Spinning top urethra: not a normal variant

Spinning top urethra (STU) is a term used to describe a widened posterior urethra seen mainly in girls. It is commonly regarded as a normal variant. The authors studied 30 girls with STU using videourodynamics. Twenty-eight showed bladder instability; 21, a congenital wide bladder neck anomaly; and 20, both instability and a wide bladder neck. One patient had a sensitive bladder. All patients had a urodynamic abnormality. The authors believe that the STU is nearly always an indication of bladder instability or wide bladder neck anomaly. The most common mechanism for the dilatation of the posterior urethra is that unstable contractions are resisted by a voluntary increase in distal sphincter tension so as to prevent leakage of urine. The resulting pressure rise produces distention of the posterior urethra, which will be maximal in subjects with a weak bladder neck mechanism as in the congenital wide bladder neck anomaly. The authors believe that STU is seldom if ever a normal variant.     

Interfollicular Fibrosis in the Thyroid of the Harbour Porpoise: An Endocrine Disruption?

Previous studies have described high levels of polychlorobiphenyls (PCB), polybrominated diphenylether (PBDE), toxaphene, p,p′-dichlorodiphenyltrichloroethane (DDT), and p,p′-dichlorodiphenyldichloroethylene (DDE) in the blubber of the harbour porpoise from the North Sea raising the question of a potential endocrine disruption in this species. In the present study, the thyroids of 57 harbour porpoises from the German and Danish (North and Baltic Seas), Norwegian, and Icelandic coasts have been collected for histological and immunohistological investigations. The number of follicles and the relative distribution of follicles, connective, and solid tissues (%) were quantified in the thyroid of each individual. Then, the potential relationship between the thyroid morphometry data and previously described organic compounds (namely, PCB, PBDE, toxaphene, DDT, and DDE) was investigated using factor analysis and multiple regressions. Thyroid morphology differed strongly between sampling sites. Porpoises from the German (North and Baltic Seas) and Norwegian coasts displayed a high percentage of connective tissues between 30 and 38% revealing severe interfollicular fibrosis and a high number of large follicles (diameter >200 μm). A correlation-based principal component analysis (PCA) revealed two principal components explaining 85.9% of the total variance. The variables PCB, PBDE, DDT, and DDE compounds loaded highest on PC1 whereas toxaphene compound loaded most on PC2. Our results pointed out a relationship between PC1 (PCBs, PBDE, DDE, and DDT compounds) and interfollicular fibrosis in the harbour porpoise thyroids. Such an association is not alone sufficient for a cause–effect relationship but supports the hypothesis of a contaminant-induced thyroid fibrosis in harbour porpoises raising the question of the long-term viability in highly polluted areas.     

Olestra is associated with slight reductions in serum carotenoids but does not markedly influence serum fat-soluble vitamin concentrations

BACKGROUND: The 1996 Food and Drug Administration approval of the fat substitute olestra (sucrose polyester) called for active postmarketing surveillance because preapproval studies showed that olestra may lower circulating concentrations of fat-soluble nutrients such as vitamins and carotenoids. OBJECTIVE: The objective of the Olestra Post-Marketing Surveillance Study was to examine whether customary consumption of olestra-containing savory snacks was associated with changes in serum fat-soluble vitamin and carotenoid concentrations among free-living persons in geographically and ethnically distinct US cities. DESIGN: Adults (n = 2535) and their children aged 12-17 y (n = 272) in Baltimore, Minneapolis, and San Diego attended clinic visits during which data were collected on diet, savory snack consumption, lifestyle, and anthropometric indexes. Blood samples were drawn to assay carotenoids and vitamins A, D, E, and K. Data and blood samples were collected both before and after the nationwide introduction of olestra. General estimating equations were used in multivariate-adjusted models that examined olestra's association with the specified serum nutrients. RESULTS: Compared with no intake, the top 2 tertiles of olestra use in adults were associated with circulating carotenoid concentrations that were modestly but significantly lower (4.3% to 22.4%). There were no significant associations of olestra with any serum nutrients among adolescents. CONCLUSIONS: This active postmarketing surveillance study of a food additive suggests that small decreases in serum fat-soluble nutrients are attributable to olestra use. Although health outcomes were not measured here, it is unlikely that these small changes in nutrient measures would adversely affect health.     

Thrombin-induced secretion of serotonin from platelets can occur in seconds

The platelet release reaction was studied by a new quenched-flow approach. Platelets labeled with 14C-serotonin were reacted for short times (up to 5 sec) with thrombin and then quenched with glutaraldehyde or paraformaldehyde. Serotonin secretion began within 1 sec and was nearly complete by 4 sec. Aggregation recorded by a resistive-particle counter was similarly fast. Therefore, the quenched-flow system reveals that serotonin secretion can occur more rapidly than estimated in earlier studies.     

Identification of sites responsible for the potentiating effect of niflumic acid on ClC-Ka kidney chloride channels

Background and purpose:

ClC-K kidney Cl⁻ channels are important for renal and inner ear transepithelial Cl⁻ transport, and are potentially interesting pharmacological targets. They are modulated by niflumic acid (NFA), a non-steroidal anti-inflammatory drug, in a biphasic way: NFA activates ClC-Ka at low concentrations, but blocks the channel above ∼1 mM. We attempted to identify the amino acids involved in the activation of ClC-Ka by NFA.

Experimental approach:

We used site-directed mutagenesis and two-electrode voltage clamp analysis of wild-type and mutant channels expressed in Xenopus oocytes. Guided by the crystal structure of a bacterial CLC homolog, we screened 97 ClC-Ka mutations for alterations of NFA effects.

Key results:

Mutations of five residues significantly reduced the potentiating effect of NFA. Two of these (G167A and F213A) drastically altered general gating properties and are unlikely to be involved in NFA binding. The three remaining mutants (L155A, G345S and A349E) severely impaired or abolished NFA potentiation.

Conclusions and implications:

The three key residues identified (L155, G345, A349) are localized in two different protein regions that, based on the crystal structure of bacterial CLC homologs, are expected to be exposed to the extracellular side of the channel, relatively close to each other, and are thus good candidates for being part of the potentiating NFA binding site. Alternatively, the protein region identified mediates conformational changes following NFA binding. Our results are an important step towards the development of ClC-Ka activators for treating Bartter syndrome types III and IV with residual channel activity.     

Specialty supplements and prostate cancer risk in the VITamins and Lifestyle (VITAL) cohort

Although there is evidence from studies of prostate cancer cell lines and rodent models that several supplements may have antiinflammatory, antioxidant, or other anticancer properties, few epidemiologic studies have examined the association between nonvitamin, nonmineral, "specialty" supplement use and prostate cancer risk. Participants, 50-76 yr, were 35,239 male members of the VITamins and Lifestyle (VITAL) cohort who were residents of western Washington state, and who completed an extensive baseline questionnaire in 2000-2002. Participants responded about their frequency (days/wk) and duration (yr) of specialty supplement uses. 1,602 incident invasive prostate cancers were obtained from the Surveillance, Epidemiology, and End Results registry. Multivariate-adjusted hazards ratios (HR) and 95% confidence intervals (95% CI) were estimated by Cox proportional hazards models. Any use of grapeseed supplements was associated with a 41% (HR 0.59, 95% CI: 0.40-0.86) reduced risk of total prostate cancer. There were no associations for use of chondroitin, coenzyme Q10, fish oil, garlic, ginkgo biloba, ginseng, glucosamine, or saw palmetto. Grapeseed may be a potential chemopreventive agent; however, as current evidence is limited, it should not yet be promoted for prevention of prostate cancer.     

Hyaluronan-dependent motility of B cells and leukemic plasma cells in blood, but not of bone marrow plasma cells, in multiple myeloma: alternate use of receptor for hyaluronan-mediated motility (RHAMM) and CD44

We investigated the ability of blood B cells, bone marrow (BM) plasma cells, and terminal leukemic plasma cells (T-PCL) from patients with multiple myeloma (MM) to migrate on extracellular matrix proteins. Hyaluronan (HA), but not collagen type I, collagen type IV, or laminin, promoted migration of MM blood B cells, as determined by time-lapse video microscopy. Between 13% and 20% of MM blood B cells migrated on HA with an average velocity of 19 micron/min, and greater than 75% of MM blood B cells exhibited vigorous cell movement and plasma membrane deformation, as did circulating T-PCL and extraskeletal plasma cells from patients with MM. In contrast, plasma cells obtained from BM of patients with MM lacked motility on all substrates tested and did not exhibit cell membrane protrusions or cellular deformation. MM blood B cells and MM plasma cells from all sources examined expressed the HA- binding receptors receptor for HA-mediated motility (RHAMM) and CD44. On circulating MM B cells, both RHAMM and CD44 participated in HA- binding, indicating their expression ex vivo in an activated conformation. In contrast, for the majority of BM plasma cells in the majority of patients with MM, expression of RHAMM or CD44 was not accompanied by HA binding. A minority of patients did have HA-binding BM plasma cells, involving both RHAMM and CD44, as evidenced by partial blocking with monoclonal antibodies (MoAbs) to RHAMM or to CD44. Despite HA binding by both RHAMM and CD44, migration of MM blood B cells on HA was inhibited by anti-RHAMM but not by anti-CD44 MoAbs, indicating that RHAMM but not CD44 mediates motility on HA. Thus, circulating B and plasma cells in MM exhibit RHAMM- and HA-dependent motile behavior indicative of migratory potential, while BM plasma cells are sessile. We speculate that a subset(s) of circulating B or plasma cells mediates malignant spread in myeloma.     

Chemoattractant-induced changes in surface expression and redistribution of a functional ligand for P-selectin on neutrophils

Adhesion between platelets and neutrophils is mediated through the interaction of P-selectin on activated platelets with a carbohydrate- containing structure on neutrophils, and occurs under both static and shear conditions. Recent studies using flow chambers have shown that neutrophils become activated after binding to surface-adherent platelets expressing P-selectin. The objective of the present study was to investigate the effect of such activation on the interactions of platelet P-selectin with its ligand on neutrophils. Flow cytometric analyses using P-selectin chimeras revealed that activation induced a rapid and marked reduction in chimera binding, with levels of binding decreased by 71% after 15 minutes of stimulation with the chemotactic agent, FMLP. Using a visual assay of platelet-neutrophil rosetting, we showed that the P-selectin ligand was translocated and clustered at the uropod of neutrophils following the shape changes and polarization induced by chemotactic stimulation. Activated neutrophils bound to surface-adherent platelets also displayed the clustering of P-selectin ligand at the uropod, and these neutrophils detached from the platelets when a shear stress (2 dynes/cm2) was applied through the adhesion chamber. These results indicate that chemotactic stimulation of neutrophils induces changes in the surface expression and distribution of a biologically relevant ligand for P-selectin, and that these changes might influence the adhesive interactions occurring between neutrophils and activated platelets.