mixotrophs, combining photosynthesis with heterotrophic assimilation of organic carbon, but the relative contribution of these two lifestyles is unclear. Here single-cell measurements reveal that Prochlorococcus at the base of the photic zone in the Eastern Mediterranean Sea obtain only ~20% of carbon required for growth by photosynthesis. This is supported by laboratory-calibrated calculations based on photo-physiology parameters and compared with in situ growth rates. Agent-based simulations show that mixotrophic cells could grow tens of metres deeper than obligate photo-autotrophs, deepening the nutricline by ~20 m. Time series from the North Atlantic and North Pacific indicate that, during thermal stratification, on average 8-10% of the Prochlorococcus cells live without enough light to sustain obligate photo-autotrophic populations. Together, these results suggest that mixotrophy underpins the ecological success of a large fraction of the global Prochlorococcus population and its collective genetic diversity.


Encephalomyelitis in two sisters who died suddenly at home.
Two sudden infant deaths of female siblings occurring at the ages of six and 5 1/2 months are reported. The temporal separation of their deaths was 14 months. Both showed virtually identical pathological findings within the central nervous system, consistent with encephalomyelitis. No causative agent, metabolic defect or common predisposing factor was identified and no evidence of a relationship to immunisation could be established.


Integrated Onco-Palliative Care Associated With Prolonged Survival Compared to Standard Care for Patients With Advanced Lung Cancer: A Retrospective Review.
Lung cancer is the leading cause of cancer-related death in the U.S. A large randomized controlled trial in advanced lung cancer found a survival advantage with an early palliative care (EPC) intervention compared to standard oncologic care. We performed retrospective analysis of our partially integrated onco-palliative care lung cancer clinic to evaluate overall survival and resource utilization. All outpatients with advanced lung cancer cared for within our institution from 2007 to 2011 were identified. Overall survival, clinical trial participation, hospice enrollment and length of stay, and chemotherapy utilization were calculated for patients treated with EPC and compared to standard oncologic care. Two hundred seven patients with advanced lung cancer were identified; 82 received EPC. EPC patients had a survival advantage (11.9 vs. 10.1 months, P = 0.031), were more likely to participate in clinical trials (29% vs. 19%, P = 0.014), and median hospice length of stay was longer (38.5 vs. 24 days, P = 0.032). No difference in chemotherapy utilization or hospice enrollment was seen between the groups. EPC in advanced lung cancer was associated with a nearly two-month survival advantage compared to standard oncologic care. This finding provides supportive evidence to previously published reports of survival benefit with EPC intervention. Clinical trial participation rates in advanced lung cancer are lacking, and we found more frequent clinical trial participation in the early PC group. No differences were seen in chemotherapy utilization or hospice enrollment. EPC patients' longer hospice length of stay did not compromise survival.