Improved survival prediction for oropharyngeal cancer beyond TNMv8.

PURPOSE: For oropharynx squamous cell carcinoma (OPSCC) this study aimed to: (i) compare 5-year overall survival (OS) stratification by AJCC/UICC TNM versions 7 (TNMv7) and 8 (TNMv8), (ii) determine whether changes to T and N stage groupings improve prognostication and (iii) develop and validate a model incorporating additional clinical characteristics to improve 5-year OS prediction. MATERIAL AND METHODS: All OPSCC treated with curative-intent at our institution between 2011 and 2017 were included. The primary endpoint was 5-year OS. Survival curves were produced for TNMv7 and TNMv8. A three-way interaction between T, N stage and p16 status was evaluated for improved prognostication. Cox proportional hazards modelling was used to derive a new predictive model. RESULTS: Of 750 OPSCC cases, 574 (77%) were p16-positive. TNMv8 was more prognostic than TNMv7 (concordance probability estimate [CPE] ±â€¯SE = 0.72 ±â€¯0.02 vs 0.53 ±â€¯0.02). For p16-positive disease, TNMv8 discriminated stages II vs I (HR 2.32, 95% CI 1.47-3.67) and III vs II (HR 1.75, 95% CI 1.13-2.72). For p16-negative disease, TNMv7 and TNMv8 demonstrated poor hazard discrimination. Different T, N stage and p16-status combinations did not improve prognostication after adjusting for other factors (CPE = 0.79 vs 0.79, p = 0.998). A model for p16-positive and p16-negative OPSCC including additional clinical characteristics improved 5-year OS prediction beyond TNMv8 (c-index 0.76 ±â€¯0.02). CONCLUSIONS: TNMv8 is superior to TNMv7 for p16-positive OPSCC, but both performed poorly for p16-negative disease. A novel model incorporating additional clinical characteristics improved 5-year OS prediction for both p16-positive and p16-negative disease.

Randomized, Controlled, Crossover trial of Prevention of Clindamycin-Induced Gastrointestinal Signs Using a Synbiotic in Healthy Research Cats.

BACKGROUND: Synbiotics often are prescribed to limit antibiotic-associated gastrointestinal signs (AAGS) in cats, but data to support this recommendation are lacking. OBJECTIVE: To determine whether synbiotic co-administration mitigates AAGS in healthy research cats treated with clindamycin. ANIMALS: 16 healthy research cats. METHODS: A randomized, double-blinded, placebo-controlled, 2-way, 2-period, crossover study with a 6-week washout was performed. Each study period consisted of a 1-week baseline and a 3-week treatment period. Cats received 75 mg clindamycin with food once daily for 3 weeks, followed 1 hour later by either 2 capsules of a synbiotic or placebo. Food consumption, vomiting, fecal score, and completion of treatment were compared using repeated measures split plot or crossover designs with covariates, with P < 0.05 considered significant. RESULTS: Cats that received the synbiotic were more likely to complete treatment in period 1 (100% vs. 50%, P = 0.04). Cats vomited less when receiving the synbiotic but this was not significant, but there were significant period effects (F-value = 11.4, P < 0.01). Cats had higher food intake while receiving the synbiotic (F-value = 31.1, P < 0.01) despite period effects (F-value = 8.6, P < 0.01). There was no significant effect of treatment on fecal scores, which significantly increased over time (F-value = 17.9, P < 0.01). CONCLUSIONS AND CLINICAL IMPORTANCE: Administration of a synbiotic 1 hour after clindamycin administration decreased hyporexia and vomiting in healthy cats. Additionally, significant period effects suggest that clinical benefits of synbiotic administration persist for at least 6 weeks after discontinuation, decreasing the severity of AAGS in cats that subsequently received clindamycin with placebo. Unlike in people, synbiotic administration did not decrease antibiotic-associated diarrhea.

Imaging hypoxia in tumours with advanced MRI.

Tumour hypoxia results in biological alterations that leads to a more aggressive disease phenotype and is associated with resistance to treatment. In this review, we discuss current magnetic resonance imaging techniques, which can be applied to evaluate tumour hypoxia, highlighting the principles of each technique, their pre-clinical and clinical deployment, as well as their strengths and limitations. The potential to combine these techniques, and also with other imaging modalities (e.g., PET imaging) using a multiparametric approach, may further improve our understanding of the complex interaction of vascular supply, oxygen diffusion and tissue metabolism in pathogenesis of tumour hypoxia; and its reversal with treatment.

Physiological levels of beta-amyloid induce cerebral vessel dysfunction and reduce endothelial nitric oxide production.

beta-amyloid (A beta), the major component of senile plaques in Alzheimer's disease (AD), normally circulates in the blood at nanomolar levels but is elevated in AD. Previous studies have found that high concentrations (10(-5)-10(-4) M) of A beta result in neuronal cell death. Here we show that physiological levels of soluble A beta can induce dysfunction in perfused rat cerebral vessels and in cultured endothelial cells. At concentrations of 10(-9)-10(-6) M, A beta induced a significant concentration-dependent reduction of NO production in endothelial cells. At 10(-8) M, A beta significantly decreased the sensitivity of cerebral vessels to acetylcholine (ACh), an endothelium dependent vasodilator. At 10(-7) M and higher concentrations, A beta significantly reduced the maximum response of vessels to ACh, and induced significant endothelial cell death. A beta (10(-9)-10(-5) M) did not cause any detectable change in nitric oxide synthase levels. The results suggest that a modest increase in the concentration of A beta above its normal physiological level in the circulation, as found in the early stages of AD, results in decreased NO production and vessel sensitivity to endothelium-dependent vasodilation that could lead to constricted blood vessels and ischemia in the surrounding tissue. Further increases in A beta concentration, which may occur in the later stages of AD, result in cell death and decreased maximum vasodilator response of cerebral vessels.

A global factor in the Hermann grid illusion or an artifact?

In the first of the present experiments, subjects were required to estimate the strength of the Hermann grid illusion in grids containing various numbers of intersections even though those grids were not actually presented. The positive relationship found by Wolfe (1984) for real grids was, nevertheless, replicated. It is argued that this suggests that a response bias might have been the source of his effect (although other possibilities are also noted). In addition, in a second experiment, subjects who were not aware of the fact that grid size was being manipulated (i.e., between subjects) showed no consistent effect of that factor, thus supporting the same suggestion.

Polarity of the transition state controls the reactivity of related charged phenyl radicals toward atom and group donors.

Polar effects are demonstrated to be a key factor in controlling the reactivities of related charged phenyl radicals in different exothermic atom and group abstraction reactions in the gas phase. The effects of various meta substituents on the phenyl radicals' reactivity were probed via the measurement of bimolecular reaction rate constants by using Fourier transform ion cyclotron resonance mass spectrometry. This approach requires an additional, charged substituent to be present in the phenyl radical to allow mass spectrometric manipulation. The m-pyridinium group was chosen for this purpose. The substrates studied were allyl iodide, dimethyl disulfide, and tert-butyl isocyanide. Two of the reactions of interest, *I and *SCH(3) transfer, are thought to occur by concerted bimolecular homolytic substitution (S(H)2), and the third one, *CN transfer, by an addition/elimination mechanism. For all three substrates, the reaction rate was found to increase in the following order for the differently substituted phenyl radicals: CH(3) approximately H < Br approximately Cl approximately COOH < NO(2) approximately CN. This trend does not arise from differences in reaction exothermicities or bond dissociation energies but via lowering the reaction barrier by electronic effects. The stabilization of the transition state is attributed to its increased polar character. A semiquantitative measure of the barrier lowering effect for each substituent is obtained from its influence on the electron affinity of the charged radical, as the calculated (B3LYP/6-31+G(d)) adiabatic electron affinities of the radical model systems (ammonium instead of pyridinium charge site) follow the same trend as the reactivities.

An integrated confocal and magnetic resonance microscope for cellular research.

Complementary data acquired with different microscopy techniques provide a basis for establishing a more comprehensive understanding of health and disease at a cellular level, particularly when data acquired with different methodologies can be correlated in both time and space. In this Communication, a brief description of a novel instrument capable of simultaneously performing confocal optical and magnetic resonance microscopy is presented, and the first combined images of live Xenopus laevis oocytes are shown. Also, the potential benefits of combined microscopy are discussed, and it is shown that the a priori knowledge of the high-resolution optical images can be used to enhance the boundary resolution and contrast of the MR images.

Potassium channel openers prevent beta-amyloid toxicity in bovine vascular endothelial cells.

There is increasing evidence that the cerebrovasculture may be involved in the pathology of Alzheimer's disease. Here, we report that potassium channel openers (KCOs) inhibit dose and time dependent necrosis induced by beta-amyloid (Abeta) in cultured vascular endothelial cells. Cell proliferation rate was assayed by a colorimetric method. Abeta cytotoxicity and inhibition by the K(ATP) channel opener diazoxide and the K(Ca) channel opener NS1619 was correlated with changes in nitric oxide (NO) production. The protective effects were partly blocked by potassium channel blockers. Toxicity of Abeta and KCO protection was verified by histological examination of endothelial cells with scanning electron microscopy. eNOS levels in endothelial cells were not changed by any of the treatments. The results suggest that disruption of K(+) channels function may be a critical step in Abeta-induced cytotoxicity in endothelial cells by alteration of NO release.

The effect of insecticides on learning in the Africanized honey bee (Apis mellifera L.).

The present study was designed to examine the effects of endosulfan, decis, baytroid, and sevin on the learning ability of Africanized honey bees (Apis mellifera L.). Although these insecticides were recommended by the government of Brazil to control the cotton boll weevil, the effects on bees have been unknown. Results of the present research show that: (1) bees readily consume each of the pesticides when placed in a sucrose solution; (2) the odors of the pesticides are not repellent to bees, and such odors can serve as conditioned stimuli; (3) learning occurs to various degrees when the insecticides are combined with the sucrose solution and used as an unconditioned stimulus; and (4) feeding the insecticides to the bees 1 h prior to conditioning leads to differing mortality. Because of the importance of bees for honey production, as well as pollination of cotton and other crops, recommendations are made for the use of decis and other measures for boll weevil control.http://link. springer-ny.com/link/service/journals/00244/bibs/37n4p529.++ +html

The protective effect of K+ channel openers on beta-amyloid induced cerebrovascular endothelial dysfunction.

Amyloid angiopathy is characterized by amyloid beta-peptide (A beta) deposition and may contribute to the cerebrovascular abnormalities that precede the onset of Alzheimer's Disease (AD). That aberrant potassium (K+) channel function occurs in AD patients is supported by deleterious effects of A beta on normal fibroblast K+ channels and prevention of A beta-induced toxicity by potassium channel openers (KCOs) in neuronal cell culture. We report here that KCOs protect cerebral and peripheral vessels against the endothelial damage induced by A beta. Pressurized posterior cerebral artery and aortic ring segments from the rat were constricted and then relaxed with the endothelium-dependent vasodilator acetylcholine before and after incubation with A beta (10(-6) M), or pre-treatment with KCOs before the addition of beta-amyloid. Vessels treated with A beta exhibited features of endothelial dysfunction: enhanced vasoconstriction and diminished endothelium-dependent vasodilation. Pre-treatment with KCOs significantly antagonized the A beta effect in both cerebral and aortic vessel segments. This protection was provided by both KCa and KATP channel openers. Endothelial damage by A beta and protection by KCOs was verified by electron microscopy. The K+ channel blocker, TEA, reversed the protective effect of KCO. The results suggest that potassium channel openers protect against A beta induced endothelial dysfunction and that KCOs may have a role in the treatment of degenerative cerebrovascular disease as seen in stroke, AD and aging.

Internal representational models of peers: implications for the development of problematic behavior.

The authors investigated the relation between children's knowledge structures for peers and externalizing behavior problems. Initial levels of aggression were evaluated in 135 boys and 124 girls (Grades 1-3; 40% African American, 60% Caucasian) in Year 1 and again in Years 6 and 9. In Year 6, 3 aspects of their social knowledge structures were assessed: quality, density, and appropriateness. Results indicate that knowledge structures are related to children's concurrent levels of externalizing behaviors and that knowledge structures are related to children's concurrent levels of externalizing behaviors and predict externalizing behaviors 3 years later even after controlling for current levels of behavior. In addition, knowledge structures in Year 6 mediate the relation between aggression in Year 1 and externalizing behaviors in Year 9. The role of knowledge structures in the maintenance and growth of children's antisocial behavior is discussed.

Estrogen protects peripheral and cerebral blood vessels from toxicity of Alzheimer peptide amyloid-beta and inflammatory reaction.

Due to increases in life expectancy, women are living 30 years or more beyond menopause. This has led to an increasing interest in the association between postmenopausal estrogen deficiency and degenerative diseases associated with aging such as cardiovascular disease, osteoporosis and dementia. Women are two times more likely to develop late-onset Alzheimer's disease (AD) than age-matched men. A large number of observational reports and a few randomized clinical trials have indicated that estrogen replacement therapy (ERT) may retard the development and severity of dementia in postmenopausal women. The mechanism underlying the protective action of estrogen in AD is under active investigation. A chronic inflammatory reaction mediated by abnormal deposition of proteins such as amyloid-beta (A beta) is central to the pathology of AD. We investigated the effect of low doses of conjugated estrogen (Premarin) in an animal model of A beta-induced vascular disruption and inflammatory reaction. This rodent model allows live videomicroscopic recording and electron microscopic analysis of peripheral vascular disruption and inflammatory reaction triggered by A beta. Estrogen prevented vascular deposition of A beta, endothelial and vessel wall disruption with plasma leakage, platelet and mast cell activation, and characteristic features of an inflammatory reaction: adhesion and transmigration of leukocytes. The beneficial effect was lost when estrogen treatment was discontinued. Estrogen also protected the cerebral blood vessels from endothelial dysfunction induced by A beta. This novel protective effect of estrogen against A beta cytotoxicity in peripheral and cerebral vasculature may contribute to the therapeutic efficacy of estrogen in AD and coronary vascular disease.

The war against junk science: the use of expert panels in complex medical-legal scientific litigation.

In the legal context, junk science is defined as evidence that is outside of mainstream scientific or medical views. Junk science does not have indicia of reliability and is not generally accepted. Despite the lack of scientific reliability, US courts, expert witnesses and juries are increasingly reliant on junk science in making causation decisions in complex medical liability cases. Courts have accepted junk science even where reliable scientific evidence is available. The United States silicone gel breast implant litigation is a prime example of this phenomenon. The issue of whether silicone breast implants are associated with disease has been a controversial subject for scientists and physicians, an emotional issue for women who have breast implants, and a lucrative business for the lawyers and expert witnesses who are the proponents of junk science. Junk science has provided to juries a quick and convenient explanation for claimed diseases or syndromes which have required years for reliable scientists to conclude are not related to breast implants. The breast implant litigation highlights the often dramatic difference between decisions based upon junk science and decisions grounded in scientific method, fact and reality. Recently, judges involved in the breast implant litigation have become concerned about the use of junk science in light of the growing body of legitimate scientific evidence that breast implants do not cause disease. Several judges have been motivated to take the unique and novel approach of convening scientific panels of independent experts to study the scientific issues and make findings to the court. Through the use of independent scientific experts, several judges have meaningfully assessed the evidence that the litigants present and have prevented or strictly limited the use of junk science in the courtroom. Using this procedure, other judges are weighing the evidence for future cases. This paper will briefly explore the background of mass tort medical products litigation and the development of junk science. The paper will then focus on the history of the breast implant litigation and the steps that the courts have already taken to combat junk science, including the use of scientific panels.

Social information-processing patterns as predictors of social adaptation and behavior problems among maltreated children in foster care.

OBJECTIVE: The goal of this investigation was to determine if social information-processing patterns were predictive of later social adaptation and behavior problems within a group of maltreated children in foster care. METHOD: A longitudinal design was used to address the study hypotheses. The sample consisted of 124 maltreated children ages 5 to 10 who had been placed into foster care. Twelve months following entrance into foster care, children were presented with age-relevant hypothetical vignettes to assess the quality of the way in which they process social information. Six to 8 months following this assessment, caregivers completed the Vineland Adaptive Scales and the Child Behavior Checklist. RESULTS: Measures reflecting unbiased and competent processing were predictive of social adaptation, whereas measures reflecting biased and incompetent processing were predictive of behavior problems. In aggregate, processing measures accounted for a significant proportion of the variance in the outcome measures. CONCLUSIONS: The findings suggest that the manner in which maltreated children process social information has a bearing on their later social adaptation and behavioral adjustment. Therefore, maltreated children in foster care may benefit from interventions that target the manner in which they process social information.

Improved psychological well-being, quality of life, and health practices in moderately overweight women participating in a 12-week structured weight loss program.

OBJECTIVE: To study the effects of a 12-week weight loss strategy involving increased physical activity, self-selected hypocaloric diet, and group support on psychological well-being, quality of life, and health practices in moderately obese women. METHODS: Eighty women aged 20-49 years weighing between 20-50% above 1983 Metropolitan Life Insurance Tables were randomly assigned to a weight loss intervention (6279 kJ/week of physical activity, 33,258-41,462 kJ/week diet and weekly meetings) or served as controls. Subjects were tested pre and post 12-weeks. RESULTS: The intervention group lost significant (p<0.001) body weight (kg) and body fat (%) compared to controls (-6.07+/-4.01 kg vs. 1.31+/-1.28 kg; 36.8%-32.5% vs. 36.2%-36.0%). Intervention subjects vs. controls achieved significant improvements (p<0.001) in body cathexis (X Change 18.6+/-16.7 vs. 0.7+/-8.6) and estimation of ability to achieve physical fitness (X Change 8.1+/-7.1 vs. 0.9+/-5.9). Various quality of life indices also improved (p<0.01) in the intervention group compared to controls (physical function: X Change 13.5.2+/-16.7 vs. 1.4+/-9.5; vitality: X change 21.7+/-17.9 vs. 2.9+/-20.8; mental health: X change 10.4+/-16.0 vs. 2.3+/-10.1). Similarly, physical activity levels also improved significantly (p<0.0001) in the intervention group (4.4+/-2.3 vs. 0.6+/-1.3; on NASA 0-7 scale). CONCLUSIONS: Practical weight loss practices such as increased activity, self-selected hypocaloric diet, and group support are effective for weight loss and yield significant health and psychological benefits in moderately obese females.