Management of chemotherapy hypersensitivity reactions and desensitization: An SGO clinical practice statement.

OBJECTIVE: The goal of this practice statement is to help members and their multidisciplinary teams recognize infusion reactions and hypersensitivity reactions in the clinical setting. It will provide recommendations to help guide response to reactions and desensitization when appropriate, to promote safe use of chemotherapeutic agents among all providers in the delivery process. METHODS: A multi-disciplinary team of healthcare professionals from the Society of Gynecologic Oncology Education Committee collaborated to review peer reviewed literature and guidelines to develop a practice statement on the management of chemotherapy hypersensitivity reactions and desensitization regimens. RESULTS: There is always potential for a patient to have a reaction to any medication, with both infusion reactions and hypersensitivity reactions potentially occurring in the treatment of gynecologic cancers. Premedication to prevent reactions should be given at least prior to infusion for regimens that include the most common agents associated with reactions. At the time when reaction is occurring it might be difficult to distinguish between an infusion reaction versus true hypersensitivity given the similarities in signs and symptoms, therefore it is important that orders to manage reactions be included in every chemotherapy order set so the infusion nurse can provide immediate interventions while waiting for the provider to arrive to assess the patient. Desensitization is a potential option to allow the patient to continue to receive the offending agent. While a variety of desensitization regimens have been presented in the literature, the goal is to minimize steps and variability to decrease opportunity for errors during chemotherapy preparation or administration. CONCLUSION: Incorporating a review of the literature and clinical experience from the SGO Education Committee, this paper provides an overview of current approaches for prevention and management of reactions to commonly used chemotherapy agents for gynecologic cancers.

EFM data mapped into 2D images of tip-sample contact potential difference and capacitance second derivative.

We report a simple technique for mapping Electrostatic Force Microscopy (EFM) bias sweep data into 2D images. The method allows simultaneous probing, in the same scanning area, of the contact potential difference and the second derivative of the capacitance between tip and sample, along with the height information. The only required equipment consists of a microscope with lift-mode EFM capable of phase shift detection. We designate this approach as Scanning Probe Potential Electrostatic Force Microscopy (SPP-EFM). An open-source MATLAB Graphical User Interface (GUI) for images acquisition, processing and analysis has been developed. The technique is tested with Indium Tin Oxide (ITO) and with poly(3-hexylthiophene) (P3HT) nanowires for organic transistor applications.

Effects of spironolactone on endothelial function, vascular angiotensin converting enzyme activity, and other prognostic markers in patients with mild heart failure already taking optimal treatment.

OBJECTIVES: To examine whether the favourable effects on endothelial function, vascular angiotensin converting enzyme (ACE) activity, cardiac remodelling, autonomic function, and QT intervals of spironolactone in combination with ACE inhibitor also occur in patients with New York Heart Association class I-II congestive heart failure (CHF) taking optimal treatment (including beta blockers). METHODS: Double blind, crossover study comparing 12.5-50 mg/24 hours spironolactone (three months) with placebo in 43 patients with class I-II CHF taking ACE inhibitors and beta blockers. RESULTS: Acetylcholine induced vasodilatation improved with spironolactone (p = 0.044). Vascular ACE activity fell (p = 0.006). QTc and QTd fell (mean (SD) QTc 473 (43.1) ms with placebo, 455 (35.4) ms with spironolactone, p = 0.002; QTd 84.5 (41.3) ms with placebo, 72.1 (32.3) ms with spironolactone, p = 0.037). beta-Type natriuretic peptide (BNP) and procollagen III N-terminal peptide (PIIINP) concentrations were also reduced by spironolactone (mean (SD) BNP 48.5 (29.6) pg/ml with placebo, 36.8 (28.5) pg/ml with spironolactone, p = 0.039; PIIINP 3.767 (1.157) microg/ml with placebo, 3.156 (1.123) microg/ml with spironolactone, p = 0.000). CONCLUSIONS: Spironolactone improves vascular function (endothelial function, vascular ACE activity) and other markers of prognosis (BNP, collagen markers, and QT interval length) in asymptomatic or mild CHF when added to optimal treatment including beta blockade. This gives support to the hypothesis that the prognostic benefit seen in RALES (randomised aldactone evaluation study) and EPHESUS (eplerenone postacute myocardial infarction heart failure efficacy and survival study) may also occur in patients with milder CHF already taking standard optimal treatment.

Discovery and development of neuronal nitric oxide synthase inhibitors.

The role of neuronally derived nitric oxide (NO) in neurotransmission and neural injury remains an area of active investigation. NO generation has been postulated to be involved in the deleterious events surrounding ischemia/reperfusion injury either directly or via the production of more reactive oxidants such as peroxynitrite. In our search for novel therapeutics for the treatment of a variety of neurological diseases including stroke, we have discovered novel, potent, and selective inhibitors of the neuronal nitric oxide synthase (nNOS) isoform. These compounds have proven to be effective in models of ischemia/reperfusion supporting the role of nNOS in these processes. The effects of these compounds as well as additional aspects critical to their development will be presented.

Radiolabeled neuronal nitric oxide synthase inhibitors: synthesis, in vivo evaluation, and primate PET studies.

UNLABELLED: The objectives of this study were to synthesize neuronal nitric oxide synthase (NOS-I)-selective imaging agents based on the 2 potent, selective inhibitors AR-R 17443 [N-(4-((2-((phenylmethyl) (methyl)-amino)ethyl)phenyl)-2-thiophenecarboximidamide)] and AR-R 18512 [(N(2-methyl-1,2,3,4-tetrahydroisoquinoline-7-yl)-2-thiophenecarboxim idamide)] in positron-emitting form and to evaluate regional brain uptake in rodents and primates. METHODS: [11C]AR-R 17443 and [11C]AR-R 18512 were produced by N-alkylation of the corresponding desmethyl precursors using [11C]iodomethane. Regional brain uptake of [11C]AR-R 17443 and [11C]AR-R 18512 was assayed in rats and NOS-I knockout mice, and PET was performed in baboons. Tracer kinetic modeling used a 2-compartment plasma and brain tissue model. RESULTS: Yields of [11C]AR-R 17443 and [11C]AR-R 18512 ranged from 8% to 16% at the end of synthesis, with specific activities of 50-178 GBq/micromol (1,350-4,800 Ci/mmol) at the end of synthesis. In rat cerebellum and cortex at 30 min after injection, [11C]AR-R 17443 showed 1.01 +/- 0.01 and 1.63 +/- 0.12 percentage injected dose per gram (%ID/g) uptake, respectively, whereas [11C]AR-R 18512 showed 0.88 +/- 0.01 and 1.30 +/- 0.07 %ID/g uptake, respectively. Attempts to block tracer uptake by pretreatment with the NOS-I-selective inhibitor 7-nitroindazole or the corresponding unlabeled inhibitor (or desmethyl precursor to AR-R 17443 of similar potency) were unsuccessful. A small but significant (20%) decrease in cerebellar uptake of [11C]AR-R 18512 was present in NOS-I knockout mice compared with control mice. PET of [11C]AR-R 18512 in baboons with concurrent regional cerebral blood flow (rCBF) determination before and after administration of blocker showed dose-related decreases in cerebellar uptake that were greater than or equal to decreases in rCBF. Plasma metabolites accounted for 27% of total activity at 30 min after injection. Kinetic modeling of binding potentials revealed a distribution volume of 334 in cerebral blood that dropped 51% after blocker administration. CONCLUSION: Rodent studies for [11C]AR-R 17443 and [11C]AR-R 18512 showed little evidence of specific NOS-I binding. In baboons, we detected a higher uptake of [11C]AR-R 18512 in the cerebellum than in the cortex (approximately 5%, accounting for decreased rCBF because of blockade), indicating minimal specific binding. Analogs of higher affinity are likely required if this class of agents is to prove viable for PET.

A deconstructive turn in chronic pain treatment: a redefined role for social work.

Chronic pain treatment programs in North America are based predominantly on a behavioral science model of contingency management, whereby the focus of treatment is directed toward the psychological aspects of pain. Treatment objectives are designed to eliminate reinforcing environmental contingencies, thus changing pain behavior and reestablishing well behavior. The purpose of this article is to displace the contingency management model with deconstruction and thus present an alternative conceptualization based on the experiences of chronic pain sufferers. Social work's value base of self-determination and empowerment upholds these challenges to the predominant treatment model. Alternative social work interventions are explored.

Lack of involvement of neuronal nitric oxide synthase in the pathogenesis of a transgenic mouse model of familial amyotrophic lateral sclerosis.

A subset of familial cases of amyotrophic lateral sclerosis are linked to missense mutations in copper/zinc superoxide dismutase type 1. Patients with missense mutations in copper/zinc superoxide dismutase type 1 develop a paralytic disease indistinguishable from sporadic amyotrophic lateral sclerosis through an unknown toxic gain of function. Nitric oxide reacts with the superoxide anion to form the strong oxidant, peroxynitrite, which participates in neuronal injury in a variety of model systems. Peroxynitrite is an alternate substrate for copper/zinc superoxide dismutase type 1, causing catalytic nitration of tyrosine residues in other proteins. Mutations in copper/zinc superoxide dismutase type 1 may disrupt the active site of the enzyme and permit greater access of peroxynitrite to copper, leading to increased nitration by peroxynitrite of critical cellular targets. To investigate whether neuronal-derived nitric oxide plays a role in the pathogenesis of familial amyotrophic lateral sclerosis, we examined the effects of three different nitric oxide synthase inhibitors: a non-selective nitric oxide synthase inhibitor, nitro-L-arginine methyl ester; a relatively selective inhibitor of neuronal nitric oxide synthase, 7-nitroindazole; and a novel highly selective neuronal nitric oxide synthase inhibitor, AR-R 17,477, in transgenic mice expressing a familial amyotrophic lateral sclerosis-linked mutant human copper/zinc superoxide dismutase type 1 (Gly-->Ala at position 93; G93A) containing a high transgene copy number and a low transgene copy number. AR-R 17,477, but not nitro-L-arginine methyl ester or 7-nitroindazole, significantly prolonged survival in both the high and low transgene transgenic mice. To determine whether neuronal nitric oxide synthase is involved in the pathogenesis resulting from the familial amyotrophic lateral sclerosis copper/zinc superoxide dismutase type 1 mutation, we produced mice with the copper/zinc superoxide dismutase type 1 mutation which lack the neuronal nitric oxide synthase gene. The transgenic mice expressing a familial amyotrophic lateral sclerosis-linked mutant human copper/zinc superoxide dismutase type 1 on neuronal nitric oxide synthase null background do not live significantly longer than transgenic mice expressing a familial amyotrophic lateral sclerosis-linked mutant human copper/zinc superoxide dismutase type 1. Western blot analysis indicates the presence of two neuronal nitric oxide synthase-like immunoreactive bands in spinal cord homogenates of the neuronal nitric oxide synthase null mice, and residual neuronal nitric oxide synthase catalytic activity ( > 7%) is detected in the spinal cord of the transgenic mice expressing a familial amyotrophic lateral sclerosis-linked mutant human copper/zinc superoxide dismutase type 1 on neuronal nitric oxide synthase null background. This amount of residual activity probably does not account for lack of protection afforded by the disrupted neuronal nitric oxide synthase gene in the familial amyotrophic lateral sclerosis-linked mutant human copper/zinc superoxide dismutase type 1 mice. Immunological nitric oxide synthase is not detected in the copper/zinc superoxide dismutase type 1 mutant mice at several different ages, thus excluding immunological nitric oxide synthase as a contributor to the pathogenesis of familial amyotrophic lateral sclerosis. Levels of neuronal nitric oxide synthase as well as Ca2+-dependent nitric oxide synthase catalytic activity in the copper/zinc superoxide dismutase type 1 mutant mice do not differ from wild type mice. Endothelial nitric oxide synthase levels may be decreased in the copper/zinc superoxide dismutase type 1 mutant mice. Together, these results do not support a significant role for neuronal-derived nitric oxide in the pathogenesis of familial amyotrophic lateral sclerosis transgenic mice.

Hodgkin's cells express a novel pattern of adhesion molecules.

Adhesion molecules play an important role in the functioning of the immune system, particularly with regard to cell-cell interactions and antigen presentation. Several adhesion molecules are expressed on Hodgkin's disease-derived cell lines and these are important in their molecular interactions as antigen presenting cells (APC). There are no data regarding the expression of many of these adhesion molecules on Reed-Sternberg cells and its mononuclear variant (Hodgkin's cells (HC)) present in pathological material. To obtain this information we undertook an immunohistological study on material from 18 cases of Hodgkin's disease using a panel of MoAbs to examine the expression of adhesion molecules on HC. The HC were shown to express the integrin beta 1 subfamily molecules, LFA-1 (CD11a) and p150,95 (CD11c) in high density but lacked CR3 (CD11b). All of the immunoglobulin gene superfamily adhesion molecules studied were present to some degree on HC, with ICAM-2, in particular, showing moderate to strong expression in most cases. The Hermes antigen CD44 was present in high density but leukosialin (CD43), another molecule present on diverse leucocyte types, was, in general, not detected on HC. These new data showing that ICAM-1, ICAM-2 and LFA-3 are, like LFA-1, expressed on HC emphasize the ability of HC to act as APC. The known adhesion molecule phenotype of the recently defined haematopoietic lineage of human dendritic cells (DC) is broadly similar to that of HC, perhaps supporting the hypothesis that some HC represent a malignancy of an APC (DC) lineage.

The Survey of Recent Life Experiences: a decontaminated Hassles Scale for adults.

A new decontaminated hassles measure for adults, the Survey of Recent Life Experiences, was developed and validated. An initial pool of 92 items was administered to 100 subjects along with the Perceived Stress Scale. Fifty-one items were selected, based on significant correlations with the latter scale. The alpha reliability of the resultant final form of the Survey of Recent Life Experiences and its correlation with perceived stress were both high. In a separate cross-replication sample of 136 adults, the alpha reliability of the Survey and its correlation against the Perceived Stress Scale remained acceptably high. Moreover, separate-sex analyses supported the reliability and validity of the Survey of Recent Life Experiences across gender. Factor analysis of the Survey yielded six interpretable factors. Intercorrelations among subscales based on these factors were generally modest, suggesting that the scale is relatively free from contamination by psychological distress.

Monocular and binocular measurements of smooth eye-pursuit by rural children in kindergarten and grade two.

Toward developing baseline data for monocular and binocular smooth eye-pursuit 22 midwestern rural Caucasian kindergarten and 24 second-grade children were asked to follow a hand-held penlight with their eyes. The examiner held the student's hand and penlight and monitored the fastest speed in inches per second that the eyes pursued the light with no observed aberration. Range of movement in inches was also noted. Analysis showed moderate correlations for 6-wk. test-retest reliability, monocular and binocular skills are different; pursuit skill of a flickering light is moderately related to that of binocular flashlight; and skills of students at Grade 2 are more advanced than those of students in kindergarten.

Results of cholecystectomy in 1000 consecutive patients.

Analysis of the results of cholecystectomy in 1000 consecutive patients revealed an overall mortality of 0.6%; among patients who underwent cholecystectomy only, there were no deaths. Wound infection occurred in 3.4% of all patients but the rate exceeded 8% among those in whom another procedure was performed or there was acute cholecystitis. Cephaloridine given prophylactically was useful in decreasing the infection rate in the two latter groups. Cystic duct cholangiography, used in 193 patients, increased the rate of stone retrieval from the bile ducts from 41 to 63%, but the incidence of both false-negative and false-positive cholangiograms was disturbingly high. Exploration was performed on clinical grounds despite a normal cholangiogram in 15 patients, with 5 positive results. Common duct exploration was productive 41% of the time when clinical judgement without cholangiography was used. While cystic duct cholangiography is useful, improvements in reliability are imperative and probably feasible, in view of the results achieved in the operating room and those in departments of radiology.