Search

PDF file - 46K, Patient Demographics and Disease Characteristics.

Recombinant interleukin (IL)-18 (SB-485232) is an immunostimulatory cytokine, with shown antitumor activity in combination with pegylated liposomal doxorubicin (PLD) in preclinical models. This phase I study evaluated the safety, tolerability, and biologic activity of SB-485232 administered in combination with PLD in subjects with recurrent ovarian cancer. The protocol comprised four cycles of PLD (40 mg/m2) on day 1 every 28 days, in combination with SB-485232 at increasing doses (1, 3, 10, 30, and 100 μg/kg) on days 2 and 9 of each cycle, to be administered over five subject cohorts, followed by discretionary PLD monotherapy. Sixteen subjects were enrolled. One subject withdrew due to PLD hypersensitivity. Most subjects (82%) were platinum-resistant or refractory, and had received a median of three or more prior chemotherapy regimens. SB-485232 up to 100 μg/kg with PLD had an acceptable safety profile. Common drug-related adverse events were grade 1 or 2 (no grade 4 or 5 adverse events). Concomitant PLD administration did not attenuate the biologic activity of IL-18, with maximal SB-485232 biologic activity already observed at 3 μg/kg. Ten of 16 enrolled subjects (63%) completed treatment, whereas five (31%) subjects progressed on treatment. A 6% partial objective response rate and a 38% stable disease rate were observed. We provide pilot data suggesting that SB-485232 at the 3 μg/kg dose level in combination with PLD is safe and biologically active. This combination warrants further study in a phase II trial. Cancer Immunol Res; 1(3); 168–78. ©2013 AACR.

This article, using Mocombeian phenomenological structural theory, argues that since their arrival on North American soil, the constitution of black American identity has been the product of their relations to the means and mode of production within the Protestant Ethic and the spirit of capitalism. As such, black Americans, and this includes the so-called black radical tradition, have never been agents in the constitution of their own identities. They have always been and remain (reactionary) pawns of capital seeking, dialectically or negative dialectically, to assimilate in the American social structure. Their assimilation takes place within the social practices of two social class language games (the black bourgeoisie and the underclass) that were historically constituted by different ideological apparatuses, the church and education on the one hand and the streets, prisons, and the athletic and entertainment industries on the other, respectively, of the global capitalist racial-class structure of inequality under American hegemony, which replaced African ideological apparatuses as found in Haiti, for example. Contemporarily, given both groups’ overrepresentation in the ideological superstructures of the American empire, they, antagonistically, have become the bearers of ideological and linguistic domination for all black youth the world-over, especially in the United Kingdom, which have tremendous consequences for their assimilation process. Under the assimilationist imperatives of the black bourgeoisie, the aim is integration and assimilation along the lines of traditional white Protestant agents of the Protestant Ethic and the spirit of capitalism with an emphasis on bourgeois prosperity, the black nuclear family, entrepreneurialism, and individualism. Conversely, the black underclass seeks integration and assimilation through the pathologies of their structural differentiation within the Protestant Ethic and the spirit of capitalism with an emphasis on identity politics, glorification of the self, wealth via sports and entertainment, and the communal thinking of the street life as the basis of black identity and culture.

“Imaged Communities” imagines Canada as a network of photographic knowledge. Co-written by six members of Canadian Photography History/Histoire de la photographie canadienne (CPH/HPC), a research team based at Concordia University in Montreal, this essay examines the meeting places created by photographic technology. The mapping of these histories addresses the central questions about photographic history and mediated experience that have motivated this research— What did Canadians know about photography, and when did they know it? –and supplements it with a third— Where did these encounters take place? The introduction establishes the sites and parameters of the contribution. First, the research draws on the digital anthology of Canadian photographic literature that the authors are putting forward as a history of the medium in Canada—a community imaged at every stage of its mutation from colony to nation and thereby imagined, in Benedict Anderson’s well-known formulation (1991). This is a fragmentary photographic history, which accounts for the polyphonic nature of this text. Second, the authors write as art historians and photographic specialists, mindful of the various turns in the humanities and sciences that have engaged with, and sometimes emerged from, discoveries in photographic studies, the spatial turn most pertinent to this inquiry. The authors point out, however, that photographic practice has more than kept pace with theory. There is much to learn from artists’, documentarians’, snapshooters’, and compilers’ projects: their uses of photography as instruments of investigation; their photographic formulations of philosophical ideas and social conditions; the heuristic circle formed by the circulation of their work; and the penetration of that circle by neglected interests. For that reason, this group includes a creation-researcher, whose art historical practice is informed by the making of a photographic work. His armchair-tourist colleagues write at the intersection of photographic knowledge and photographic experience; the introduction seeks to elucidate the structure of that space. A third element of the introduction is an explanation of the lack of an authoritative history of Canadian photography, and how CPH/HPC and its network of individual and institutional collaborators are working within that gap to create new historiographical models. Five short studies follow, each using the intersection of photography and place as an organizing principle. In the first, a brief survey of photographic literature on or about the Canadian West focusses on two bodies of work: a professional tourist’s travelogue of the West (and further West) as he constructed it in 1909 from his railcar, his hotel, and his campground; and a photographer/filmmaker’s lifelong investment in the representation of his diverse community, the North End of Winnipeg, Manitoba. The second study closes in on a single city—Toronto—as celebrated and chronicled in two nineteenth-century publications, and as revisited in a late twentieth-century exhibition and catalogue project based on the photographic collection of Library and Archives Canada. These curatorial perspectives on the city illuminate the social values of their day. In the third study, post-Centennial selection and uses of photographs from the Isaac Erb studio (c1870-1924) in Saint John, New Brunswick, are closely compared with the uses of those photographs at the time of their making and with a more complete version of the Erb oeuvre preserved in the provincial archives, revealing a photographic record of material culture that reflects the port city’s emergence as a transnational, consumer economy. The fourth study moves to another Canadian port via the photographic holdings of the Canadian Museum of Immigration at Pier 21 in Halifax, Nova Scotia, an ocean liner terminal and immigration shed-turned-museum. Through online display of its primarily digital collection, this doorway to Canada, selectively open between 1928 and 1971, is photographically preserved as a relational space, forever in between . Finally, a contemporary artist’s photographic study of photography and walking, conducted on boulevard Saint-Laurent in Montreal, creates a processual space of creation, bringing this essay full circle to the image and its imaginer. The conclusion underscores the dialogical structure of our relationships with photography, wherever we find it. Abstract: L’article «Les communautes imagees»imagine le Canada comme un reseau de connaissances photographiques. Coredige par six membres de Canadian Photography History/Histoire de la photographie canadienne (CPH/HPC) – une equipe de recherche de l’Universite Concordia a Montreal–, le present article examine les points de rencontre crees par la technologie photographique. La cartographie de ces histoires traite de questions centrales a l’histoire photographique et a l’experience mediatisee qui ont motive cette recherche – Que connaissent les Canadiens au sujet de la photographie, et quand l’ont-ils appris? – et ajoute une troisieme question : Ou sont ces points de rencontre? L’introduction presente les sites et les parametres de la contribution. Tout d’abord, la recherche se sert de l’anthologie numerique de la litterature photographique canadienne que les auteurs utilisent comme une histoire de ce support au Canada – une communaute prise en images a chaque stade de sa mutation de colonie a nation, et donc imaginee, selon la formulation bien connue de Benedict Anderson (1991). Il s’agit d’une histoire photographique fragmentaire, qui tient compte de la nature polyphonique de ce texte. Puis, les auteurs deviennent des historiens de l’art et des specialistes de la photographie en restant conscients des divers courants dans les lettres, les sciences humaines et la science qui ont fait partie et ont meme parfois emerge de decouvertes dans les etudes photographiques (le courant spatial le plus pertinent pour cette recherche). Les auteurs font remarquer toutefois que la pratique photographique est restee bien a la hauteur de la theorie. On peut en apprendre beaucoup des projets d’artistes, de documentaristes, d’auteurs d’instantanes et de compilateurs: leurs utilisations de la photographie comme un instrument d’enquete, leurs formulations photographiques d’idees philosophiques et de conditions sociales, le cercle heuristique forme par la diffusion de leurs œuvres ainsi que la penetration de ce cercle par des interets negliges. Pour cette raison, ce groupe comprend un chercheur-creation dont la pratique de l’histoire de l’art est eclairee par la realisation d’une œuvre photographique. Ses collegues et touristes de salon ecrivent au carrefour de la connaissance et de l’experience photographiques; l’introduction cherche a elucider la structure de cet espace. Un troisieme element de cette introduction est une explication du fait qu’il n’existe pas d’histoire documentee de la photographie canadienne, et de comment l’equipe CPH/HPC et son reseau de collaborateurs particuliers ou membres d’un etablissement essaient de compenser cette lacune et de creer de nouveaux modeles historiographiques. Cinq courtes dissertations suivent, chacune se servant de l’intersection de la photographie et du lieu comme principe d’organisation. Dans la premiere, un bref examen des ecrits sur l’histoire photographique de l’Ouest canadien met l’accent sur deux ensembles d’œuvres: le carnet de voyage d’un touriste professionnel de l’Ouest (et encore plus a l’ouest), tel qu’il l’a compose en 1909 a partir de son wagon de train, de son hotel et de son lieu de camping, et l’investissement d’un photographe/cineaste tout au long de sa vie dans la representation de sa communaute diversifiee – l’extremite nord de Winnipeg (Manitoba). La deuxieme dissertation vise une seule ville – Toronto – telle que celebree et documentee dans deux publications du XIXe siecle, puis reexaminee dans une exposition et un catalogue au XXe siecle en se fondant sur la collection photographique de Bibliotheque et Archives Canada. Ces points de vue curatoriaux de la ville illustrent les valeurs sociales de cette epoque. Dans la troisieme dissertation, une comparaison attentive est faite des utilisations contemporaines et posterieures au centenaire de Saint John (Nouveau-Brunswick) des photos du studio d’Isaac Erb (v. 1870-1924), avec une version plus complete de ses œuvres, telles que preservees dans les archives provinciales. Cette comparaison revele un registre photographique de la culture materielle qui reflete l’emergence de l’economie de consommation transnationale de cette ville portuaire. La quatrieme dissertation traite d’un autre port canadien avec la collection de photos du Musee canadien de l’immigration au Quai 21 a Halifax (Nouvelle-Ecosse) – un terminal de navires de ligne et un hangar d’immigration devenu musee. Avec une exposition en ligne de sa collection principalement numerique, cette fenetre sur le Canada, ouverte de maniere selective entre 1928 et 1971, est preservee a l’aide de photos comme un lieu intermediaire . Enfin, l’etude photographique d’un artiste contemporain sur la photographie a pied, realisee sur le boulevard Saint-Laurent a Montreal, presente un lieu processuel de creation et termine cet article en revenant a l’image et son imagineur. La conclusion de l’article souligne la structure dialogique de nos rapports avec la photographie, quelle que soit sa source.

To compare the pregnancy outcomes in all T1DMP attending at combined (diabetes-obstetric) outpatients clinics in three university teaching hospitals in Dublin from 1995 to 2006 with a non-diabetic control population (C) attending at antenatal outpatient clinics at the same hospitals over the same period.T1DMP (n = 600) were compared with control non-diabetic pregnancies (n = 142,498).The spontaneous abortion rate was 15% in T1DMP versus 8% in C (p0.0001). Perinatal mortality rate was 3.3% in T1DMP compared to 0.9% in C (p0.001). The incidence of foetal macrosomia was 29% in T1DMP versus 16% in C (p0.001).Pregnancy outcomes in T1DMP remain worse than in the general population despite management of T1DMP in combined obstetric/diabetes clinics in a single centre using similar management protocols. These outcomes in our study population of T1DMP in Dublin appear better than some previously reported studies.

Graduate employers are faced with the challenges posed by an increasingly complex graduate labour market as well as increasing graduate recruitment and retention problems. In the light of these issues this paper considers graduate attitudes and behaviour towards sales jobs, and employers’ response to recruitment of graduates into sales. Results from interviews with key UK graduate employers and a survey of final year students at a Northern Business School show that there is a need for employers to enhance the status of sales and for universities to improve the employability and career management skills of students.

We have previously shown that when tested in the morning, older men and women, pretreated with metyrapone to block endogenous cortisol synthesis, exhibit delayed suppression of plasma ACTH in response to cortisol infusion. To confirm this finding and to determine whether aging-related changes in feedback responsiveness are exaggerated near the time of the circadian nadir in adrenocortical secretion, we performed a similar study in the evening. Healthy young (20-35 yr, n = 22) and old (>65 yr, n = 21) men and women were administered metyrapone orally (750 mg) at 1600 and 1900 h, followed by a cortisol infusion of 0.06 mg/kg/h for 150 min. Blood samples were taken at 15-min intervals for 4 h following infusion onset for measurement of plasma ACTH, cortisol, 11-deoxycortisol, and corticosteroid binding globulin. When corrections were made for differences in circulating cortisol concentrations achieved among age and gender subgroups, feedback inhibition of ACTH was found to be significantly greater in young than in old subjects of both genders. Our studies support the hypothesis that glucocorticoid responses to stress in aging individuals are likely to be prolonged due to blunted and delayed inhibition of ACTH secretion, thus increasing the total exposure to glucocorticoids.

Differences in hypothalamic-pituitary-adrenal (HPA) axis responsiveness to lumbar puncture (LP) stress were studied in normal elderly subjects and Alzheimer's disease (AD) patients of both genders. Elderly normal subjects had larger peak cortisol and ACTH responses than AD patients. These results contrast with some previous reports of increased HPA-axis responsivity associated with AD and suggest that AD-related changes in HPA responsiveness depend on the type of stressor involved and are mediated 'upstream' to the final common pathway to ACTH secretion. HPA-axis responsiveness also differed by gender, with higher peaks and prolonged elevations in elderly female subjects than in elderly males.

Central nervous system (CNS) adrenergic systems are involved in regulation of behavior and blood pressure. The effects of Alzheimer's disease (AD) and normal aging on resting CNS adrenergic activity were estimated by measuring cerebrospinal fluid (CSF) epinephrine (EPI) concentrations in 74 persons with AD, 42 cognitively normal healthy older persons, and 54 healthy young persons. The responsiveness of CSF EPI to the alpha-2 adrenergic antagonist yohimbine and the alpha-2 adrenergic agonist clonidine was measured in smaller subject groups. Resting CSF EPI was higher in AD than in older or young subjects, and increased with dementia severity in AD subjects. There was no relationship between resting CSF EPI and blood pressure. CSF EPI increased following yohimbine in AD and older subjects but not in young subjects. CSF EPI was unaffected by clonidine in all subject groups. The agitation increase following yohimbine was substantially greater in AD subjects than in older or young subjects. CNS adrenergic activity seems increased in AD, may further increase as AD progresses, and may be involved in the pathophysiology of agitation.

To assess the effects of aging on hypothalamic-pituitary-adrenal (HPA) axis responsivity, we compared the plasma cortisol and adrenocorticotropin (ACTH) responses to hypertonic saline infusion between normal older and young human volunteers. We administered a 90 min hypertonic saline infusion (5% sodium chloride at 0.06 ml/kg/min) and a 90 min placebo infusion (0.9% sodium chloride at 0.06 ml/kg/min) to normal young subjects (n = 13, age = 29 +/- 2 years) and normal older subjects (n = 8, age = 63 +/- 3 years). Plasma cortisol, ACTH, osmolality and arginine vasopressin (AVP) were measured before and at 30 min intervals during the infusions. The rate of increase in plasma osmolality and AVP induced by hypertonic saline infusion was similar between groups. The plasma cortisol increase during hypertonic saline infusion was greater in normal older subjects than in young subjects (p = .03), but a stimulatory effect of hypertonic saline infusion on plasma ACTH was not apparent in either older or young subjects. These results suggest increased sensitivity with human aging to stimulation of cortisol release by hypertonic saline infusion at the adrenocortical level of the HPA axis.

Casopitant is a potent and selective neurokinin-1 receptor antagonist formerly under development for a number of indications, including the treatment of chemotherapy-induced nausea and vomiting. This study was an open-label, randomized, multi-center, two-period crossover casopitant-cyclophosphamide interaction study. Subjects were cancer patients receiving cyclophosphamide based chemotherapy. The objectives of the study were to assess the effect of 3-day, repeat-dose, 150 mg oral casopitant on the pharmacokinetics (PK), safety, tolerability, and pharmacodynamics (white blood cell count) of single-dose IV cyclophosphamide. PK data from 14 evaluable subjects showed the geometric least-squares mean ratios (90% CI) for cyclophosphamide and the metabolite 4-hydroxycyclophosphamide AUC (with:without casopitant) were 1.03 (0.975, 1.09) and 0.948 (0.835, 1.08), respectively. Administration of casopitant was well tolerated and did not impact the safety profile of the treatment regimen. Casopitant did not affect the expected bone marrow toxicity of cyclophosphamide. Co-administration of 150 mg oral casopitant with single-dose IV cyclophosphamide did not appear to result in a clinically relevant change in cyclophosphamide or 4-hydroxycyclophosphamide exposure or safety.

We determined whether transient tachypnoea of the newborn (TTN) is more common in macrosomic versus normal weight infants and in those delivered by caesarean section versus vaginally, in a retrospective cohort analysis of 212 type 1 diabetes pregnancies. Caesarean section and macrosomia were both associated with higher TTN rates.

National governments worldwide work to improve education and health outcomes for children and youth and influence their behaviours. Also heavily engaged are national non-governmental organisations (NGOs) in the voluntary and non-profit sector. While individual agencies and non-profit organisations are often concerned with specific issues of interest related to their charge, constituency or membership, they often develop allegiances with like-minded groups to accomplish broader goals. Two such collaborations in the United States are the focus of this discussion, the National Co-ordinating Committee on School Health and Safety (NCCSHS) and the Friends of School Health (hereafter, "the Friends"). This article reviews these two significant partnerships of public health and education NGOs and outlines successful strategies and lessons learned from the development of these large-scale partnerships. NCCSHS is a collaboration of 64 NGOs and six U.S. government departments representing both the fields of public health and education. Nearly all major NGOs working in fields related to school health are represented, and the six primary governmental agencies all have at least some responsibility for students' health and safety. The group is the primary intersection of NGOs and the Federal government related to school health at the national level. The Friends of School Health ("the Friends") is the primary school health advocacy coalition at the national level in the United States. Sixty-one education and public health NGOs participate. The coalition serves as a communication mechanism and venue for collaborative action on issues before the U.S. Congress and state legislatures that relate to school health. Since the coalition advocates to legislators and other decision makers, no government agencies participate. The paper describes the strategies relating to the initial development of the collaboratives and their ongoing operation. A common theme in development of both of these examples of large-scale partnerships is trust. Like any partnership, the ability to work and grow is dependent on the level of trust among the partners. Both the National Coordinating Committee on School Health and Safety and the Friends of School Health work together successfully within and across their collaborations, to improve health and educational outcomes for children and youth. While both experience challenges, and neither would indicate that its work is near completion, they provide important insight into how these collaboratives can initially develop and subsequently operate productively while providing important contributions to the promotion of healthy schools, and ultimately, healthy nations.

PUBLISHED, Homozygosity for the T allele of the C677T polymorphism of the gene encoding the folate dependent enzyme 5,10-methylenetetrahydrofolate reductase (MTHFR) is a risk factor for neural tube defects.1 Both the homozygous (TT) and heterozygous (CT) genotypes are associated with lower tissue concentrations of folate, higher homocysteine concentrations, and lower enzyme activity than the wild type (CC) genotype; these effects are more marked in homozygotes. Low folate and raised homocysteine levels in early pregnancy are risk factors for neural tube defects.2 We investigated the possibility that the CT genotype would also increase the risk of these malformations.

Background: The resting cerebrospinal fluid (CSF) norepinephrine concentration is unchanged or even increased in patients with Alzheimer's disease (AD). These in vivo findings appear to be inconsistent with the postmortem locus ceruleus neuronal loss that is reported in patients with AD. Methods: The effects of AD and advanced age on central nervous system noradrenergic status were estimated by comparing CSF norepinephrine concentrations following the administration of yohimbine hydrochloride, clonidine hydrochloride, and placebo in outpatients with AD and older and young normal subjects. Levels of yohimbine, its metabolite 11-hydroxy-yohimbine, and clonidine were measured in CSF and plasma samples. Behavioral responses were quantified by rating the Tension, Excitement, and Anxiety items on the Brief Psychiatric Rating Scale. Results: Yohimbine-induced increases of CSF norepinephrine concentrations were greater in both patients with AD and normal older subjects than in normal young subjects. Clonidine-induced decreases of CSF norepinephrine concentrations did not differ among groups. Behavioral arousal following the administration of yohimbine was greater in patients with AD than in the other groups. Conclusions: Central nervous system noradrenergic responsiveness is enhanced in normal older subjects, and this age effect is retained in patients with AD. Behavioral sensitivity to increased central nervous system noradrenergic activity is enhanced in patients with AD.

Intraventricular hemorrhage (IVH) is the most common brain lesion documented at autopsy in 40% to 50% of preterm infants with birth weights less than 1,500 g (Papile, Burstein, Burstein, & Kofler, 1978). The incidence of IVH remains high in the very low birth weight preterm population because of improved survival rates of infants with increasingly shorter gestations in whom IVH insult can be expected (Shinnar, Molteni, Gammon, D’Souva, Altman, & Freeman, 1982). Ultrasonographic studies conducted within 2 to 10 days of preterm birth can detect IVH in approximately one-third of infants of very low birth weight (less than 1,500 g) (Ahmann, Lazzara, Dykes, Brann, & Schwartz, 1978; Papile et al., 1978).