Efficacy of Canakinumab vs. triamcinolone acetonide according to multiple gouty arthritis-related health outcomes measures.

AIM: Canakinumab (CAN), a selective, fully human, anti-IL-1ß monoclonal antibody, has demonstrated long-term benefits in gouty arthritis (GA) patients, who have contraindications for, or are unresponsive or intolerant of, non-steroidal anti-inflammatory drugs (NSAIDs) or colchicine (two trials:ß-RELIEVED [n = 228]; ß-RELIEVED II [n = 226]). The trials collected different responses, including patient-reported outcomes (PRO). A composite response end-point (CRE) was used to interpret each patient's overall response to treatment. METHODS: Data from ß-RELIEVED trials were pooled for this retrospective analysis. The CRE representing overall change in GA-related health outcomes, from baseline to 12 weeks, included clinical markers; PROs from the Gout Impact Scale (GIS); and the SF-36 bodily pain scale. Response to each variable (i.e. markedly important difference) was determined a priori. Variable values [1 (responder) or 0 (non-responder)] were summed to create a CRE score for each patient. RESULTS: For eight of 12 variables measured, the percentage of CAN responders was significantly greater than for TA (p < 0.05). On average, patients receiving CAN met a higher percentage of response criteria (65%) than patients receiving triamcinolone acetonide (TA) (49%), p < 0.001. Mean CRE scores were significantly higher for CAN vs. TA (mean [SD]; 4.7 [2.7] vs. 3.7 [2.4], p < 0.001). Treatment differences remained even after serially removing individual responder variables and domains from the composite end-point, indicating that the differences between CAN and TA were robust. CONCLUSION: CAN was superior to TA across multiple health-outcome variables comprising clinical markers and PRO over 12 weeks in patients contraindicated, intolerant or unresponsive to NSAIDs and/or colchicine.

Reliability and validity of the Ocular Surface Disease Index.

OBJECTIVE: To evaluate the validity and reliability of the Ocular Surface Disease Index (OSDI) questionnaire. METHODS: Participants (109 patients with dry eye and 30 normal controls) completed the OSDI, the National Eye Institute Visual Functioning Questionnaire (NEI VFQ-25), the McMonnies Dry Eye Questionnaire, the Short Form-12 (SF-12) Health Status Questionnaire, and an ophthalmic examination including Schirmer tests, tear breakup time, and fluorescein and lissamine green staining. RESULTS: Factor analysis identified 3 subscales of the OSDI: vision-related function, ocular symptoms, and environmental triggers. Reliability (measured by Cronbach alpha) ranged from good to excellent for the overall instrument and each subscale, and test-retest reliability was good to excellent. The OSDI was valid, effectively discriminating between normal, mild to moderate, and severe dry eye disease as defined by both physician's assessment and a composite disease severity score. The OSDI also correlated significantly with the McMonnies questionnaire, the National Eye Institute Visual Functioning Questionnaire, the physical component summary score of the Short Form-12, patient perception of symptoms, and artificial tear usage. CONCLUSIONS: The OSDI is a valid and reliable instrument for measuring the severity of dry eye disease, and it possesses the necessary psychometric properties to be used as an end point in clinical trials.

Cholecystokinin in vivo reduces binding to rat hypothalamic beta-adrenergic sites.

Intraperitoneal injection of sulfated cholecystokinin octapeptide (CCK-8; 10 micrograms/kg) resulted in an increase in the IC50 for isoproterenol (4.2 microM to 23.3 microM) in displacing 1 nM 3H-dihydroalprenolol binding to rat hypothalamic membranes. 3H-p-Aminoclonidine binding was also lower in membranes prepared from CCK-treated rats, but the decrease was not statistically significant. In vitro, CCK(1-100 nM) had no effect on either alpha- or beta-adrenergic binding or on the 5'-guanylylimidodiphosphate modulation of binding. The results indicate that CCK does not act directly upon adrenergic receptors, but may reduce beta-adrenergic affinity through indirect means.

Opiate and muscarinic ligand binding in five limbic areas after bilateral olfactory bulbectomy.

Bilateral olfactory bulbectomy (BBX) in mice leads to a variety of neutrochemical changes in 5 limbic areas associated with the bulbs. Within one week after BBX, opiate ligand binding declined by 73% in the amygdala, rose by 82% in the hypothalamus and then returned to sham levels by 4 weeks in both areas. Opiate binding also declined by 47% in the olfactory tubercle and to essentially zero in the piriform cortex and the olfactory peduncle after 16 weeks. Muscarinic cholinergic binding declined in the amygdala and hypothalamus at 16 weeks after BBX, but reductions in muscarinic binding were observed in the piriform cortex and the olfactory peduncle by two weeks postsurgery. Muscarinic binding in the olfactory tubercle was unaffected by BBX, as was binding of beta-adrenergic and benzodiazepine ligands in the limbic areas. Binding of [3H]spiroperidol rose 61% in the olfactory tubercle two weeks after surgery and then declined to normal levels. Choline acetyltransferase activity rose by 64% within one week after BBX in the piriform cortex and remained elevated throughout the study. Activity of this enzyme also rose in the olfactory peduncle and the olfactory tubercle after surgery. BBX had only moderate effects on glutamic acid decarboxylase in the limbic areas, and enzyme activity increased 25% in the olfactory tubercle and the piriform cortex 4 weeks after BBX. BBX also resulted in a moderate decrease (22%) in DOPA decarboxylase activity in the olfactory tubercle two weeks after BBX. The implications of these neurochemical changes are discussed in terms of what is known about bulb-limbic system connections.

L-[3H]Carnosine binding in the olfactory bulb. II. Biochemical and biological studies.

During the first 10 days after peripheral deafferentation of the mouse olfactory bulb stereoselective binding of L-[3H]carnosine declines markedly. The initial phase of this decline is due to a decrease in binding site stereoselectivity, which is then followed by a loss of assayable binding sites. The specificity of inhibition of L-[3H]carnosine binding by various peptides is also altered after denervation. Competitive inhibitors of carnosine binding become less potent after denervation, while analogues which are not competitive inhibitors remain equipotent before and after denervation. Several carnosine analogues that are normally poor inhibitors become more potent after denervation. Treatment of bulb membranes with trypsin, RNase and hyaluronidase, but not DNase or collagenase, resulted in significant alterations in carnosine binding. L-, but not D-carnosine, protected the binding site from trypsin digestion, and induced additional binding in bulb membranes in a dose-and temperature-dependent fashion. Preincubation of membranes with L-carnosine also led to the induction of additional carnosine binding in membranes from cerebral cortex, cerebellum and deafferentated bulbs but not from muscle. Bulbs from newborn mice contain about one-half of the adult levels of binding and no significant sex differences in carnosine binding were detected in bulbs from adult rats. L-[3H]carnosine binding was two-fold higher in the anterior compared to the posterior portion of the bulb, but there were no significant differences in binding of opiate, GABA, alpha-adrenergic, muscarinic cholinergic, benzodiazepine of glutamic acid receptor ligands.

Influence of unilateral olfactory bulbectomy on opiate and other binding sites in the contralateral bulb.

The neurochemical consequences of unilateral olfactory bulbectomy (UBX) in mice were determined in the remaining olfactory bulb at various times after surgery. The most significant finding was a progressive decline in opiate ligand (dihydromorphine) and naloxone) binding that appeared within 11 days after surgery and persisted throughout the study. Statistically significant declines in spiroperidol (-67%), clonidine (-48%) and muscimol (-16%) binding were also observed 90 days after surgery. At 180 days postsurgery we observed a 20% increase in diazepam binding. No effect of UBX on dihydroalprenolol, quinucludinylbenzilate or serotonin ligand binding was observed. Bulbectomy resulted in a moderate decrease (-28%) in DOPA decarboxylase activity 14 days after surgery, which returned to normal by 30 days. Glutamic acid decarboxylase activity decreased by 37% 7 days after UBX, returned to normal by 14 days after surgery and then increased by 25% 90 days after UBX. Unilateral bulbectomy had no effect on cholineacetyltransferase activity in the remaining bulb. Thus, following a unilateral procedure, one bulb cannot necessarily serve as a valid control for the other. Possible explanations for the neurochemical changes observed are discussed.

Cell suspensions from rat olfactory neuroepithelium: biochemical and histochemical characterization.

Cell suspensions were generated from rat olfactory epithelium by digestion with collagenase and hyaluronidase followed by gentle mechanical disruption. These cell suspensions excluded nigrosin dye and synthesized RNA, protein and carnosine from radiolabeled precursors. Sustentacular cells, repiratory epithelial cells and olfactory neurons but not basal cells could be identified by phase-contrast microscopy. Sedimentation of these cell suspensions at unit gravity in discontinuous gradients of buffered bovine serum albumin resulted in partial separation of the various cell types as indicated by the distribution of several biochemical markers. Olfactory marker protein and carnosine synthetase activity were found in the upper gradient fractions, while carnosinase activity was present predominantly in the lower gradient fractions. Cellular localization of olfactory neuron marker protein and non-neuronal S-100 protein by immunoperoxidase staining of gradient-fractionated cells indicated that neuronal cells were only partially separated from non-neuronal cells by our fractionation techniques. Evaluation of gradient fractionated cells by histochemical staining for carbohydrates demonstrated that secretory Bowman's gland cells were quite efficiently separated from neurons. This study demonstrates the ease with which cell suspensions may be produced from the olfactory epithelium, and emphasizes the importance of utilizing both biochemical and histochemical approaches in studies of mixed populations of cells, particularly when the purity of the cell fractions is a consideration.

Ligand binding studies in the mouse olfactory bulb: identification and characterization of a L-[3H]carnosine binding site.

Binding sites for the dipeptide L-carnosine (beta-alanyl-L-histidine) have been detected in membranes prepared from mouse olfactory bulbs. The binding of L-[3H]-carnosine was saturable, reversible and stereospecific and had a Kd of about 770 nM. The stereospecific binding of L-carnosine represented about 30% of the total binding at pH 6.8, and decreased markedly with increasing pH. Binding was stimulated by calcium, unaffected by zinc, magnesium or manganese and inhibited by sodium and potassium. Carnosine binding was sensitive to trypsin and phospholipases A and C, but not to neuraminidase. Nystatin and filipin, which interact with membrane lipids, also interferred with binding. Some peptide analogues of carnosine were potent inhibitors of binding, but a variety of drugs serving as potent inhibitors in other binding systems had no effect on carnosine binding. Carnosine binding to mouse olfactory bulb membranes was 15-fold higher than that seen in membranes prepared from cerebral hemispheres, 5-fold higher than that seen in membranes prepared from cerebral hemispheres, 5-fold higher than in cerebellum membranes and 3-fold higher than in membranes from spinal medulla and the olfactory tubercle-lateral olfactory tract area. Binding sites for 6 other radiolabeled receptor ligands were also detected in bulb membranes. Peripheral deafferentation of the olfactory bulbs by intranasal irrigation with ZnSO4 led to a loss greater than 90% of the L-[3H]carnosine binding in 4--5 days with much smaller losses in binding of the other 6 ligands over a 180-day observation period. This initial loss of carnosine binding after denervation was due to a loss of binding site stereo-specificity followed by a loss of binding sites. The characteristics of the carnosine binding site in olfactory bulb fulfil 6 of the 7 criteria considered relevant for a functional receptor.

Binding of beta-carboline-3-carboxylic acid ethyl ester to mouse brain benzodiazepine receptors in vivo.

beta-Carboline-3-carboxylic acid ethyl ester (beta-CEE) displaced [3H] flunitrazepam from the mouse brain benzodiazepine receptor in vivo with an i.v. ED50 of 2.1 mg/kg, an i.p. ED50 and 53.4 mg/kg, and an i.g. ED50 of 450 mg/kg. At 2.1 mg/kg i.v. beta-CEE displaced 37 +/- 9% of the label from hippocampal membranes and 76 +/- 7% from cerebellar membranes. The results suggest that the in vitro binding specificity of beta-CEE is also expressed in vivo and that the drug may act in vivo by binding to the benzodiazepine receptor.

In vitro and in vivo effects on brain GABA metabolism of (S)-4-amino-5-fluoropentanoic acid, a mechanism-based inactivator of gamma-aminobutyric acid transaminase.

The effects of intraperitoneal administration of (S)-4-amino-5-fluoropentanoic acid, a mechanism-based covalent inactivator of gamma-aminobutyric acid transaminase (GABA-T), on whole brain GABA metabolism in mice were investigated. A dose-dependent and time-dependent irreversible inactivation of GABA-T was observed with a concomitant increase in whole brain GABA levels. The compound exhibited no in vitro nor in vivo time-dependent inhibition of glutamate decarboxylase (GAD), alanine transaminase, or aspartate transaminase (Asp-T). It was, however, a potent competitive reversible inhibitor of GAD and a weak competitive inhibitor of Asp-T. The chloro analogue, (S)-4-amino-5-chloropentanoic acid, was ineffective.

Photolabeling of benzodiazepine receptors spares [3H]propyl beta-carboline binding.

When the benzodiazepine receptor in mouse cerebellar, striatal, and hippocampal membranes was photoaffinity labeled with nonradioactive flunitrazepam, specific [3H]diazepam binding determined with either unlabeled diazepam or ethyl beta-carboline-3-carboxylate (betaCCE) as displacer declined greater than 80%. In contrast, specific propyl beta-carboline-3-carboxylate (PrCC) binding in these regions determined with betaCCE as displacer was basically unaltered after photolabeling. Photolabeling lowered specific [3H]PrCC binding with diazepam as displacer to an intermediate extent in the three regions. In cerebellum photolabeling had little effect on either the Kd or Bmax for specific [3H]PrCC binding determined with betaCCE as displacer but significantly lowered the Bmax for specific [3H]PrCC binding determined with diazepam as displacer. These results do not support the idea that [3H]PrCC and [3H]diazepam have a common recognition site on the benzodiazepine receptor. Instead, they suggest that the benzodiazepine receptor is a multicomponent complex.

Heterogeneity of benzodiazepine binding sites: a review of recent research.

This paper reviews selected aspects of benzodiazepine binding site heterogeneity. These include receptor heterogeneity revealed by biochemical determinations of receptor numbers, autoradiographic localization in histological sections of brain, lesion studies, solubilization of receptors, and photoaffinity labelling. The data summarized support the concept of benzodiazepine receptor multiplicity. In addition, we have reviewed recent work on peripheral-type benzodiazepine binding sites and suggest that further study of these sites may increase our understanding of both the central and peripheral actions of benzodiazepines and other ligands.

Oncology nurses' attitudes, perceptions, and knowledge of quality-of-life assessment in patients with cancer.

PURPOSE/OBJECTIVES: To provide an overview of the current attitudes and perceptions of oncology nurses regarding the relevance and measurability of quality of life (QOL) in patients with cancer. DESIGN AND SETTING: Exploratory survey conducted at a scientific exhibit of QOL instruments at the 1990 Oncology Nursing Society Congress held in Washington, DC. SAMPLE: Convenience sample of 621 nurses visiting the exhibit. METHODS: Subjects completed two questionnaires addressing opinions regarding the impact of treatment on QOL, the importance of QOL as an outcome measure, the current status of QOL assessment, barriers to measuring QOL, and knowledge about QOL measurement tissues. MAIN OUTCOME MEASURES: Results of answers to questionnaire items overall as well as selected demographic variables. FINDINGS: Chemotherapy was thought to have the greatest negative impact on QOL, and vomiting, nausea, and tiredness were judged to be the side effects of treatment that most commonly affected QOL. QOL was judged as important an outcome measure as tumor response, toxicity, and survival. Generally, nurses were knowledgeable regarding QOL measurement issues; however, many of the respondents indicated that they believed valid QOL instruments did not exist or that QOL could not be objectively quantified. CONCLUSIONS: Nurses value QOL as an outcome measure of cancer treatment but lack knowledge regarding its measurability, particularly with respect to reliable tools and available time to assess it well. IMPLICATIONS FOR NURSING PRACTICE: Nurses can be instrumental in incorporating QOL measurement as an outcome of treatment and development of brief self-administered tools. Commentary on this research and author response is included at the conclusion of the article.

A new look at dry eye disease and its treatment.

This review examines the impact of moderate to severe dry eye disease on daily life and medical-resource utilization. The results suggest that current treatment paradigms can lead to unacceptable costs in both quality of life and progressive use of healthcare resources. Evidence linking this disease to T-cell-mediated inflammatory processes lays the foundation for understanding the clinical benefits of topical cyclosporine, an immunomodulatory and anti-inflammatory agent.

Costs incurred by outpatient surgical centers in managing postoperative nausea and vomiting.

STUDY OBJECTIVE: To estimate the financial costs incurred by outpatient surgical centers in managing postoperative nausea and vomiting (PONV). DESIGN: Prospective, observational study. SETTING: 6 hospital-based outpatient surgery centers. PATIENTS: 211 adult patients undergoing outpatient surgery for laparoscopy, dilatation and curettage, knee arthroscopy, or hernia repair. MEASUREMENTS AND MAIN RESULTS: Of the 211 patients studied, 34 experienced PONV in the recovery room. For those patients experiencing PONV, personnel, supply, and drug costs for management of this condition averaged $14.94 per patient. In addition, PONV increased the centers' operating costs by delaying patient discharge by an average of 24 minutes. A minimum estimate of this cost, based on nurses' wage rates, was $7.12. This estimate is appropriate only for short-run considerations in outpatient surgery centers that operate at low capacity. An appropriate valuation for long-run considerations and for centers operating near capacity is based on the revenue that centers lose as a result of extended stays. Lost revenue was estimated to be $415 per patient experiencing PONV. CONCLUSIONS: PONV substantially increases the costs incurred by outpatient surgical centers.

Health care utilization in patients with gout.

OBJECTIVE: To study health care utilization patterns in patients with gout. METHODS: In a gout population from primary care and rheumatology clinics in 3 U.S. metropolitan cities, we collected data on gout-related utilization (primary care, rheumatology, urgent care, emergency room, and other) in the past year. We evaluated the association of comorbidities, age, gender, gout characteristics (time since last gout attack and tophi), and gout severity ratings (mean of serum uric acid, patient-rated, and physician-rated gout severity) and with emergency/urgent care and primary care utilization using regression and correlation analyses. RESULTS: Of the 296 patients who reported visiting at least 1 type of health practitioner for gout in the past year, the percentage of patients utilizing the service at least once and annual utilization rates among utilizers were as follows: primary care physician, 60%, 3.0 ± 3.4; nurse practitioner/physician assistant, 26%, 2.7 ± 2.5; rheumatologist, 51%, 3.7 ± 5.7; urgent care, 23%, 2.1 ± 2.2; emergency room, 20%, 2.0 ± 1.7; and hospitalization, 7%, 2.1 ± 1.4. Higher overall gout severity was associated with greater use of each resource type and with overall gout-related utilization. Nonemergency/nonurgent care utilization (primary care physician, nurse practitioner, physician's assistant, and rheumatologist for gout) was the strongest predictor of gout-related emergency/urgent care utilization. Patients with more comorbidities had greater gout-related primary care utilization. CONCLUSIONS: Overall gout severity was associated with all types of gout-related utilization. This may help to screen high utilizers for targeted behavioral and therapeutic interventions. Having a higher number of comorbid conditions was a risk factor for higher gout-related primary care utilization.

Pharmacological and physiological properties of benzodiazepine binding sites in rodent brown adipose tissue.

[3H]Diazepam and [3H] Ro5 -4864 were used as ligands to identify and characterize peripheral-type benzodiazepine binding sites in mouse and rat brown adipose tissue (BAT) membranes. [3H]Diazepam and [3H] Ro5 -4864 binding sites in BAT are pharmacologically similar to peripheral-type benzodiazepine binding sites in other tissues. Stimulators of central-type benzodiazepine receptors had no effect on or inhibited ligand binding to BAT membranes. Brown adipose tissue benzodiazepine binding sites are highly localized to mitochondria-containing subcellular fractions. These binding sites decrease with age in BAT from Fischer 344 rats. Stimulation of BAT thermogenesis in mice with 1-norepinephrine led to a decrease in [3H] Ro5 -4864 binding in the tissue.

beta-Carboline-3-carboxylic acid ethyl ester antagonizes diazepam activity.

Analogous to the progression of events in the opiate receptor-enkaphalin area, the first reports that benzodiazepines have selective and specific high-affinity binding sites in brain have stimulated a search for the endogenous 'ligand' or substance that might normally act at these sites. Braestrup and co-workers have extracted from human urine a gamma-fraction (ref. 10) which they have recently identified as beta-carboline-3-carboxylic acid ethyl ester (beta CEE). They reported that this substance is extremely potent in displacing 3H-diazepam from brain binding sites and proposed that a beta-carboline-3-carboxylic acid derivative might, in part, be the endogenous ligand for the brain benzodiazepine receptor. We have examined several synthetically derived beta-carboline-3-carboxylic acid analogues and now present data obtained from testing only the beta CEE described by Braestrup et al. In addition to confirming these workers' observation that this compound is a potent displacer of 3H-diazepam from brain tissue, our pharmacological data indicate that beta CEE has activity that is opposite to, rather than similar to, that of diazepam.