[Instruments for Measuring the Effects of Early Intervention on Maintaining and Restoring Ability to Work in Germany: Opinion of an Interdisciplinary Working Group]. / Instrumente zur Messung von Effekten einer Frühintervention auf den Erhalt bzw. die Wiederherstellung der Arbeitsfähigkeit in Deutschland ­ Stellungnahme einer interdisziplinären Arbeitsgruppe.

OBJECTIVE: In projects on early intervention, a wide variety of instruments is used for the measurement of intervention effects on preservation or restoration of ability to work. The aim of the present work was to propose an appropriate instrument or a range of appropriate instruments that enable diverse interventional approaches to be compared, and data quality to be improved. METHODS: A systematic literature search was conducted to map the currently existing measuring instruments. In addition, based on structured interviews with leaders of existing early intervention projects or representatives of other interventional approaches, knowledge and application of the measuring instruments in Germany were determined. In the context of a working meeting, a recommendation was formulated based on the results of the literature search and interviews. RESULTS AND COMMENTS: There is currently no instrument that could be recommended without reservation for the stated purpose. Based on the results of the literature search and the interviews, the working group recommends using, as a first step, the Work Ability Index (WAI, focus on work ability) and the Work Productivity and Activity Impairment Questionnaire (WPAI, focus on absenteeism and presenteeism). German-language versions of both questionnaires are freely available and offer a good compromise in terms of psychometric quality criteria, as well as of practicality and applicability. The measuring instruments should be developed further, with the goal of establishing an optimized instrument that combines the strengths of the two instruments. CONCLUSION: In Germany, use of WAI and the WPAI in as many early intervention approaches as possible will help improve the database, allowing better comparability. However, the focus of further research must be to develop an optimized instrument from elements of WAI and WPAI, in order to be able to measure ability to work as well as the effects of an intervention on preservation or restoration of the ability to work, regardless of the setting.

[Health care expenditures and the aging population]. / Gesundheitsausgaben und demografischer Wandel.

The impact of a longer life on future health care expenditures will be quite moderate because of the high costs of dying and the compression of mortality in old age. If not age per se but proximity to death determines the bulk of expenditures, a shift in the mortality risk to higher ages will not significantly affect lifetime health care expenditures, as death occurs only once in every life. A calculation of the demographic effect on health care expenditures in Germany up until 2050 that explicitly accounts for costs in the last years of life leads to a significantly lower demographic impact on per-capita expenditures than a calculation based on crude age-specific health expenditures.

Velocity bias in intrusive gas-liquid flow measurements.

Gas-liquid flows occur in many natural environments such as breaking waves, river rapids and human-made systems, including nuclear reactors and water treatment or conveyance infrastructure. Such two-phase flows are commonly investigated using phase-detection intrusive probes, yielding velocities that are considered to be directly representative of bubble velocities. Using different state-of-the-art instruments and analysis algorithms, we show that bubble-probe interactions lead to an underestimation of the real bubble velocity due to surface tension. To overcome this velocity bias, a correction method is formulated based on a force balance on the bubble. The proposed methodology allows to assess the bubble-probe interaction bias for various types of gas-liquid flows and to recover the undisturbed real bubble velocity. We show that the velocity bias is strong in laboratory scale investigations and therefore may affect the extrapolation of results to full scale. The correction method increases the accuracy of bubble velocity estimations, thereby enabling a deeper understanding of fundamental gas-liquid flow processes.

Mechanics of fibroblast locomotion: quantitative analysis of forces and motions at the leading lamellas of fibroblasts.

Shapes, motions, and forces developed in lamellipodia and ruffles at the leading edges of primary chick embryo heart fibroblasts were characterized by differential interference contrast microscopy and digital video enhancement techniques. The initial extension of the cell edge to form a thin, planar lamellipodium parallel to the substrate surface was analyzed in two dimensions with temporal and spatial resolution of 3 s and 0.2 micron, respectively. An extension begins and ends with brief, rapid acceleration and deceleration separated by a long period of nearly constant velocity in the range of 4-7 microns/min. Extensions and retractions were initiated randomly over time. As demonstrated by optical sectioning microscopy, the extended lamellipodia formed ruffles by sharply bending upward at hinge points 2-4 microns behind their tips. Surprisingly, ruffles continued to grow in length at the same average rate after bending upward. They maintained a straight shape in vertical cross section, suggesting the ruffles were mechanically stiff. The forces required to bend ruffles of these cells and of BC3H1 cells were measured by pushing a thin quartz fishpole probe against the tip of a ruffle 7-10 microns from its base either toward or away from the center of the cell. Force was determined by measuring the bending of the probe monitored by video microscopy. Typically the probe forced the ruffle to swing rigidly in an arc about an apparent hinge at is base, and ruffles rapidly, and almost completely, recovered their shape when the probe was removed. Hence, ruffles appeared to be relatively stiff and to resist bending with forces more elastic than viscous, unlike the cell body. Ruffles on both types of cells resisted bending with forces of 15-30 mudyn/microns of displacement at their tips when pushed toward or away from the cell center. The significance of the observations for mechanisms of cell locomotion is discussed.

Kinetics of binding, endocytosis, and recycling of EGF receptor mutants.

This report describes analysis of factors which regulate the binding of EGF to EGF receptor, receptor internalization, and receptor recycling. Three different methods were used to inhibit high-affinity EGF binding as measured at equilibrium: treatment of cells with an active phorbol ester (PMA), binding of a mAb directed against the EGF receptor (mAb108), and truncation of most of the cytoplasmic domain of the receptor. These treatments reduced the rate at which low concentrations of EGF bound to cells, but did not affect the rate of EGF dissociation. We conclude that high-affinity EGF binding on living cells results from a difference in the apparent on rate of EGF binding. We then used these conditions and cell lines to test for the rate of EGF internalization at different concentrations of EGF. We demonstrate that internalization of the EGF receptor is stimulated roughly 50-fold at saturating concentrations of EGF, but is stimulated an additional two- to threefold at low concentrations (less than 1 nM). Four treatments reduce the rate of internalization of low concentrations of EGF to the rate seen at saturating EGF concentrations. Phorbol ester treatment and mAb108 binding to "wild type" receptor reduce this rate (and reduce high-affinity binding). Point mutation at Lys721 (kinase negative EGF receptor) and point mutation at Thr654 (removing a major site of protein kinase C phosphorylation) reduce the internalization rate, without affecting high-affinity binding. We suggest that while EGF stimulates endocytosis for all receptors, high-affinity receptors bind and are internalized more quickly than low-affinity receptors. Tyrosine kinase activity and the Thr654 region appear necessary for this response.

Large deletions in the cytoplasmic kinase domain of the epidermal growth factor receptor do not affect its laternal mobility.

The lateral diffusion coefficients of various epidermal growth factor (EGF) receptor mutants with increasing deletions in their carboxy-terminal cytoplasmic domain were compared. A full size cDNA construct of human EGF receptor and different deletion constructs were expressed in monkey COS cells. The EGF receptor mutants expressed on the cell surface of the COS cells were labeled with rhodamine-EGF, and the lateral diffusion coefficients of the labeled receptors were determined by the fluorescence photo-bleaching recovery method. The lateral mobilities of three deletion mutants, including a mutant that has only nine amino acids in the cytoplasmic domain, are all similar (D approximately equal to 1.5 X 10(-10) cm2/s) to the lateral mobility of the "wild-type" receptor, which possess 542 cytoplasmic domain of EGF receptor, including its intrinsic protein kinase activity and phosphorylation state, are not required for the restriction of its lateral mobility.

Annexin I is phosphorylated in the multivesicular body during the processing of the epidermal growth factor receptor.

We have previously shown that an active epidermal growth factor receptor (EGF-R) kinase is necessary for efficient sorting of the EGF-R to the lysosome, and we have shown that this occurs in the multivesicular body (MVB), where EGF-R are sorted away from recycling receptors by being removed to the internal vesicles of the MVB. The aim of the present study was to identify substrates of the EGF-R kinase associated with MVBs which might play a role in this sorting process. We used a density shift technique to isolate MVBs and show that the major substrates phosphorylated in vitro within MVBs which contain an active EGF-R kinase are the EGF-R itself and annexin I. Annexin I is associated with both plasma membrane and MVBs in a calcium-independent manner but can be phosphorylated in vitro only in MVBs. Phosphorylation of calcium-independent annexin I in isolated MVBs converts it to a form that requires calcium for membrane association. In cells with an active EGF-R kinase the amount of calcium-independent annexin I in MVBs is reduced, suggesting that a phosphorylation-induced conversion of the calcium independent to the calcium-dependent form also occurs in vivo. Our observations, together with the known properties of annexin I in mediating membrane fusion, suggest that inward vesiculation in MVBs is induced by the EGF-R and is mediated by phosphorylated annexin I.

High-affinity epidermal growth factor binding is specifically reduced by a monoclonal antibody, and appears necessary for early responses.

We have tested the effects of an mAb directed against the protein core of the extracellular domain of the human EGF receptor (mAb108), on the binding of EGF, and on the early responses of cells to EGF presentation. We used NIH 3T3 cells devoid of murine EGF receptor, transfected with a cDNA encoding the full-length human EGF receptor gene, and fully responsive to EGF. The binding to saturation of mAb108 to the surface of these cells at 4 degrees C and at other temperatures specifically reduced high-affinity binding of EGF, but did not change the dissociation constant or the estimated number of binding sites for low-affinity binding of EGF. The kinetics of EGF binding to the transfected cells were measured to determine the effects of the mAb on the initial rate of EGF binding at 37 degrees C. Interestingly, high-affinity EGF receptor bound EGF with an intrinsic on-rate constant 40-fold higher (9.8 x 10(6) M-1.s-1) than did low-affinity receptor (2.5 x 10(5) M-1.s-1), whereas the off-rate constants, measured at 4 degrees C were similar. Cells treated with the mAb or with phorbol myristate acetate displayed single on-rate constants similar to that for the low-affinity receptors. At low doses of EGF ranging from 0.4 to 1.2 nM, pretreatment of cells with mAb108 inhibited by 50-100% all of the early responses tested, including stimulation of tyrosine-specific phosphorylation of the EGF receptor, turnover of phosphatidyl inositol, elevation of cytoplasmic pH, and release of Ca2+ from intracellular stores. At saturating doses of EGF (20 nM) the inhibition of these early responses by prebinding of mAb108 was overcome. On the basis of these results, we propose that the high-affinity EGF receptors are necessary for EGF receptor signal transduction.

Effect of phospholipase C-gamma overexpression on PDGF-induced second messengers and mitogenesis.

Platelet-derived growth factor (PDGF) stimulates phospholipase C (PLC) activity and the phosphorylation of the gamma isozyme of PLC (PLC-gamma) in vitro and in living cells. The role of PLC-gamma in the phosphoinositide signaling pathway was addressed by examining the effect of overexpression of PLC-gamma on cellular responses to PDGF. Overexpression of PLC-gamma correlated with PDGF-induced tyrosine phosphorylation of PLC-gamma and with PDGF-induced breakdown of phosphatidylinositol 4,5-bisphosphate (PIP2). However, neither bradykinin- nor lysophosphatidic acid-induced phosphoinositide metabolism was enhanced in the transfected cells, suggesting that the G protein-coupled phosphoinositide responses to these ligands are mediated by other PLC isozymes. The enhanced PDGF-induced generation of inositol trisphosphate (IP3) did not enhance intracellular calcium signaling or influence PDGF-induced DNA synthesis. Thus, enzymes other than PLC-gamma may limit PDGF-induced calcium signaling and DNA synthesis. Alternatively, PDGF-induced calcium signaling and DNA synthesis may use biochemical pathways other than phosphoinositide metabolism for signal transduction.

Gastric neuroendocrine neoplasias: manifestations and comparative outcomes.

Although gastric neuroendocrine neoplasias (gNEN) are an orphan disease, their incidence is rising. The heterogeneous clinical course powers the ongoing discussion of the most appropriate classification system and management. Prognostic relevance of proposed classifications was retrospectively analysed in 142 patients from a single tertiary referral centre. Baseline, management and survival data were acquired for statistical analyses. The distribution according to the clinicopathological typification was gNEN-1 (n = 86/60.6%), gNEN-2 (n = 7/4.9%), gNEN-3 (n = 24/16.9%) and gNEN-4 (n = 25/17.6%), while hypergastrinemia-associated gNEN-1 and -2 were all low-grade tumours (NET-G1/2), formerly termed sporadic gNEN-3 could be subdivided into gNEN-3 with grade 1 or 2 and gNEN-4 with grade 3 (NEC-G3). During follow-up 36 patients died (25%). The mean overall survival (OS) of all gNEN was 14.2 years. The OS differed statistically significant across all subgroups with either classification system. According to UICC 2017 TNM classification, OS differed for early and advanced stages, while WHO grading indicated poorer prognosis for NEC-G3. Cox regression analysis confirmed the independent prognostic validity of either classification system for survival. Particularly careful analysis of the clinical course of gNEN-1 (ECLomas, gastric carcinoids) confirmed their mostly benign, but recurrent and extremely slowly progressive behaviour with low risk of metastasis (7%) and an efficient long-term control by repetitive endoscopic procedures. Our study provides evidence for the validity of current classifications focusing on typing, grading and staging. These are crucial tools for risk stratification, especially to differentiate gNEN-1 as well as sporadic gNET and gNEC (gNEN-3 vs -4).

SH2 domains exhibit high-affinity binding to tyrosine-phosphorylated peptides yet also exhibit rapid dissociation and exchange.

src homology 2 (SH2) domains of intracellular signaling molecules such as phospholipase C-gamma and phosphatidylinositol 3'-kinase-associated protein p85 represent recognition motifs for specific phosphotyrosine-containing regions on activated growth factor receptors. The binding of SH2 domains to activated growth factor receptors controls the interaction with signaling molecules and the regulation of their activities. In this report, we describe the kinetic parameters and binding affinities of SH2 domains of p85 toward short phosphotyrosine-containing peptides with the amino acid sequence motif YMXM, derived from a major insulin receptor substrate, IRS-1, by using real time biospecific interaction analysis (BIAcore). Associations were specific and of very high affinity, with dissociation constants of 0.3 to 3 nM, between phosphopeptides and the two separate SH2 domains contained within p85. Nonphosphorylated peptides showed no measurable binding, and the interactions were specific for the primary sequence very close to the phosphotyrosine residue. Moreover, the interactions between phosphopeptides and SH2 domains of other signaling molecules were of much lower affinity. Interestingly, the binding of the SH2 domains to the tyrosine-phosphorylated peptides was of high affinity as a result of a very high on rate, of 3 x 10(7) to 40 x 10(7)/M/s; at the same time, the rate of dissociation, of 0.11 to 0.19/s, was rapid, allowing for rapid exchange of associating proteins with the tyrosine phosphorylation sites.

[Susceptibility to strategy of the drug component of the IPHCC+RxGroups classification system in a risk-adjusted morbidity compensation scheme--a conceptional and data-supported analysis]. / Zur Strategieanfälligkeit der Arzneimittelkomponente des IPHCC+RxGroups-Klassifikationssystems in einem morbiditätsorientierten Risikostrukturausgleich--Eine konzeptionelle und datengestützte Analyse.

BACKGROUND: A report commissioned by the German Ministry of Health recommends to the existing scheme for calculating risk-adjusted transfers to sickness funds supplement with the IPHCC+RxGroups method. The method is based on inpatient diagnoses and prescribed drugs as health status measures deduced from prior use. OBJECTIVE: The present study investigates the sickness fund's expected net return from gaming based on the drug component of the risk adjuster. METHODS: The study explores three possible strategies using the RxGroups method. For the stimulations, insurees are assigned to additional indications or to higher valued RxGroups within the same indication. Then, costs and financial benefits attributable to the altered drug use are estimated and compared with the status quo. The study uses 2000 and 2001 sample data of more than 370,000 insurees of Germany's company-based sickness funds system (BKK). RESULTS: While upgrading increases overall costs, it can be beneficial for the individual sickness funds. Their net return crucially depends on the number of sickness funds gaming the system: the more participating in the game, the smaller is the average net return. Moreover, not participating often is even worse, which in turn points to a prisoner's dilemma. CONCLUSIONS: When extending the risk adjustment scheme in social health insurance, the German legislator should take into account the perverse incentives of risk adjusters such as the described prescription drug model.

[Endoscopic therapy for gastroduodenal neuroendocrine neoplasms]. / Endoskopische Therapie gastroduodenaler neuroendokriner Neoplasien.

Neuroendocrine neoplasms (NEN) represent a group of potentially malignant tumors, which can be located in every section of the gastrointestinal tract, the pancreas and the bronchopulmonary system. Gastroduodenal NENs have a relatively good prognosis in comparison to other subentities, e.g. pancreatic or ileojejunal NENs. In the stomach there are four different types of NENs, while in the duodenum there are five types and all vary in the malignant potential and the therapeutic approach. Due to the simple access endoscopic methods not only have diagnostic but also important therapeutic relevance in this subgroup. Lesions smaller than 1 cm can easily be resected with forceps or snare resection and for larger lesions up to 2 cm more invasive strategies, such as endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD) are available. Important criteria in gastric NEN for the risk evaluation of endoscopic treatment alone are the size of the lesion, depth of invasion and the tumor biology, e.g. neuroendocrine tumor (NET) G1/G2 versus neuroendocrine carcinoma (NEC) G3. In duodenal NEN the aforementioned risk factors also apply and in addition only lesions outside the ampulla of Vater should be endoscopically resected whereas periampullary lesions need to be addressed surgically. As an individualized therapeutic approach the possibility of a combined endoscopic and laparoscopic resection technique exists. Follow-up endoscopic investigations are necessary, especially in gastric type 1 NENs, which have a tendency to relapse.

Value of Holter monitoring in predicting long-term efficacy and inefficacy of amiodarone used alone and in combination with class 1A antiarrhythmic agents in patients with ventricular tachycardia.

The value of two reported and two new ambulatory electrocardiographic (Holter) criteria was studied in 80 patients taking amiodarone for refractory recurrent sustained ventricular tachycardia. In the 80 patients, the four Holter criteria were as follows: I-85% or greater reduction of ventricular premature complexes and abolition of couplets and nonsustained ventricular tachycardia in 74 patients who had 10 or more ventricular premature complexes/h, or any couplets or nonsustained ventricular tachycardia/24 hours at baseline; II-abolition of nonsustained ventricular tachycardia in 51 patients who had nonsustained ventricular tachycardia at baseline; III-85% or greater reduction of ventricular premature complexes and abolition of nonsustained ventricular tachycardia in 64 patients who had 30 or more ventricular premature complexes/h at baseline; and IV-85% or greater reduction of ventricular premature complexes and abolition of nonsustained ventricular tachycardia in 73 patients who had 10 or more ventricular premature complexes/h at baseline. Amiodarone was judged effective in, respectively, 51 of 74, 44 of 51, 51 of 64 and 61 of 73 patients by criterion I, II, III or IV. During the follow-up period (19 +/- 20 months), there were 19 instances of recurrence of ventricular arrhythmia or sudden death. Actuarial arrhythmia-free survival rate at 24 months was 84, 74, 86 and 85%, respectively, in patients with efficacy by criterion I, II, III or IV and 61, 43, 48 and 39%, respectively, in patients with inefficacy (p less than 0.015 for all). Many patients with efficacy by Holter criteria, however, had a recurrence of arrhythmia, suggesting insensitivity of these Holter criteria.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of programmed stimulation and Holter monitoring for predicting long-term efficacy and inefficacy of amiodarone used alone or in combination with a class 1A antiarrhythmic agent in patients with ventricular tachyarrhythmia.

The values of two Holter ambulatory electrocardiographic monitoring criteria and one programmed stimulation efficacy criterion reported to be predictive of the efficacy of amiodarone were compared in 70 patients taking amiodarone for sustained ventricular tachyarrhythmias. At baseline, all patients had ventricular tachycardia inducible by programmed stimulation. After amiodarone loading (935 +/- 271 mg for 16 +/- 7 days), efficacy was determined by a programmed stimulation criterion (ventricular tachycardia no longer inducible or less than or equal to 15 beats) and two Holter monitoring criteria (Holter I = greater than or equal to 85% reduction of ventricular premature complexes and abolition of couplets and triplets in 64 patients who had greater than or equal to 10 ventricular premature complexes/h or couplets or triplets or both before therapy; Holter II = abolition of triplets in 41 patients who had triplets before therapy). Amiodarone was effective in 12 of 70 patients by the programmed stimulation criterion, in 49 of 64 patients by Holter criterion I and in 37 of 41 patients by Holter criterion II. In assessing efficacy of amiodarone, programmed stimulation and Holter criteria were discordant in 69% of patients or more (p less than 0.001). There were 16 recurrences or sudden deaths during the entire follow-up period (19 +/- 19 months). Arrhythmia-free survival rates at 24 months of patients with efficacy and inefficacy by each criterion, respectively, were 90 and 78% by programmed stimulation, 84 and 62% by Holter criterion I (p less than 0.05) and 73 and 50% by Holter criterion II (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Forces in cell locomotion.

The molecular mechanisms that drive animal cell locomotion are partially characterized, but not definitively understood. It seems likely that actin polymerization contributes to the forward protrusion of the leading edge of a migrating cell. Both myosin-dependent contractile forces and selective detachment of adhesive interactions with the substratum seem to contribute to release of the posterior of an extended cell. It is probable, but not certain, that a separate 'traction' force advances the cell body towards the forward anchorage sites formed by the advancing lamellipodium. The molecular mechanism of this force is unknown. Determining the role of traction forces in migrating fibroblasts and keratocytes is complicated by the fact that the primary functions of the relatively strong forces exerted on the substratum by these cells may be to establish tissue 'tone' and to remodel tissue matrices, rather than to drive locomotion. In accordance with this notion, rapidly moving cells such as neutrophils and Dictyostelium amoebae exert weaker forces on the substratum as they migrate. The traction force in cell migration may be distinct from traction forces with tissue functions. Ultimately, the mechanism may be revealed by using molecular genetics to disrupt the motors that provide this force. Reconstituted tissues provide systems in which to investigate the regulation of cell forces and their contribution to tissue mechanical properties and development.

Electrophysiologic effects and clinical efficacy of mexiletine used alone or in combination with class IA agents for refractory recurrent ventricular tachycardias or ventricular fibrillation.

The electrophysiologic effects and clinical efficacy of mexiletine used alone or in combination with class IA agents were studied in 35 patients with recurrent sustained ventricular tachycardia (VT) or ventricular fibrillation refractory to nonexperimental antiarrhythmic agents. At baseline before therapy, all patients had inducible VT by programmed stimulation (1 to 3 extrastimuli) and frequent (at least 30/hour) ventricular premature complexes (VPCs) during Holter monitoring. Mexiletine therapy was effective by programmed stimulation (VT no longer inducible or 15 or less beats) in 8 and ineffective in 27 patients. Twenty patients were discharged with mexiletine (14 of whom took an additional class IA agent). The discharge regimen was effective by programmed stimulation in 6 of these 20 patients. In 14 patients the discharge regimen was ineffective by programmed stimulation, but all patients had a marked reduction of ventricular ectopic activity (at least 83% reduction of VPCs and abolition of non sustained VT). During the follow-up period of 18 +/- 13 months (mean +/- standard deviation), 4 patients had recurrences (3 with an ineffective regimen by programmed stimulation and 1 with an effective regimen by programmed stimulation). Arrhythmia-free survival rates at 12 and 24 months were 86% and 77%, as determined by the Kaplan-Meier method, in patients with an ineffective regimen by programmed stimulation, and 80% and 80% in patients with an effective regimen by programmed stimulation (p = 0.979 by log rank test).(ABSTRACT TRUNCATED AT 250 WORDS)

Prognostic value of the changes in the mode of ventricular tachycardia induction during therapy with amiodarone or amiodarone and a class 1A antiarrhythmic agent.

The prognostic value of 3 previously reported programmed stimulation efficacy criteria was studied in 70 patients taking amiodarone for sustained ventricular tachycardia (VT). At baseline all patients had VT inducible by programmed stimulation. After amiodarone loading (935 +/- 271 mg/day for 16 +/- 7 days), efficacy of amiodarone was determined by 3 programmed stimulation criteria (criterion I = VT not inducible or 15 beats or less; criterion II = VT not inducible or harder to induce; criterion III = VT not easier to induce). Amiodarone was effective in 12, 25 and 49 of 70 patients by criteria I, II and III, respectively. There were 16 recurrences or cardiac arrest during the follow-up period (19 +/- 19 months). Actuarial arrhythmia-free survival rates at 1 and 2 years were: 90% and 90% in patients with efficacy by criterion I and 78% and 78% in patients with inefficacy, respectively; 84% and 84% in patients with efficacy by criterion II and 78% and 78% in patients with inefficacy, respectively; and 80% and 80% in patients with efficacy by criterion III and 79% and 79% in patients with inefficacy, respectively (difference not significant for all). From the results of follow-up at 2 years, sensitivities of criteria I, II and III were 92%, 75% and 33%, respectively. Specificities were 17%, 26% and 70%, respectively, and predictive accuracies were 43%, 43% and 67%, respectively. Thus, patients with efficacy by criterion I appear to have a better prognosis when compared with patients with inefficacy. However, many patients with inefficacy by criterion I had a good outcome (nonspecificity).(ABSTRACT TRUNCATED AT 250 WORDS)

Human glioblastoma cell lines have neuropeptide receptors for bombesin/gastrin-releasing peptide.

Bombesin/gastrin-releasing peptide receptors were characterized in human glioblastoma cell lines. [125I]Gastrin-releasing peptide or ([125I]Tyr4)bombesin bound with high affinity to these cell lines. Binding to cell line U-118 was time dependent, reversible, and specific. ([125I]Tyr4)Bombesin bound with high affinity (Kd = 1.6 nM) to a single class of sites (Bmax = 30,000/cell). The C-terminal of bombesin- or gastrin-releasing peptide was essential for high-affinity binding. Bombesin- or gastrin-releasing peptide elevated the cytosolic Ca2+ levels in a dose-dependent manner. Because gastrin-releasing peptide, but not gastrin-releasing peptide, increased the cytosolic Ca2+ levels, the C-terminal but not the N-terminal of GRP is essential for biological activity. These data indicate that biologically active bombesin receptors are present in human glioblastoma cell lines.

Effect of Duchenne muscular dystrophy on enzymes of energy metabolism in individual muscle fibers.

Individual muscle fibers from patients with Duchenne muscular dystrophy at an early stage in their disease, and from apparently normal boys of similar age, were analyzed for 13 enzymes of energy metabolism. This approach avoided the serious problems with muscle homogenate assays from increases in nonparenchymal components and permitted assessment of disease changes in different fiber types. Some enzymes of glycogenolysis (phosphorylase, phosphoglucomutase, and pyruvate kinase) were decreased in dystrophic fibers of all types. Phosphofructokinase was decreased in presumptive type II fibers. Lactate dehydrogenase was increased in type I fibers and essentially unchanged in type II. Phosphoglucoisomerase was near normal. Two enzymes of glucose metabolism not involved in glycogenolysis, hexokinase and glycogen synthase, were near normal, but a third, fructose bisphosphatase, was sharply reduced. Two enzymes of oxidative metabolism, citrate synthase, and beta-hydroxyacyl CoA dehydrogenase, were unchanged or increased. Two enzymes of high energy phosphate transfer, creatine kinase and adenylokinase, were only marginally affected. The net result is to leave the type II fibers, which normally exert the greatest force, with a severe deficit in the glycogenolytic enzyme machinery to maintain that force.