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.

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).

[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.

[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.

[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.

[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.

Outcome prediction in critical care: physicians' prognoses vs. scoring systems.

BACKGROUND AND OBJECTIVE: To compare the accuracy of prognoses made by intensive care physicians with the performance of two indicators, the original Simplified Acute Physiology Score (SAPS) II and a modified version optimized to the patient sample. METHODS: Data from 412 patients consecutively admitted to intensive care units of Göttingen University Hospital, Germany, were collected according to the original score criteria. Information necessary for the computation of SAPS II and the vital status on hospital discharge was recorded. To customize the original SAPS II in our cohort, the database was randomly divided into two subgroups. Logistic regression analysis with physiological values as explanatory variables was used. A bootstrap procedure completed the process. Furthermore, physicians were asked to indicate their prognostic judgement concerning the patients' hospital mortality. RESULTS: Discrimination analysis showed the following areas under receiver operating characteristic curves: physicians' prognoses 0.84 (confidence interval (CI): 0.79-89), SAPS II 0.75 (CI: 0.69-0.80) and customized SAPS 0.72 (CI: 0.66-0.78). The physician's forecast was significantly better, while the customized and the original SAPS were not substantially different as regards their accuracy. CONCLUSIONS: Prognoses made by physicians are superior to objective models. This may result from more extensive knowledge and other kinds of information available to clinicians. A clinician's action also depends on his/her prognosis at the beginning of the treatment, giving raise to a possible correlation between medical outcome and the clinician's prognosis. Our findings indicate that physicians do not limit their prognosis to the objective factors at their disposal, but indicate that they base their decisions on experience and individual observations.

[Cost of miniplate osteosynthesis for treatment of mandibular fractures: a prospective evaluation]. / Kosten der Unterkieferfrakturversorgung: Eine prospektive Untersuchung.

PURPOSE: Up to now in maxillofacial surgery almost all inpatient treatments were reimbursed at the hospital's per diem rate. The real treatment cost is unknown and there is a lack of publications in this sphere. This study calculates the cost of surgical treatment of mandibular fractures. METHOD: The prospective study includes 104 patients whose mandibular fractures were treated using miniplate osteosynthesis. For each patient we took into account the time input by physicians and specialised nurses and calculated labour cost using the relevant wage rates. We added the cost for materials and drugs as well as for laboratory and radiographic examinations. Finally, we incorporated charges for the hotel and nursing components of inpatient treatment. RESULTS: The cost for the surgical treatment of mandibular fractures varied between 642 euro; for single and 1,070 euro; for triple fractures. The share of labour cost is about 1/3. Treatment cost varies with the length of hospital stay: 1,132 euro; for four days and 1,628 euro; for seven days on average. CONCLUSION: This prospective study can be compared with the recently published corresponding G-DRG rates. Moreover, the reported cost figures allow comparison with corresponding cost studies from other public health systems.

Reply to: Econometric issues in testing the age neutrality of health care expenditure.

Salas and Raftery allege that in our paper, (1) remaining life expectancy is an endogenous explanatory variable of health care expenditure and (2) the parameter designed to correct for sample selection bias in fact represents a hidden relationship between health care expenditure and age. We argue that claim (1) is not supported by the available empirical evidence, while claim (2) seems to derive from a too cursory reading of our paper.

The nucleus-encoded HCF107 gene of Arabidopsis provides a link between intercistronic RNA processing and the accumulation of translation-competent psbH transcripts in chloroplasts.

To understand the functional significance of RNA processing for the expression of plastome-encoded photosynthesis genes, we investigated the nuclear mutation hcf107 of Arabidopsis. The mutation is represented by two alleles, both of which lead to a defective photosystem II (PSII). In vivo protein labeling, in vitro phosphorylation, and immunoblot experiments revealed that the psbB gene product (CP47) and an 8-kD phosphoprotein, the psbH gene product (PsbH), are absent in mutant plants. PsbH and PsbB are essential requirements for PSII assembly in photosynthetic eukaryotes, and their absence in hcf107 is consistent with the PSII-less mutant phenotype. RNA gel blot hybridizations showed that the hcf107 mutation specifically impairs the accumulation of some but not all oligocistronic psbH transcripts that are released from the pentacistronic psbB-psbT-psbH-petB-petD precursor RNA by intergenic endonucleolytic cleavage. In contrast, neither the levels nor the sizes of psbB-containing RNAs are affected. S1 nuclease protection analyses revealed that psbH RNAs are lacking only where psbH is the leading cistron and that they are processed at position -45 in the 5' leader segment of psbH. These data and additional experiments with the cytochrome b(6)f complex mutant hcf152, which is defective in 3' psbH processing, suggest that only those psbH-containing transcripts that are processed at their -45 5' ends can be translated. Secondary structure analysis of the 5' psbH leader predicted the formation of stable stem loops in the nonprocessed transcripts, which are unfolded by processing at the -45 site. We propose that this unfolding of the psbH leader segment as a result of RNA processing is essential for the translation of the psbH reading frame. We suggest further that HCF107 has dual functions: it is involved in intercistronic processing of the psbH 5' untranslated region or the stabilization of 5' processed psbH RNAs, and concomitantly, it is required for the synthesis of CP47.

[Evaluation of the public health service law of the Saxony-Anhalt region--community affairs, transfer of power and loss of control]. / Evaluation des Gesundheitsdienstgesetzes des Landes Sachsen-Anhalt--Kommunalisierung, Konnexität und Kontrollverlust.

AIM: In the state of Saxony-Anhalt, a new Public Health Service law came into force in 1998. Our study investigated whether this new legislation has led to an extension of duties performed by regional health departments and to a subsequent increase in expenditure. METHODS: Guided interviews at all administrative levels of the public health system were conducted. The catalogue of duties was systematized and a questionnaire was developed and distributed to all regional health departments (response rate: 17 out of 24). Data concerning revenues and expenditures of the regional health departments were analysed on the basis of the administrative districts' budget data. RESULTS: Regional health departments stated that there had been practically no change in their activities over the last few years. When questioned about the coverage of 58 specific duties, a considerable disparity was evident between departments. A core group of "classical" duties comprising environmental health and hygiene, child health protection, individual health appraisal, and public health supervision are carried out on an established basis. Some duties were handled by external institutions, others, mostly community health duties, were not performed on an extensive scale. When asked about the desired model for their health department, most departments preferred the model of being an executor of sovereign duties, however a corporate model was deemed to be almost as acceptable. The following fields will gain increasing significance in the future: environmental medicine, health reporting, preventive medicine, co-ordination of regional health care, and health promotion. Since 1995, staff has been reduced in all regional health departments (-10.4%; 1999: 2.92 employees per 10,000 inhabitants). In 1999, expenditures amounted to an average of 24.64 German Marks per capita (range 14.20-44.58 DM). The number of inhabitants and the revenue of the regional districts were determinants of their health budgets. CONCLUSION: Our results showed that no uncompensated additional expenditure by regional authorities resulted from this law. So far, most districts have not perceived regional health as a community affair offering possible competitive advantages. The federal state lost considerable influence at the regional level. Recommended are regional health priorities, conjoint staff development, and state guidance by a head agency providing leadership and support, while leaving responsibility with the districts.

Health care expenditure in the last months of life.

In OECD countries, a considerable share of health care expenditure (HCE) is spent for the care of the terminally ill. This paper derives the demand for HCE in the last 2 years of life from a model that accounts for age, mortality risk and wealth. The empirical tests are based on data of deceased members of a major Swiss sick fund. The empirical evidence confirms most of the hypotheses derived from the model, i.e., (i) HCE increases with closeness to death, (ii) for retired individuals, HCE decreases with age, and (iii) low-income individuals, as compared to high-income individuals, incur lower HCE in the last months of life.

Ageing of population and health care expenditure: a red herring?

This paper studies the relationship between health care expenditure (HCE) and age, using longitudinal rather than cross-sectional data. The econometric analysis of HCE in the last eight quarters of life of individuals who died during the period 1983-1992 indicates that HCE depends on remaining lifetime but not on calendar age, at least beyond 65+. The positive relationship between age and HCE observed in cross-sectional data may be caused by the simple fact that at age 80, for example, there are many more individuals living in their last 2 years than at age 65. The limited impact of age on HCE suggests that population ageing may contribute much less to future growth of the health care sector than claimed by most observers.

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.

Combinatorial chemistry reveals a new motif that binds the platelet fibrinogen receptor, gpIIbIIIa.

Among cell adhesion molecules, the classic Arg-Gly-Asp (RGD) motif is the best studied. We used combinatorial chemical and affinity immunochemical methods to find a novel motif of unnatural peptide ligands for the fibrinogen receptor of platelets, gpIIbIIIa (alphaIIbbeta3). The new d-amino acid motif, p(f/y)l, is unique among the ligands that bind the RGD pocket: It lacks the carboxylic acid group that is believed to coordinate with calcium in the MIDAS motif of the receptor. With an IC50 of 14 microM for the most potent compound, these linear p(f/y)l peptides had affinities similar to those of linear peptides containing RGD, and reversed sequences failed to compete with binding up to 1 mM. As the new motif was so different, molecular modeling was employed to suggest a model for molecular recognition. A reversed binding mechanism common for d-amino acid mimics of natural l-amino acid peptides offers an attractive hypothesis that suggests three points of contact similar to those made by the RGD-mimicking monoclonal antibody, OPG2. Interestingly, the model proposes that pi-electrons in the new motif may substitute for the carboxylate group present in all other RGD-types of ligands. Although modeling linear peptides is subjective, the pi-bonding model provides intriguing possibilities for medicinal chemistry after appropriate confirmatory studies.

Costs of dying: alternatives to rationing.

In western industrialised countries, about 30% of health-care expenditure of retired people is incurred by individuals in their last year of life. The corresponding high costs of dying have led medical philosophers to ask for a rationing of health-care services according to age. By contrast, this paper pursues an individualistic approach. High costs of dying are identified as a consequence of moral hazard on both the demand and supply side of the health-care sector. Health insurance prevents demand for health-care services from decreasing when an individual's residual life expectancy shrinks. Age-related moral hazard can be limited by a coinsurance scheme with a deductible that increases with the age of the insured. Given the high costs of dying, the optimal insurance policy links the coinsurance rate to the age-specific mortality risk.

One-bead-one-structure combinatorial libraries.

Combinatorial libraries employing the one-bead-one-compound technique are reviewed. Two distinguishing features characterize this technique. First, each compound is identified with a unique solid support, enabling facile segregation of active compounds. Second, the identity of a compound on a positively reacting bead is elucidated only after its biological relevance is established. Direct methods of structure identification (Edman degradation and mass spectroscopy) as well as indirect "coding" methods facilitating the synthesis and screening of nonpeptide libraries are discussed. Nonpeptide and "scaffold" libraries, together with a new approach for the discovery of a peptide binding motif using a "library of libraries," are also discussed. In addition, the ability to use combinatorial libraries to optimize initially discovered leads is illustrated with examples using peptide libraries.

Expression of epidermal growth factor receptor changes in the hypothalamus during the onset of female puberty.

Recent findings have led to the concept that transforming growth factor alpha (TGF alpha) contributes to the neuroendocrine regulation of female puberty by stimulating the release of luteinizing hormone-releasing hormone (LHRH), the neurohormone controlling sexual development. It was postulated that this effect is mediated by epidermal growth factor receptors (EGFR) and that EGFR may not be located on LHRH neurons, so that TGF alpha-induced LHRH release would require an intermediate cell-to-cell interaction, presumably of glial-neuronal nature. The present study was undertaken to characterize the presence of EGFR in rat hypothalamus and to determine if changes in EGFR gene expression and EGFR protein occur at the time of puberty. RNA blot hybridization demonstrated that the hypothalamus expresses all mRNA species known to encode EGFR. RNase protection assays revealed that alternative splicing of the EGFR primary mRNA transcript occurs in the hypothalamus and produces a predominant transcript encoding the full-length EGFR and a much less abundant, shorter mRNA encoding a truncated, and presumably secreted form of EGFR. EGFR-like immunoreactive material was found in several hypothalamic regions including the organum vasculosum of the lamina terminalis, supraoptic, suprachiasmatic, and paraventricular nuclei, ependymal cells lining the third ventricle, some astrocytes associated with blood vessels, astrocytes of the pial surface, and tanycytes and glial cells of the median eminence (ME). Low levels of EGFR mRNA were detected by hybridization histochemistry in cells of the same areas containing EGFR-like immunoreactivity. Double-immunohistochemistry revealed that even though LHRH neurons are in close proximity to EGFR-positive cells, they do not contain EGFR. In the ME, EGFR-immunonegative LHRH nerve terminals tightly coexist with EGFR-positive cells, presumably tanycytes and glial astrocytes. EGFR mRNA levels measured by quantitative reverse transcription-polymerase chain reaction assay (RT-PCR) in the ME-arcuate nucleus region at the time of puberty decreased in the morning of the first proestrus, i.e., preceding the first preovulatory surge of gonadotropins, and rebounded at the time of the surge. Functional EGFR protein levels, detected by the ability of the receptor to autophosphorylate in response to ligand or divalent antibody-induced activation, changed in a similar manner at the time of puberty. No such changes were observed in the cerebellum, a brain region irrelevant to neuroendocrine reproductive control. These results demonstrate the existence of EGF receptors in the prepubertal female rat hypothalamus and suggest that changes in EGFR gene expression and biologically active EGFR protein contributes to the neuroendocrine process underlying the first preovulatory surge of gonadotropins.(ABSTRACT TRUNCATED AT 250 WORDS)

One bead, one chemical compound: use of the selectide process for anticancer drug discovery.

A technology for chemical synthesis and testing of libraries of millions of chemical entities has been developed for rapid molecular and cellular screening for drug leads. Each individual compound in the library is on a separate resin bead. Screening for binding activity can be conducted directly on the beads. Biological activity is assessed in solution phase assay by cleaving a portion of the compound from each bead. The molecular structure of the compound of interest is obtained by automated peptide sequencing from the bead of origin. We have applied this technology to anticancer drug discovery as well as to other pharmaceutical targets. For anticancer drug development, current molecular targets include B-cell lymphoma, the EGF receptor, and the HER2-neu receptor. Solution phase screening with dual cleavable libraries is being used for growth inhibition of human tumor cell lines. Initial in vitro leads have been identified in each of these areas of anticancer drug discovery.