Random bladder biopsies and the risk of recurrent superficial bladder cancer: a prospective study in 1026 patients

Summary We prospectively studied random bladder biopsies of normal-looking mucosa in 1026 unselected patients with primary superficial papillary transitional-cell carcinoma of the bladder. In a univariate analysis, the risk for recurrent disease was only slightly higher in patients with an abnormal biopsy result, the 2-year actuarial risk for recurrent disease being 47.5% in these subjects vs 44.5% in patients with a normal biopsy result (P=0.09, log-rank test). However, after correction for other prognostic factors using the Cox proportional-hazards model, an abnormal biopsy result had no prognostic value additional to that of conventional histo-pathology of the tumour with regard to the risk for recurrent disease. Additional therapy after transurethral resection of the tumour (P<0.001), tumour stage (P<0.001), the number of bladder areas affected by tumour (P<0.01) and tumour multiplicity (P=0.09) had significant prognostic value. We conclude that random biopsies of normal-looking mucosa during transurethral resection of superficial papillary bladder tumours are of little additional prognostic value with respect to the risk for recurrent disease.This study was financially supported by three regional Dutch comprehensive cancer centres: IKO, IKZ, and IKA/stedendriehoek Twente     

Results of a questionnaire among Dutch urologists and general practitioners concerning diagnostics and treatment of patients with prostatitis syndromes.

By means of a questionnaire, all Dutch urologists (n = 250, 136 responded) and regional general practitioners (GPs; n = 400, 176 responded) were contacted concerning current diagnostics and treatment modalities applied in patients with prostatitis syndromes. The patients seen by urologists seem to be younger (30-40 years) and they mostly complain of pain in the perineum, penis or scrotum, while GPs see older patients (> 40 years) mainly presenting with micturition complaints. Urologists think nonbacterial causes (40%) most important, while GPs mention bacterial infections (63%) as the most important cause. The first choice of therapy is antibiotics, mostly co-trimoxazole Sulfatrim for 3 weeks, but patients seen by urologists are more resistant to this therapy. If not successful, urologists frequently prescribe a second course with antibiotics. However, many urologists think psychosomatic causes are an important factor in the etiology of prostatitis.     

Glycosphingolipids are modulators of disease pathogenesis in amyotrophic lateral sclerosis

Recent genetic evidence suggests that aberrant glycosphingolipid metabolism plays an important role in several neuromuscular diseases including hereditary spastic paraplegia, hereditary sensory neuropathy type 1, and non-5q spinal muscular atrophy. Here, we investigated whether altered glycosphingolipid metabolism is a modulator of disease course in amyotrophic lateral sclerosis (ALS). Levels of ceramide, glucosylceramide, galactocerebroside, lactosylceramide, globotriaosylceramide, and the gangliosides GM3 and GM1 were significantly elevated in spinal cords of ALS patients. Moreover, enzyme activities (glucocerebrosidase-1, glucocerebrosidase-2, hexosaminidase, galactosylceramidase, α-galactosidase, and β-galactosidase) mediating glycosphingolipid hydrolysis were also elevated up to threefold. Increased ceramide, glucosylceramide, GM3, and hexosaminidase activity were also found in SOD1^G93A mice, a familial model of ALS. Inhibition of glucosylceramide synthesis accelerated disease course in SOD1^G93A mice, whereas infusion of exogenous GM3 significantly slowed the onset of paralysis and increased survival. Our results suggest that glycosphingolipids are likely important participants in pathogenesis of ALS and merit further analysis as potential drug targets.Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by selective loss of motor neurons (MNs) within the CNS. Although our understanding of the genetic basis of ALS has advanced greatly in recent years (1), the adverse biological processes that converge on the neuromuscular axis to drive both MN death and neuropathological features in additional cell types remain largely unknown. Glycosphingolipids (GSLs) are a heterogeneous group of membrane lipids formed through the covalent linkage of a glycan moiety to ceramide (Cer; see SI Appendix, Fig. S1 for an overview of GSL metabolism). Glucosylceramide (GlcCer) and galactosylceramide (GalCer) are GSLs with a single sugar residue: glucose and galactose respectively. The successive addition of galactose and sialic acid moieties to GlcCer results in the synthesis of gangliosides (e.g., GM3, GM2, and GM1) (2). GSLs are especially abundant in the CNS and have bioactive roles in metabolism, growth factor signaling, oligodendrocyte differentiation, neuroinflammation, angiogenesis, and pathways of cell death (2–9)—all of which are thought to participate in ALS disease pathogenesis.Several lines of evidence suggest that aberrant changes in GSL homeostasis may contribute to disease pathogenesis in ALS. Evidence includes the detection of unique gangliosides (10), high titer serum auto-antibodies to GM2 and GM1 (11, 12), and elevated GM2 levels within the motor cortex of ALS patients (13). Furthermore, a number of neuromuscular diseases are associated with mutations in genes that regulate the metabolism of Cer and GSLs. For example, hereditary sensory neuropathy type I (HSNT1), a disease that features dorsal root ganglion cell and MN degeneration, is attributed to mutations in serine palmitoyltransferase long chain base subunit-1 (SPTLC1), the rate-limiting enzyme in Cer synthesis. Notably, certain mutations in SPTLC1 associated with HSNT1 result in elevated levels of Cer and GlcCer (14). In addition, mutations in acid ceramidase (ASHA1), an enzyme that mediates the hydrolysis of Cer, are linked to forms of spinal muscular atrophy that are not caused by the more frequent mutations in the survival motor neuron 1 gene (non-5q SMA) (15). Moreover, hereditary spastic paraplegia (HSP), a disease with corticospinal tract and in some cases, spinal cord MN degeneration, is attributed to mutations in GM2 synthase (16) and the nonlysosomal glucosylceramidase, GBA2 (17). Last, patients with adult-onset Tay-Sachs disease (GM2 gangliosidosis), a disease triggered by a deficiency in hexosaminidase (HEX), a lysosomal enzyme that hydrolyzes GM2 to GM3, have been reported in some instances to display a disease phenotype that closely mimics ALS (18–20). Interestingly, HEX mRNA is up-regulated within MNs of transgenic mice expressing the mutant human SOD1 protein (i.e., SOD1^G93A mice), a familial model of ALS (21, 22). Collectively, these findings suggest that titration of GSLs is important to maintaining neuromuscular system homeostasis. Similar to other metabolic aspects thought to influence ALS disease progression (23), GSL bioactivity in the neuromuscular system is likely exerted through an inverted U-shaped dose–response curve (SI Appendix, Fig. S1). Healthy (or eustatic) GSL levels are achieved in the central, optimal range of the curve, whereas GSL levels that promote features of disease (or cacostasis) are associated with either end of the curve (i.e., instances of GSL insufficiency or excess). Here, we investigated whether disrupted GSL homeostasis contributes to neurodegeneration in ALS. We show that altered GSL metabolism is a manifestation of sporadic and familial ALS and that modulation of GSL levels in SOD1^G93A mice significantly affects disease course.     

Pharmacokinetics and pharmacodynamic effects of digoxin in dilated cardiomyopathies. Influence of nicardipine

Numerous studies have been devoted to the effect of slow calcium channel inhibitors on plasma digoxin concentrations. The principal drugs tested, verapamil and nifedipine, were found to increase significantly plasma digoxin levels mainly by reducing digoxin total clearance. Very few studies on the nicardipine-digoxin interaction have been reported. The dual purpose of the present study was to evaluate the influence of orally administered nicardipine on plasma digoxin concentrations over 24 hours and to measure possible variations in the pharmacodynamic effects of digoxin in 9 patients with chronic congestive heart failure. The pharmacodynamic assessment involved simple and cross-sectional echocardiography, systolic time interval measurements and cardiac catheterization. In these patients under chronic digoxin treatment, oral nicardipine had little effect on plasma digoxin concentrations which increased but not significantly; no sign of digitalis toxicity was observed. Nicardipine improved left ventricular function and myocardial contractility by reducing after-load, the nicardipine-induced peripheral vasodilatation tending to counteract the digoxin-induced vasoconstriction.     

Single alteration of p53 or E-cadherin genes can alter the surgical resection benefit in an experimental model of colon cancer

PURPOSE:p53 and E-cadherin mutations are associated with a high risk of metastatic potential and local recurrence after colorectal surgery. LoVo, a human colon cancer cell line expressing a wild-typep53 and a normal E-cadherin, was studied. Clone LoVo-XC17 was obtained from LoVo cells transfected with a vector bearing ap53 273his mutation. Clone LoVo-92R4 was obtained from LoVo by culture cells with an E-cadherin down-regulation. LoVo, LoVo-XC17, and LoVo-92R4 were studied forin vivo behavior in a surgical intracolonic graft model. METHODS: Ten nude mice were used per cell line. A colonic tumor was obtained by tumor implantation into the cecal wall. The cecal tumor was resected at Day 15; at this time the volumes of the different tumors were similar. RESULTS: Surgical resection of the LoVo tumor led to 100 percent disease-free animals at one month. Surgical resection of mice grafted with the LoVo-XC17 line did not cure any mice (0/10;P = 0.001). Mice had local recurrences (10/10), mesenteric lymph node metastases (9/10), liver metastases (2/10), and peritoneal carcinomatosis (8/10). Surgical resection of LoVo-92R4 tumors led to cures in 30 percent (3/10), whereas 70 percent had isolated mesenteric lymph node metastases (7/10;P = 0.003). CONCLUSION: In this model surgical tumor resection was consistently effective for colonic tumors with functionalp53 and E-cadherin, it was consistently ineffective with tumors displaying a mutatedp53, and it was partially effective with E-cadherin-deficient tumors. This study shows that the alteration of a single gene can be associated with a profound alteration of surgical resection benefit.Supported in part by the Ligue Nationale contre le Cancer and by the Société Nationale Française de Gastroentérologie, with grants for Marc Pocard. Philip Debruyne is a research assistant with the Bijzonder Onderzoeks Fonds Universiteit Gent, supported in part by the Belgian Cancer association and the Fund for Scientific Research—Flanders.Read at The American Society of Colon and Rectal Surgeons' 100th Anniversary and Tripartite Meeting, Washington, D.C., May 1 to 6, 1999.     

Kisspeptin-54 triggers egg maturation in women undergoing in vitro fertilization

BACKGROUND. Patients with mutations that inactivate kisspeptin signaling are infertile. Kisspeptin-54, the major circulating isoform of kisspeptin in humans, potently stimulates reproductive hormone secretion in humans. Animal studies suggest that kisspeptin is involved in generation of the luteinizing hormone surge, which is required for ovulation; therefore, we hypothesized that kisspeptin-54 could be used to trigger egg maturation in women undergoing in vitro fertilization therapy.METHODS. Following superovulation with recombinant follicle-stimulating hormone and administration of gonadotropin-releasing hormone antagonist to prevent premature ovulation, 53 women were administered a single subcutaneous injection of kisspeptin-54 (1.6 nmol/kg, n = 2; 3.2 nmol/kg, n = 3; 6.4 nmol/kg, n = 24; 12.8 nmol/kg, n = 24) to induce a luteinizing hormone surge and egg maturation. Eggs were retrieved transvaginally 36 hours after kisspeptin injection, assessed for maturation (primary outcome), and fertilized by intracytoplasmic sperm injection with subsequent transfer of one or two embryos.RESULTS. Egg maturation was observed in response to each tested dose of kisspeptin-54, and the mean number of mature eggs per patient generally increased in a dose-dependent manner. Fertilization of eggs and transfer of embryos to the uterus occurred in 92% (49/53) of kisspeptin-54–treated patients. Biochemical and clinical pregnancy rates were 40% (21/53) and 23% (12/53), respectively.CONCLUSION. This study demonstrates that a single injection of kisspeptin-54 can induce egg maturation in women with subfertility undergoing in vitro fertilization therapy. Subsequent fertilization of eggs matured following kisspeptin-54 administration and transfer of resulting embryos can lead to successful human pregnancy.TRIAL REGISTRATION. ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01667406","term_id":"NCT01667406"}}NCT01667406.FUNDING. Medical Research Council, Wellcome Trust, and National Institute for Health Research.     

Synthesis of Geopolymer from a Novel Aluminosilicate-Based Natural Soil Precursor Using Electric Oven Curing for Improved Mechanical Strength

Natural soil (NS)-based geopolymers (GPs) have shown promise as environmentally friendly construction materials. The production of ordinary Portland cement is known to release significant amounts of greenhouse gas (CO₂) into the atmosphere. The main objective of this work is to synthesize a geopolymer (GP) from an uncommon aluminosilicate-based NS and a sodium silicate (SS) activating solution that would not only minimize the emission of harmful gases, but also offer improved mechanical strength. Samples of different compositions were produced by varying the wt.% of NS from 50% to 80% and adding a balancing amount of SS solution. The drying and curing of the samples were carried out in an electric oven at specific temperatures. The degree of geopolymerization in the samples was measured by Fourier transform infrared spectroscopy, and microstructural analysis was performed using a scanning electron microscope. Mechanical tests were conducted to evaluate the range of compressive strength values of the prepared GP samples. A minimum compressive strength of 10.93 MPa at a maximum porosity of 37.56% was observed in a sample with an NS to SS ratio of 1:1; while a ratio of 3:1 led to the maximum compressive strength of 26.39 MPa and the minimum porosity of 24.60%. The maximum strength (26.39 MPa) was found to be more than the reported strength values for similar systems. Moreover, an improvement in strength by a factor of three has been observed relative to previously developed NS-based GPs. It may be inferred from the findings that for the given NS, with almost 90% aluminosilicate content, the extent of geopolymerization increases significantly with its increasing proportions, yielding better mechanical strength.