Mathematical optimization of high dose-rate brachytherapy-derivation of a linear penalty model from a dose-volume model.

High dose-rate brachytherapy is a method for cancer treatment where the radiation source is placed within the body, inside or close to a tumour. For dose planning, mathematical optimization techniques are being used in practice and the most common approach is to use a linear model which penalizes deviations from specified dose limits for the tumour and for nearby organs. This linear penalty model is easy to solve, but its weakness lies in the poor correlation of its objective value and the dose-volume objectives that are used clinically to evaluate dose distributions. Furthermore, the model contains parameters that have no clear clinical interpretation. Another approach for dose planning is to solve mixed-integer optimization models with explicit dose-volume constraints which include parameters that directly correspond to dose-volume objectives, and which are therefore tangible. The two mentioned models take the overall goals for dose planning into account in fundamentally different ways. We show that there is, however, a mathematical relationship between them by deriving a linear penalty model from a dose-volume model. This relationship has not been established before and improves the understanding of the linear penalty model. In particular, the parameters of the linear penalty model can be interpreted as dual variables in the dose-volume model.

Phase IV head-to-head randomized controlled trial comparing ingenol mebutate 0·015% gel with diclofenac sodium 3% gel for the treatment of actinic keratosis on the face or scalp.

BACKGROUND: Ingenol mebutate (IngMeb) and diclofenac sodium (DS) are approved treatments for actinic keratosis (AK). OBJECTIVES: To compare the efficacy and safety of IngMeb 0·015% gel with DS 3% gel (NCT02406014). METHODS: Patients with 4-8 visible, discrete AK lesions on the face/scalp in a 25 cm2 contiguous area of skin were randomized 1:1 to IngMeb once-daily for three consecutive days or DS twice-daily for 90 days. Patients with AK lesions at Week 8 following IngMeb were offered a second IngMeb course. Primary end point was complete clearance of AK lesions (AKCLEAR 100) at end of first treatment course (Week 8, IngMeb; Week 17, DS). Secondary end points included AKCLEAR 100 at end of last treatment course and Week 17; adverse events (AEs) were assessed at these time points. Patients completed treatment satisfaction questionnaires for medication (TSQM; Week 17). RESULTS: AKCLEAR 100 at end of first treatment course was higher with IngMeb (34%) vs. DS (23%; P = 0·006). AKCLEAR 100 at end of last IngMeb course (53%) and Week 17 (45%) was higher than DS (both P < 0·001). The most frequent AE was application-site erythema (IngMeb 19%; DS 12%). Treatment-related AE (TRAE) duration was shorter with IngMeb. TRAE withdrawals were lower for IngMeb (2%) vs. DS (6%). TSQM scores for global satisfaction (P < 0·001) and effectiveness (P = 0·002) were higher with IngMeb, as was dosing instruction adherence (≥ 90% vs. 70%). CONCLUSIONS: AKCLEAR 100, patient treatment satisfaction and effectiveness were significantly higher with IngMeb compared with DS, demonstrating superiority of IngMeb for AK treatment on face/scalp.

Effect of systemically increasing human full-length Klotho on glucose metabolism in db/db mice.

The metabolic effects of antiaging Klotho were previously investigated in vivo by genetic manipulation. We have here studied the metabolic effect of physiologic levels of circulating full length Klotho in db/db mice. Increasing the full-length human Klotho levels has a positive effect on blood glucose through increasing insulin secretion.

Efficacy and safety of follow-up field treatment of actinic keratosis with ingenol mebutate 0·015% gel: a randomized, controlled 12-month study.

BACKGROUND: Ingenol mebutate (IngMeb) is a novel patient-applied topical field therapy for actinic keratosis. OBJECTIVES: To demonstrate the efficacy and safety of follow-up IngMeb field treatment of actinic keratoses (AKs) present at 8 weeks after initial treatment or emerging in a previously cleared field. METHODS: In this phase III, randomized, double-blind study in patients with 4-8 clinically visible AKs within a contiguous 25-cm(2) treatment area on the face or scalp, all patients were treated initially with IngMeb 0·015% gel for three consecutive days. If lesions were present in the field at 8 weeks, or emerged at weeks 26 or 44, patients were randomized (2 : 1) to follow-up IngMeb or vehicle gel for three consecutive days. The main outcome was complete clearance rates of AKs 8 weeks after randomization. RESULTS: Of 450 patients who received initial treatment with IngMeb, 61·6% demonstrated complete clearance at 8 weeks. Patients with AKs present at 8 weeks or emerging at weeks 26 or 44 were randomized to IngMeb (n = 134) or vehicle (n = 69). IngMeb achieved a higher complete clearance rate than vehicle 8 weeks after randomization in AKs present at 8 weeks (46·7% vs. 18·4%; P < 0·01) and in emergent AKs (59·5% vs. 25·0%; P = 0·01). Based on those who completed 12 months of follow-up (n = 340), the overall 12-month clearance rate was estimated at 50·0%. Follow-up IngMeb treatment was well tolerated. CONCLUSIONS: This study demonstrated the long-term benefit of IngMeb 0·015% gel for initial and follow-up therapy of AKs.

A randomized trial comparing simultaneous vs. sequential field treatment of actinic keratosis with ingenol mebutate on two separate areas of the head and body.

BACKGROUND: Actinic keratoses (AKs) are precursors to invasive squamous cell carcinoma and can progress if untreated. Limited data support the use of ingenol mebutate to treat AKs on more than one area of the body simultaneously. OBJECTIVE: To investigate safety, efficacy and treatment satisfaction when treating separate areas simultaneously or sequentially with different concentrations of ingenol mebutate gel. METHODS: In this phase IIIb study (NCT01787383), patients with clinically visible, non-hyperkeratotic AKs on two separate treatment areas (face/scalp and trunk/extremities) were randomized to simultaneous or sequential treatment with ingenol mebutate gel (0.015% and 0.05%). Endpoints included composite local skin response (LSR) score 3 days after first application, complete AK clearance and percentage reduction in AKs at week 8. RESULTS: There were no statistically significant differences between simultaneous (n = 101) and sequential (n = 98) groups in composite LSR score (10.4 vs. 9.7), complete clearance (52.7% vs. 46.9%) or percentage reduction in AKs (83.4% vs. 79.1%). Mean composite LSR scores on face/scalp and trunk/extremities were similar for both groups. Adverse event (AE) incidence was comparable between groups, the most common treatment-related AEs being pruritus and pain at the application site. CONCLUSION: Treating AKs with ingenol mebutate simultaneously or sequentially gave similar results in terms of tolerability (LSR score, AEs) and efficacy (complete clearance). Therefore, the physician and patient can select the most convenient treatment regimen, with confidence in achieving a similar outcome.

Dietary acid load, kidney function, osteoporosis, and risk of fractures in elderly men and women.

SUMMARY: Because kidney dysfunction reduces the ability to excrete dietary acid excess, we hypothesized that underlying kidney function may have confounded the mixed studies linking dietary acid load with the risk of osteoporosis and fractures in the community. In a relatively large survey of elderly men and women, we report that dietary acid load did neither associate with DEXA-estimated bone mineral density nor with fracture risk. Underlying kidney function did not modify these null findings. Our results do not support the dietary acid-base hypothesis of bone loss. INTRODUCTION: Impaired renal function reduces the ability to excrete dietary acid excess. We here investigate the association between dietary acid load and bone mineral density (BMD), osteoporosis, and fracture risk by renal function status. METHODS: An observational study was conducted in 861 community-dwelling 70-year-old men and women (49% men) with complete dietary data from the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS). The exposure was dietary acid load as estimated from 7-day food records by the net endogenous acid production (NEAP) and potential renal acid load (PRAL) algorithms. Renal function assessed by cystatin C estimated glomerular filtration rate was reduced in 21% of the individuals. Study outcomes were BMD and osteoporosis state (assessed by DEXA) and time to fracture (median follow-up of 9.2 years). RESULTS: In cross-section, dietary acid load had no significant associations with BMD or with the diagnosis of osteoporosis. During follow-up, 131 fractures were validated. Neither NEAP (adjusted hazard ratios (HR) (95% confidence interval (CI)), 1.01 (0.85-1.21), per 1 SD increment) nor PRAL (adjusted HR (95% CI), 1.07 (0.88-1.30), per 1 SD increment) associated with fracture risk. Further multivariate adjustment for kidney function or stratification by the presence of kidney disease did not modify these null associations. CONCLUSIONS: The hypothesis that dietary acid load associates with reduced BMD or increased fracture risk was not supported by this study in community-dwelling elderly individuals. Renal function did not influence on this null finding.

A cascade classifier for diagnosis of melanoma in clinical images.

Computer aided diagnosis of medical images can help physicians in better detecting and early diagnosis of many symptoms and therefore reducing the mortality rate. Realization of an efficient mobile device for semi-automatic diagnosis of melanoma would greatly enhance the applicability of medical image classification scheme and make it useful in clinical contexts. In this paper, interactive object recognition methodology is adopted for border segmentation of clinical skin lesion images. In addition, performance of five classifiers, KNN, Naïve Bayes, multi-layer perceptron, random forest and SVM are compared based on color and texture features for discriminating melanoma from benign nevus. The results show that a sensitivity of 82.6% and specificity of 83% can be achieved using a single SVM classifier. However, a better classification performance was achieved using a proposed cascade classifier with the sensitivity of 83.06% and specificity of 90.05% when performing ten-fold cross validation.

Vitamin D metabolites and/or analogs: which D for which patient?

Numerous drugs with vitamin D activity are available for clinical use and it may not be easy for the nonspecialist to select the most suitable for the individual patient. In this paper we review the main characteristics of the available drugs and provide evidence about any potential specific clinical indications, with special emphasis on renal patients, in order to facilitate the optimal choice. Natural vitamin D products (i.e. those identical to natural metabolites) are first examined, followed by the most frequently used synthetic molecules (i.e. bioengineered molecules not-existing in nature), which are generally indicated as " analogs". Either cholecalciferol, ergocalciferol or calcifediol can be employed in subjects with normal renal function and in CKD stage 3-5 patients to correct vitamin D deficiency and improve, respectively, age- or growth-related bone disease and secondary hyperparathyroidism. Calcifediol can be considered more rapid and effective. In all cases, especially with increasing doses, the risk of hypercalcemia must be taken into account. Calcitriol, which can be regarded as the active hormonal form of vitamin D, has the most potent hypercalcemic effect in both normal and renal failure patients. In renal patients calcitriol is a potent inhibitor of parathyroid activity, but the risk of hypercalcemia, now regarded as harmful, is evident whenever pharmacologic doses are used. Alfacalcidol, requiring 25-hydroxylation to become the active hormonal form of vitamin D3, is prescribed in normal subjects to treat osteoporosis and in renal patients to cure hyperparathyroidism and renal bone disease. Doxercalciferol, transformed into the active hormonal form of vitamin D2 following 25-hydroxylation, is mostly studied in renal patients in whom it cures secondary hyperparathyroidism, possibly with a lower calcemic effect than calcitriol. Paricalcitol, a vitamin D2 analog not requiring activation, has been specifically developed to suppress PTH in renal patients with a limited calcemic effect. As such it is now regarded as a powerful drug useful to treat even severe cases of secondary hyperparathyroidism. Importantly, reno-protective and cardio-protective effects of this analog have been recently evaluated by means of randomized clinical trials in renal patients with partially positive renal effects and negative cardiac results, thus additional studies are needed for confirmation. 22-oxacalcitriol, a vitamin D3 analog with a limited calcemic effect available in Japan, is mostly used in renal patients affected by secondary hyperparathyroidism. The clinical activity of some vitamin D analogs is such that they can be employed in diseases like cancer and autoimmunity. The clinical activity of some vitamin D analogs is such that they can be employed in diseases like cancer and autoimmunity. In summary, available drugs with vitamin D like activity are not all the same either in terms of pharmacological actions, and side-effects. They have specific characteristics that may be useful to know in order to operate the best choice in the individual patient.

Characterization of the neuropeptide Y system in the frog Silurana tropicalis (Pipidae): three peptides and six receptor subtypes.

Neuropeptide Y and its related peptides PYY and PP (pancreatic polypeptide) are involved in feeding behavior, regulation of the pituitary and the gastrointestinal tract, and numerous other functions. The peptides act on a family of G-protein coupled receptors with 4-7 members in jawed vertebrates. We describe here the NPY system of the Western clawed frog Silurana (Xenopus) tropicalis. Three peptides, NPY, PYY and PP, were identified together with six receptors, namely subtypes Y1, Y2, Y4, Y5, Y7 and Y8. Thus, this frog has all but one of the ancestral seven gnathostome NPY-family receptors, in contrast to mammals which have lost 2-3 of the receptors. Expression levels of mRNA for the peptide and receptor genes were analyzed in a panel of 19 frog tissues using reverse transcriptase quantitative PCR. The peptide mRNAs had broad distribution with highest expression in skin, blood and small intestine. NPY mRNA was present in the three brain regions investigated, but PYY and PP mRNAs were not detectable in any of these. All receptor mRNAs had similar expression profiles with high expression in skin, blood, muscle and heart. Three of the receptors, Y5, Y7 and Y8, could be functionally expressed in HEK-293 cells and characterized with binding studies using the three frog peptides. PYY had the highest affinity for all three receptors (K(i) 0.042-0.34 nM). Also NPY and PP bound to the Y8 receptor with high affinity (0.14 and 0.50 nM). The low affinity of NPY for the Y5 receptor (100-fold lower than PYY) differs from mammals and chicken. This may suggest a less important role of NPY on Y5 in appetite stimulation in the frog compared with amniotes. In conclusion, our characterization of the NPY system in S. tropicalis with its six receptors demonstrates not only greater complexity than in mammals but also some interesting differences in ligand-receptor preferences.

LDL-associated apolipoprotein J and lysozyme are associated with atherogenic properties of LDL found in type 2 diabetes and the metabolic syndrome.

OBJECTIVES: Exchangeable low-density lipoprotein (LDL)-associated proteins can affect the atherogenic properties of LDL. Our aim was to analyse the protein composition of LDL from individuals with or without type 2 diabetes and the metabolic syndrome (T2DM) in relation to other LDL particle characteristics, to assess whether certain proteins associate more with certain subclasses of LDL typical for T2DM, such as small, apoCIII-rich LDL. DESIGN: Low-density lipoprotein from two cohorts of 61-year-old men (n = 19 and 64) with or without T2DM was isolated using size-exclusion chromatography or deuterium oxide-based ultracentrifugation. LDL-associated proteins were identified using mass spectrometry and quantified using two-dimensional gel electrophoresis or enzyme-linked immunosorbent assay. Differently expressed LDL-associated proteins apolipoprotein (apo)J and lysozyme were also measured in serum from a third cohort of women (n = 71) with or without T2DM. Lysozyme binding to advanced glycation end product (AGE)-LDL was examined in vitro. RESULTS: ApoJ and lysozyme were increased in LDL particles with increased apoCIII content and decreased cholesterol content. When isolated with size-exclusion chromatography, LDL from individuals with T2DM contained more apoJ and lysozyme and less apoA1 than LDL from control individuals. LDL content of apoJ correlated with a smaller LDL particle size. Serum levels of lysozyme, but not apoJ, were increased in individuals with T2DM. In vitro, lysozyme associated more with AGE-LDL than with unmodified LDL. CONCLUSIONS: Our results indicate that apoJ and lysozyme are increased in LDL with characteristics of small dense LDL in T2DM. Small dense LDL is easily glycated, and the increased affinity of lysozyme for AGE-LDL provides a possible partial explanation for an increase lysozyme in LDL from those with type 2 diabetes.

Relation between fibroblast growth factor-23, body weight and bone mineral density in elderly men.

SUMMARY: We evaluated the relation between serum FGF23 and bone mineral density (BMD) in a community-based cohort of elderly men. There was a weak correlation between FGF23 and BMD, which was primarily dependent on body weight. INTRODUCTION: FGF23 is a hormonal factor produced in bone and regulates serum levels of phosphate (Pi) and vitamin D. FGF23 over-expression is associated with skeletal abnormalities, including rickets/osteomalacia. The relation between FGF23 and Bone Mineral Density (BMD) in the community remains unexplored. METHODS: We employed a large, population-based cohort of 3014 Swedish men aged 69-80 years, without known renal disease. BMD was measured with dual X-ray absorptiometry (DXA) in the hip and lumbar spine. Serum intact FGF23 was analyzed with a two-site monoclonal ELISA. RESULTS: There was a weak but significant correlation between FGF23 and BMD in femoral neck (r = 0.04, p < 0.05), femoral trochanter (r = 0.05, p = 0.004), total hip (r = 0.06, p = 0.0015) and lumbar spine (r = 0.07, p = 0.0004). The correlations remained significant when adjusting for biochemical covariates (Pi, calcium, PTH, 25(OH)D and renal function). However, the association became insignificant in all regions when adjusting for established confounding variables including age, height, weight and smoking. Further analysis confirmed a significant correlation between FGF23 and body weight (r = 0.13, p < 0.0001). CONCLUSIONS: The weak correlation between FGF23 and BMD in elderly male subjects is mainly due to an association between FGF23 and body weight. Therefore, FGF23 may not play a significant role in the hormonal regulation of BMD.

Birth and death of neuropeptide Y receptor genes in relation to the teleost fish tetraploidization.

Extensive evidence exists for a genome duplication in the fish lineage leading to the species-rich clade of the teleosts, comprising > 99% of the known actinopterygian (ray-finned) fish species. Our previous studies of the neuropeptide Y receptor (NPYR) gene family suggested an ancestral gnathostome repertoire of 7 genes in 3 subfamilies. However, studies in the zebrafish have earlier identified only 5 NPYR genes, despite the expected increase in gene number due to the teleost tetraploidization. Notably, receptors Y(1), Y(5) and Y(6) were missing in the zebrafish genome database and only Y(8) had been duplicated. We report here an investigation of the evolutionary history of the Y(1) subfamily (Y(1), Y(4), Y(6) and Y(8)) and the Y(5) receptor. Seven basal actinopterygian species and a shark were investigated and a total of 22 gene fragments were cloned and analyzed. Our results show that subtypes Y(1), Y(5) and Y(6) still exist in species representing basal actinopterygian lineages (bichir, sturgeon, gar and bowfin) as well as in some basal teleost lineages. Surprisingly we identified a zebrafish Y(1) receptor, the first Y(1) receptor found in euteleosts. Thus, these findings confirm the ancestral gnathostome repertoire of 7 NPYR genes and show that many of these receptors are present in basal actinopterygians as well as some basal teleosts. NPYR losses seem to have occurred relatively recently in euteleosts because Y(1), Y(5) and Y(6) are absent in the genome databases of two pufferfishes as well as medaka and stickleback and Y(5) and Y(6) are absent in the zebrafish database. A duplicate of Y(8) seems to be the only remaining receptor gene resulting from the teleost tetraploidization. The unexpected absence of the two appetite-stimulating receptors Y(1) and Y(5) in some euteleosts, along with our discovery of duplicates of the peptide ligands NPY and PYY, has implications for the role of the NPY system in euteleost feeding behavior.

Thermodynamic stability and crystal structures for polymorphs and solvates of formoterol fumarate.

Polymorph screening of formoterol fumarate was performed in 12 solvents, followed by evaluations of thermodynamic stability. Three anhydrates, a dihydrate, a diethanolate, a diisopropanolate, and a dibensylalcoholate were found. The crystal structure of three solvated modifications and of the most stable anhydrate was investigated. This indicated that solvation is needed to get a stable and well packed crystal structure. Thermodynamic testing suggests that five crystal modifications are thermodynamically stable, at different conditions, since they are all reversibly related to each other.

Expression and functional analysis of fibulin-1 (Fbln1) during normal and abnormal placental development of the mouse.

The extracellular matrix protein fibulin-1 (FBLN1) is an important component of blood vessel walls, as shown by the lethality of mice with homozygous targeted deletion of the Fbln1 gene. Here, we show that a murine placental overgrowth phenotype is associated with elevated Fbln1 transcript levels, suggesting that the gene and its product have a functional role in placentation. Fbln1 exhibits a specific expression pattern in the mouse placenta. Transcripts could not be detected prior to day 12. In subsequent stages, Fbln1 was expressed strongly in the spongiotrophoblast. Other sites of expression were endothelia of large fetal blood vessels, a tissue type reported to not express this gene. In addition, a subset of giant cells expressed the gene. This giant cell specific expression was strongly increased in hyperplastic placentas. Analysis of the placentation in fibulin null mice did not show any abnormality. Attempts to rescue the placental phenotypes of a congenic model of interspecies hybrid placental dysplasia (IHPD) by normalizing expression of Fbln1 proved that Fbln1 alone is not the key cause of phenotypes in these models of placental hyperplasia.

Exacerbations of COPD: quantifying the patient's perspective using discrete choice modelling.

Patient-centred care is the current vogue in chronic obstructive pulmonary disease (COPD), but it is only recently that robust techniques have become available to determine patients' values and preferences. In this international cross-sectional study, patients' concerns and expectations regarding COPD exacerbations were explored using discrete choice modelling. A fractional factorial design was used to develop scenarios comprising a combination of levels for nine different attributes. In face-to-face interviews, patients were presented with paired scenarios and asked to choose the least preferable. Multinomial logit (with hierarchical Bayes) methods were used to estimate utilities. A total of 125 patients (82 males; mean age 66 yrs; 4.6 mean exacerbations.yr-1) were recruited. The attributes of exacerbations considered most important were impact on everyday life (20%), need for medical care (16%), number of future attacks (12%) and breathlessness (11%). The next most important attributes were speed of recovery, productive cough and social impact (all 9%), followed by sleep disturbance and impact on mood (both 7%). Importantly, analysis of utility shifts showed that patients most feared being hospitalised, housebound or bedridden. These issues were more important than symptom improvement. Strategies for the clinical management of chronic obstructive pulmonary disease should clearly address patients' concerns and focus on preventing and treating exacerbations to avoid these feared outcomes.

Species-specific isotope dilution with permeation tubes for determination of gaseous mercury species.

Instrumentation and methodology for determination of the gaseous mercury species Hg0, (CH3)2Hg, and CH3Hg+ has been developed. The method is based on continuous addition of gaseous isotopically enriched Hg species (tracers) at the point of sample acquisition, in combination with reduced pressure sampling on Carbotrap adsorbent tubes. Permeation tubes are used for generation of the tracers. Collected species are thermally desorbed and purged through an aqueous sodium tetraethylborate solution for derivatization of CH3Hg+. The purged gas is dried with a Nafion membrane, and the Hg species are subsequently collected on a smaller Tenax TA adsorbent tube. Species are then thermally desorbed from the Tenax TA and introduced into a gas chromatograph connected to an inductively coupled plasma mass spectrometer for separation and detection. To be able to add tracers during field sampling, we developed a portable device, supplying the permeation tubes with a thermostated and mass flow-controlled air stream of 5.0 +/- 0.1 degrees C and 50.0 mL min(-1), respectively. Typical permeation rates obtained during a period of more than 6 weeks were 12.93 +/- 0.56, 0.42 +/- 0.01, and 0.49 +/- 0.03 (mean +/- standard deviation) pg of Hg min(-1) for a set of 199Hg0, (CH3)2 198Hg, and CH3 200Hg+ tubes, respectively. Methodological detection limits (3sigma) were determined to 700 pg of Hg m(-3) for Hg0 and 50 pg of Hg m(-3) for (CH3)2Hg and CH3Hg+. The collection efficiencies for sampled volumes of 400 L of synthetic air on the Carbotrap tubes used in this study were 13 +/- 2, 102 +/- 2, and 99 +/- 4% for Hg0, (CH3)2Hg, and CH3Hg+, respectively. Desorption efficiencies for the above species and tubes were 98 +/- 2, 98 +/- 1, and 90 +/- 4%, respectively. Fractions (20-40%) of the added (CH3)2 198Hg and CH3 200Hg+ tracers were found to be transformed during the analytical processing of collected air samples. Determined concentrations in the research laboratory air, corrected for species transformations, were 3-53, 8-11, and 1-2 ng of Hg m(-3) for Hg0, (CH3)2Hg, and CH3Hg+, respectively. Concentrations in the ambient air were determined to be 2.1-2.6 ng m(-3) for Hg0 and below the detection limit for (CH3)2Hg and CH3Hg+.

Prevalence of stress incontinence in nulliparous elite trampolinists.

During trampoline jumping the pelvic floor is exposed to high forces. There has been a general belief that physically fit women have a strong pelvic floor as a result of their regular training, thus preventing urinary incontinence. The aim of this study was to survey the prevalence of stress urinary incontinence in female elite trampolinists. The prevalence of urinary incontinence was assessed by a questionnaire, sent to all 35 elite trampolinists (mean age 15, range 12-22 years) in Sweden. Eighty percent of the trampolinists reported involuntary urinary leakage, but only during trampoline training. The leakage started after 2.5 (range 1-4) years of training. Age (P < 0.001), duration of training (P = 0.04), and training frequency (P = 0.01) were significantly associated with leakage. All women above 15 years of age (n = 23) reported urinary leakage (P < 0.001). Eighteen incontinent women continued the study and their leakage was verified by a pad test. The leakage averaged 28 g during a jump session. The muscle strength was measured with perineometry in 10 women and showed good strength in the pelvic floor muscles.

Helicobacter pylori-binding gangliosides of human gastric adenocarcinoma.

Acidic and neutral glycosphingolipids were isolated from a human gastric adenocarcinoma, and binding of Helicobacter pylori to the isolated glycosphingolipids was assessed using the chromatogram binding assay. The isolated glycosphingolipids were characterized using fast atom bombardment mass spectrometry and by binding of antibodies and lectins. The predominating neutral glycosphingolipids were found to migrate in the di- to tetraglycosylceramide regions as revealed by anisaldehyde staining and detection with lectins. No binding of H. pylori to these compounds was obtained. The most abundant acidic glycosphingolipids, migrating as the GM3 ganglioside and sialyl-neolactotetraosylceramide, were not recognized by the bacteria. Instead, H. pylori selectively interacted with slow-migrating, low abundant gangliosides not detected by anisaldehyde staining. Binding-active gangliosides were isolated and characterized by mass spectrometry, proton nuclear magnetic resonance, and lectin binding as sialyl-neolactohexaosylceramide (NeuAcalpha3Galbeta4GlcNAcbeta3Galbeta4GlcNAcbeta3Galbeta4Glcbeta1Cer) and sialyl-neolactooctaosylceramide (NeuAcalpha3Galbeta4GlcNAcbeta3Galbeta4GlcNAcbeta3Galbeta4GlcNAcbeta3Galbeta4Glcbeta1Cer).

Diagnosis of a patient with oncogenic osteomalacia using a phosphate uptake bioassay of serum and magnetic resonance imaging.

A previously healthy man with no family history of fractures presented with muscle pain, back pain and height loss. Investigations revealed hypophosphataemia, phosphaturia, undetectable serum 1,25-dihydroxyvitamin D and severe osteomalacia on bone biopsy, suggestive of a diagnosis of oncogenic osteomalacia. Thorough physical examination did not locate a tumour. Support for the diagnosis was obtained by detection of phosphate uptake inhibitory activity in a blinded sample of the patient's serum using a renal cell bioassay. On the basis of detection of this bioactivity, a total body magnetic resonance (MR) examination was performed. A small tumour was located in the right leg. Removal of the tumour resulted in the rapid reversal of symptoms and the abnormal biochemistry typical of oncogenic osteomalacia. Inhibitory activity was also demonstrated using the bioassay in serum from two other patients with confirmed or presumptive oncogenic osteomalacia, but not in serum from two patients with hypophosphataemia of other origin. This is the first case to be reported in which the diagnosis of oncogenic osteomalacia was assisted by demonstration of inhibitory activity of the patient's serum in a renal cell phosphate bioassay that provided an impetus for total body MR imaging.