Intermediate-term survival of robot-assisted versus open radical cystectomy for muscle-invasive and high-risk non-muscle invasive bladder cancer in The Netherlands.

BACKGROUND: Radical cystectomy with pelvic lymph node dissection is the recommended treatment in non-metastatic muscle-invasive bladder cancer (MIBC). In randomised trials, robot-assisted radical cystectomy (RARC) showed non-inferior short-term oncological outcomes compared with open radical cystectomy (ORC). Data on intermediate and long-term oncological outcomes of RARC are limited. OBJECTIVE: To assess the intermediate-term overall survival (OS) and recurrence-free survival (RFS) of patients with MIBC and high-risk non-MIBC (NMIBC) who underwent ORC versus RARC in clinical practice. METHODS AND MATERIALS: A nationwide retrospective study in 19 Dutch hospitals including patients with MIBC and high-risk NMIBC treated by ORC (n = 1086) or RARC (n = 386) between January 1, 2012 and December 31, 2015. Primary and secondary outcome measures were median OS and RFS, respectively. Survival outcomes were estimated using Kaplan-Meier curves. A multivariable Cox regression model was developed to adjust for possible confounders and to assess prognostic factors for survival including clinical variables, clinical and pathological disease stage, neoadjuvant therapy and surgical margin status. RESULTS: The median follow-up was 5.1 years (95% confidence interval ([95%CI] 5.0-5.2). The median OS after ORC was 5.0 years (95%CI 4.3-5.6) versus 5.8 years after RARC (95%CI 5.1-6.5). The median RFS was 3.8 years (95%CI 3.1-4.5) after ORC versus 5.0 years after RARC (95%CI 3.9-6.0). After multivariable adjustment, the hazard ratio for OS was 1.00 (95%CI 0.84-1.20) and for RFS 1.08 (95%CI 0.91-1.27) of ORC versus RARC. Patients who underwent ORC were older, had higher preoperative serum creatinine levels and more advanced clinical and pathological disease stage. CONCLUSION: ORC and RARC resulted in similar intermediate-term OS and RFS in a cohort of almost 1500 MIBC and high-risk NMIBC.

Protocolised inpatient care of diabetes mellitus.

BACKGROUND: The prevalence of hyperglycaemia in patients with diabetes mellitus at admission is high. Prevention and treatment is important to prevent further clinical complications. We have conducted a study evaluating implementation of a new protocol to standardise inpatient care of patients with diabetes mellitus. METHODS: A retrospective study including all glucose measurements of adult patients with diabetes mellitus type 1 o r 2 , admitted to a surgery department, was performed before and after implementation of the new protocol. This protocol included direct consultation of an internist and diabetes specialist nurse at admission, who initiated a daily treatment program and adjustment scheme based on glucose measurements four times a day by the HemoCue201DM glucose point of care device. We compared the prevalence of hyperglycaemia and hypoglycaemia before and after implementation with logistic regression analyses adjusted for age and gender. RESULTS: Overall, 360 patients with diabetes mellitus type 1 or 2 with 5322 glucose measurements were included. The risk of developing hyperglycaemia was significantly reduced after implementation of the protocol (22 patients with 65 hyperglycaemias) compared with before the intervention (70 patients with 417 hyperglycaemias) (RR adjusted 0.24 (95% confidence interval 0.19; 0.32)). Overall, 45 patients experienced 95 episodes of hypoglycaemia, which did not differ significantly between the two groups. CONCLUSION: After implementation of a new protocol to standardise inpatient care of diabetes mellitus we established a decrease in the risk to develop hyperglycaemia of 76% without an increased risk of developing hypoglycaemia. Implementation of this protocol required frequent glucose measurements which are facilitated by point of care glucose measurements.

Effect of leg length on ROM, VJ and leg dexterity in dance.

We investigated the associations between leg length and specific ballet movements in different skill groups. Volunteers were from an undergraduate dance programme (n=18), a pre-professional school (n=43) and from an elite classical ballet company (n=45). Individual data were collected for anthropometry, vertical jump, leg dexterity, and leg active and passive ROM. ANCOVA identified both main effects as significant with regard to vertical jump (gender P<0.001 and skill P=0.017); leg length was also identified as a significant covariate (P=0.023). Analysis of leg dexterity identified no significant effects with gender, skill or leg length. Active and passive range of motion noted gender (P=0.001) and skill (P<0.001) differences. Leg length was found to be negatively associated with both active and passive ROM (P=0.002). In conclusion, the present data highlight the diverse and conflicting effects of leg length on fundamental ballet skills. The longer legs that benefit vertical jump have a negative influence on range of motion and leg dexterity except for highly skilled dancers, who through skill, seem to have overcome the effects of some of these dichotomies.

Tuberculosis and silica exposure in South African gold miners.

AIMS: To examine the effect of silica exposure, in the absence of silicosis, on the prevalence of pulmonary tuberculosis (PTB), which is epidemic among South African gold miners. METHODS: Cross-sectional study of 520 gold miners over 37 years of age. Length of service, and cumulative and average dust and quartz exposure indices were derived for each miner. Chest radiographs were read for PTB by two NIOSH "B" readers. PTB was defined as a self-reported history of PTB or PTB on chest radiograph. Logistic regression was used to adjust for age, smoking, and silicosis. PTB effects of different exposure metrics for silica, scaled on their interquartile range (IQR), were compared. RESULTS: Means (ranges) were: age 46.7 (37.1-59.9) years; length of service 21.8 (6.3-34.5) years; average intensity of respirable quartz 0.053 (0-0.095) mg/m3. PTB prevalence was 19.4% (95% CI 16.0 to 22.8) on history alone, and 35.2% (95% CI 31.1 to 39.3) on history or on chest radiograph. Length of service was poorly predictive of PTB, while all exposure indices which included dust or quartz yielded prevalence odds ratios (PORs) of approximately 1.4 (95% CI approximately 1.1 to 1.8) for changes of one interquartile range in exposure. Controlling for silicosis--by adjustment or restriction--did not modify these results. Drillers and winch operators had the highest PTB prevalences and the highest dust and silica exposures. CONCLUSION: Older in-service gold miners in South Africa have a high prevalence of PTB, which is significantly associated with dust and silica exposure, even in the absence of silicosis. Limitations include a survivor workforce and the use of cumulative exposures based on current exposures. Dust control is an important component in control of the PTB epidemic in South African gold mines.

Silicosis prevalence and exposure-response relations in South African goldminers.

AIMS: To measure the prevalence of silicosis among black migrant contract workers on a South African goldmine and to investigate exposure-response relations with silica dust. METHODS: In a cross sectional study, 520 black goldminers (aged >37 years) were interviewed and had chest radiographs taken. Silicosis was defined as International Labour Organisation Classification radiological profusion of 1/1 or greater. RESULTS: Mean length of service was 21.8 years (range 6.3-34.5). The mean intensity of respirable dust exposure was 0.37 mg/m3 (range 0-0.70) and of quartz 0.053 mg/m3 (range 0-0.095). The prevalence of silicosis was 18.3-19.9% depending on reader. Significant trends were found between the prevalence of silicosis and length of service, mean intensity of exposure, and cumulative exposure. CONCLUSION: Results confirm a large burden of silicosis among older black workers in the South African goldmining industry, which is likely to worsen as such miners spend longer periods in continuous employment in dusty jobs. An urgent need for improved dust control in the industry is indicated. If the assumption of stability of average dust concentrations on this mine over the working life of this group of workers is correct, these workers developed silicosis while exposed to a quartz concentration below the recommended occupational exposure limit (OEL) of 0.1 mg/m3. This accords with a mounting body of evidence that an OEL of 0.1 mg/m3 is not protective against silicosis.

CJ-15,801, a novel antibiotic from a fungus, Seimatosporium sp.

A novel antibiotic, CJ-15,801 (I), was isolated from the fermentation broth of a fungus, Seimatosporium sp. CL28611. The structure was determined to be a pantothenic acid analog having an alpha,beta-unsaturated carboxylic acid moiety by spectroscopic analyses. The compound inhibits the growth of multi-drug resistant (MDR) Staphylococcus aureus strains with MIC ranging from 6.25 to 50 microg/ml.

Effects of skyrin, a receptor-selective glucagon antagonist, in rat and human hepatocytes.

Peptidic glucagon antagonists have been shown to lower blood glucose levels in diabetic models (1-3), but attempts to identify small molecular weight glucagon receptor-binding antagonists have met with little success. Skyrin, a fungal bisanthroquinone, exhibits functional glucagon antagonism by uncoupling the glucagon receptor from adenylate cyclase activation in rat liver membranes (1). We have examined the effects of skyrin on cells transfected with the human glucagon receptor and on isolated rat and human hepatocytes. The skyrin used was isolated from Talaromyces wortmanni American Type Culture Collection 10517. In rat hepatocytes, skyrin (30 micromol/l) inhibited glucagon-stimulated cAMP production (53%) and glucose output (IC50 56 micromol/l). There was no detectable effect on epinephrine or glucagon-like peptide 1 (GLP-1) stimulation of these parameters, which demonstrates skyrin's selective activity. Skyrin was also evaluated in primary cultures of human hepatocytes. Unlike cell lines, which are largely unresponsive to glucagon, primary human hepatocytes exhibited glucagon-dependent cAMP production for 14 days in culture (EC50 10 nmol/l). Skyrin (10 micromol/l) markedly reduced glucagon-stimulated cAMP production (55%) and glycogenolysis (27%) in human hepatocytes. The inhibition of glucagon stimulation was a specific property displayed by skyrin and oxyskyrin but not shared by other bisanthroquinones. Skyrin is the first small molecular weight nonpeptidic agent demonstrated to interfere with the coupling of glucagon to adenylate cyclase independent of binding to the glucagon receptor. The data presented in this study indicate that functional uncoupling of the human glucagon receptor from cAMP production results in metabolic effects that could reduce hepatocyte glucose production and hence alleviate diabetic hyperglycemia.

Dose-response relationship between plasma ACTH and serum cortisol in the insulin-hypoglycaemia test in 25 healthy subjects and 109 patients with pituitary disease.

OBJECTIVE: The insulin hypoglycaemia test (IHT) is believed to be the most reliable test for evaluating the entire hypothalamo-pituitary-adrenal (HPA) axis. The lower limit for the normal peak serum cortisol response has been reported to be between 500 and 580 nmol/l. Reference levels for a normal plasma ACTH response have not been reported recently. DESIGN AND PATIENTS: We performed the IHT in 25 healthy subjects and in 109 patients with proven or suspected pituitary disorders with serial measurements of serum or plasma cortisol and of plasma ACTH, in order to establish reference levels and to study the dose-response relationship between ACTH and cortisol in this test. In most patients, other pituitary hormonal axes were evaluated in addition. RESULTS: With the cortisol kit from Diagnostic Products Corporation (DPC), serum cortisol was about 13% lower than plasma (EDTA) levels with an excellent correlation between serum and plasma (r = 0.976; P<0.001). In the normals, the lower limit of the cortisol response (mean cortisol peak level minus 2 SD.) was 570 nmol/l for plasma and 500 nmol/l (calculated) for serum, while the lower limit of the ACTH response was 17.6 pmol/l (80 ng/l). In normals, the cortisol response was independent of the magnitude of the ACTH response. Seventeen out of 30 patients with ACTH responses to levels < 8.8 pmol/l (< 40 ng/l) had subnormal cortisol responses. However, 38 of the patients with pituitary disease had normal cortisol responses in spite of subnormal ACTH responses (group 2), while 47 patients had completely normal IHT results (group 1). Patients in group 2 had more often additional pituitary hormone deficiencies than those of group 1. The dose-response relationship between ACTH and cortisol in the patients resembled a dose-response curve that had been set up previously in normal subjects who received incremental doses of subcutaneous human ACTH (1-39). CONCLUSIONS: The normal increment of plasma ACTH in the IHT is greater than necessary for stimulating serum cortisol to levels > 500 nmol/l. Patients with a subnormal ACTH but normal cortisol response in the IHT have a decreased ACTH secretory reserve. It is unlikely that they are at increased risk of developing an adrenal crisis perioperatively or in other stressful situations unless pituitary function deteriorates. The ACTH-cortisol relationship in the IHT performed in patients with pituitary disease shows no sharp dividing line between normality and disease, and whether a patient needs permanent glucocorticoid substitution is a discretionary decision.

Vaginitis, cervicitis, and cervical length in pregnancy.

OBJECTIVE: We sought to determine the possible association among vaginitis, cervicitis, and cervical length in pregnancy. STUDY DESIGN: Primigravid volunteers, between 20 and 36 weeks' gestation (n = 210), were examined. Vaginitis was diagnosed by pH determination and wet mount smear, cervicitis was diagnosed by cervicography, and cervical length was diagnosed by vaginal ultrasonographic measurement. Patients with both vaginitis and cervicitis (n = 70) were compared with those without any trace of infection (n = 23). The remainder (n = 117) had variable degrees of infection and were excluded. RESULTS: The mean gestational age was 28.3 weeks. No significant association was found among vaginitis, cervicitis, and cervical length. In the infection group (n = 70), however, a significant association between an elevated vaginal pH (>5) and a shortened cervical length (r = 0.29) was noted. CONCLUSION: No significant association exists among vaginitis, cervicitis, and cervical length, but in patients with clinical signs of infection, an elevated pH appears to be associated with a decreased cervical length.

Novel lactone compounds from Mortierella verticillata that induce the human low density lipoprotein receptor gene: fermentation, isolation, structural elucidation and biological activities.

Among methods of controlling hypercholesterolemia and hyperlipidemia is the direct stimulation of hepatic low density lipoprotein (LDL) receptors. Two novel lactone compounds, CJ-12,950 and CJ-13,357, containing and unusual oxime moiety, were isolated from a zygomycete Mortierella verticillata. These lactones are potent inducers of the LDL receptor gene in vitro, that enhanced LDL receptor expression in human hepatocytes 2-fold at 100 nM.

New quinolone compounds from Pseudonocardia sp. with selective and potent anti-Helicobacter pylori activity: taxonomy of producing strain, fermentation, isolation, structural elucidation and biological activities.

Eight novel quinolones with anti-Helicobacter pylori activity were isolated from the actinomycete Pseudonocardia sp. CL38489. The quinolones were very potent against H. pylori with MICs up to 0.1 ng/ml. The quinolones appear to be specific for H. pylori, since they did not show antimicrobial activity when tested against a panel of other microorganisms.

CJ-12,954 and its congeners, new anti-Helicobacter pylori compounds produced by Phanerochaete velutina: fermentation, isolation, structural elucidation and biological activities.

Seven new phthalide compounds with anti-Helicobacter pylori activities were isolated from the basidiomycete Phanerochaete velutina CL6387. The two most potent phthalide compounds, CJ-12,954 and CJ-13,014, have MICs of 5 ng/ml. The structure-activity relationship shows that the presence of a spiroketal part in addition to the phthalide part, greatly enhances the activity. The phthalide compounds appear to be specific for H. pylori, since they did not show antibacterial activities when tested against a panel of other microorganisms.

Influence of forskolin and carbachol on intestinal absorption of horseradish peroxidase in the goldfish (Carassius auratus).

The transepithelial route for mucosa-to-serosa transport of the tracer macromolecule horseradish peroxidase (HRP; MW 40 kDa) and modulation of this transport by forskolin and carbachol have been studied in vi-tro in stripped goldfish intestinal epithelium mounted in Ussing-type chambers. Uptake and transport have been investigated by measuring the HRP flux from the muco-sal to serosal sides by an enzymatic method and by visualising HRP reaction products in the mucosa with electron-microscopical techniques. Both the cholinergic agonist carbachol (which is thought to increase intracellular Ca2+ and activate protein kinase C activity) and forskolin (a direct activator of adenylylcyclase) affect the amount of enzymatically active HRP in the tissue. In control tissue, HRP product is found only within the epithelial cells, the transepithelial flux reaching a constant value of about 1.5 pmoles/cm2 per h. Carbachol increases the amount of HRP product in the cells, but has no significant effect on the HRP flux compared with control values. Forskolin decreases the amount of HRP product in the cells; however, in the presence of forskolin, the lateral intercellular spaces become filled with HRP product. HRP is found in the lamina propria and the transepithelial protein flux increases more than 2.5-fold. In the presence of forskolin plus carbachol, the results are no different from the control. It is concluded that carbachol increases the endocytotic uptake of HRP, whereas forskolin inhibits the uptake but increases the paracellular permeability for HRP in goldfish intestine.

Chloride secretion induced by phorbol dibutyrate and forskolin in the human colonic carcinoma cell line HT-29Cl.19A is regulated by different mechanisms.

The human colonic carcinoma cell line HT-29cl.19A responds to the protein kinase C activator PDB (4-beta-phorbol 12,13-dibutyrate), as it does to forskolin (an activator of adenylyl cyclase), with a secretory response when the cells are grown on filters and studied at 36 degrees C. Previously, we showed that when cells were grown on Petri dishes and studied at about 25 degrees C with the cell-attached patch-clamp technique, forskolin, but not PDB, could activate 8-pS chloride channels (cystic fibrosis transmembrane conductance regulator, CFTR, channels). The present work was carried out to study this discrepancy. Experiments in Ussing chambers, at different temperatures, showed that the responses to PDB and forskolin differ in their temperature sensitivity. This was also found following conventional microelectrode and Ussing chamber studies with nystatin-permeabilized epithelial layers carried out at 25 degrees C and at 36 degrees C. Pre-incubation with the microtubular disruptive agents nocodazole or colcemid did not affect the response to PDB or forskolin, suggesting that chloride secretion induced by these agonists in these cells is independent of the microtubular structure. Pre-incubation with brefeldin A strongly inhibited the response to PDB, but the response to forskolin was hardly affected. The differing effect of temperature and brefeldin A on the responses to forskolin and PDB may be due to the activation of two distinct mechanisms by protein kinases A and C.