Predictors of outcome after liver transplantation for hepatocellular carcinoma (HCC) beyond Milan criteria.

The Milan criteria have been the cornerstone of selection policies for patients with hepatocellular carcinoma (HCC) awaiting liver transplantation (LT) globally for over two decades. Many groups have proposed the transplantation of patients with larger and more numerous tumors achieving comparable results. Many of these use radiologic morphometric criteria as surrogates for explant pathology to predict outcomes. Several other indices have been developed both within and beyond Milan incorporating biological indices as well as dynamic markers of response to pre-transplant locoregional treatments and waiting time. These have allowed for successful expansion of transplant selection criteria without compromising outcomes with limited organ supplies. In this review we will discuss the predictors of outcome in patients beyond Milan criteria.

Asymmetry in genitalia does not increase the rate of their evolution.

Left-right asymmetry is a frequently encountered phenomenon in the copulation organs of insects. While various causes have been proposed for genital asymmetry, we raise the question of whether asymmetry might facilitate, or even accelerate, morphological divergence of genitalia between species. We tested this hypothesis in the scarab chafer genus Schizonycha, which comprises species with symmetric as well as asymmetric male genitalia. Morphometric analyses were conducted in the context of their phylogeny, inferred from mitochondrial and nuclear ribosomal DNA sequence data (cox1, rrnL, and 28S) for a sample of 99 South African specimens, including 34 species and 5 outgroup taxa. Trees were reconstructed with maximum likelihood and Bayesian analysis. The extent of asymmetry and the variation of male copulation organs were analyzed with Generalized Procrustes analysis (GPA), by quantifying shape divergence of the parameres. We found a continuous transition in the degree of asymmetry among the investigated species. Ancestral state reconstruction revealed multiple origins and a high degree of evolutionary plasticity of paramere asymmetry in Schizonycha. However, no significant correlation between evolutionary rates of paramere shape divergence and the degree of paramere asymmetry was found, and so we conclude that asymmetric genitalia in Schizonycha do not increase the rate of genital shape divergence.

Vascular hippocampal plasticity after aerobic exercise in older adults.

Aerobic exercise in young adults can induce vascular plasticity in the hippocampus, a critical region for recall and recognition memory. In a mechanistic proof-of-concept intervention over 3 months, we investigated whether healthy older adults (60-77 years) also show such plasticity. Regional cerebral blood flow (rCBF) and volume (rCBV) were measured with gadolinium-based perfusion imaging (3 Tesla magnetic resonance image (MRI)). Hippocampal volumes were assessed by high-resolution 7 Tesla MRI. Fitness improvement correlated with changes in hippocampal perfusion and hippocampal head volume. Perfusion tended to increase in younger, but to decrease in older individuals. The changes in fitness, hippocampal perfusion and volume were positively related to changes in recognition memory and early recall for complex spatial objects. Path analyses indicated that fitness-related changes in complex object recognition were modulated by hippocampal perfusion. These findings indicate a preserved capacity of the aging human hippocampus for functionally relevant vascular plasticity, which decreases with progressing age.

[Managed competition in the health-care services - the Dutch experience]. / Regulierter Wettbewerb im Gesundheitswesen - Erfahrungen aus den Niederlanden.

For some years in Switzerland, in Germany and in the Netherlands some experience has been gathered with managed competition in health care. Efficiency reserves in the health service should be opened up by stronger competition orientation. Since the fundamental reform of the health insurance system in the Netherlands in 2006 the longest experience with the new governance model exists in this country. Health system experts in Germany and Switzerland maybe interested to include the experiences from the Netherlands into their further reforms. The analysis of relevant statistics and publications shows that, after 6 years, the results of the health reform in the Netherlands are to be called rather "sobering up". The competition activities of the health insurances, the insured persons and the providers are rather weak. However the expenditures for health are rising continuously. The intended goals of managed competition (reduction of costs and efficiency increase) could not be achieved in the Netherlands so far. The role of the health insurance companies and the competition readiness of the insured persons were obviously overrated, at the same time as well as the market power of the provider was rather underestimated.

Appropriateness of proton pump inhibitor recommendations at hospital discharge and continuation in primary care.

Background: Inappropriate prescriptions of proton pump inhibitors (PPI) in hospital and primary care have been widely reported. Recommendations from hospital have been implicated as one reason for inappropriate prescriptions of PPI in primary care. Objective: To quantify the amount of appropriate PPI recommendations in hospital discharge letters and the influence of these recommendations on general practitioners' (GPs') PPI-prescriptions. Materials and Methods: This is an observational study in 31 primary care practices. We identified patients discharged from hospital with PPI recommendation between 2006 and 2007 and assessed practice records and PPI prescription six months prior and after hospital admission. Hospital recommendation for continuous PPI-treatment and continuation by GPs was classified as appropriate, inappropriate or uncertain. Logistic regression analysis was used to calculate factors associated with indicated and non-indicated PPI continuation. Results: In 263 (58%) out of 506 patients discharged from 35 hospitals with a PPI recommendation no indication could be found. Non-indicated PPIs were continued by GPs in 58% for at least 1 month. Indicated PPIs were discontinued in 33%. Two thirds of non-indicated PPIs were initiated in hospital. The strongest factor associated with non-indicated continuation was a PPI-prescription prior to hospital admission [OR: 3.0; 95% confidence interval (CI): 1.7-5.4]. This was also the strongest factor for continuation of an indicated PPI medication (OR: 3.2; 95% CI: 1.4-7.5). Conclusions: We found a strong influence of hospital recommendations and previous prescriptions on PPI prescriptions after discharge. Hospitals should critically review their practice of recommending PPI and document indications. GPs should carefully assess hospital recommendations and their medication prior to admission to avoid over- and under-prescribing.

Why barcode? High-throughput multiplex sequencing of mitochondrial genomes for molecular systematics.

Mitochondrial genome sequences are important markers for phylogenetics but taxon sampling remains sporadic because of the great effort and cost required to acquire full-length sequences. Here, we demonstrate a simple, cost-effective way to sequence the full complement of protein coding mitochondrial genes from pooled samples using the 454/Roche platform. Multiplexing was achieved without the need for expensive indexing tags ('barcodes'). The method was trialled with a set of long-range polymerase chain reaction (PCR) fragments from 30 species of Coleoptera (beetles) sequenced in a 1/16th sector of a sequencing plate. Long contigs were produced from the pooled sequences with sequencing depths ranging from ∼10 to 100× per contig. Species identity of individual contigs was established via three 'bait' sequences matching disparate parts of the mitochondrial genome obtained by conventional PCR and Sanger sequencing. This proved that assembly of contigs from the sequencing pool was correct. Our study produced sequences for 21 nearly complete and seven partial sets of protein coding mitochondrial genes. Combined with existing sequences for 25 taxa, an improved estimate of basal relationships in Coleoptera was obtained. The procedure could be employed routinely for mitochondrial genome sequencing at the species level, to provide improved species 'barcodes' that currently use the cox1 gene only.

[Polypharmacy: a dilemma in primary care? Results of group discussions with general practitioners]. / Polypharmazie: ein hausärztliches Dilemma? Ergebnisse aus Gruppendiskussionen mit Allgemeinärztinnen und Allgemeinärzten.

BACKGROUND: Due to the aging population and the associated increase in multi-morbidity, polypharmacy will become an important issue. Little is known about general practitioners' perception of polypharmacy. We have explored this issue within the framework of a research course organised by the German Society for General Practice and Family Medicine (Deutsche Gesellschaft für Allgemeinmedizin und Familienmedizin, DEGAM.) METHODS: A total of 21 participants were divided in three homogeneous groups and one heterogeneous group according to their professional concentration (full-time general practitioners, junior researchers, senior researchers). Each group was supervised by two non-directing moderators. A two-step analysis was performed. In a fist step, mind maps were generated and in a second step, mind maps were interpreted according to the grounded theory. RESULTS: We identified three core aspects of polypharmacy in general practice: overview of prescribed medication, communication between doctors, patients and other health care professionals as well as evidence for managing multi-morbidity. General practitioners are torn between providing individual medical care and guideline stipulations. Pharmacotherapy is influenced by interprofessional communication, prescriptions by multiple physicians, patient expectations, adherence, advertisements, guidelines and costs. One's view on polypharmacy is influenced by professional background and experience. CONCLUSIONS: From the general practitioner's perspective, interprofessional and doctor-patient communication are highly important for a good medication overview as well as dealing with uncertainties in daily medical care. Simply improving evidence for the care of patients with multi-morbidities in the form of meta-guidelines would not be sufficient to overcome the effects of the many other influencing factors.

[Health economy and health promotion -- self-responsibility for health?]. / Gesundheitsökonomie und Gesundheitsförderung - Eigenverantwortung für Gesundheit?

The social insurance systems in Germany are about to face radical changes, predominantly due to demographic developments. The solution might be an increasing self-responsibility of the population. The suitability of this health economical concept is to be verified for health insurance. The starting point of the health economic debate, discussing the issue of responsibility, is its description, and therefore the health of populations and the fundamental determinants for the maintenance of health and for illness. This is followed by a theoretical health economic discussion on the question whether insurants and patients are suitable market partners shoulder the responsibility transferred to them. The description of empiric evidence of the effects of co-payment questions the concept of self-responsibility and finally leads to discussing the individual versus social responsibility for health and illness.

Trends in self-reported cigarette smoking, Wisconsin, 1984-1999.

The purpose of this study is to assess trends in self-reported cigarette smoking among adults in Wisconsin. Behavioral Risk Factor Survey data from 1984-1999 were analyzed to determine changes in smoking prevalence. Results of this analysis show almost no change in overall adult smoking prevalence over the past 15 years. Smoking prevalence rates did, however, decrease slightly for men from 29% in 1984 to 22% in 1999. Moreover, smoking prevalence for adults 18 to 24 years of age increased from 25% in 1994 to 36% in 1999. These results show that despite state and national efforts over the past 15 years to reduce cigarette smoking among adults, minimal progress has been made. Furthermore, the increase in smoking rates among 18 to 24 year olds highlights the need for additional prevention and cessation efforts targeted toward this group. Understanding past trends in cigarette smoking is critical for the Wisconsin Tobacco Control Board and other public health advocates to monitor progress toward the goal of reducing tobacco use.

Lung cancer mortality report card: measuring progress in Wisconsin's counties, 1979-1998.

PURPOSE: To compare and contrast trends in lung cancer mortality in Wisconsin's 72 counties, as a measure of long-term progress in tobacco control. METHODS: Lung cancer mortality data were abstracted from the Centers for Disease Control and Prevention's WONDER database from 1979 to 1998. Percent change in lung cancer mortality rates were analyzed at the county and national levels from 1979-1983 to 1994-1998. RESULTS: In Wisconsin, lung cancer mortality rates increased 23%, compared to a 19% increase in the United States. There was more variation in lung cancer mortality trends between Wisconsin counties than between states, with increases in 67 of Wisconsin's 72 counties. Lung cancer mortality rates increased for men in 44 counties and for women in 68 counties. Only 4 counties in Wisconsin had fewer lung cancer deaths in 1994-1998 compared with 1979-1983. CONCLUSIONS: Progress in reducing lung cancer mortality in Wisconsin--a long-term measure of progress in tobacco control--has lagged behind the rest of the United States. Nevertheless, some Wisconsin counties have experienced more progress in reducing the health burden from lung cancer, suggesting that differences exist between communities in the effectiveness of their tobacco control efforts.

Saturable binding of the echinoderm microtubule-associated protein (EMAP) on microtubules, but not filamentous actin or vimentin filaments.

The echinoderm microtubule-associated protein (EMAP) is a 75-kDa, WD-repeat protein associated with the mitotic spindle apparatus. To understand EMAP's biological role, it is important to determine its affinity for microtubules (MTs) and other cytoskeletal components. To accomplish this goal, we utilized a low-cost, bubble-column bioreactor to express EMAP as a hexahistidine fusion (6his) protein in baculovirus-infected insect cells. After optimizing cell growth conditions, up to 30 mg of EMAP was obtained in the soluble cell lysate from a 1-liter culture. EMAP was purified to homogeneity in a two-step process that included immobilized metal-affinity chromatography (IMAC) and anion-exchange chromatography. In vitro binding studies on cytoskeletal components were performed with the 6his-EMAP. EMAP bound to MTs, but not actin or vimentin filaments, with an intrinsic dissociation constant of 0.18 microM and binding stoichiometry of 0.7 mol EMAP per mol tubulin heterodimer. In addition, we show that a strong MT binding domain resides in the 137 amino acid, NH(2)-terminus of EMAP and a weaker binding site in the WD-domain. Previous work has shown that the EMAP concentration in the sea urchin egg is over 4 microM. Together, these results show that there is sufficient EMAP in the egg to regulate the assembly of a large pool of maternally stored tubulin.

Carbon dioxide absorption during extraperitoneal and transperitoneal endoscopic hernioplasty.

UNLABELLED: Transabdominal preperitoneal (TAPP) or total extraperitoneal (TEP) hernioplasty are probably associated with differing degrees of CO(2) absorption which can influence anesthetic management and perioperative morbidity. We studied 20 patients with either TAPP or TEP for perioperative CO(2) absorption (calculated from CO(2) elimination and metabolic CO(2) production) and ventilatory changes required to maintain normocapnia (blood gas analyses). CO(2) absorption reached plateau values in the TAPP group, but increased over time in the TEP group. Median CO(2) absorption during insufflation was 61 mL/min (range 43-78) for TAPP and 114 mL/min (range 75-178) for TEP, with a maximum of 114 mL/min (range 75-178) for TAPP and 258 mL/min (range 112-585) for TEP. Median minute ventilation (V(E)) required for maintaining normocapnia was 9. 5 L/min (range 7.7-11.5) for TAPP and 12.9 L/min (range 9.0-22.6) for TEP (P: < 0.01). Seven patients in the TEP group required over 18 L/min V(E), although no patient in the TAPP group required more than 14 L/min V(E). All patients in the TEP group had significant subcutaneous emphysema resulting in one case of delayed tracheal extubation. We conclude that CO(2) absorption is consistently less with TAPP. IMPLICATIONS: The greater magnitude of carbon dioxide absorption during total extraperitoneal hernioplasty puts an additional load on the lungs and could pose a risk for patients with chronic lung disease who might be unable to eliminate excess carbon dioxide.

Conservation of the WD-repeat, microtubule-binding protein, EMAP, in sea urchins, humans, and the nematode C. elegans.

The echinoderm microtubule-associated protein (EMAP) is the most abundant microtubule-binding protein in the first cleavage mitotic apparatus in sea urchin embryos. The first goal of this study was to determine whether there is sufficient EMAP in the egg and embryo to modify microtubule dynamics during the early cleavages divisions and whether EMAP functions at a specific time or place in the embryo. To accomplish this goal, we examined the relative abundance, tissue distribution, and temporal pattern of EMAP expression during embryonic development. The second goal of this study was to identify important functional domains within the EMAP coding sequence. A conserved sequence might reveal a potential microtubule-binding domain. We cloned, sequenced and compared overlapping EMAP cDNAs from two different sea urchin species that diverged approximately 80 million years ago, and compared these with cDNA sequences from a vertebrate and nematode species. From quantitative immunoblots, we determined the EMAP concentration in eggs to be 4 microM. The steady-state levels of EMAP mRNA and protein accumulated during development, and all three germ layers expressed EMAP. During the early stages of development, EMAP and tubulin were both abundant in the ectoderm, mesoderm and endoderm. However, during late gastrulation and the formation of the early pluteus larvae, EMAP was enriched in the mesoderm, while tubulin staining was most abundant in the archenteron. These results indicate that EMAP may have tissue-specific functions in the late stage embryo. To identify conserved functional domains, we compared the predicted amino acid sequence encoded by Strongylocentrotus purpuratus and Lytechinus variegatus EMAP cDNAs, and determined that these two sea urchin EMAPs were 95% conserved and shared an identical domain organization. A parsimonious analysis of these sea urchin protein sequences, as well as human and C. elegans EMAP sequences was used to construct a gene tree. Together these results suggest that EMAP is an important microtubule protein required at all developmental stages of sea urchins, and whose cellular function may be conserved amongst metazoans.

[Comparative presentation of current economic evaluation studies for phenylketonuria screening]. / Vergleichende Darstellung bisheriger ökonomischer Evaluationsstudien zum Screening auf Phenylketonurie.

A systematic review was undertaken to assess the economic value of PKU screening in the framework of newborn screening for inborn errors of metabolism. Therefore, seven international studies on this topic were connected and examined with regard to differences and similarities. The relation between costs and benefits of PKU-screening programmes goes from 1:1,2 up to 1:9,25. The differences can be explained by varying incidence of PKU (in international comparison) and particularly by methodical differences in the respective study designs. This aspect is pointed out while taking up and emphasising the necessity of standardisation in economic evaluation studies. Furthermore, future developments (chances, trends, changes) in newborn screening are discussed, based on the potential use of new technologies.

Expression of matrix metalloproteinase 9 (96-kd gelatinase B) in human rheumatoid arthritis.

OBJECTIVE: To determine the expression of matrix metalloproteinase 9/gelatinase B (MMP-9) in synovial fluid (SF), plasma, and synovial tissue from individuals with rheumatoid arthritis (RA), inflammatory arthritis (IA), and osteoarthritis (OA), using specific monoclonal antibody reagents. METHODS: Gelatinolytic activity in the SF and plasma of patients with RA, IA, and OA was assessed by gelatin zymography. A mouse monoclonal antiserum, 277.13, which selectively recognizes soluble latent forms of human MMP-9, was used to quantitate MMP-9 levels in patient synovial effusions, plasma, and synovial tissue with a capture sandwich enzyme-linked immunosorbent assay (ELISA). Fifty-one SF samples (31 RA, 9 OA, 11 IA) were analyzed. Immunolocalization of MMP-9 in RA, OA, and normal synovium was investigated using MMP-9-specific antisera. RESULTS: MMP-9 antigen levels in synovial effusions were elevated 67-fold in RA samples compared with OA samples. In addition, although MMP-9 antigen levels in IA synovial effusions were 2.7-fold less than the values in RA samples, they were elevated 34-fold over the values in OA samples. These data indicate an association between increased MMP-9 levels and inflammatory arthritis. A predominant 92-kd gelatinolytic activity (specifically inhibited by EDTA) was evident in RA and IA samples, but no activity was observed in OA samples. Among 86 plasma samples (17 RA, 9 IA, 60 normal controls) analyzed for MMP-9 antigen levels by immunocapture ELISA, MMP-9 antigen levels were elevated 7-fold in RA plasma compared with normal plasma. RA synovial tissue extracts demonstrated elevated levels of MMP-9 antigen compared with OA synovial tissue. MMP-9 immunolocalization studies demonstrated expression in infiltrating leukocytes (neutrophils and macrophages), endothelial cells, and synovial fibroblasts in RA synovium. CONCLUSION: Latent MMP-9 and/or MMP-9-tissue inhibitor of metalloproteinases 1 (TIMP-1) complexes are elevated in RA and IA SF compared with OA SF. In addition, MMP-9 is increased in RA plasma versus normal control plasma. Synovial tissue levels of MMP-9 antigen are also elevated in RA versus OA. The tissue distribution of MMP-9 within RA synovium is localized to sites of inflammation comprising surface synovial lining cells, endothelium, and leukocytes. Taken together, these observations suggest that connective tissue turnover occurs as a result of excessive MMP activity over TIMP action in the invading pannus, periarticular tissue, or SF. Further studies such as those used in the present investigation will help elucidate the role of a number of different enzymes and inhibitors in the destructive arthropathies.