Hemangiomas of the nasal tip: an approach to a therapeutic challenge.

OBJECTIVE: Hemangiomas of the nasal tip (HNT) are commonly described as "Cyrano" or "Pinocchio nose". They may cause significant aesthetic and functional impairment. It is still controversial how and when HNT should be treated. The risk of severe complications like irreversible contour deformities, growth disturbance, ulcerations, and nasal obstruction may obligate a therapeutic intervention. The aim of this study is to overview and to analyze different therapeutic approaches which were practiced over the last decade in two specialized centers. METHODS: This is a retrospective study which includes the analysis of demographic parameters, extent of the lesion, therapeutic interventions, outcome, and follow-up interventions. The analysis includes a blinded evaluation of photographic series for evaluation of the extension at the time of presentation and of the final outcome. RESULTS: Twenty-three children with HNT were analyzed who presented from 04/01/1998 to 03/31/2009. The age at presentation ranged from 1 to 63 months. On 6 patients (26%) conventional surgery was performed, 6 (26%) were treated with Nd:YAG laser, 6 (26%) were only observed, in 3 cases (13%) cryotherapy and in 2 patients (9%) treatment with Propranolol was performed. The results were evaluated between 9 months and 10.5 years after treatment (mean: 35.5 months). Limited lesions which were only observed showed a good tendency of regression. Significant wound healing disturbance and scar formation was observed after Nd:YAG laser therapy. Secondary rhinoplasty in adulthood was recommended to two patients. CONCLUSION: Limited lesions do not require therapy. The results with Propranolol are encouraging. Laser- and cryo-therapy have to be critically reevaluated. Treatment of choice for lesions that are not suitable for beta blockers and residual disease is conventional surgery.

Distribution of neuromedin U binding sites in the rat CNS revealed by in vitro receptor autoradiography.

Neuromedin U (NMU), a neuropeptide implicated in feeding, inflammation, pain control and anxiety-related behaviours, is widely distributed in peripheral organs and the CNS. These effects are thought to be mediated by its receptors NMU(1) and NMU(2). Since its precise sites of interaction in the CNS were to date unknown, we studied the distribution of in vitro binding sites for (125)I-NMU-23 in the rat CNS by receptor autoradiography. High-density specific binding was found in discrete areas of the brain and spinal cord, namely in the limbic system (hippocampal formation, septohippocampal nucleus, indusium griseum, hypothalamus, amygdaloid nuclei), superior colliculus, dorsal raphé, and substantia gelatinosa of the spinal cord. Our findings provide further supportive evidence for a multifunctional role for the peptide in the brain and spinal cord.

Quality control in interstitial brachytherapy of the breast using pulsed dose rate: treatment planning and dose delivery with an Ir-192 afterloading system.

BACKGROUND AND PURPOSE: In the Radiotherapy Department of Leuven, about 20% of all breast cancer patients treated with breast conserving surgery and external radiotherapy receive an additional boost with pulsed dose rate (PDR) Ir-192 brachytherapy. An investigation was performed to assess the accuracy of the delivered PDR brachytherapy treatment. Secondly, the feasibility of in vivo measurements during PDR dose delivery was investigated. MATERIALS AND METHODS: Two phantoms are manufactured to mimic a breast, one for thermoluminescent dosimetry (TLD) measurements, and one for dosimetry using radiochromic films. The TLD phantom allows measurements at 34 dose points in three planes including the basal dose points. The film phantom is designed in such a way that films can be positioned in a plane parallel and orthogonal to the needles. RESULTS: The dose distributions calculated with the TPS are in good agreement with both TLD and radiochromic film measurements (average deviations of point doses <+/-5%). However, close to the interface tissue-air the dose is overestimated by the TPS since it neglects the finite size of a breast and the associated lack of backscatter (average deviations of point doses -14%). CONCLUSION: Most deviations between measured and calculated doses, are in the order of magnitude of the uncertainty associated with the source strength specification, except for the point doses measured close to the skin. In vivo dosimetry during PDR brachytherapy treatment was found to be a valuable procedure to detect large errors, e.g. errors caused by an incorrect data transfer.

Analysis of intermolecular disulfide bonds and free sulfhydryl groups in hepatitis B surface antigen particles.

The envelope proteins of hepadnaviruses are highly cross-linked by disulfide bonds in complete virions and 20 nm subviral envelope particles. We have previously shown which of the cysteines in the envelope proteins of the human hepatitis B virus (HBV) are essential for assembly and secretion of 20 nm particles and for the structure of the major antigenic determinants (HBsAg). Now we have analyzed the intermolecular disulfide bonds between S proteins. We have constructed mutants lacking cysteines and have analyzed their capacity for oligomerization in COS-7 cells. We demonstrate that C121 and C147 located in the second hydrophilic region carrying the major antigenic determinants of the HBV S protein participate in intermolecular disulfide bonding. A disulfide bond involving C124 blocks the accessibility of arginine/lysine at position 122, as shown by trypsin digestion of cysteine mutants. Alkylation studies using N-ethyl-maleimide indicate that C76, C90, and/or C221 carry the only free sulfhydryl group(s) present in 20 nm particles secreted from cell lines.

Membrane responses evoked by organic buffers in identified leech neurones

Using single-electrode current-clamp and two-electrode voltage-clamp, different identified neurones of the leech (Hirudo medicinalis L.) were shown to hyperpolarize, or to exhibit outward currents (usually >2 nA), during bath application of the organic buffers Mops, Pipes and Mes (10 mmol l-1). Tris and Hepes had little or no effect on the membrane properties of neurones when they were added to a bathing saline buffered by CO2-HCO3- at a constant pH of 7.4. Outward currents evoked by buffers obtained from two suppliers, Roth and Sigma, were not significantly different, except in the case of Pipes. Steady-state currents evoked by Pipes supplied by Roth were eightfold larger than steady-state currents evoked by Pipes from Sigma. A transient current peak always present in responses evoked by Pipes from Roth was never present in responses evoked by Pipes from Sigma. Outward currents evoked by buffers were due to a conductance increase and appeared to be carried by Cl-. In low-Cl- saline, hyperpolarizations evoked by Mops in Retzius cells were reduced. When Cl- was injected into heart motor neurones, the hyperpolarizations evoked by Mops reversed. Tetraethylammonium (TEA+) injected into heart interneurones did not block Mops-evoked hyperpolarizations. Mops-evoked outward currents in Retzius cells were partially blocked by d-tubocurarine and bicuculline methiodide, and the latter also partially blocked Mops-evoked hyperpolarizations in HE cells. Since d-tubocurarine partially blocked acetylcholine-evoked Cl- currents in Retzius cells and bicuculline methiodide partially blocked carbachol-evoked hyperpolarizations in HE cells, Mops appears to act on the cholinergic receptors of these neurones by mediating a Cl- conductance.

Secretion and antigenicity of hepatitis B virus small envelope proteins lacking cysteines in the major antigenic region.

Disulfide bonds are of crucial importance for the structure and antigenic properties of the hepatitis B virus (HBV) envelope. We have evaluated the role of the eight highly conserved cysteines of the major antigenic region for assembly, secretion, and antigenicity of the envelope proteins. Mutants carrying single or multiple substitutions of alanine for cysteine were analyzed using epitope tagging and transient expression in COS-7 cells. The only single cysteines found to be indispensable for efficient secretion were Cys-107 and Cys-138, but double mutation of Cys-137 and Cys-139 also created a block to secretion. Poorly secreted mutants formed aberrant oligomeric structures. The antigenicity of the secreted or intracellularly retained mutants was analyzed using a panel of six monoclonal antibodies recognizing group- and subtype-specific determinants. We demonstrate that Cys-107 is critical for the structure of the group determinant a, whereas Cys-147, previously implicated in intramolecular disulfide bonding, is dispensable. Mutant proteins lacking Cys-121 and -124, -137, -147, or -149 have grossly distorted structures of the y subtype determinant. Our data raise the possibility that HBV strains carrying cysteine mutations are nonreactive in hepatitis B surface antigen-specific immunoassays.

Mutational analysis of HBsAg assembly.

The 20-nm noninfectious empty envelope particles carrying the hepatitis B surface antigen are secreted in large excess from hepatocytes during a hepatitis B infection. Similar particles produced in cell lines or yeast are an efficient vaccine against hepatitis B virus. We have analyzed the assembly of 20-nm particles using a mutagenesis approach. Specific mutations were introduced into the S gene and the preS region encoding the viral envelope proteins using recombinant DNA techniques. The mutant genes were expressed in cell lines to identify the amino acid residues that are critical for the assembly and the secretion of the 20-nm particles.

Phase II trial of edatrexate in patients with advanced pancreatic adenocarcinoma.

BACKGROUND: The methotrexate analogue 10-ethyl-10-deazaaminopterin (10-EdAM, or edatrexate) has shown antitumor activity in preclinical testing and clinical studies of patients with breast, lung and head and neck carcinomas. A phase II study was conducted in patients with advanced pancreatic adenocarcinoma. PATIENTS AND METHODS: Forty patients were enrolled on the clinical trial. Edatrexate was administered intravenously at a dose of 80 mg/m2 weekly for 5 weeks. The treatment course was repeated every 6 weeks. RESULTS: Two partial responses were observed. Both of these patients had partial responses which lasted 2 and 3.5 months. The median survival for all patients was 3.5 months. Serious (grade 3 or 4) toxic effects were primarily mucosal, hematologic, and dermatologic. Two patients experienced severe pulmonary toxic reactions. CONCLUSION: At the dose and schedule used, edatrexate was poorly tolerated and did not demonstrate significant antitumor activity.

Mutational analysis of the cysteine residues in the hepatitis B virus small envelope protein.

The small envelope protein of hepatitis B virus is the major component of the viral coat and is also secreted from cells as a 20-nm subviral particle, even in the absence of other viral proteins. Such empty envelope particles are composed of approximately 100 copies of this polypeptide and host-derived lipids and are stabilized by extensive intermolecular disulfide cross-linking. To study the contribution of disulfide bonds to assembly and secretion of the viral envelope, single and multiple mutants involving all 14 cysteines in HepG2 and COS-7 cells were analyzed. Of the six cysteines located outside the region carrying the surface antigen, Cys-48, Cys-65, and Cys-69 were each found to be essential for secretion of 20-nm particles, whereas Cys-76, Cys-90, and Cys-221 were dispensable. By introduction of an additional cysteine substituting serine 58, the yield of secreted particles was increased. Of four mutants involving the eight cysteines located in the antigenic region, only the double mutant lacking Cys-121 and Cys-124 was secreted with wild-type efficiency. Secretion-competent envelope proteins were intracellularly retained by secretion-deficient cysteine mutants. According to alkylation studies, both intracellular and secreted envelope proteins contained free sulfhydryl groups. Disulfide-linked oligomers were studied by gel electrophoresis under nonreducing conditions.