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The aim of this study was to explore treatment options for chronic urinary retention (CUR) in men, including complications and consequences. Male patients diagnosed with a non-neurogenic, symptomatic and/or high-risk, CUR > 150 mL were included. Data for treatments, complications, and consequences were recorded and incidence rate ratios (IRRs) calculated. We enrolled 177 patients, most initially received a urethral catheter (74%) and some form of catheterization as final treatment (87%), 49 (28%) underwent de-obstructive prostate surgery. Catheterization was more likely to be stopped after surgery (16/49 patients), compared with non-surgical cases (8/128 patients) (IRR 4.18; p< 0.001). Urinary tract infection (IRR 3.68; p< 0.001) and macroscopic hematuria (IRR 5.35; p< 0.001) were more common with catheterization, but post-renal problems were more likely in patients without catheterization (IRR 25.36; p< 0.001). The lowest complication rate was with clean intermittent catheterization. In conclusion, most patients received catheterization for CUR, with clean intermittent catheterization preferred due to its comparatively lower complication risk. De-obstructive prostate surgery increases the chance of stopping catheterization.

Muscarine-receptorantagonisten en de β3-agonist mirabegron vormen de basis van de medicamenteuze behandeling van het overactieveblaassyndroom (OAB). De effectiviteit van muscarine-receptorantagonisten en mirabegron is vergelijkbaar en de combinatie solifenacine en mirabegron is minimaal effectiever dan dezelfde middelen als monotherapie. De bijwerkingen van antimuscarinica zijn onder andere een droge mond en obstipatie en die van mirabegron zijn vergelijkbaar met placebo. Weinig patiënten gebruiken deze middelen langdurig vanwege een gebrek aan effectiviteit ervan en vanwege de bijwerkingen. Er lijken op dit moment geen middelen met een nieuw werkingsmechanisme in ontwikkeling te zijn en de kans is klein daar op korte termijn verandering in komt. Omdat OAB een symptoomcomplex is, met mogelijk verschillende onderliggende pathologieën en symptoomcombinaties, is het onwaarschijnlijk dat nieuwe middelen duidelijk effectiever zullen zijn. De belangrijkste prioriteiten voor de toekomst zijn niet alleen de ontdekking van nieuwe therapeutische targets, maar ook identificatie van subgroepen met dezelfde symptomatologie of onderliggende pathologie. Biomarkers zouden een rol kunnen spelen bij deze zoektocht.

Zusammenfassung: Die schwere ambulant erworbene sowie die nosokomiale Pneumonie sind in Deutschland häufige Infektionskrankheiten, die eine besondere Herausforderung im klinischen Alltag darstellen und mit einer hohen Mortalität v. a. des älteren multimorbiden Patienten einhergehen. Während der CRB65 („confusion, respiratory rate, blood pressure, 65 years“) einfach und zuverlässig eine Risikostratifizierung der ambulant erworbenen Pneumonie zulässt, existiert für die nosokomiale Pneumonie kein entsprechend validierter Score. Ein rascher Beginn einer geeigneten empirischen Antibiotikatherapie ist für das Outcome des Patienten essenziell. Multiresistente Erreger stellen v. a. bei der nosokomialen Pneumonie ein Problem dar und müssen bei entsprechenden Risikofaktoren in der Initialtherapie berücksichtigt werden. Bewusst wird auf schwere Verlaufsformen fokussiert, es werden ein Überblick über die aktuellen Empfehlungen der entsprechenden Leitlinien gegeben und neue Erkenntnisse der letzten Jahre diskutiert.

Organic-soluble extracts of the twigs of Aglaia oligophylla collected in Vietnam yielded four insecticidal cyclopentatetrahydrobenzofurans of the rocaglamide type including one new natural product (compound 4). Moreover, two cyclopentatetrahydrobenzopyran derivatives, belonging to the aglain and aglaforbesin types, respectively, were also isolated. The aglaforbesin derivative 6 proved likewise to be a new natural product. All isolated rocaglamide, aglain, and aglaforbesin derivatives have a characteristic methylenedioxy substituent linked to C-6 and C-7 or to C-7 and C-8, respectively. Structure elucidation of the new natural products and the determination of the absolute configuration of compound 1 by calculation of its CD spectrum with molecular dynamics simulation are described. All isolated rocaglamide derivatives exhibited strong insecticidal activity toward neonate larvae of the polyphageous pest insect Spodoptera littoralis when incorporated into an artificial diet, with LC50 values varying between 2.15 and 6.52 ppm.

Predictive models of fall risk in the elderly living in the community may contribute to the identification of elderly at risk for recurrent falling.

OBJECTIVE: To evaluate whether a programme of multifactorial home visits reduces falls and impairments in mobility in elderly people living in the community. DESIGN: Randomised controlled trial with 18 months of follow up. SETTING: Six general practices in Hoensbroek, the Netherlands. PARTICIPANTS: 316 people aged 70 and over living in the community, with moderate impairments in mobility or a history of recent falls. INTERVENTION: Five home visits by a community nurse over a period of one year. Visits consisted of screening for medical, environmental, and behavioural factors causing falls and impairments in mobility, followed by specific advice, referrals, and other actions aimed at dealing with the observed hazards. MAIN OUTCOME MEASURES: Falls and impairments in mobility. RESULTS: No differences were found in falls and mobility outcomes between the intervention and usual care groups. CONCLUSION: Multifactorial home visits had no effects on falls and impairments in mobility in elderly people at risk who were living in the community. Because falls and impairments in mobility remain a serious problem among elderly people, alternative strategies should be developed and evaluated.

Objectives: To describe for the province of Limburg, the Netherlands, the incidence of lower limb amputation (LLA), the demographic characteristics of the amputees, reason and level of amputation, care the amputees receive, prosthetic supply and functional level after one year.Design: A prospective descriptive cohort study.Methods: Anonymized data on all amputees in all nine hospitals were collected during 1994. Follow–up was one year.Results: 191 major lower limb amputations in 164 patients. Incidence was 17.1 per 100,000. Amputation levels: 77 trans–tibial, 52 trans–femoral and 43 knee disarticulation. Twenty (20) patients died during hospitalisation. Eighty–seven (87) amputees gave permission for follow–up, 60 could be actually followed. Twenty–two (22) patients received in–patient rehabilitation, 16 primary day–care, 21 went to a nursing home and one went home without rehabilitation. The mean duration of rehabilitation was 35 weeks. In 53 patients a functional prosthesis was indicated. Forty–three (43) of these patients walked with the prosthesis after one year, 7 of whom more than 500 metres. Nineteen (19) amputees performed the Get Up and Go Test (GUGT) safely. Amputees on average have a low level of functioning, as indicated by SIP68 and Barthel Index Scores. The ability to walk is closely related to this daily function and quality of life.Conclusion: After one year the majority of amputees have low walking skills and the walking distance is limited. They are often ADL–dependent and their amputation greatly limits their daily function.

Objectives: To describe for the province of Limburg, the Netherlands, the incidence of lower limb amputation (LLA), the demographic characteristics of the amputees, reason and level of amputation, care the amputees receive, prosthetic supply and functional level after one year.Design: A prospective descriptive cohort study.Methods: Anonymized data on all amputees in all nine hospitals were collected during 1994. Follow-up was one year.Results: 191 major lower limb amputations in 164 patients. Incidence was 17.1 per 100,000. Amputation levels: 77 trans-tibial, 52 trans-femoral and 43 knee disarticulation. Twenty (20) patients died during hospitalisation. Eighty-seven (87) amputees gave permission for follow-up, 60 could be actually followed. Twenty-two (22) patients received in-patient rehabilitation, 16 primary day-care, 21 went to a nursing home and one went home without rehabilitation. The mean duration of rehabilitation was 35 weeks. In 53 patients a functional prosthesis was indicated. Forty-three (43) of these patients walked with the prosthesis after one year, 7 of whom more than 500 metres. Nineteen (19) amputees performed the Get Up and Go Test (GUGT) safely. Amputees on average have a low level of functioning, as indicated by SIP68 and Barthel Index Scores. The ability to walk is closely related to this daily function and quality of life.Conclusion: After one year the majority of amputees have low walking skills and the walking distance is limited. They are often ADL-dependent and their amputation greatly limits their daily function.

The kinase domain receptor (KDR) of vascular endothelial growth factor (VEGF) is the main human receptor responsible for the angiogenic activity of VEGF. The extracellular region of KDR is comprised of seven immunoglobulin-like domains, of which the first three have been shown to be required for ligand binding. We have previously described antibodies directed against the extracellular region of KDR, including MAB383 and MAB664, which were shown to block the binding of VEGF to the receptor and to inhibit both VEGF-induced mitogenesis of human endothelial cells in vitro and tumor growth in vivo. Here we generated a series of KDR deletion mutants consisting of truncated extracellular regions and mapped out the domain(s) responsible for binding to VEGF and the neutralizing anti-KDR antibodies. All neutralizing antibodies were found to require domain 3 for efficient binding. Alanine-scanning mutagenesis of domain 3 identified two different sets of five residues, Ile(256), Asp(257), Glu(261), Leu(313), and Thr(315) and Tyr(262), Pro(263), Ser(264), Ser(265), and Lys(266), that were critical for binding to MAB383 and MAB664, respectively. Combination of alanine mutations affecting both MAB383 and MAB664 binding resulted in a variant that also lost binding to VEGF. These results suggest that the residues within this region of domain 3 are critical for VEGF binding. Our studies provide a basis for the mechanism of action of our anti-KDR antibodies and establish a functional foundation for the development of other classes of antagonists to the receptor.

In 11 species of the flea beetle genus Longitarsuswe investigated whether the insects sequester the pyrrolizidine alkaloids (PAs) present in their host plants of the families Asteraceae and Boraginaceae. In all cases where PAs could be detected in the leaves of the local host plant, they could also be detected in the corresponding beetles. In one host plant, Pulmonaria officinalis, no PAs could be detected in the leaves, yet were present in the beetles collected from them. We suggest this is due to uptake of PAs during the root-feeding larval stage. By comparing the GC-MS pattern of PAs found in the beetles with those of their hosts, we investigated the specificity of this sequestration. Furthermore, we compared the pattern of sequestered PAs across beetle species that had been feeding on the same plant, and across hosts in Longitarsusspecies that feed on different plants in the field. This allowed us to analyze to what extent the PA pattern in the insects is specific for the beetle species and depends on the local food plant. Our data indicate that the PAs found in the beetles are largely determined by the host plant, e.g., whether alkaloids typical of the Boraginaceae or Asteraceae are present. However, there are some indications for a selective uptake of PAs and apparently the beetles are able to metabolize them.

In endothelial cells, vascular endothelial growth factor (VEGF) induces an accumulation of stress fibers associated with new actin polymerization and rapid formation of focal adhesions at the ventral surface of the cells. This cytoskeletal reorganization results in an intense motogenic activity. Using porcine endothelial cells expressing one or the other type of the VEGF receptors, VEGFR1 or VEGFR2, or human umbilical vein endothelial cells pretreated with a VEGFR2 neutralizing antibody, we show that VEGFR2 is responsible for VEGF-induced activation of the stress-activated protein kinase-2/p38 (SAPK2/p38), phosphorylation of focal adhesion kinase (FAK), and enhanced migratory activity. Activation of SAPK2/p38 triggered actin polymerization whereas FAK, which was phosphorylated independently of SAPK2/p38, initiated assembly of focal adhesions. Both processes contributed to the formation of stress fibers. Geldanamycin, an inhibitor of HSP90 blocked tyrosine phosphorylation of FAK, assembly of focal adhesions, actin reorganization, and cell migration, all of which were reversed by overexpressing HSP90. We conclude that VEGFR2 mediates the physiological effect of VEGF on cell migration and that two independent pathways downstream of VEGFR2 regulate actin-based motility. One pathway involves SAPK2/p38 and leads to enhanced actin polymerization activity. The other involves HSP90 as a permissive signal transduction factor implicated in FAK phosphorylation and assembly of focal adhesions.

OBJECTIVE: To assess the effects of preventive home visits to elderly people living in the community. DESIGN: Systematic review. SETTING: 15 trials retrieved from Medline, Embase, and the Cochrane controlled trial register. MAIN OUTCOME MEASURES: Physical function, psychosocial function, falls, admissions to institutions, and mortality. RESULTS: Considerable differences in the methodological quality of the 15 trials were found, but in general the quality was considered adequate. Favourable effects of the home visits were observed in 5 out of 12 trials measuring physical functioning, 1 out of 8 measuring psychosocial function, 2 out of 6 measuring falls, 2 out of 7 measuring admissions to institutions, and 3 of 13 measuring mortality. None of the trials reported negative effects. CONCLUSIONS: No clear evidence was found in favour of the effectiveness of preventive home visits to elderly people living in the community. It seems essential that the effectiveness of such visits is improved, but if this cannot be achieved consideration should be given to discontinuing these visits.

Bioassay-guided fractionation of an extract obtained from roots of Aglaia duperreana led to the isolation of 17 1H-cyclopenta[b]benzofurans of the rocaglamide type. Of the compounds isolated, four rocaglamide derivatives (2, 6, 11, and 16) were obtained as new natural products, and their structure elucidation was conducted by spectral methods. For bioassay-guided fractionation and determination of LC50 and EC50 values, neonate larvae of Spodoptera littoralis were employed. The results of chronic feeding assays have shown new aspects of the structure−activity relationship of rocaglamide derivatives. The substitution of a hydroxyl group at C-8b by a methoxyl substituent leads to a loss of insecticidal activity in a manner not previously documented in this compound class.

The pupillary membrane (PM) is a transient ocular capillary network, which can serve as a model system in which to study the mechanism of capillary regression. Previous work has shown that there is a tight correlation between the cessation of blood flow in a capillary segment and the appearance of apoptotic capillary cells throughout the segment. This pattern of cell death is referred to as synchronous apoptosis (Lang, R. A., Lustig, M., Francois, F., Sellinger, M. and Plesken, H. (1994) Development 120, 3395-3404; Meeson, A., Palmer, M., Calfon, M. and Lang, R. A. (1996) Development 122, 3929-3938). In the present study, we have investigated whether the cause of synchronous apoptosis might be a segmental deficiency of either oxygen or a survival factor. Labeling with the compound EF5 in a normal PM indicated no segmental hypoxia; this argued that oxygen deprivation was unlikely to be the cause of synchronous apoptosis. When rat plasma was used as a source of survival factors in an in vitro PM explant assay, inhibition of vascular endothelial growth factor (VEGF) all but eliminated the activity of plasma in suppressing apoptosis. This argued that VEGF was an important plasma survival factor. Furthermore, inhibition of VEGF in vivo using fusion proteins of the human Flk-1/KDR receptor resulted in a significantly increased number of capillaries showing synchronous apoptosis. This provides evidence that VEGF is necessary for endothelial cell survival in this system and in addition, that VEGF deprivation mediated by flow cessation is a component of synchronous apoptosis.

Three new meliacarpin derivatives, namely 1,3-dicinnamoyl-11-hydroxymeliacarpin, 1-cinnamoyl-3-methacrylyl-11-hydroxymeliacarpin and 1-cinnamoyl-3-acetyl-11-hydroxymeliacarpin, were isolated as the principal insecticidal and growth disrupting constituents of Melia azedarach leaves. Their structures were unambiguously established on the basis of MS spectrometric and NMR spectroscopic data ( H , C , COSY, H -detected direct and long-range C - H correlations) and by comparison with known compounds. The insecticidal properties of the new meliacarpin derivatives were examined using larvae of the polyphagous pest insect Spodoptera littoralis . When incorporated into artificial diet and offered to larvae in a chronic feeding bioassay, 1-cinnamoyl-3-acetyl-11-hydroxymeliacarpin exhibited an EC 50 of 0.27 ppm and a LC 50 of 0.48 ppm and is thus comparable with regard to insecticidal activity to the well known natural insecticide azadirachtin. Furthermore, all three meliacarpin derivatives had a pronounced detrimental influence on larval metamorphosis.

Glypican-1 is a member of a family of glycosylphosphatidylinositol anchored cell surface heparan sulfate proteoglycans implicated in the control of cellular growth and differentiation. The 165-amino acid form of vascular endothelial growth factor (VEGF165) is a mitogen for endothelial cells and a potent angiogenic factor in vivo. Heparin binds to VEGF165 and enhances its binding to VEGF receptors. However, native HSPGs that bind VEGF165 and modulate its receptor binding have not been identified. Among the glypicans, glypican-1 is the only member that is expressed in the vascular system. We have therefore examined whether glypican-1 can interact with VEGF165. Glypican-1 from rat myoblasts binds specifically to VEGF165 but not to VEGF121. The binding has an apparent dissociation constant of 3 x 10(-10) M. The binding of glypican-1 to VEGF165 is mediated by the heparan sulfate chains of glypican-1, because heparinase treatment abolishes this interaction. Only an excess of heparin or heparan sulfates but not other types of glycosaminoglycans inhibited this interaction. VEGF165 interacts specifically not only with rat myoblast glypican-1 but also with human endothelial cell-derived glypican-1. The binding of 125I-VEGF165 to heparinase-treated human vascular endothelial cells is reduced following heparinase treatment, and addition of glypican-1 restores the binding. Glypican-1 also potentiates the binding of 125I-VEGF165 to a soluble extracellular domain of the VEGF receptor KDR/flk-1. Furthermore, we show that glypican-1 acts as an extracellular chaperone that can restore the receptor binding ability of VEGF165, which has been damaged by oxidation. Taken together, these results suggest that glypican-1 may play an important role in the control of angiogenesis by regulating the activity of VEGF165, a regulation that may be critical under conditions such as wound repair, in which oxidizing agents that can impair the activity of VEGF are produced, and in situations were the concentrations of active VEGF are limiting.

Cuscuta reflexa, Lupinus angustifolius, Quinolizidine Alkaloids, Parasitism During parasitism on Lupinus angustifolius the phanerogamic parasite Cuscuta reflexa takes up quinolizidine alkaloids from L. angustifolius via haustoria that tap xylem and phloem ves­sels of the host. The alkaloid pattern of the haustorial region of C. reflexa as revealed by GLC as well as by GLC-M S closely resembles that of infested lupin stems. With increasing distance from the haustoria towards the apex of C. reflexa the complex alkaloid pattern of the host is significantly reduced. Whereas alkaloid esters such as 13-benzoyloxylupanine and 13-cinnamoyloxy-lupanine are prominent peaks in the alkaloid profiles of the host as well as of the haustorial region of the parasite they are not detected in the apex of C. reflexa but are replaced by their respective alcohol com ponent 13-hydroxylupanine. This change of alkaloid profiles is accompanied by a strong decline of alkaloid concentration which drops from ap­ proximately 11 m g/g dry wt. in the haustorial region of C. reflexa to 0.2 m g/g dry wt. in the apex. Alkaloid analyses of xylem sap and phloem exudate from L. angustifolius suggest that uptake of host plant alkaloids by C. reflexa is mainly via the phloem even though a contribu­tion of xylem sap to the supply of alkaloids to the parasite can not be excluded.

About 28 quinolizidine alkaloids and the dipiperidine alkaloids am modendrine, dehydroammodendrine and N -formylammodendrine were identified in the alkaloidal extracts of Retama raetam, Retama sphaerocarpa and Retama monosperma by capillary GLC and GLCMS. Alkaloid profiles of the three Retama species with a Mediterranean distribution are more similar than alkaloid patterns of different organs of the same plant. Whereas sparteine and retamine are the major components of stems, lupanine, retam ine, N-methylcytisine and cytisine dominate in flowers and pods, and cytisine in seeds indicating a high degree of organ specificity of alkaloid storage.

The alkaloid patterns during germination and seedling development of Lupinus polyphyllus, L. angustifolius, L. albus, L. pubescens, Cytisus scoparius, Baptisia australis, Spartium junceum and Laburnum anagyroides were studied by capillary glc and EI-MS and CI-MS. The alkaloid contents were relatively high in the seeds and decreased by 20-100% during germination and the early developmental stages. The plants with fully developed leaves were able to synthesize new alkaloids. The decrease of alkaloid concentrations during germination was interpreted in terms of alkaloid turnover and use of the alkaloidal nitrogen for seedling development. The ability of plants to rely on the alkaloidal nitrogen as a nitrogen source could also be shown in lupin cell cultures which could survive and even grow on media which contained sparteine as the sole nitrogen source.

The enzymatic sequence responsible for the biosynthesis of tetracyclic quinolizidine alkaloids could be localized in chloroplasts isolated from Lupinus polyphyllus leaves and L. albus seedlings by differential centrifugation. Upon feeding of cadaverine to isolated chloroplasts lupanine is produced as the main alkaloid. Chloroplasts treated with digitonine produce sparteine and 17-oxosparteine instead of lupanine, thus indicating that the biosynthetic sequence is interrupted. The intermediacy of 17-oxosparteine could be confirmed since exogeneous 17-oxosparteine is converted into lupanine by intact chloroplasts. 17-Oxosparteine synthase (see Z. Naturforsch. 34 c, 704 1979) the key enzyme of quinolizidine alkaloid biosynthesis could be solubilized from chloro­ plasts treated with detergents or osmotic shock.

Analysis of the tropical marine sponge Axinella carteri afforded six unusual alkaloids, including the new brominated guanidine derivative 3-bromo-hymenialdisine. The structure elucidation of the new alkaloid is described. The alkaloid patterns of sponges collected in Indonesia or in the Philippines were shown to be qualitatively identical suggesting de novo synthesis by the sponge or by endosymbiontic microorganisms rather than uptake by filterfeeding. All alkaloids were screened for insecticidal activity as well as for cytotoxicity. The guanidine alkaloids hymenialdisine and debromohymenialdisine exhibited insecticidal activity towards neonate larvae of the polyphagous pest insect Spodoptera littoralis (LD50s of 88 and 125 ppm, respectively), when incorporated into artificial diet and offered to the larvae in a chronic feeding bioassay. The remaining alkaloids, including the new compound, were inactive in this bioassay. Cytotoxicity was studied in vitro using L5178y mouse lymphoma cells. Debromohymenialdisine was again the most active compound (ED501.8 µg/ml) followed by hymenialdisine and 3-bromohymenialdisine, which were essentially equitoxic and exhibited ED50s of 3.9 µg/ml in both cases. The remaining alkaloids were inactive against this cell line

Physical therapy in ankylosing spondylitis (AS) is considered important for maintaining or improving mobility, fitness, functioning, and global health. We studied the influence of disease duration on the short term effects of supervised individual therapy. One hundred forty-four AS outpatients (modified New York Criteria; mean age: 43 years; median duration of disease: 4 years; range: 0–33) received 12 supervised individual treatments in a 6-week course of 30 minutes. Endpoints were: spinal mobility (thoracic and lumbar flexion and extension, chest expansion, cervical rotation), fitness (maximum work capacity by ergometry), functioning (Sickness Impact Profile (SIP) and the Functional Index (FI)), and global patient assessment of change on a visual analogue scale. After 6 weeks patients had improved in all endpoints, but only significantly in rotation (8 degrees, 10%), fitness (6 watt, 4%), and SIP (0.6, 14%; t-test, p<0.05). Global patient assessment improved by 1.1 (22%). Plots of change scores and disease duration showed no evident relation. We also divided the population into two groups, with the median disease duration as a cut-off. No relevant difference in improvement was found between ’short duration’ and ’long duration’ groups (t-test of change scores, p>0.05). In addition, no relevant correlation was found between change scores and disease duration (p>0.01). It may be concluded that irrespective of disease duration, short term supervised individual therapy is effective in AS, slightly improving mobility, fitness, functioning and global health.