Response of multicellular tumor spheroids to liposomes containing TNF-α

Summary This publication describes a new model to investigate the influence of tumor necrosis factor- (TNF-) on a three-dimensional glial cell aggregate under defined, standardized, reproducible conditions using the glioma cell line A 172.The cells are initially grown as normal monolayer culture until they reach a cell density of up to 1×10⁶. Subsequently they are grown as spheroids by the liquid overlay technique. Spheroids grown in this way were divided into ten groups of more than 50 cell aggregates. Three groups were coincubated with free TNF- in increasing dosages (100 ng/ml, 200 ng/ml and 1000 ng/ml); three groups were incubated with empty liposomes (0.2 mg/ml, 0.4 mg/ml and 2 mg/ml); three groups received liposomes which had been loaded with TNF-, and one group, which received no treatment, served as control.The diameter of the spheroids ranged from 80 m to 350 m. There was no significant difference in growth between the 3 groups treated with free TNF-. Comparing spheroids treated with TNF- with those which had been coincubated with empty liposomes, there was a significant difference (p<0.001) in growth, which correlated with the amount of liposomes. Similarly, free TNF- had a significantly (P<0.001) stronger growth-inhibiting effect as compared to liposomes loaded with TNF-. Comparing the groups treated with liposomes only to those treated with liposomes loaded with TNF-, the latter exhibited a more marked (although not significantly) growth-inhibiting effect.The preliminary conclusion is that the major growth-inhibiting effect seems to be mediated by the liposomes. This phenomenon is in agreement with results obtained in monolayer cultures.     

Overdrainage and shunt technology

When vertical body position is simulated, conventional differential pressure valves show an absolutely unphysiological flow, which is 2–170 times the normal liquor production rate. Although this is compensated in part by the resistance of the silicon tubes, which may produce up to 94% of the resistance of the complete shunt system, a negative intracranial pressure (ICP) of up to 30–44 cmH₂O is an unavoidable consequence, which can be followed by subdural hematomas, slit ventricles, and other well-known complications. Modern shunt technology offers programmable, hydrostatic, and flow-controlled valves and anti-siphon devices; we have tested 13 different designs from 7 manufacturers (56 specimens), using the Heidelberg Valve Test Inventory with 16 subtests. Programmable valves reduce, but cannot exclude, unphysiological flow rates: even in the highest position and in combination with a standard catheter typical programmable Medos-Hakim valves allow a flow of 93–232 ml/h, Sophy SU-8-valves 86–168 ml/h with 30 cmH₂O. The effect of hydrostatic valves (Hakim-Lumbar, Chhabra) can be inactivated by movements of daily life. The weight of the metal balls in most valves was too low for adequate flow reduction. Antisiphon devices are highly dependent on external, i.e. subcutaneous, pressure which has unpredictable influences on shunt function, and clinically is sometimes followed by shunt insufficiency. Two new Orbis-Sigma valves showed relatively physiological flow rates even when the vertical position (30 cmH₂O) was simulated. One showed an insufficient flow (5.7 ml/h), and one was primarily obstructed. These have by far the smallest outlet of all valves. Additionally, the ruby pin tends to stick. Therefore, a high susceptibility to obliterations and blockade is unavoidable. Encouraging results obtained in pediatric patients contrast with disappointing experiences in some German and Swedish hospitals, which suggests that our laboratory findings are confirmed by clinical results. The concept of strict flow limitation seems to be inadaequate for adult patients, who need a relatively high flow during (nocturnal) ICP crises. The problem of shunt overdrainage remains unsolved.This paper is an updated version of an oral presentation held at the Consensus Conference: Hydrocephalus '92 Assisi, Italy, 26–30 April 1992Deceased     

Effects of female sex steroids on Parkinson's disease in postmenopausal women

There are conflicting reports about estrogen modulating the activity of nigrostriatal dopaminergic neurons. Furthermore, modulation may be influenced by progesterone levels. Therefore, the clinical effects of sex steroids on parkinsonian symptoms in postmenopausal women with Parkinson's disease (PD) were analyzed in the present study. Patients (n = 12) were under the age of 80, able to perform the motor function tests, and showed no contraindications for estrogen suppletion. Motor function was assessed using the Unified Parkinson's Disease Rating Scale (UPDRS) and a patient interview on subjective changes. In a placebo-controlled, randomized, double-blind trial lasting 8 weeks, no significant dopaminergic effect of estradiol (E2) could be demonstrated, whereas in an open trial phase lasting 2 weeks, progesterone seemed to have an antidopaminergic effect. Several mechanisms are discussed that can account for the fact that we found no effect of E2 on motor functioning in our patients with PD.     

3-Nitropropionic acid induces a spectrum of Huntington's disease-like neuropathology in rat striatum

Systemic administration of the mitochondrial toxin 3-nitropropionic acid (3-NP) to rats results in selective striatal lesions and serves as an experimental model of Huntington's disease (HD). However, the effects of the 3-NP treatment are unpredictable and result in lesions of variable severity. The present study was aimed at further characterizing the variability of the striatal lesions induced by systemic administration of 3-NP using osmotic pumps. Hematoxylin-eosin (HE) and Nissl stains as well as immunohistochemical labelling of astrocytes and striatal neurones were performed to analyse the neurotoxic effects of 3-NP. In general, chronic systemic administration of 3-NP resulted in obvious bilateral striatal lesions, which ranged from mild to severe, together with a subtle, but detectable behavioural lesion. Severe type lesions showed marked neuronal loss and an increased expression of glial fibrillary acidic protein (GFAP) in astrocytes surrounding the lesion area, whereas in the core of the lesion GFAP-immunoreactivity was absent. The mild type lesion was characterized by a substantial loss of striatal neurones and an increased expression of GFAP-positive astrocytes throughout the lesion. In a number of 3-NP-treated animals, neither type of lesion was observed, although these animals demonstrated behavioural changes in the paw test compared to controls. In the striatum of these tested 3-NP-treated animals, compromised rk' neurones were detected, suggestive of subtle and early 3-NP-induced neuronal injury. Similar dark neurones were also detected in mild and severe lesions and were immunocytochemically characterized as gamma-aminobutyric acid (GABA) and substance P containing spiny neurones, which belong to the neuronal population that is affected in early HD. These results indicate that systemic administration of 3-NP to rats may result in a spectrum of striatal pathology of which the morphology of the mild type lesion resembles the characteristic HD neuropathology most closely.     

Quality of Life following Radical Surgical Treatment of Gastric Carcinoma

Quality of life (QOL) in patients with gastric cancer who underwent total gastrectomy has so far not been studied using the EORTC QLQ-C30 (Quality of Life Core Questionnaire of the European Organization for Research and Treatment of Cancer) as a standardized European QOL instrument. The aim of this study was to evaluate the effect of radical procedures such as extensive lymph node resection and combined resection of adjacent organs on patients' QOL. From 1992 to 1996, 152 patients underwent total gastrectomy. All patients alive on July 1, 1996 were included in the study (77/152). For assessing QOL, the EORTC QOL questionnaire QLQ-C30 version 2.0 and a validated gastric cancer module were sent home to the patients for self-completion. The response rate was 91%. It was possible to evaluate the questionnaires of 62 patients who had undergone resection with curative intent including 13 extended gastrectomies (21%). Of the 62 resections, 50 were combined with D2 lymphadenectomy (80.6%). The global health status was not negatively influenced by D2 lymphadenectomy and extended gastrectomy. Patients with splenectomy were more affected by treatment than patients without splenectomy. Radical gastrectomy combined with D2 lymphadenectomy is the treatment of choice for gastric cancer patients, concerning not just survival but QOL as well.     

Oral supplements as adjunctive treatment to nutritional counseling in malnourished HIV-infected patients: randomized controlled trial

AIMS:To compare nutritional counseling with and without oral supplements in HIV-infected patients with recent weight loss. DESIGN: Randomized non-blinded controlled trial, stratified for change in antiretroviral treatment at baseline. PATIENTS: HIV-infected patients with recent weight loss (> 5% of total, and >3% in the last month). INTERVENTION: Nutritional counseling to increase dietary intake by 600 kcal/day over 8 weeks; in group A (n=24) by normal food, and in group B (n=26) by a range of fortified drink supplements with a calorific value of 0.6 to 1.5 kcal/ml. METHODS: Body composition by bioelectrical impedance analysis, dietary intake by 24 h recall. RESULTS: Fat free mass increased from baseline to week 8 (P<0.05) with no difference between groups A and B (P=0.97). Body cell mass and weight gain were not significant and equal between groups. Assessed at weeks 2 and 4, group B patients consumed 11 +/- 6 kcal/kg as supplements, and their total energy intake was 6 kcal/kg higher than in group A (P<0.01). Total energy intake was not different between groups at weeks 6 and 8. DISCUSSION: Nutritional counseling and oral supplements are both feasible methods to restore food energy intake in malnourished HIV-infected patients. Although normal food intake is partially replaced, oral supplements may improve the adherence to a weight gain regimen.     

161. Postoperative Syndrome nach Gastrektomie und unterschiedlichen Verfahren des Magenersatzes

Zusammenfassung 60 gastrektomierte Patienten mit 5 Verfahren des Magenersatzes wurden nachuntersucht. Beschwerden durch einen jejuno-oesophagealen Reflux werden nur von der Patienten mit einer Jejunuminterposition geklagt. Bei der Jejunoplicatio und der Interposition findet sich endoskopisch-histologisch die Oesophagitis qualitativ und quantitativ geringer ausgeprägt. Manometrisch kann nur bei 5 von 16 Gastrektomierten ein funktionstüchtiger unterer Oesophagussphincter nachgewiesen werden. Der Sphincterverlust muß als Mitursache des Refluxes angesehen werden.     

Physician recertification and outcomes assessment

Physician recertification poses a unique challenge to member boards of the American Board of Medical Specialties (ABMS) charged with the responsibility of credentialing physicians. The key issue that emerges in recertification programs is how to evaluate performance in practice. Although some test of knowledge may be appropriate, an evaluation of clinical performance has become essential in recertification programs. To meet this challenge, ABMS boards have adopted methods to evaluate performance in practice. However, regardless of the methods chosen, criteria are needed to serve as standards. This article considers the application of outcomes assessment in the definition of standards for recertification. When direct outcome assessment may not be possible, outcome-validated process measures may provide a suitable alternative.